Nicotinamide

Role of this compound Phosphoribosyltransferase (NAMPT) in NAD+ Salvage

CD38 Glycohydrolase Regulation and Immunomodulation

This compound plays a significant role in modulating the immune system, primarily through its interaction with the ecto-enzyme CD38. CD38 is a major consumer of NAD+ in mammalian cells, functioning as an NAD+ glycohydrolase that breaks down NAD+ and its precursor, this compound mononucleotide (NMN). nih.govmdpi.com This enzymatic activity of CD38 is crucial in regulating cellular NAD+ levels, which in turn has wide-ranging implications for various biological processes, including infection, aging, and cancer. nih.gov

The expression of CD38 is often upregulated on immune cells following activation. mdpi.com By degrading NAD+, CD38 can influence the activity of other NAD+-dependent enzymes that are critical for immune cell function, such as sirtuins and poly (ADP-ribose) polymerases (PARPs). mdpi.comresearchgate.net For instance, the depletion of NAD+ by CD38 can limit the activity of SIRT1, a sirtuin that plays a role in T-cell fate determination and metabolic regulation. mdpi.comencyclopedia.pub

Furthermore, the products of CD38's enzymatic activity, such as cyclic ADP-ribose (cADPR), act as second messengers that can mobilize intracellular calcium, a key step in T-cell activation and proliferation. mdpi.comencyclopedia.pub However, it's noteworthy that CD38 is an inefficient cyclase, meaning it hydrolyzes a large amount of NAD+ to produce a small amount of cADPR. nih.govmdpi.com

In the context of the tumor microenvironment, the regulation of NAD+ metabolism via the inhibition of CD38 has been proposed as a strategy to enhance the efficacy of immune-based therapies. nih.gov CD38's role in regulating the metabolism and immunomodulation of the tumor microenvironment is an active area of research. nih.gov Some studies also suggest that CD38 may be involved in the transfer of mitochondria between cells, a process that can have implications for cancer cell survival. nih.gov

ATP Production and Mitochondrial Respiration

This compound is a critical component in the maintenance of cellular energy, primarily through its role as a precursor to NAD+, a key coenzyme in mitochondrial respiration and ATP production. mit.edu Mitochondria, the powerhouses of the cell, utilize NAD+ to convert nutrients into ATP, the cell's main energy currency, through a process called oxidative phosphorylation. mit.eduresearchgate.net The reduced form of NAD+, NADH, donates electrons to the electron transport chain, which drives the production of ATP. researchgate.netbiorxiv.org

Studies have shown that this compound can enhance cellular metabolism and promote ATP production. mdpi.com For example, this compound has been observed to significantly promote the activation of the AMPK pathway, which in turn induces intracellular ATP synthesis. mdpi.com Research also indicates that the transport of NAD+ into the mitochondria is a crucial process for maintaining mitochondrial respiration. mit.edu The protein MCART1 (also known as SLC25A51) has been identified as a likely transporter of NAD+ into human mitochondria. mit.edubiorxiv.org Cells lacking MCART1 exhibit significantly lower oxygen consumption, reduced respiration, and decreased ATP production. mit.edu

By replenishing cellular NAD+ pools, this compound and its derivatives like this compound mononucleotide (NMN) can support the tricarboxylic acid (TCA) cycle and the electron transport chain, leading to enhanced metabolic flux and ATP generation. mdpi.com This is particularly important under conditions of cellular stress, where energy demands are high.

Mitochondrial Biogenesis and Function Enhancement

One of the key pathways involved is the PGC-1α-dependent mitochondrial biogenesis pathway. clinicaltrials.gov NAD+ precursors, such as this compound riboside (NR), have been shown to boost this pathway, leading to increased transcription of genes involved in oxidative phosphorylation. clinicaltrials.gov Studies in mice have demonstrated that NR treatment can robustly induce mitochondrial biogenesis in skeletal muscle and brown adipose tissue. embopress.org This leads to an increase in mitochondrial mass, as indicated by increased citrate synthase activity, and an enhanced capacity for oxidative ATP production. embopress.org

Furthermore, this compound supplementation has been found to upregulate mitochondrial proteins and increase proteins related to mitochondrial functions, including oxidative phosphorylation, fatty acid oxidation, and the TCA cycle. nih.gov In human studies, long-term supplementation with NR has been shown to increase the number and density of muscle mitochondria and increase muscle mitochondrial DNA (mtDNA). nutraingredients-usa.com This enhancement of mitochondrial biogenesis and function can help to prevent mitochondrial ultrastructural abnormalities and mtDNA deletion formation. mdpi.comembopress.org

Enhancement of DNA Repair Mechanisms

This compound plays a crucial role in maintaining genomic stability by enhancing DNA repair mechanisms. oup.comnih.gov This protective effect is largely attributed to its role as a precursor for NAD+, which is an essential substrate for the nuclear enzyme poly (ADP-ribose) polymerase-1 (PARP-1). oup.compatsnap.com PARP-1 is a key player in the DNA damage response, particularly in the repair of single-strand DNA breaks. patsnap.com When DNA damage occurs, PARP-1 is activated and utilizes NAD+ to synthesize poly (ADP-ribose) chains, which recruit other DNA repair proteins to the site of damage. patsnap.com

Cellular genotoxic stress can lead to a depletion of NAD+, which in turn impairs the activity of PARP-1 and compromises DNA repair. nih.gov Studies have shown that this compound supplementation can prevent this NAD+ depletion and stimulate DNA repair processes. nih.gov For example, in human keratinocytes exposed to ultraviolet (UV) radiation, this compound has been shown to enhance the repair of DNA damage, including cyclobutane pyrimidine dimers (CPDs) and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8oxoG). oup.com It achieves this by increasing both the proportion of cells undergoing excision repair and the rate of repair within each cell. oup.com

The ability of this compound to enhance DNA repair is linked to its capacity to prevent the decline in cellular ATP levels that often occurs after DNA damage. oup.com DNA repair is an energy-intensive process, and by ensuring a sufficient supply of ATP, this compound supports the efficient functioning of repair pathways. mdpi.com Research has demonstrated that this compound can enhance different DNA repair pathways, supporting its potential as an agent for protecting against DNA damage. oup.comresearchgate.net

Chromatin Remodeling and Epigenetic Modification

This compound also influences genomic integrity and gene expression through its effects on chromatin remodeling and epigenetic modifications. pnas.orgnih.gov Chromatin, the complex of DNA and proteins (primarily histones) in the nucleus, can be modified to either allow or restrict access to DNA for transcription and repair. cd-genomics.com These modifications are a key aspect of epigenetic regulation.

