Hypoxia is a key environmental factor linked to neurodevelopmental complications, primarily through its impact on mitochondrial dysfunction. Given that sirtuins regulate mitochondrial and cellular metabolism, we aimed to investigate whether pharmacological modulation of sirtuins could protect neurons from hypoxia-induced mitochondrial dysfunction and cell death. To explore this, primary cortical neurons from male Wistar rats (control) and Spontaneously Hypertensive Rats (a model for neonatal hypoxia and schizophrenia) were exposed to cobalt chloride (CoCl2) to chemically induce hypoxia. Neurons were also treated with Nicotinamide (50 μM), Resveratrol (0.5 μM), and Sirtinol (5 μM) to modulate sirtuin activity. We first assessed histone deacetylation, cell death, mitochondrial calcium retention capacity, mitochondrial membrane potential, and levels of reactive oxygen species (ROS). In addition, we analysed the expression of genes related to mitochondrial metabolism, dynamics, and biogenesis, as well as high-energy compound levels. Our data indicate that both chemical and neonatal hypoxia caused mitochondrial depolarization, reduced calcium retention, increased ROS levels, and elevated Nfe2l2 expression in primary cortical neurons. Hypoxia also led to increased expression of genes associated with mitochondrial biogenesis and fission, as well as reduced ATP levels and elevated pyruvate and lactate levels. Importantly, treatment with sirtuin modulators enhanced neuron viability, likely by further increasing Nfe2l2 expression and reducing ROS production. These modulators also improved metabolic outcomes, including higher ATP levels, and normalised pyruvate and lactate production, as well as mitochondrial fusion gene expression. Collectively, our findings suggest that sirtuin modulators could mitigate hypoxia-induced damage and may represent a potential therapeutic strategy for managing neurodevelopmental disorders.

As a non-communicable disease, cardiovascular disorders have become the leading cause of death for men and women. Of additional concern is that cardiovascular disease is linked to chronic comorbidity disorders that include nonalcoholic fatty liver disease (NAFLD). NAFLD, also termed metabolic-dysfunction-associated steatotic liver disease, is the greatest cause of liver disease throughout the world, increasing in prevalence concurrently with diabetes mellitus (DM), and can progress to nonalcoholic steatohepatitis that leads to cirrhosis and liver fibrosis. Individuals with metabolic disorders, such as DM, are more than two times likely to experience cardiac disease, stroke, and liver disease that includes NAFLD when compared individuals without metabolic disorders. Interestingly, cardiovascular disorders and NAFLD share a common underlying cellular mechanism for disease pathology, namely the silent mating type information regulation 2 homolog 1 (SIRT1; Saccharomyces cerevisiae). SIRT1, a histone deacetylase, is linked to metabolic pathways through nicotinamide adenine dinucleotide and can offer cellular protection though multiple avenues, including trophic factors such as erythropoietin, stem cells, and AMP-activated protein kinase. Translating SIRT1 pathways into clinical care for cardiovascular and hepatic disease can offer significant hope for patients, but further insights into the complexity of SIRT1 pathways are necessary for effective treatment regimens.

Chronic obstructive pulmonary disease (COPD) is a frequently occurring disorder. The aim of this study is to explore the mechanism of traditional Chinese medicine Morin monomer in the treatment of COPD via regulating autophagy based on the long non-coding RNA (lncRNA) H19/microRNA (miR)-194-5p/Sirtuin (SIRT)1 signal axis.

The COPD rat model was constructed, and the lung tissues were collected. The pathological analysis was performed using hematoxylin-eosin (HE), Masson, and periodic acid-Schiff (PAS) staining. Autophagosomes were observed using transmission electron microscope. LncRNA H19, miR-194-5p, SIRT1 genes in the rat lung tissues were detected using reverse transcription-quantitative real-time polymerase chain reaction (RT-qPCR). The autophagy-related proteins including SIRT1, mammalian/mechanistic target of rapamycin (mTOR), phosphorylated (p)-mTOR, microtubule-associated protein light chain 3 (LC3), Beclin-1, autophagy-related (ATG)7, and p62 in each group were detected using Western blot.

