New Insights for nicotinamide Metabolic disease autophagy and mTOR

Abstract

Metabolic disorders, such as diabetes mellitus (DM), are increasingly becoming significant risk factors for the health of the global population and consume substantial portions of the gross domestic product of all nations. Although conventional therapies that include early diagnosis, nutritional modification of diet, and pharmacological treatments may limit disease progression, tight serum glucose control cannot prevent the onset of future disease complications. With these concerns, novel strategies for the treatment of metabolic disorders that involve the vitamin nicotinamide, the mechanistic target of rapamycin (mTOR), mTOR Complex 1 (mTORC1), mTOR Complex 2 (mTORC2), AMP activated protein kinase (AMPK), and the cellular pathways of autophagy and apoptosis offer exceptional promise to provide new avenues of treatment. Oversight of these pathways can promote cellular energy homeostasis, maintain mitochondrial function, improve glucose utilization, and preserve pancreatic β-cell function. Yet, the interplay among mTOR, AMPK, and autophagy pathways can be complex and affect desired clinical outcomes, necessitating further investigations to provide efficacious treatment strategies for metabolic dysfunction and DM.

Activation of autophagy triggers mitochondrial loss and changes acetylation profile relevant for mechanotransduction in bladder cancer cells

“…NAM is already considered as a potential treatment for metabolic disorders. Most metabolic diseases feature a similar dysregulation of their NAD + /NADH homeostasis, such as Diabetes Mellitus (Maiese 2020) or Danon (Del Favero et al 2020a) and Leigh (Lee et al 2019) disease. In line with our results, a leading cause of this imbalance is mitochondrial dysfunction.…”

Therapeutic Potential of Emerging NAD+-Increasing Strategies for Cardiovascular Diseases

“…Conversely, NR-mediated restoration of NAD+ pools improved the mitochondrial unfolded protein response and mitochondrial health in cultured cardiomyocytes subjected to mitochondrial stress conditions [ 114 ]. The latter finding suggests that NAM not only confers direct cellular protection against oxidation to vascular cells but also prevents cellular apoptosis during free radical exposure and blocks inflammatory vascular cell activation [ 115 ] by preventing membrane phosphatidylserine exposure [ 116 ], which is an apoptotic inducer [ 117 ]. In line with this assertion, NAD+ depletion is linked to macrophage apoptosis [ 118 ], whereas its repletion with NAD+ precursors (NA and NAM) protects cells against apoptosis [ 86 , 119 ].…”

Neurodegeneration, memory loss, and dementia: the impact of biological clocks and circadian rhythm

“…Yet, there exist other risks for developing vascular cognitive loss that can affect the efficacy of treatments such as tobacco use, alcohol consumption, hypertension, and a low level of education [20,39,[54][55][56][57]. With reference to metabolic disease, tight glucose control in the serum in combination with early diagnosis of DM may assist to limit the progression of the disease, but complications from DM can still ensue [6,[58][59][60][61][62][63][64][65][66][67][68][69]. Given the need for novel strategies directed against memory loss and dementia, exciting new avenues of development are now focusing upon biological clock mechanisms and include the pathways of the mechanistic target of rapamycin (mTOR), its associated pathways of mTOR Complex 1 (mTORC1), mTOR Complex 2 (mTORC2), the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), mammalian forkhead transcription factors (FoxOs), the growth factor erythropoietin (EPO), and the wingless pathway of Wnt pathway (Fig.…”

“…This removal of toxic intracellular substances may be important to maintain memory and cognition. As part of a programmed cell death pathway, autophagy is tied to oxidative stress [2,29,66,67,71,[141][142][143][144][145]. Autophagy pathways can recycle cytoplasmic organelles and components for tissue remodeling [19,146] and can eliminate non-functional organelles [6,71,142,147].…”

“…Through SIRT1 pathways, the coenzyme ß-nicotinamide adenine dinucleotide (NAD + ) has an important function with clock genes that is linked to mTOR [ 20 , 66 , 72 , 192 , 205 ]. Control of circadian rhythm by SIRT1 and melatonin can impact glucose tolerance in cells [ 102 ].…”