This compound is a known inhibitor of sirtuins, a class of NAD+-dependent deacetylases. researchgate.net Sirtuins, such as SIRT1, play a significant role in chromatin remodeling by deacetylating histones and other proteins, which can affect gene expression. patsnap.com By inhibiting sirtuins, this compound can influence the acetylation status of histones and thereby modulate chromatin structure and gene transcription.

Furthermore, this compound's role as a precursor to NAD+ connects it to the activity of PARPs, which are also involved in chromatin modification. nih.gov PARP1 can influence chromatin structure through the poly-ADP-ribosylation of histones and other chromatin-associated proteins. nih.govoup.com This modification can alter the local chromatin architecture, making it more accessible for DNA repair machinery or transcription factors.

Management of Reactive Oxygen Species (ROS)

This compound (NAM) plays a significant role in managing cellular levels of reactive oxygen species (ROS), thereby mitigating oxidative stress. nih.govmdpi.com Oxidative stress arises from an imbalance between the production of ROS and the cell's ability to detoxify these reactive products, leading to damage of cellular components like DNA, proteins, and lipids. mdpi.com NAM, a precursor to this compound adenine dinucleotide (NAD+) and its phosphorylated form NADPH, contributes to cellular homeostasis and ROS management. nih.govmdpi.com

Research has demonstrated that NAM supplementation can effectively reduce ROS levels and protect cells from their detrimental effects. mdpi.com For instance, in human primary keratinocytes and 3D epidermal models, NAM has been shown to decrease oxidative stress induced by UVB radiation. mdpi.com Similar protective effects against oxidative stress have been observed in primary keratinocytes from fields of cancerization and in a mouse model of optical nerve injury where NAM supplementation reduced both oxidative stress and neuroinflammation. mdpi.com

Upregulation of Antioxidant Gene Expression

This compound has been shown to upregulate the expression of various antioxidant genes, thereby enhancing the cell's endogenous defense mechanisms against oxidative stress. researchgate.net This is a crucial aspect of its protective role, as it strengthens the cellular machinery responsible for neutralizing ROS.

One of the key pathways influenced by this compound is the Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. Nrf2 is a transcription factor that regulates the basal and inducible expression of a wide array of antioxidant and detoxifying enzymes. ahajournals.orgresearchgate.net Under conditions of cellular stress, such as increased ROS production, Nrf2 is activated and translocates to the nucleus, where it binds to antioxidant response elements (AREs) in the promoter regions of its target genes. ahajournals.org

Research indicates that this compound can modulate the Nrf2 pathway. For example, in a model of Cockayne syndrome, a premature aging disorder, this compound supplementation was found to counteract the repression of the NRF2 pathway. aging-us.com Furthermore, studies have shown that this compound mononucleotide (NMN), a precursor to NAD+, can restore redox balance in the liver of aged mice through the SIRT3-Nrf2 axis, protecting against oxidative stress-induced damage. researchgate.net In silica-induced lung injury in mice, NMN treatment upregulated the expression of antioxidant genes by promoting the expression and nuclear translocation of Nrf2. mdpi.com

This compound's influence extends to the expression of specific antioxidant enzymes. In gestational diabetic rats, this compound supplementation was shown to upregulate the mRNA expression of superoxide dismutase (SOD) and catalase (CAT) genes in the liver. researchgate.net Similarly, in human keratinocytes, a compound containing this compound was reported to promote the expression of antioxidant genes, including CAT and GPX1. researchgate.net Overexpression of this compound phosphoribosyltransferase (Nampt), the rate-limiting enzyme in the NAD+ salvage pathway, has been shown to increase the expression of antioxidant genes like superoxide dismutase 2 and catalase, which is mediated by SIRT1 activation. nih.gov

Cell Cycle Progression and Senescence Modulation

This compound plays a multifaceted role in the regulation of cell cycle progression and cellular senescence. nih.govmdpi.com Cellular senescence is a state of irreversible cell cycle arrest that can be triggered by various stressors, including DNA damage and oxidative stress. mdpi.comfrontiersin.org this compound's influence in this context is closely linked to its role as a precursor for NAD+ and its impact on NAD+-dependent enzymes like sirtuins. nih.govmdpi.commdpi.com

Studies have shown that this compound can modulate the cell cycle. In the protozoan parasite Giardia duodenalis, this compound was found to induce a strong arrest in the G2 phase of the cell cycle. nih.gov In human cells, this compound treatment has been observed to alter cell cycle profiles. nih.gov For instance, it can attenuate the increased levels of p21WAF1, a key cell cycle inhibitor, in a p53-independent manner. nih.gov However, it's important to note that while this compound can influence the cell cycle, it does not appear to reinitiate proliferation in cells that are already senescent. nih.gov

This compound's effect on senescence is complex. It has been demonstrated to delay the onset of senescence and extend the replicative lifespan of primary human fibroblasts by suppressing ROS production. nih.govresearchgate.net By keeping ROS accumulation low, this compound can attenuate the expression of senescence-associated phenotypes. nih.govresearchgate.net The decline in the expression of this compound phosphoribosyltransferase (Nampt) during aging leads to NAD+ deficiency and reduced activity of Sirtuin 1 (SIRT1), contributing to cell senescence. mdpi.com Supplementation with this compound or its precursor, this compound mononucleotide (NMN), can restore NAD+ levels and counteract signs of senescence. mdpi.com Overexpression of Nampt has been shown to delay cellular senescence in mouse embryonic fibroblasts by increasing SIRT1 activity. nih.govaging-us.com SIRT1, a NAD+-dependent deacetylase, is involved in regulating the cell cycle, DNA repair, and cell survival. ijmio.com

Apoptosis and Cell Survival Pathways

This compound exerts significant influence over the intricate balance between apoptosis (programmed cell death) and cell survival. mdpi.comresearchgate.net Its mechanisms of action involve the modulation of key signaling pathways and effector molecules that govern these fundamental cellular processes.