The rats in the control group had normal lung structure. Alveolar enlargement and destruction could be found in the rat lung tissues in the model group, accompanied with obvious infiltration of inflammatory cells, thickened bronchial walls, enlarged alveolar septum, collagen fibers deposition, and goblet cells proliferation. In comparison with the model group, Morin treatment relieved the lung injuries, which was optimized in the moderate- and high-dose groups. The number of autophagosomes in the lung tissues of the model rats was dramatically increased compared with the normal rats. However, the number of autophagosomes in each Morin treatment group was obviously less than that in the model group. LncRNA H19 and SIRT1 expression was significantly increased in the model group, and miR-194-5p was significantly decreased (P<0.05). Morin and 3-methyladenine (3-MA) could obviously reduce the lncRNA H19 and SIRT1 expression, and increase the miR-194-5p expression (P<0.05). Relative to control rats, ATG7, Beclin-1, LC3II/I and SIRT1 levels in the model group increased obviously, while the expression of p62, and p-mTOR/mTOR decreased (P<0.05). Morin treatment reduced the expression of ATG7, Beclin-1, SIRT1, LC3II/I significantly, and increased the p-mTOR/mTOR and p62 expression (P<0.05).

Morin decreased lncRNA H19 expression, resulting in upregulation of miR-194-5p expression, downregulation of SIRT1 expression, and increased of p-mTOR/mTOR expression. Furthermore, cell autophagy was inhibited, contributing to the COPD treatment.

NAD+-dependent deacetylase sirtuin-1 (Sirt1) belongs to the sirtuins family, known to be longevity regulators, and exerts a key role in the prevention of vascular aging. By aging, the expression levels of Sirt1 decline with a severe impact on vascular function, such as the rise of endothelial dysfunction, which in turn promotes the development of cardiovascular diseases. In this context, the impact of Sirt1 activity in preventing endothelial senescence is particularly important. Given the key role of Sirt1 in counteracting endothelial senescence, great efforts have been made to deepen the knowledge about the intricate cross-talks and interactions of Sirt1 with other molecules, in order to set up possible strategies to boost Sirt1 activity to prevent or treat vascular aging. The aim of this review is to provide a proper background on the regulation and function of Sirt1 in the vascular endothelium and to discuss the recent advances regarding the therapeutic strategies of targeting Sirt1 to counteract vascular aging.

Metabolic disorders and diabetes (DM) impact more than five hundred million individuals throughout the world and are insidious in onset, chronic in nature, and yield significant disability and death. Current therapies that address nutritional status, weight management, and pharmacological options may delay disability but cannot alter disease course or functional organ loss, such as dementia and degeneration of systemic bodily functions. Underlying these challenges are the onset of aging disorders associated with increased lifespan, telomere dysfunction, and oxidative stress generation that lead to multi-system dysfunction. These significant hurdles point to the urgent need to address underlying disease mechanisms with innovative applications. New treatment strategies involve non-coding RNA pathways with microRNAs (miRNAs) and circular ribonucleic acids (circRNAs), Wnt signaling, and Wnt1 inducible signaling pathway protein 1 (WISP1) that are dependent upon programmed cell death pathways, cellular metabolic pathways with AMP-activated protein kinase (AMPK) and nicotinamide, and growth factor applications. Non-coding RNAs, Wnt signaling, and AMPK are cornerstone mechanisms for overseeing complex metabolic pathways that offer innovative treatment avenues for metabolic disease and DM but will necessitate continued appreciation of the ability of each of these cellular mechanisms to independently and in unison influence clinical outcome.

Life expectancy is increasing throughout the world and coincides with a rise in non-communicable diseases (NCDs), especially for metabolic disease that includes diabetes mellitus (DM) and neurodegenerative disorders. The debilitating effects of metabolic disorders influence the entire body and significantly affect the nervous system impacting greater than one billion people with disability in the peripheral nervous system as well as with cognitive loss, now the seventh leading cause of death worldwide. Metabolic disorders, such as DM, and neurologic disease remain a significant challenge for the treatment and care of individuals since present therapies may limit symptoms but do not halt overall disease progression. These clinical challenges to address the interplay between metabolic and neurodegenerative disorders warrant innovative strategies that can focus upon the underlying mechanisms of aging-related disorders, oxidative stress, cell senescence, and cell death. Programmed cell death pathways that involve autophagy, apoptosis, ferroptosis, and pyroptosis can play a critical role in metabolic and neurodegenerative disorders and oversee processes that include insulin resistance, β-cell function, mitochondrial integrity, reactive oxygen species release, and inflammatory cell activation. The silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), AMP activated protein kinase (AMPK), and Wnt1 inducible signaling pathway protein 1 (WISP1) are novel targets that can oversee programmed cell death pathways tied to β-nicotinamide adenine dinucleotide (NAD+), nicotinamide, apolipoprotein E (APOE), severe acute respiratory syndrome (SARS-CoV-2) exposure with coronavirus disease 2019 (COVID-19), and trophic factors, such as erythropoietin (EPO). The pathways of programmed cell death, SIRT1, AMPK, and WISP1 offer exciting prospects for maintaining metabolic homeostasis and nervous system function that can be compromised during aging-related disorders and lead to cognitive impairment, but these pathways have dual roles in determining the ultimate fate of cells and organ systems that warrant thoughtful insight into complex autofeedback mechanisms.

