Novel Avenues of Drug Discovery and Biomarkers for Diabetes Mellitus

Maiese, Kenneth; Chong, Zhao Zhong; Shang, Yan; Hou, Jin-lin

doi:10.1177/0091270010362904

Cited by 47 publications

(37 citation statements)

References 453 publications

(751 reference statements)

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“…At the cellular level, a significant mediator that leads to injury during DM involves oxidative stress and the release of reactive oxygen species (ROS) (8, 13, 77-80). Several genetic polymorphisms in oxidative stress pathways have recently been linked to the complications of DM (81).…”

Section: Cellular Injury With Diabetes Mellitusmentioning

confidence: 99%

FoxO Transcription Factors and Regenerative Pathways in Diabetes Mellitus

Maiese¹

2015

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Mammalian forkhead transcription factors of the O class (FoxO) are exciting targets under consideration for the development of new clinical entities to treat metabolic disorders and diabetes mellitus (DM). DM, a disorder that currently affects greater than 350 million individuals globally, can become a devastating disease that leads to cellular injury through oxidative stress pathways and affects multiple systems of the body. FoxO proteins can regulate insulin signaling, gluconeogenesis, insulin resistance, immune cell migration, and cell senescence. FoxO proteins also control cell fate through oxidative stress and pathways of autophagy and apoptosis that either lead to tissue regeneration or cell demise. Furthermore, FoxO signaling can be dependent upon signal transduction pathways that include silent mating type information regulation 2 homolog 1 (S. cerevisiae) (SIRT1), Wnt, and Wnt1 inducible signaling pathway protein 1 (WISP1). Cellular metabolic pathways driven by FoxO proteins are complex, can lead to variable clinical outcomes, and require in-depth analysis of the epigenetic and post-translation protein modifications that drive FoxO protein activation and degradation.

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Section: Cellular Injury With Diabetes Mellitusmentioning

confidence: 99%

FoxO Transcription Factors and Regenerative Pathways in Diabetes Mellitus

Maiese¹

2015

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“…As a result, recent investigations have concentrated upon pathways that involve anti-oxidant therapies (3, 23, 27, 30, 53, 71, 75), mammalian forkhead transcription factors (9, 37, 47, 150, 151), protein tyrosine phosphatases (6, 15, 152), and growth factors (11–13, 50, 65, 70, 104). In addition, new therapeutic strategies are now focusing upon the role of extracellular matrix associated proteins such as the CCN family of proteins (153, 154).…”

Section: Wisp1 and Dmmentioning

confidence: 99%

“…AMPK that phosphorylates TSC2 and inhibits mTORC1 activity (21, 199) can increase the cellular NAD + /NADH ratio leading to the deacetylation of downstream SIRT1 targets that include the peroxisome proliferator-activated receptor-gamma coactivator 1 (PGC-1α), FoxO1 (37), and FoxO3a (253). AMPK also can increase NAMPT during glucose restriction that results in increased NAD + and decreased levels of nicotinamide (254), an inhibitor of SIRT1 (3). SIRT1 activators, such as resveratrol, also can activate AMPK through SIRT1 dependent and independent mechanisms (253, 255).…”

Section: Sirt1 and Dmmentioning

confidence: 99%

“…A strong case can be made for clinical programs that assist with the early diagnosis of DM given that a significant portion of the population currently remains undiagnosed with DM (10, 19). Furthermore, the incidence of impaired glucose tolerance in the young also raises additional concerns (3). Individuals with impaired glucose tolerance have more than twice the risk for the onset of diabetic complications than individuals with normal glucose tolerance (20).…”

Section: Introductionmentioning

confidence: 99%

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Programming Apoptosis and Autophagy with Novel Approaches for Diabetes Mellitus

Maiese¹

2015

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According to the World Health Organization, diabetes mellitus (DM) in the year 2030 will be ranked the seventh leading cause of death in the world. DM impacts all systems of the body with oxidant stress controlling cell fate through endoplasmic reticulum stress, mitochondrial dysfunction, alterations in uncoupling proteins, and the induction of apoptosis and autophagy. Multiple treatment approaches are being entertained for DM with Wnt1 inducible signaling pathway protein 1 (WISP1), mechanistic target of rapamycin (mTOR), and silent mating type information regulation 2 homolog) 1 (S. cerevisiae) (SIRT1) generating significant interest as target pathways that can address maintenance of glucose homeostasis as well as prevention of cellular pathology by controlling insulin resistance, stem cell proliferation, and the programmed cell death pathways of apoptosis and autophagy. WISP1, mTOR, and SIRT1 can rely upon similar pathways such as AMP activated protein kinase as well as govern cellular metabolism through cytokines such as EPO and oral hypoglycemics such as metformin. Yet, these pathways require precise biological control to exclude potentially detrimental clinical outcomes. Further elucidation of the ability to translate the roles of WISP1, mTOR, and SIRT1 into effective clinical avenues offers compelling prospects for new therapies against DM that can benefit hundreds of millions of individuals throughout the globe.

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“…Another eight million individuals also have metabolic disorders but remain undiagnosed at present (23–25). Impaired glucose tolerance in the young (5, 26) and the presence of obesity increases the risk of developing DM in these individuals (19). …”

Section: Introductionmentioning

confidence: 99%

Novel Treatment Strategies for the Nervous System: Circadian Clock Genes, Non-coding RNAs, and Forkhead Transcription Factors

Maiese¹

2018

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BACKGROUND With the global increase in life span expectancy, neurodegenerative disorders continue to affect an ever increasing number of individuals throughout the world. New treatment strategies for neurodegenerative diseases are desperately required given the lack of current treatment modalities. METHODS Here we examine novel strategies for neurodegenerative disorders that include circadian clock genes, non-coding ribonucleic acids (RNAs), and the mammalian forkhead transcription factors of the O class (FoxOs). RESULTS Circadian clock genes, non-coding RNAs, and FoxOs offer exciting prospects to potentially limit or remove the significant disability and death associated with neurodegenerative disorders. Each of these pathways have an intimate relationship with the programmed death pathways of autophagy and apoptosis and share a common link to the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1) and the mechanistic target of rapamycin (mTOR). Circadian clock genes are necessary to modulate autophagy, limit cognitive loss, and prevent neuronal injury. Non-coding RNAs can control neuronal stem cell development and neuronal differentiation and offer protection against vascular disease such as atherosclerosis. FoxOs provide exciting prospects to block neuronal apoptotic death and to activate pathways of autophagy to remove toxic accumulations in neurons that can lead to neurodegenerative disorders. CONCLUSIONS Continued work with circadian clock genes, non-coding RNAs, and FoxOs can offer new prospects and hope for the development of vital strategies for the treatment of neurodegenerative diseases. These innovative investigative avenues have the potential to significantly limit disability and death from these devastating disorders.

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Novel Avenues of Drug Discovery and Biomarkers for Diabetes Mellitus

Cited by 47 publications

References 453 publications

FoxO Transcription Factors and Regenerative Pathways in Diabetes Mellitus

FoxO Transcription Factors and Regenerative Pathways in Diabetes Mellitus

Programming Apoptosis and Autophagy with Novel Approaches for Diabetes Mellitus

Novel Treatment Strategies for the Nervous System: Circadian Clock Genes, Non-coding RNAs, and Forkhead Transcription Factors

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