One of the central ways this compound promotes cell survival is through the activation of the Protein Kinase B (Akt) signaling pathway. mdpi.com Akt can phosphorylate and inactivate pro-apoptotic proteins such as Bad, thereby preventing the initiation of the apoptotic cascade. mdpi.com this compound has been shown to promote the phosphorylation of Bad through an Akt-mediated pathway. mdpi.com Furthermore, Akt can inhibit the transcriptional activity of the pro-apoptotic protein p53 and prevent the release of cytochrome c from the mitochondria, a critical step in the intrinsic apoptotic pathway. mdpi.com

This compound's influence extends to the Bcl-2 family of proteins, which are key regulators of apoptosis. nih.gov This family includes both anti-apoptotic members (e.g., Bcl-2, Bcl-xL) and pro-apoptotic members (e.g., Bax, Bak). nih.govhaematologica.org Studies have indicated that this compound can modulate the expression of these proteins. For instance, a derivative of this compound, 2-amino-nicotinamide, has been shown to suppress the levels of the anti-apoptotic protein Bcl-2 while increasing the levels of the pro-apoptotic protein Bax in prostate cancer cells. ajol.info

Moreover, this compound impacts the activity of caspases, a family of proteases that execute the final stages of apoptosis. mdpi.comresearchgate.net By potentially regulating caspase activity through Akt, this compound can interfere with the apoptotic process. mdpi.com this compound has been shown to block both early apoptotic events, such as phosphatidylserine exposure on the cell surface, and late events like nuclear DNA degradation. mdpi.comresearchgate.net The enzyme this compound phosphoribosyltransferase (Nampt), which is crucial for NAD+ synthesis, plays a vital role in cell survival by inhibiting apoptosis. ahajournals.orgahajournals.org Downregulation of Nampt leads to increased caspase-3 cleavage and cytochrome c release, key markers of apoptosis. ahajournals.orgahajournals.org

Regulation of Inflammatory Pathways and Cytokine Release

This compound has demonstrated significant anti-inflammatory properties by modulating key inflammatory pathways and suppressing the release of pro-inflammatory cytokines. nih.govmdpi.com A central target of this compound's anti-inflammatory action is the Nuclear Factor-kappa B (NF-κB) signaling pathway. nih.govresearchgate.net NF-κB is a critical transcription factor that orchestrates the expression of numerous genes involved in inflammation, including various cytokines. researchgate.netmdpi.com

Research has shown that this compound can inhibit the activity of NF-κB. nih.gov This inhibition can occur indirectly through the enhancement of DNA damage repair, which in turn reduces the inflammatory signals that activate NF-κB. nih.gov Studies have demonstrated that niacin, a form of vitamin B3, can disrupt NF-κB signaling, leading to the suppression of inflammatory cytokines. researchgate.net In human aortic endothelial cells, niacin was shown to inhibit TNF-α-induced NF-κB transcriptional activity. researchgate.net Furthermore, this compound mononucleotide (NMN) has been found to alleviate lipopolysaccharide (LPS)-induced inflammation by downregulating TLR4 signaling, which subsequently reduces the phosphorylation of NF-κB p65. mdpi.com In a mouse model of sepsis-induced acute lung injury, NMN was shown to protect against the condition by modulating macrophage polarization via the SIRT1/NF-κB pathway. tandfonline.com

This compound's regulatory effects extend to a broad range of cytokines. In human whole blood stimulated with endotoxin, this compound was found to profoundly inhibit the release of pro-inflammatory cytokines such as Interleukin-1β (IL-1β), Interleukin-6 (IL-6), Interleukin-8 (IL-8), and Tumor Necrosis Factor-alpha (TNF-α). nih.gov In human keratinocytes exposed to UVB radiation, this compound significantly downregulated the mRNA expression of IL-6, Interleukin-10 (IL-10), Monocyte Chemoattractant Protein-1 (MCP-1), and TNF-α. researchgate.net Similarly, in activated CD4+ T-cells, this compound treatment resulted in reduced production of the pro-inflammatory cytokines IL-2, Interferon-gamma (IFNγ), and IL-17. mdpi.com

The following table summarizes the effects of this compound on various inflammatory cytokines:

Protein Acetylation and Deacetylation Processes

The reversible acetylation of lysine residues on proteins is a critical post-translational modification that regulates a vast array of cellular processes. This dynamic equilibrium is maintained by the opposing actions of two enzyme families: lysine acetyltransferases (KATs) and lysine deacetylases (KDACs). spandidos-publications.com this compound plays a significant role in modulating this balance, primarily through its interaction with a specific class of deacetylases.

Protein acetylation involves the transfer of an acetyl group from a donor molecule, typically acetyl-coenzyme A (acetyl-CoA), to the ε-amino group of a lysine residue on a target protein. acs.org This action is catalyzed by KATs (formerly known as histone acetyltransferases or HATs). spandidos-publications.com The addition of the acetyl group neutralizes the positive charge of the lysine residue, which can alter the protein's conformation, stability, localization, and interactions with other molecules, including DNA. acs.orgwikipedia.org Conversely, KDACs (formerly histone deacetylases or HDACs) remove these acetyl groups, restoring the lysine's positive charge and reversing the effects of acetylation. researchgate.net

KDACs are categorized into four main classes. Classes I, II, and IV are zinc-dependent enzymes, while Class III, known as sirtuins, are mechanistically distinct, requiring this compound adenine dinucleotide (NAD+) as a cofactor for their deacetylase activity. acs.orgnih.gov this compound's primary role in this regulatory network is as a direct inhibitor of the sirtuin family of enzymes. scbt.commdpi.com

The catalytic mechanism of sirtuins involves the cleavage of NAD+ into this compound and ADP-ribose. The acetyl group from the lysine substrate is transferred to the ADP-ribose moiety, resulting in a deacetylated protein, this compound, and O-acetyl-ADP-ribose. plos.org As a product of this reaction, this compound functions as a physiological feedback inhibitor. windows.net Its mechanism of inhibition is based on intercepting a key reaction intermediate (an ADP-ribosyl-enzyme-acetyl peptide intermediate), which promotes the reverse reaction, known as base exchange, thereby regenerating NAD+ and preventing the completion of the deacetylation process. nih.gov This action effectively switches the enzyme's function from deacetylation to base exchange. biorxiv.org

By inhibiting sirtuins (SIRT1-7), this compound leads to an increase in the acetylation levels, or hyperacetylation, of numerous sirtuin substrates. mdpi.com This includes both histone proteins, which affects chromatin structure and gene expression, and a large and growing number of non-histone proteins that regulate diverse cellular functions. spandidos-publications.comrsc.org For instance, treatment of cells with this compound has been shown to increase the acetylation of synthetic non-histone substrates, demonstrating its direct impact on deacetylase activity in vivo. rsc.org

Research has quantified the inhibitory effect of this compound on various sirtuin isoforms. The half-maximal inhibitory concentration (IC50) values show that this compound inhibits different sirtuins with varying potency, suggesting that physiological fluctuations in this compound concentration can regulate the activity of specific sirtuins. scbt.comwindows.net

Table 1: Inhibitory Concentration (IC50) of this compound on Human Sirtuin Isoforms

The consequences of sirtuin inhibition by this compound are far-reaching. For example, the inhibition of SIRT1 can increase the acetylation of transcription factors like p53, which is involved in apoptosis and cell cycle arrest. plos.org In mitochondria, this compound-induced inhibition of SIRT3 leads to increased acetylation of metabolic enzymes, such as pyruvate dehydrogenase (PDH) and ATP synthase, thereby modulating their activity.