As a significant non-communicable disease, cardiovascular disease is the leading cause of death for both men and women, comprises almost twenty percent of deaths in most racial and ethnic groups, can affect greater than twenty-five million individuals worldwide over the age of twenty, and impacts global economies with far-reaching financial challenges. Multiple factors can affect the onset of cardiovascular disease that include high serum cholesterol levels, elevated blood pressure, tobacco consumption and secondhand smoke exposure, poor nutrition, physical inactivity, obesity, and concurrent diabetes mellitus. Yet, addressing any of these factors cannot completely eliminate the onset or progression of cardiovascular disorders. Novel strategies are necessary to target underlying cardiovascular disease mechanisms. The silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), a histone deacetylase, can limit cardiovascular injury, assist with stem cell development, oversee metabolic homeostasis through nicotinamide adenine dinucleotide (NAD+) pathways, foster trophic factor protection, and control cell senescence through the modulation of telomere function. Intimately tied to SIRT1 pathways are mammalian forkhead transcription factors (FoxOs) which can modulate cardiac disease to reduce oxidative stress, repair microcirculation disturbances, and reduce atherogenesis through pathways of autophagy, apoptosis, and ferroptosis. AMP activated protein kinase (AMPK) also is critical among these pathways for the oversight of cardiac cellular metabolism, insulin sensitivity, mitochondrial function, inflammation, and the susceptibility to viral infections such as severe acute respiratory syndrome coronavirus that can impact cardiovascular disease. Yet, the relationship among these pathways is both intricate and complex and requires detailed insight to successfully translate these pathways into clinical care for cardiovascular disorders.

Almost three million individuals suffer from multiple sclerosis (MS) throughout the world, a demyelinating disease in the nervous system with increased prevalence over the last five decades, and is now being recognized as one significant etiology of cognitive loss and dementia. Presently, disease modifying therapies can limit the rate of relapse and potentially reduce brain volume loss in patients with MS, but unfortunately cannot prevent disease progression or the onset of cognitive disability. Innovative strategies are therefore required to address areas of inflammation, immune cell activation, and cell survival that involve novel pathways of programmed cell death, mammalian forkhead transcription factors (FoxOs), the mechanistic target of rapamycin (mTOR), AMP activated protein kinase (AMPK), the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), and associated pathways with the apolipoprotein E (APOE-ε4) gene and severe acute respiratory syndrome coronavirus (SARS-CoV-2). These pathways are intertwined at multiple levels and can involve metabolic oversight with cellular metabolism dependent upon nicotinamide adenine dinucleotide (NAD+). Insight into the mechanisms of these pathways can provide new avenues of discovery for the therapeutic treatment of dementia and loss in cognition that occurs during MS.

It is estimated that, at minimum, 500 million individuals suffer from cellular metabolic dysfunction, such as diabetes mellitus (DM), throughout the world. Even more concerning is the knowledge that metabolic disease is intimately tied to neurodegenerative disorders, affecting both the central and peripheral nervous systems as well as leading to dementia, the seventh leading cause of death. New and innovative therapeutic strategies that address cellular metabolism, apoptosis, autophagy, and pyroptosis, the mechanistic target of rapamycin (mTOR), AMP activated protein kinase (AMPK), growth factor signaling with erythropoietin (EPO), and risk factors such as the apolipoprotein E (APOE-ε4) gene and coronavirus disease 2019 (COVID-19) can offer valuable insights for the clinical care and treatment of neurodegenerative disorders impacted by cellular metabolic disease. Critical insight into and modulation of these complex pathways are required since mTOR signaling pathways, such as AMPK activation, can improve memory retention in Alzheimer's disease (AD) and DM, promote healthy aging, facilitate clearance of β-amyloid (Aß) and tau in the brain, and control inflammation, but also may lead to cognitive loss and long-COVID syndrome through mechanisms that can include oxidative stress, mitochondrial dysfunction, cytokine release, and APOE-ε4 if pathways such as autophagy and other mechanisms of programmed cell death are left unchecked.

