Novel directions for diabetes mellitus drug discovery

Maiese, Kenneth; Chong, Zhao Zhong; Shang, Yan; Wang, Shaohui

doi:10.1517/17460441.2013.736485

Cited by 61 publications

(59 citation statements)

References 120 publications

(190 reference statements)

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“…The disposal of "tagged" cells may assist with the repair and regeneration of injured tissues to remove non-functional dying cells, but also at times may lead to the removal of otherwise functional cells if not kept in-check [50,51]. The later apoptotic phase involving the cleavage of genomic DNA into fragments usually does not allow for the repair or recovery of cells [41,52,53]. As a result, at least a minimal presence of TSC2 appears necessary to promote the ability of WISP1 to prevent both early and late phases of apoptotic cell injury that may involve limiting mTOR activity.…”

Section: Discussionmentioning

confidence: 99%

Tuberous Sclerosis Protein 2 (TSC2) Modulates CCN4 Cytoprotection During Apoptotic Amyloid Toxicity in Microglia

Shang¹,

Chong²,

Wang³

et al. 2012

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More than 110 million individuals will suffer from cognitive loss worldwide by the year 2050 with a majority of individuals presenting with Alzheimer's disease (AD). Yet, successful treatments for etiologies that involve β-amyloid (Aβ) toxicity in AD remain elusive and await novel avenues for drug development. Here we show that Wnt1 inducible signaling pathway protein 1 (WISP1/ CCN4) controls the post-translational phosphorylation of Akt1, p70S6K, and AMP activated protein kinase (AMPK) to the extent that tuberous sclerosis complex 2 (TSC2) (Ser 1387 ) phosphorylation, a target of AMPK, is decreased and TSC2 (Thr 1462 ) phosphorylation, a target of Akt1, is increased. The ability of WISP1 to limit TSC2 activity allows WISP1 to increase the activity of p70S6K, since gene silencing of TSC2 further enhances WISP1 phosphorylation of p70S6K. However, a minimal level of TSC2 activity is necessary to modulate WISP1 cytoprotection that may require modulation of mTOR activity, since gene knockdown of TSC2 impairs the ability of WISP1 to protect microglia against apoptotic membrane phosphatidylserine (PS) exposure, nuclear DNA degradation, mitochondrial membrane depolarization, and cytochrome c release during Aβ exposure.

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Section: Discussionmentioning

confidence: 99%

Tuberous Sclerosis Protein 2 (TSC2) Modulates CCN4 Cytoprotection During Apoptotic Amyloid Toxicity in Microglia

Shang¹,

Chong²,

Wang³

et al. 2012

CNR

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“…SIRT1 can control stem cell survival by modulating autophagic flux (147). SIRT1 also can have an inverse relationship with mTOR in embryonic stem cells (20, 110) and block mTOR to promote autophagy and protect embryonic stem cells during oxidative stress (148). In regards to apoptotic pathways, SIRT1 activation can block external membrane PS exposure during the early phases of apoptosis in mature cells (70, 149–151).…”

Section: Circadian Clock Genesmentioning

confidence: 99%

“…SIRT1 pathways are involved in vascular survival and senescence (88, 152, 161), atherosclerosis (162–166), lifespan extension (4, 167–169), diabetic retinopathy (170), cellular metabolism and DM (14, 17, 20, 115, 145, 171, 172), oxidative stress pathways (58, 148, 173–179), and neuronal survival and cognition (11, 113, 180–183). …”

Section: Sirt1 and Non-coding Rnasmentioning

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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“…Oxidative stress is an important determinant of cell injury in DM (4, 21, 71–76). Oxidant stress that results in the generation of reactive oxygen species (ROS) can significantly affect cellular metabolism and lead to cell injury during DM (77, 78) and contribute to disability that involves impaired cognitive function (79–81), cerebral ischemia (77, 82), and epigenetic linked disease (83–87).…”

Section: Dm Involvement Of Multiple Organ Systems and Oxidative mentioning

confidence: 99%

“…The programed cell death pathways of apoptosis (4, 23, 27, 70, 75, 124) as well as autophagy (2, 21, 125, 126) play significant roles during DM and oxidative stress (127). Necroptosis, another pathway involved in programmed cell death, does not presently appear to contribute significantly to cell survival in DM (128), but further published work may change these observations.…”

Section: Dm Apoptosis and Autophagymentioning

confidence: 99%

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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Novel directions for diabetes mellitus drug discovery

Cited by 61 publications

References 120 publications

Tuberous Sclerosis Protein 2 (TSC2) Modulates CCN4 Cytoprotection During Apoptotic Amyloid Toxicity in Microglia

Tuberous Sclerosis Protein 2 (TSC2) Modulates CCN4 Cytoprotection During Apoptotic Amyloid Toxicity in Microglia

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

Programming Apoptosis and Autophagy with Novel Approaches for Diabetes Mellitus

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