Alzheimer's Disease Pathology and Cognitive Function

Impaired brain energy metabolism and oxidative stress are implicated in the cognitive decline and pathological hallmarks of Alzheimer's disease (AD), such as the accumulation of amyloid β-peptide (Aβ) and hyperphosphorylated tau. nih.gov Research in animal models suggests that this compound can mitigate these effects. In a mouse model of AD, this compound treatment for eight months led to improved cognitive performance and a reduction in Aβ and hyperphosphorylated tau in the hippocampus and cerebral cortex. nih.gov The mechanism appears to involve the preservation of mitochondrial integrity and the enhancement of autophagy, a cellular cleaning process. nih.gov

Another form of vitamin B3, this compound riboside (NR), has also shown promise in AD research. In a mouse model mimicking human Alzheimer's, NR treatment reduced tau pathology, decreased DNA damage, and improved cognitive and physical function. drugtargetreview.com These benefits are thought to stem from the normalization of NAD+ levels, which are crucial for cellular energy, DNA repair, and resistance to neuronal stress. drugtargetreview.comalzdiscovery.org However, it's important to note that a clinical trial with high-dose this compound in patients with early-stage Alzheimer's did not show a significant reduction in tau protein levels, indicating that promising results in animal models may not always translate directly to humans. psypost.org

Table 1: Effects of this compound and its Derivatives in Alzheimer's Disease Models

Parkinson's Disease Models and Motor Deficits

Parkinson's disease (PD) is characterized by the loss of dopamine-producing neurons, leading to motor deficits. Research suggests that this compound may offer neuroprotection in PD models. In a cellular model of Parkinson's, high doses of this compound were found to prevent mitochondrial dysfunction and oxidative stress. nih.gov Furthermore, in a Drosophila (fruit fly) model of PD, this compound improved motor function. nih.gov

Studies using this compound riboside (NR) have also demonstrated positive outcomes. In C. elegans (roundworm) and mouse models of PD, NR rescued mitochondrial dysfunction and behavioral deficits. biorxiv.org It is believed to work by activating the mitochondrial unfolded protein response, a protective mechanism. biorxiv.org However, some research has yielded conflicting results. One study in a rat model of Parkinson's found that high doses of this compound actually exacerbated motor symptoms and neurodegeneration, highlighting the complexity of its effects. parkinsonsnewstoday.comresearchgate.net

Huntington's Disease Models and Neuronal Health

Huntington's disease (HD) is an inherited neurodegenerative disorder. nih.govfrontiersin.org While research on the direct effects of this compound in HD is less extensive than for AD and PD, the general neuroprotective properties of this compound and its role in maintaining NAD+ levels are relevant. nih.gov NAD+ metabolism is crucial for neuronal survival, and its dysregulation is a factor in neurodegeneration. mdpi.com The enzyme NMNAT, which is involved in NAD+ synthesis, has been shown to restore neuronal integrity in models of Huntington's disease by counteracting the toxicity of mutant huntingtin protein aggregates. mdpi.com This suggests that strategies to boost NAD+ levels, such as with this compound, could be beneficial for neuronal health in HD.

Neuroprotection in Ischemic and Traumatic Brain Injury

This compound has demonstrated significant neuroprotective effects in models of both ischemic and traumatic brain injury (TBI). nih.govnih.govresearchgate.net Following a TBI, this compound has been shown to reduce the breakdown of the blood-brain barrier and decrease apoptosis (programmed cell death). nih.govresearchgate.net In animal models, this compound administration after a cortical contusion injury significantly reduced neuronal cell loss and lesion cavity size. nih.gov

Similarly, in models of cerebral ischemia (stroke), this compound has been found to be neuroprotective. nih.govfrontiersin.org The precursor to NAD+, this compound mononucleotide (NMN), has also been shown to have neuroprotective effects in cerebral ischemia mice by improving mitochondrial metabolism and reducing oxidative stress. nih.gov In rats with TBI, NMN administration attenuated histological damage, neuronal death, and brain edema, while also improving neurological and cognitive deficits. nih.govmedsci.org

Brain Inflammation and Microglial Activation

Neuroinflammation, often mediated by the activation of microglia and astrocytes, is a common feature of many neurodegenerative diseases and brain injuries. medsci.orgnih.govresearchgate.net this compound and its precursors have been shown to modulate this inflammatory response. In a mouse model of TBI, this compound mononucleotide (NMN) treatment suppressed the activation of astrocytes and microglia and inhibited the expression of inflammatory factors. nih.govmedsci.org

In a mouse model of type 1 diabetes, this compound supplementation prevented brain inflammation and microglial activation. nih.gov It achieved this by increasing NAD+ content in the brain, which in turn led to a decrease in markers of inflammation and microglial activation. nih.gov Research also indicates that this compound can reduce the number of immune cells and activated microglia in the ischemic hemisphere following a stroke. researchgate.net Furthermore, in a model of vascular dementia, NAD+ administration attenuated microglial activation and the expression of the pro-inflammatory cytokine TNFα. acs.org

Photoprotective Effects and UV Radiation Damage

Ultraviolet (UV) radiation from sun exposure is a primary cause of skin damage, leading to DNA mutations, inflammation, and depletion of cellular energy, which can culminate in photoaging and skin cancer. nad.comnih.gov this compound has demonstrated significant photoprotective effects by addressing these UV-induced cellular changes. researchgate.net

One of the key mechanisms of this compound's photoprotective action is its ability to prevent the depletion of adenosine triphosphate (ATP) in irradiated skin cells. nih.govresearchgate.net DNA repair is an energy-intensive process, and by maintaining cellular energy levels, this compound enhances the repair of UV-induced DNA damage. researchgate.netoup.com Specifically, it has been shown to enhance the repair of cyclobutane pyrimidine dimers (CPDs) and 8-oxoguanine (8oxoG), two major forms of DNA damage caused by UV radiation. oup.com

Furthermore, this compound helps to mitigate UV-induced immunosuppression. oup.comresearchgate.net Exposure to UV radiation can suppress the skin's immune response, hindering its ability to eliminate cancerous cells. researchgate.net Studies have shown that both topical and oral this compound can protect against this immunosuppression. researchgate.netmdpi.com For instance, research has demonstrated that this compound can prevent the suppression of the Mantoux reaction (a tuberculin sensitivity test) following UV exposure. dermnetnz.org This immune-protective effect is crucial for preventing the development of skin cancers. researchgate.net