To investigate the effects of rumen-protected choline (RPC) and rumen-protected nicotinamide (RPM) on liver metabolic function based on transcriptome in periparturient dairy cows, 10 healthy Holstein dairy cows with similar parity were allocated to RPC and RPM groups (n = 5). The cows were fed experimental diets between 14 days before and 21 days after parturition. The RPC diet contained 60 g RPC per day, and the RPM diet contained 18.7 g RPM per day. Liver biopsies were taken 21 days after calving for the transcriptome analysis. A model of fat deposition hepatocytes was constructed using the LO2 cell line with the addition of NEFA (1.6 mmol/L), and the expression level of genes closely related to liver metabolism was validated and divided into a CHO group (75 μmol/L) and a NAM group (2 mmol/L). The results showed that the expression of a total of 11,023 genes was detected and clustered obviously between the RPC and RPM groups. These genes were assigned to 852 Gene Ontology terms, the majority of which were associated with biological process and molecular function. A total of 1123 differentially expressed genes (DEGs), 640 up-regulated and 483 down-regulated, were identified between the RPC and RPM groups. These DEGs were mainly correlated with fat metabolism, oxidative stress and some inflammatory pathways. In addition, compared with the NAM group, the gene expression level of FGF21, CYP26A1, SLC13A5, SLCO1B3, FBP2, MARS1 and CDH11 in the CHO group increased significantly (p < 0.05). We proposed that that RPC could play a prominent role in the liver metabolism of periparturient dairy cows by regulating metabolic processes such as fatty acid synthesis and metabolism and glucose metabolism; yet, RPM was more involved in biological processes such as the TCA cycle, ATP generation and inflammatory signaling.

Among the extracellular vesicles, apoptotic bodies (ABs) are only formed during the apoptosis and perform a relevant role in the pathogenesis of different diseases. Recently, it has been demonstrated that ABs from human renal proximal tubular HK-2 cells, either induced by cisplatin or by UV light, can lead to further apoptotic death in naïve HK-2 cells. Thus, the aim of this work was to carry out a non-targeted metabolomic approach to study if the apoptotic stimulus (cisplatin or UV light) affects in a different way the metabolites involved in the propagation of apoptosis. Both ABs and their extracellular fluid were analyzed using a reverse-phase liquid chromatography-mass spectrometry setup. Principal components analysis showed a tight clustering of each experimental group and partial least square discriminant analysis was used to assess the metabolic differences existing between these groups. Considering the variable importance in the projection values, molecular features were selected and some of them could be identified either unequivocally or tentatively. The resulting pathways indicated that there are significant, stimulus-specific differences in metabolites abundancies that may propagate apoptosis to healthy proximal tubular cells; thus, we hypothesize that the share in apoptosis of these metabolites might vary depending on the apoptotic stimulus.

Huntington's disease (HD) is an incurable and progressive neurodegenerative disease affecting the basal ganglia of the brain. HD is caused due to expansion of the polyglutamine tract in the protein Huntingtin resulting in aggregates. The increased PolyQ length results in aggregation of protein Huntingtin leading to neuronal cell death. Vitamin B6, B12 and folate are deficient in many neurodegenerative diseases. We performed an integrated analysis of transcriptomic, metabolomic and cofactor-protein network of vitamin B6, B12 and folate was performed. Our results show considerable overlap of pathways modulated by Vitamin B6, B12 and folate with those obtained from transcriptomic and metabolomic data of HD patients and model systems. Further, in yeast model of HD we showed treatment of B6, B12 or folate either alone or in combination showed impaired aggregate formation. Transcriptomic analysis of yeast model treated with B6, B12 and folate showed upregulation of pathways like ubiquitin mediated proteolysis, autophagy, peroxisome, fatty acid, lipid and nitrogen metabolism. Metabolomic analysis of yeast model shows deregulation of pathways like aminoacyl-tRNA biosynthesis, metabolism of various amino acids, nitrogen metabolism and glutathione metabolism. Integrated transcriptomic and metabolomic analysis of yeast model showed concordance in the pathways obtained. Knockout of Peroxisomal (PXP1 and PEX7) and Autophagy (ATG5) genes in yeast increased aggregates which is mitigated by vitamin B6, B12 and folate treatment. Taken together our results show a role for Vitamin B6, B12 and folate mediated modulation of pathways important for preventing protein aggregation with potential implications for HD.