Additionally, this compound has been found to reduce the production of reactive oxygen species (ROS) in skin cells exposed to UVB radiation, thereby limiting oxidative stress and cellular damage. nad.commdpi.com Pre-treatment of skin cells with this compound has been shown to diminish the harmful effects of UVB by bolstering DNA repair mechanisms and reducing inflammation. nad.com

Chemoprevention of Non-Melanoma Skin Cancers and Actinic Keratosis

Non-melanoma skin cancers (NMSCs), including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), are the most common types of human cancers, with UV radiation being the principal cause. nih.gov Actinic keratoses are precancerous lesions that can develop into SCCs. mdpi.com this compound has emerged as a promising agent for the chemoprevention of these conditions. nih.govactasdermo.org

The primary mechanism behind this compound's chemopreventive effects lies in its ability to enhance DNA repair and prevent UV-induced immunosuppression. actasdermo.org By providing a substrate for the production of NAD+, this compound helps to maintain cellular energy levels, which are crucial for the energy-dependent process of DNA repair. oup.com It also inhibits the enzyme poly(ADP-ribose) polymerase-1 (PARP-1), which, when overactivated by extensive DNA damage, can lead to cellular energy depletion and cell death. nih.govijdvl.com

Clinical research has provided strong evidence for the efficacy of oral this compound in reducing the incidence of NMSCs and actinic keratoses in high-risk individuals. nih.gov A landmark Phase 3 randomized controlled trial, the Oral this compound to Reduce Actinic Cancer (ONTRAC) study, demonstrated that oral this compound significantly reduced the rates of new NMSCs and actinic keratoses in patients with a history of these lesions. nih.govcancernetwork.com

The following table summarizes the key findings from a pivotal clinical trial on the chemopreventive effects of this compound:

It is important to note that the protective effects of this compound appear to cease after discontinuation of the supplement. actasdermo.org

Inflammatory Skin Disorders (e.g., Acne Vulgaris, Rosacea, Atopic Dermatitis)

This compound exhibits significant anti-inflammatory properties, making it a valuable therapeutic agent for a range of inflammatory skin disorders. nih.govdermnetnz.org Its mechanism of action involves the inhibition of inflammatory cytokines and the modulation of various cellular processes that contribute to inflammation. nih.govactasdermo.org

In the context of acne vulgaris , this compound's anti-inflammatory effects help to reduce the redness and swelling associated with acne lesions. dermnetnz.org It has also been suggested that this compound can reduce sebum production, a key factor in the development of acne. dermnetnz.orgbioscmed.com

For rosacea , a chronic inflammatory condition characterized by facial erythema and inflammatory lesions, topical this compound has shown promise in alleviating symptoms. nih.govmdpi.com A metabolite of this compound, N-methylthis compound, has also been studied for its effectiveness in treating rosacea. mdpi.com

In atopic dermatitis , a condition characterized by a compromised skin barrier and inflammation, this compound has been shown to improve skin barrier function and reduce inflammation. nih.govnih.gov It helps to decrease transepidermal water loss (TEWL) and increase skin hydration, which are crucial for managing this condition. dermnetnz.orgresearchgate.net

The anti-inflammatory actions of this compound are attributed to its ability to inhibit the nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1), which plays a role in the expression of pro-inflammatory cytokines such as IL-1β, IL-6, IL-8, and TNF-α. actasdermo.orgijdvl.com

Autoimmune Bullous Diseases (e.g., Bullous Pemphigoid)

Autoimmune bullous diseases are a group of disorders characterized by the formation of blisters on the skin and mucous membranes. Bullous pemphigoid is one of the most common of these conditions. jwatch.org The anti-inflammatory properties of this compound have led to its investigation as a therapeutic option for these diseases. nih.govijdvl.com

The proposed mechanism for this compound's efficacy in autoimmune blistering disorders is its ability to suppress the inflammatory cascade. ijdvl.com By inhibiting pro-inflammatory cytokines, this compound can help to reduce the inflammation that contributes to blister formation. ijdvl.com

Clinical studies have explored the use of this compound, often in combination with tetracycline, as an alternative to systemic steroids for the treatment of bullous pemphigoid. jwatch.orgnih.gov A randomized, open-label trial compared the combination of this compound and tetracycline to prednisone therapy in patients with bullous pemphigoid. nih.gov The results suggested that the combination therapy was a useful alternative with a favorable side-effect profile compared to prednisone. nih.gov

The following table summarizes the response to treatment in a clinical trial for bullous pemphigoid:

Research has also reported successful use of this compound in combination with tetracyclines for other autoimmune blistering diseases, including cicatricial pemphigoid, lichen planus pemphigoides, and dermatitis herpetiformis. ijdvl.comjscimedcentral.com

Pigmentation Disorders (e.g., Melasma, Hyperpigmentation)

This compound has been investigated for its effects on pigmentation disorders such as melasma and post-inflammatory hyperpigmentation. nih.govdermnetnz.org Its mechanism of action in this context is primarily attributed to its ability to inhibit the transfer of melanosomes from melanocytes to surrounding keratinocytes. dr-hermans.comresearchgate.net This action helps to reduce the accumulation of melanin in the epidermis, leading to a lightening of hyperpigmented areas. dr-hermans.com

Clinical studies have evaluated the efficacy of topical this compound in treating melasma. One study compared a 4% niacinamide cream to a 4% hydroquinone cream (a common treatment for hyperpigmentation) in patients with melasma. researchgate.net The results showed that both treatments led to pigment improvement, with niacinamide demonstrating a significant reduction in hyperpigmentation. researchgate.netmelasmaclinic.com.au Furthermore, niacinamide was found to reduce mast cell infiltration and improve solar elastosis in the affected skin. researchgate.net

The following table summarizes the results of a comparative study on the treatment of melasma:

These findings suggest that this compound is a safe and effective therapeutic agent for melasma, offering an alternative to hydroquinone with a potentially better side-effect profile. dr-hermans.comresearchgate.net

Skin Barrier Function and Transepidermal Water Loss

A healthy skin barrier is essential for maintaining skin hydration and protecting against environmental aggressors. Transepidermal water loss (TEWL) is a key indicator of skin barrier function, with higher TEWL values indicating a compromised barrier. researchgate.net this compound has been shown to improve skin barrier function by reducing TEWL and enhancing the production of key components of the stratum corneum. nih.govdermnetnz.org

Topical application of this compound has a stabilizing effect on the epidermal barrier. nih.gov It has been shown to increase the synthesis of ceramides and free fatty acids in the stratum corneum, which are crucial lipids for maintaining barrier integrity. ijdvl.com this compound also stimulates the production of proteins like keratin, involucrin, and filaggrin, which are important for the formation of the cornified envelope, the outermost layer of the skin. dermatologytimes.com

Studies have demonstrated the efficacy of both topical and oral this compound in reducing TEWL. In one study, a 2% this compound cream applied twice daily for four weeks significantly reduced TEWL compared to a vehicle. ijdvl.com Another study involving patients with atopic dermatitis found that a 2% this compound cream was more effective at reducing TEWL and increasing stratum corneum hydration than white petrolatum. researchgate.net

A randomized controlled trial also evaluated the effect of oral this compound on TEWL and found a significant reduction in TEWL on the forehead and limbs over a 12-month period. researchgate.netthe-hospitalist.org

The following table shows the relative reduction in TEWL with oral this compound in a clinical trial:

These findings highlight this compound's role in strengthening the skin barrier, making it a beneficial ingredient for conditions associated with impaired barrier function, such as dry skin and atopic dermatitis. nih.govijdvl.com

Skin Aging Pathogenesis and Rejuvenation Studies

Skin aging is a complex process influenced by both intrinsic and extrinsic factors, such as UV radiation (photoaging). mdpi.com It is characterized by changes such as wrinkles, fine lines, hyperpigmentation, and loss of elasticity. mdpi.com this compound has been shown to address several aspects of skin aging through various mechanisms. nih.govdermnetnz.org

Topical application of this compound has been demonstrated to improve the appearance of aging skin. nih.gov It can reduce fine lines and wrinkles, red blotchiness, and skin sallowness (yellowing). mdpi.com The anti-aging effects of this compound are attributed to its ability to:

Stimulate collagen production: In vitro studies suggest that this compound increases the synthesis of dermal collagen, which helps to improve skin structure and reduce wrinkles. dermatologytimes.comnih.gov

Inhibit protein glycation: this compound can reduce the deposition of cross-linked collagen and elastin molecules, which contribute to skin stiffness and reduced elasticity. dermatologytimes.com

Improve skin barrier function: As discussed previously, this compound enhances the skin's barrier, which can become compromised with age. dermnetnz.orgdermatologytimes.com

Reduce hyperpigmentation: By inhibiting melanosome transfer, this compound can help to even out skin tone and reduce age spots. nih.gov

A clinical study of a topical 5% niacinamide emulsion showed a 21% improvement in fine lines, a 14% improvement in skin tone clarity, and a 15% improvement in radiance over 12 weeks. dermatologytimes.com Another study demonstrated that a cosmetic containing 4% this compound improved wrinkles after 8 weeks of application. nih.gov

Lipid Metabolism and Diet-Induced Obesity

Endothelial Function and Inflammation

Chronic Kidney Disease Progression and Inflammation

Chronic kidney disease (CKD) is often characterized by a state of chronic inflammation and the accumulation of uremic toxins. nih.govresearchgate.net Research indicates that NAD+ levels are often diminished in both acute kidney injury (AKI) and CKD. mdpi.com

In animal models of adenine-induced CKD, supplementation with this compound has been shown to reduce both kidney inflammation and fibrosis, thereby impeding the progression of the disease. nih.govresearchgate.netfrontiersin.org This therapeutic effect is attributed to the restoration of NAD+ levels, which in turn enhances NAD+-consuming metabolic pathways. nih.govresearchgate.net Specifically, this compound administration was found to lessen the accumulation of metabolites from glycolysis and the Krebs cycle that typically occurs in renal failure. nih.govresearchgate.net

Studies in various animal models, including those with unilateral ureteral obstruction and diabetic nephropathy, have further substantiated the nephroprotective effects of this compound and other NAD+ precursors. frontiersin.org In these models, this compound has demonstrated the ability to suppress tubular atrophy, inflammation, and fibrosis. frontiersin.org However, it is noteworthy that some conflicting results exist. For instance, one study reported that while this compound riboside (a this compound precursor) was beneficial in a mouse model of ischemic AKI, it did not prevent the progression of CKD. nih.gov This suggests that the effectiveness of this compound may vary depending on the specific type and stage of kidney disease. nih.govunige.ch

Table 1: Effects of this compound in Chronic Kidney Disease Models

Acute Kidney Injury Models

Acute kidney injury (AKI) is a condition marked by a sudden decline in kidney function. frontiersin.org NAD+ deficiency has been identified as a key factor in the pathophysiology of AKI. nih.gov Preclinical studies have explored the potential of this compound and its derivatives to mitigate this condition.

In mouse models of ischemia-reperfusion injury (IRI) and cisplatin-induced AKI, supplementation with this compound riboside was shown to prevent the elevation of plasma urea and creatinine and reduce tubular injury. nih.govunige.ch Another NAD+ precursor, this compound mononucleotide (NMN), has been observed to reduce tubular cell DNA damage and subsequent cellular senescence in both in vitro (human proximal tubular cells) and in vivo (unilateral ischemia-reperfusion injury mouse model) settings. frontiersin.org Importantly, the protective effects of NMN were seen even when administered during the recovery phase of ischemic AKI. frontiersin.org

Age-Related Hearing Loss Studies

Age-related hearing loss (ARHL) is a prevalent sensory disability. nih.gov Studies in animal models suggest that NAD+ depletion plays a significant role in the progression of ARHL. biospace.com

Long-term supplementation with this compound riboside (NR) in mice has been shown to halt the progression of ARHL, particularly at high frequencies. nih.govnad.com Mechanistically, NR appears to enhance synaptic transmission between auditory neurons and hair cells. nih.gov It has also been shown to preserve the magnitude of auditory nerve responses, indicating a preservation of the auditory pathway. nad.com Research from the National Institute on Aging has demonstrated that NR exerts these protective effects against hearing deficits in mice. nad.com While some human clinical trials have not shown a statistically significant improvement in hearing ability with this compound mononucleotide (NMN) supplementation, a trend toward improvement has been observed. probiologists.comnmn.com

Noise-Induced Hearing Damage Prevention

Exposure to loud noise can cause damage to the synapses connecting the nerves and hair cells in the cochlea, leading to noise-induced hearing loss (NIHL). gladstone.orgcornell.edu

Studies in mice have demonstrated that the administration of this compound riboside (NR), either before or after noise exposure, can successfully prevent damage to these synaptic connections, thereby avoiding both short-term and long-term hearing loss. gladstone.orgcornell.eduhearingreview.com The protective effect of NR is attributed to its role as a precursor to NAD+, which increases the activity of the protein sirtuin 3 (SIRT3). gladstone.orgcornell.eduhearingreview.com SIRT3 is critically involved in mitochondrial function, and its activation by NR helps to protect cochlear nerve cells from injury. gladstone.orgcornell.eduhearingreview.comcornell.edu This discovery points to a unique pathway and a potential therapeutic strategy for the prevention and treatment of NIHL. gladstone.orgcornell.edu