The online version contains supplementary material available at 10.1007/s13205-023-03525-y.

A high-fat diet is one of the causative factors of obesity. The dietary profile of fatty acids is also an important variable in developing obesity, as saturated fatty acids are more obesogenic than monounsaturated and polyunsaturated fatty acids. Overweight and obesity are inseparably connected with the excess of adipose tissue in the body, characterized by hypertrophy and hyperplasia of fat cells, which increases the risk of developing metabolic syndrome. Changes observed within hypertrophic adipocytes result in elevated oxidative stress, unfolded protein accumulation, and increased endoplasmic reticulum (ER) stress. One of the processes involved in preservation of cellular homeostasis is autophagy, which is defined as an intracellular lysosome-dependent degradation system that serves to recycle available macromolecules and eliminate damaged organelles. In obesity, activation of autophagy is increased and the process appears to be regulated by different types of dietary fatty acids. This review describes the role of autophagy in adipose tissue and summarizes the current understanding of the effects of saturated and unsaturated fatty acids in autophagy modulation in adipocytes.

Disorders of metabolism affect multiple systems throughout the body but may have the greatest impact on both central and peripheral nervous systems. Currently available treatments and behavior changes for disorders that include diabetes mellitus (DM) and nervous system diseases are limited and cannot reverse the disease burden. Greater access to healthcare and a longer lifespan have led to an increased prevalence of metabolic and neurodegenerative disorders. In light of these challenges, innovative studies into the underlying disease pathways offer new treatment perspectives for Alzheimer's Disease, Parkinson's Disease, and Huntington's Disease. Metabolic disorders are intimately tied to neurodegenerative diseases and can lead to debilitating outcomes, such as multi-nervous system disease, susceptibility to viral pathogens, and long-term cognitive disability. Novel strategies that can robustly address metabolic disease and neurodegenerative disorders involve a careful consideration of cellular metabolism, programmed cell death pathways, the mechanistic target of rapamycin (mTOR) and its associated pathways of mTOR Complex 1 (mTORC1), mTOR Complex 2 (mTORC2), AMP-activated protein kinase (AMPK), growth factor signaling, and underlying risk factors such as the apolipoprotein E (APOE-ε4) gene. Yet, these complex pathways necessitate comprehensive understanding to achieve clinical outcomes that target disease susceptibility, onset, and progression.

Nicotinamide (NAM) is the amide form of niacin and an important precursor of nicotinamide adenine dinucleotide (NAD), which is needed for energy metabolism and cellular functions. Additionally, it has shown neuroprotective properties in several neurodegenerative diseases. Herein, we sought to investigate the potential protective mechanisms of NAM in an intraperitoneal (i.p) 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD) mouse model (wild-type mice (C57BL/6N), eight weeks old, average body weight 25-30 g). The study had four groups (n = 10 per group): control, MPTP (30 mg/kg i.p. for 5 days), MPTP treated with NAM (500 mg/kg, i.p for 10 days) and control treated with NAM. Our study showed that MPTP increased the expression of α-synuclein 2.5-fold, decreased tyrosine hydroxylase (TH) 0.5-fold and dopamine transporters (DAT) levels up to 0.5-fold in the striatum and substantia nigra pars compacta (SNpc), and impaired motor function. However, NAM treatment significantly reversed these PD-like pathologies. Furthermore, NAM treatment reduced oxidative stress by increasing the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) between 0.5- and 1.0-fold. Lastly, NAM treatment regulated neuroinflammation by reducing Toll-like receptor 4 (TLR-4), phosphorylated nuclear factor-κB, tumor (p-NFκB), and cyclooxygenase-2 (COX-2) levels by 0.5- to 2-fold in the PD mouse brain. Overall, these findings suggest that NAM exhibits neuroprotective properties and may be an effective therapeutic agent for PD.