Table 2: this compound Precursors in Hearing Loss Research

Lung Adenocarcinoma and Tumor Suppressor Gene Re-activation

This compound has been investigated for its potential role in cancer therapy, particularly in lung adenocarcinoma, through the re-activation of epigenetically silenced tumor suppressor genes. aacrjournals.orgnih.gov One such gene is Runt-related transcription factor 3 (RUNX3), a tumor suppressor that is inactivated in approximately 70% of lung adenocarcinomas. aacrjournals.orgnih.gov this compound, acting as a sirtuin inhibitor, has demonstrated the ability to reactivate RUNX3 that has been silenced epigenetically in cancer cells. aacrjournals.orgnih.gov

The proposed mechanism involves the inhibition of sirtuins by this compound, which in turn activates p300, leading to the activation of RUNX3. aacrjournals.org This has been previously observed in other cancer models, where this compound upregulated p300 and RUNX3 levels. aacrjournals.org

Table 1: Clinical Trial of this compound in Stage IV Lung Adenocarcinoma

Data from a randomized double-blind (Phase IIb) trial. aacrjournals.orgnih.gov

Anti-Tumorigenic Effects in Preclinical Models

Preclinical studies have demonstrated the tumor-suppressive capabilities of this compound in various cancer models. nih.gov These studies show that this compound administration can disrupt key cancer processes such as proliferation and apoptosis. nih.gov

In a mouse model of carcinogen-induced lung adenocarcinoma, this compound treatment was found to increase levels of the tumor suppressor gene RUNX3 and inhibit the growth of lung cancer. aacrjournals.orgnih.gov Specifically, treatment with 0.5% and 1% this compound reduced the average cancer volume to 37% and 31%, respectively. aacrjournals.org

Similarly, in a mouse model of N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN)-induced bladder cancer, this compound supplementation was shown to inhibit tumor formation. plos.org Supplementation with 0.5% this compound reduced the tumor formation ratio from 100% to 74%, and 1% this compound further reduced it to 52%. plos.org Tumor volume was also significantly reduced with increasing concentrations of this compound. plos.org

Another this compound-related compound, this compound mononucleotide (NMN), has also shown anti-tumorigenic effects. In a mouse model of colitis-associated colorectal cancer, NMN supplementation reduced the number of colon tumors. nih.gov In lung adenocarcinoma cell and mouse models, high-dose NMN was found to inhibit tumor growth by promoting a form of cell death called ferroptosis. mdpi.com

Table 2: Anti-Tumorigenic Effects of this compound in Preclinical Cancer Models

Musculoskeletal Health and Sarcopenia

Sarcopenia, the age-related loss of skeletal muscle mass and function, is a significant health concern in older adults. nih.govmdpi.com this compound precursors, such as this compound mononucleotide (NMN) and this compound riboside (NR), have been investigated for their potential to mitigate sarcopenia by increasing levels of this compound adenine dinucleotide (NAD+). nih.govnih.gov A decline in NAD+ during aging is linked to reduced mitochondrial function and other cellular changes that contribute to sarcopenia. nih.gov

Preclinical models have suggested that improving NAD+ levels can decrease inflammatory cytokines and improve muscle strength. nih.gov However, evidence for the effects of this compound precursors in older adults remains inconclusive. nih.govnih.gov A systematic review and meta-analysis of randomized controlled trials found that NMN supplementation did not significantly improve skeletal muscle index, handgrip strength, or gait speed in adults with a mean age over 60 years. nih.gov Similarly, NMN did not show improvements in knee extension strength or thigh muscle mass. nih.govnih.gov While some studies have suggested a link between endogenous this compound levels and muscle health, dietary intake does not appear to be the primary factor. jci.org

Table 3: Effects of NMN Supplementation on Sarcopenia Measures in Older Adults

Data from a systematic review and meta-analysis.

Ocular Health and Retinal Degeneration

This compound has shown considerable promise in the context of ocular health, particularly in protecting against retinal degeneration. vision-and-eye-health.comnutravision.com.au It is considered beneficial for supporting the health of retinal ganglion cells, which are crucial for transmitting visual information from the retina to the brain. vision-and-eye-health.comnutravision.com.au The protective effects of this compound are largely attributed to its role as a precursor to this compound adenine dinucleotide (NAD+), a vital coenzyme for cellular energy production and repair. vision-and-eye-health.com

By boosting NAD+ levels, this compound helps protect retinal ganglion cells from oxidative stress and mitochondrial dysfunction, which are key factors in the progression of glaucoma. vision-and-eye-health.comnutravision.com.au A clinical study involving glaucoma patients demonstrated that those who received this compound for 12 weeks, in addition to their standard treatments, showed significant improvements in inner retinal function. vision-and-eye-health.comnutravision.com.au

Furthermore, research has indicated that this compound can inhibit aggressive cell transformations that occur during wound healing in the eye, which can lead to fibrotic diseases and vision loss. mountsinai.org In vitro studies with human adult retinal pigment epithelium cells showed that this compound could slow down these harmful cellular transformations and even promote a reversal to a healthier cell type. mountsinai.org

Studies on the related compound this compound mononucleotide (NMN) have also shown positive results. In a mouse model of macular degeneration, treatment with NMN restored the structure of the retina and reduced cellular senescence. nmn.com In a human cell model of macular degeneration, NMN treatment was found to eliminate senescent cells and reduce DNA damage by 50%. nmn.com

Gastrointestinal Tract Physiology

This compound, a form of vitamin B3, and its derivatives play a crucial role in maintaining the integrity and function of the gastrointestinal (GI) tract. It is a precursor to this compound adenine dinucleotide (NAD+), a vital coenzyme in cellular metabolism and energy production. mdpi.com The GI tract is a significant site for the absorption and metabolism of NAD+ precursors. mdpi.comnih.gov While dietary NAD+ precursors are primarily absorbed in the upper GI tract, circulating this compound from the host can enter the gut lumen and support the NAD+ synthesis of the gut microbiome. nih.govbiorxiv.org In turn, the gut microbiota can convert host-derived this compound into nicotinic acid, which can be used for NAD+ synthesis in host tissues. nih.gov