Alzheimer's disease (AD) is one of the biggest human health threats due to increases in aging of the global population. Unfortunately, drugs for treating AD have been largely ineffective. Interestingly, downregulation of macroautophagy (autophagy) plays an essential role in AD pathogenesis. Therefore, targeting autophagy has drawn considerable attention as a therapeutic approach for the treatment of AD. However, developing new therapeutics is time-consuming and requires huge investments. One of the strategies currently under consideration for many diseases is "drug repositioning" or "drug repurposing". In this comprehensive review, we have provided an overview of the impact of autophagy on AD pathophysiology, reviewed the therapeutics that upregulate autophagy and are currently used in the treatment of other diseases, including cancers, and evaluated their repurposing as a possible treatment option for AD. In addition, we discussed the potential of applying nano-drug delivery to neurodegenerative diseases, such as AD, to overcome the challenge of crossing the blood brain barrier and specifically target molecules/pathways of interest with minimal side effects.

Cellular quality control systems have gained much attention in recent decades. Among these, autophagy is a natural self-preservation mechanism that continuously eliminates toxic cellular components and acts as an anti-ageing process. It is vital for cell survival and to preserve homeostasis. Several cell-type-dependent canonical or non-canonical autophagy pathways have been reported showing varying degrees of selectivity with regard to the substrates targeted. Here, we provide an updated review of the autophagy machinery and discuss the role of various forms of autophagy in neurodegenerative diseases, with a particular focus on Parkinson's disease. We describe recent findings that have led to the proposal of therapeutic strategies targeting autophagy to alter the course of Parkinson's disease progression.

Cardiovascular diseases are the leading cause of death worldwide. Aging and/or metabolic stress directly impact the cardiovascular system. Over the last few years, the contributions of altered nicotinamide adenine dinucleotide (NAD+) metabolism to aging and other pathological conditions closely related to cardiovascular diseases have been intensively investigated. NAD+ bioavailability decreases with age and cardiometabolic conditions in several mammalian tissues. Compelling data suggest that declining tissue NAD+ is commonly related to mitochondrial dysfunction and might be considered as a therapeutic target. Thus, NAD+ replenishment by either genetic or natural dietary NAD+-increasing strategies has been recently demonstrated to be effective for improving the pathophysiology of cardiac and vascular health in different experimental models, as well as human health, to a lesser extent. Here, we review and discuss recent experimental evidence illustrating that increasing NAD+ bioavailability, particularly by the use of natural NAD+ precursors, may offer hope for new therapeutic strategies to prevent and treat cardiovascular diseases.

Introduction: Dementia and cognitive loss impact a significant proportion of the global population and present almost insurmountable challenges for treatment since they stem from multifactorial etiologies. Innovative avenues for treatment are highly warranted. Methods and results: Novel work with biological clock genes that oversee circadian rhythm may meet this critical need by focusing upon the pathways of the mechanistic target of rapamycin (mTOR), 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 Wnt pathway. These pathways are complex in nature, intimately associated with autophagy that can maintain circadian rhythm, and have an intricate relationship that can lead to beneficial outcomes that may offer neuroprotection, metabolic homeostasis, and prevention of cognitive loss. However, biological clocks and alterations in circadian rhythm also have the potential to lead to devastating effects involving tumorigenesis in conjunction with pathways involving Wnt that oversee angiogenesis and stem cell proliferation. Conclusions: Current work with biological clocks and circadian rhythm pathways provide exciting possibilities for the treating dementia and cognitive loss, but also provide powerful arguments to further comprehend the intimate and complex relationship among these pathways to fully potentiate desired clinical outcomes.

Neurodegenerative disorders affect fifteen percent of the world's population and pose a significant financial burden to all nations. Cognitive impairment is the seventh leading cause of death throughout the globe. Given the enormous challenges to treat cognitive disorders, such as Alzheimer's disease, and the inability to markedly limit disease progression, circadian clock gene pathways offer an exciting strategy to address cognitive loss. Alterations in circadian clock genes can result in age-related motor deficits, affect treatment regimens with neurodegenerative disorders, and lead to the onset and progression of dementia. Interestingly, circadian pathways hold an intricate relationship with autophagy, the mechanistic target of rapamycin (mTOR), the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), mammalian forkhead transcription factors (FoxOs), and the trophic factor erythropoietin. Autophagy induction is necessary to maintain circadian rhythm homeostasis and limit cortical neurodegenerative disease, but requires a fine balance in biological activity to foster proper circadian clock gene regulation that is intimately dependent upon mTOR, SIRT1, FoxOs, and growth factor expression. Circadian rhythm mechanisms offer innovative prospects for the development of new avenues to comprehend the underlying mechanisms of cognitive loss and forge ahead with new therapeutics for dementia that can offer effective clinical treatments.

Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease caused by the specific destruction of pancreatic islet β cells and is characterized as the absolute insufficiency of insulin secretion. Current insulin replacement therapy supplies insulin in a non-physiological way and is associated with devastating complications. Experimental islet transplantation therapy has been proven to restore glucose homeostasis in people with severe T1DM. However, it is restricted by many factors such as severe shortage of donor sources, progressive loss of donor cells, high cost, etc. As pluripotent stem cells have the potential to give rise to all cells including islet β cells in the body, stem cell therapy for diabetes has attracted great attention in the academic community and the general public. Transplantation of islet β-like cells differentiated from human pluripotent stem cells (hPSCs) has the potential to be an excellent alternative to islet transplantation. In stem cell therapy, obtaining β cells with complete insulin secretion in vitro is crucial. However, after much research, it has been found that the β-like cells obtained by in vitro differentiation still have many defects, including lack of adult-type glucose stimulated insulin secretion, and multi-hormonal secretion, suggesting that in vitro culture does not allows for obtaining fully mature β-like cells for transplantation. A large number of studies have found that many transcription factors play important roles in the process of transforming immature to mature human islet β cells. Furthermore, PDX1, NKX6.1, SOX9, NGN3, PAX4, etc., are important in inducing hPSC differentiation in vitro. The absent or deficient expression of any of these key factors may lead to the islet development defect in vivo and the failure of stem cells to differentiate into genuine functional β-like cells in vitro. This article reviews β cell maturation in vivo and in vitro and the vital roles of key molecules in this process, in order to explore the current problems in stem cell therapy for diabetes.

Neurodegenerative disorders impact more than one billion individuals worldwide and are intimately tied to metabolic disease that can affect another nine hundred individuals throughout the globe. Nicotinamide is a critical agent that may offer fruitful prospects for neurodegenerative diseases and metabolic disorders, such as diabetes mellitus. Nicotinamide protects against multiple toxic environments that include reactive oxygen species exposure, anoxia, excitotoxicity, ethanolinduced neuronal injury, amyloid (Aß) toxicity, age-related vascular disease, mitochondrial dysfunction, insulin resistance, excess lactate production, and loss of glucose homeostasis with pancreatic β-cell dysfunction. However, nicotinamide offers cellular protection in a specific concentration range, with dosing outside of this range leading to detrimental effects. The underlying biological pathways of nicotinamide that involve the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), the mechanistic target of rapamycin (mTOR), AMP activated protein kinase (AMPK), and mammalian forkhead transcription factors (FoxOs) may offer insight for the clinical translation of nicotinamide into a safe and efficacious therapy through the modulation of oxidative stress, apoptosis, and autophagy. Nicotinamide is a highly promising target for the development of innovative strategies for neurodegenerative disorders and metabolic disease, but the benefits of this foundation depend greatly on gaining a further understanding of nicotinamide's complex biology.

Metabolic disorders that include diabetes mellitus present significant challenges for maintaining the welfare of the global population. Metabolic diseases impact all systems of the body and despite current therapies that offer some protection through tight serum glucose control, ultimately such treatments cannot block the progression of disability and death realized with metabolic disorders. As a result, novel therapeutic avenues are critical for further development to address these concerns. An innovative strategy involves the vitamin nicotinamide and the pathways associated with the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), the mechanistic target of rapamycin (mTOR), mTOR Complex 1 (mTORC1), mTOR Complex 2 (mTORC2), AMP activated protein kinase (AMPK), and clock genes. Nicotinamide maintains an intimate relationship with these pathways to oversee metabolic disease and improve glucose utilization, limit mitochondrial dysfunction, block oxidative stress, potentially function as antiviral therapy, and foster cellular survival through mechanisms involving autophagy. However, the pathways of nicotinamide, SIRT1, mTOR, AMPK, and clock genes are complex and involve feedback pathways as well as trophic factors such as erythropoietin that require a careful balance to ensure metabolic homeostasis. Future work is warranted to gain additional insight into these vital pathways that can oversee both normal metabolic physiology and metabolic disease.