Research has highlighted the importance of NAD+ in intestinal health. Depletion of NAD+ has been associated with increased intestinal inflammation, compromised gut barrier function, and an imbalance in the gut microbiota (dysbiosis). mdpi.com Conversely, therapeutic strategies that increase NAD+ levels have shown protective effects against intestinal inflammation in both experimental models and human patients. mdpi.com These beneficial effects are thought to be mediated, at least in part, by favorable changes in the composition of the gut microbiota. mdpi.com For instance, the administration of this compound riboside, another NAD+ precursor, has been shown to improve the gut bacterial composition. helsinki.fi

Studies in mice have demonstrated that this compound riboside supplementation can alter the gut microbial composition, leading to an enrichment of butyrate-producing Firmicutes. asm.orgnih.gov This shift in the microbiome was associated with increased energy expenditure and protection against high-fat diet-induced weight gain. asm.orgnih.gov Furthermore, the gut microbiome is essential for the full NAD+-boosting effect of orally delivered precursors like this compound and this compound riboside. biorxiv.org

The metabolism of NAD+ is intricately linked to intestinal homeostasis and the production of incretin hormones like glucagon-like peptide-1 (GLP-1), which regulates postprandial glucose levels. mdpi.com High-fat diets can impair NAD+ biosynthesis in the intestines, and boosting intestinal NAD+ with precursors like this compound mononucleotide (NMN) can augment GLP-1 production. mdpi.com

Table 1: Impact of this compound and its Precursors on Gastrointestinal Physiology

Response to Viral Infections (e.g., COVID-19)

This compound and the broader NAD+ metabolism have emerged as significant areas of research in the context of viral infections, including COVID-19. mdpi.commdpi.com Viral infections are known to disrupt cellular NAD+ homeostasis, often leading to a depletion of NAD+ levels. mdpi.commdpi.com In COVID-19 patients, dysregulated NAD+ metabolism has been observed, characterized by decreased NAD+ levels. mdpi.com This depletion is considered a risk factor for severe COVID-19 and is linked to the inflammatory response and oxidative stress associated with the infection. mdpi.com

The mechanism behind NAD+ depletion in COVID-19 involves the upregulation of NAD+-consuming enzymes, such as poly(ADP-ribose) polymerases (PARPs). mdpi.commdpi.com SARS-CoV-2 infection can induce the expression of certain PARPs, accelerating the consumption of NAD+. mdpi.com

Restoring NAD+ levels through supplementation with precursors like this compound is being investigated as a therapeutic strategy. mdpi.com Research suggests that this compound supplementation may help modulate the gut microbiome and accelerate recovery in patients with mild-to-moderate COVID-19. bioengineer.orgresearch-in-germany.org A clinical trial involving a specialized tablet that releases this compound in the gut demonstrated that patients, particularly those with risk factors for severe COVID-19, regained their normal physical performance more quickly compared to a placebo group. research-in-germany.org

Furthermore, in vitro studies have shown that this compound can enhance the antiviral activity of the human cathelicidin LL37, an antimicrobial peptide that can disrupt the membrane of SARS-CoV-2. biorxiv.org Another NAD+ precursor, this compound riboside, is being studied for its potential to protect kidney function in hospitalized COVID-19 patients with acute kidney injury. uthscsa.edu

Table 2: Research on this compound and NAD+ in COVID-19

Genetic Disorders (e.g., Friedreich's Ataxia)

This compound has shown promise in therapeutic research for Friedreich's ataxia, a rare, inherited neurodegenerative disorder. ecrin.org The disease is caused by abnormally low levels of the protein frataxin due to a gene mutation. nihr.ac.ukimperial.ac.uk this compound is being investigated for its ability to increase frataxin levels. nihr.ac.ukimperial.ac.uk

The proposed mechanism of action involves this compound acting as an epigenetic modifier. nihr.ac.ukimperial.ac.uk It is thought to inhibit class III histone deacetylases (sirtuins), which leads to an "opening up" of the frataxin gene, making it more accessible for transcription and thereby increasing the production of frataxin protein. nihr.ac.ukimperial.ac.ukfrontiersin.org This epigenetic effect has been observed in cell models and in patients. nihr.ac.ukfrontiersin.orgcurefa.org

Early-phase clinical trials have explored the effects of high-dose this compound in patients with Friedreich's ataxia. nihr.ac.ukimperial.ac.uk These studies have shown that this compound can be well-tolerated and can increase frataxin protein levels to those seen in asymptomatic carriers of the genetic mutation. nihr.ac.ukimperial.ac.uk An open-label, dose-escalation trial reported a significant and sustained increase in frataxin mRNA and protein levels. frontiersin.org However, this short-term trial did not observe an effect on neurological parameters. frontiersin.org

A larger, multinational, randomized, double-blind, placebo-controlled study called NICOFA was initiated to evaluate the long-term efficacy and safety of high-dose this compound in patients with Friedreich's ataxia over a two-year period. ecrin.orgresearchgate.netucl.ac.ukorpha.net The primary endpoint of this study was the change in a neurological rating scale. researchgate.net

Table 3: Clinical Trials of this compound in Friedreich's Ataxia

Hematological Disorders (e.g., Sickle Cell Disease)

This compound is being explored as a potential therapeutic agent for sickle cell disease (SCD), a group of inherited red blood cell disorders. google.com The pathophysiology of SCD involves the polymerization of abnormal hemoglobin S (HbS), leading to red blood cell sickling, damage, and a range of complications. mdpi.comhaematologica.org Oxidative stress plays a significant role in the complex pathophysiology of SCD. google.com

Red blood cells from individuals with SCD are more susceptible to oxidative damage. nih.gov A key area of investigation is the role of this compound adenine dinucleotide (NAD+) and its reduced form, NADH, in maintaining the redox balance within red blood cells. google.com Studies have shown that sickle red blood cells have a significantly decreased NADH/[NAD+ + NADH] ratio, indicating a lower redox potential, which may contribute to their increased oxidant sensitivity. nih.gov

The therapeutic rationale for using this compound in SCD is based on its role as a direct precursor for NAD+ synthesis. haematologica.orgashpublications.org It is hypothesized that by boosting NAD+ levels, this compound could improve the redox potential of sickle red blood cells, reduce oxidative stress, and thereby alleviate some of the disease's manifestations. haematologica.orgashpublications.org

Preclinical research using a mouse model of SCD has provided encouraging results. ashpublications.org Chronic oral supplementation with this compound was found to decrease the retention of mitochondria in red blood cells (a source of reactive oxygen species), reduce reactive oxygen species levels, improve the NAD redox potential, and ameliorate anemia. ashpublications.org

These findings have prompted clinical investigations. A randomized controlled trial has been designed to compare the effects of an oral medication combination with and without this compound in subjects with high-risk SCD. centerwatch.comdrugbank.com

Table 4: Research on this compound in Sickle Cell Disease