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Simple Summary: In tackling the daunting challenge of glioblastoma, a severe form of brain tumor, researchers have been exploring ways to disrupt its abnormal energy production, focusing on a molecule called NAD. The drug FK866, known to deplete NAD, shows potential in curbing tumor growth but faces limitations when used alone. This study introduces a novel approach using fluorinated versions of NAD precursors, specifically a compound named F-NR, which when, combined with FK866, significantly boosts its effectiveness against glioblastoma cells. F-NR works by competing with the endogenous metabolism of NR, leading to reduced NAD levels and enhancing FK866's ability to kill cancer cells. Another key finding is the role of SARM1, activated by one of F-NR's metabolites, which contributes to the enhanced cell-killing effect. The sequence of events—NAD depletion followed by energy loss and ultimately, widespread cell death—highlights the potential of this strategy to improve FK866's therapeutic impact. This research not only deepens our understanding of NAD metabolism in glioblastoma but also provides a potential strategy for treating the brain cancer. Glioblastoma, a formidable brain tumor characterized by dysregulated NAD metabolism, poses a significant therapeutic challenge. The NAMPT inhibitor FK866, which induces NAD depletion, has shown promise in controlling tumor proliferation and modifying the tumor microenvironment. However, the clinical efficacy of FK866 as a single drug therapy for glioma is limited. In this study, we aim to disrupt NAD metabolism using fluorinated NAD precursors and explore their synergistic effect with FK866 in inducing cytotoxicity in glioblastoma cells. The synthesized analogue of nicotinamide riboside (NR), ara-F nicotinamide riboside (F-NR), inhibits nicotinamide ribose kinase (NRK) activity in vitro, reduces cellular NAD levels, and enhances FK866's cytotoxicity in U251 glioblastoma cells, indicating a collaborative impact on cell death. Metabolic analyses reveal that F-NR undergoes conversion to fluorinated nicotinamide mononucleotide (F-NMN) and other metabolites, highlighting the intact NAD metabolic pathway in glioma cells. The activation of SARM1 by F-NMN, a potent NAD-consuming enzyme, is supported by the synergistic effect of CZ-48, a cell-permeable SARM1 activator. Temporal analysis underscores the sequential nature of events, establishing NAD depletion as a precursor to ATP depletion and eventual massive cell death. This study not only elucidates the molecular intricacies of glioblastoma cell death but also proposes a promising strategy to enhance FK866 efficacy through fluorinated NAD precursors, offering potential avenues for innovative therapeutic interventions in the challenging landscape of glioblastoma treatment. [ABSTRACT FROM AUTHOR]

Precision oncology hinges on linking tumour genotype with molecularly targeted drugs1; however, targeting the frequently dysregulated metabolic landscape of cancer has proven to be a major challenge2. Here we show that tissue context is the major determinant of dependence on the nicotinamide adenine dinucleotide (NAD) metabolic pathway in cancer. By analysing more than 7,000 tumours and 2,600 matched normal samples of 19 tissue types, coupled with mathematical modelling and extensive in vitro and in vivo analyses, we identify a simple and actionable set of 'rules'. If the rate-limiting enzyme of de novo NAD synthesis, NAPRT, is highly expressed in a normal tissue type, cancers that arise from that tissue will have a high frequency of NAPRT amplification and be completely and irreversibly dependent on NAPRT for survival. By contrast, tumours that arise from normal tissues that do not express NAPRT highly are entirely dependent on the NAD salvage pathway for survival. We identify the previously unknown enhancer that underlies this dependence. Amplification of NAPRT is shown to generate a pharmacologically actionable tumour cell dependence for survival. Dependence on another rate-limiting enzyme of the NAD synthesis pathway, NAMPT, as a result of enhancer remodelling is subject to resistance by NMRK1-dependent synthesis of NAD. These results identify a central role for tissue context in determining the choice of NAD biosynthetic pathway, explain the failure of NAMPT inhibitors, and pave the way for more effective treatments. NAD metabolic pathway choice in cancer is largely dependent on the tissue of origin, with implications for the development of precision treatments. [ABSTRACT FROM AUTHOR]

While breast cancer treatments have advanced significantly nowadays, yet metastatic, especially triple-negative breast cancer (TNBC), remains challenging with lowsurvival. Cancer immunotherapy, a promising approach for HER2-positive and TNBC, still faces resistance hurdles. Recently, numerous studies have set their sights on the resistance of immunotherapy for breast cancer. Our study provides a thorough comprehension of the current research landscape, hotspots, and emerging breakthroughs in this critical area through a meticulous bibliometric analysis. As of March 26, 2024, a total of 1341 articles on immunology resistance in breast cancer have been gathered from Web of Science Core Collection, including 765 articles and 576 reviews. Bibliometrix, CiteSpace and VOSviewer softwarewere utilized to examine publications and citations per year, prolific countries, contributive institutions, high-level journals and scholars, as well as highly cited articles, references and keywords. The research of immunotherapy resistance in breast cancer has witnessed a remarkable surge over the past seven years. The United States and China have made significant contributions, with HarvardMedical School being the most prolific institution and actively engaging in collaborations. The most contributive author is Curigliano, G from the European Institute of Oncology in Italy, while Wucherpfennig, K. W. from the Dana-Farber Cancer Institute in the USA, had the highest citations. Journals highly productive primarily focus on clinical, immunology and oncology research. Common keywords include "resistance", "expression", "tumor microenvironment", "cancer", "T cell", "therapy", "chemotherapy" and "cell". Current research endeavors to unravel the mechanisms of immune resistance in breast cancer through the integration of bioinformatics, basic experiments, and clinical trials. Efforts are underway to develop strategies that improve the effectiveness of immunotherapy, including the exploration of combination therapies and advancements in drug delivery systems. Additionally, there is a strong focus on identifying novel biomarkers that can predict patient response to immunology. This study will provide researchers with an up-to-date overview of the present knowledge in drug resistance of immunology for breast cancer, serving as a valuable resource for informed decision-making and further research on innovative approaches to address immunotherapy resistance. [ABSTRACT FROM AUTHOR]

Inflammatory bowel disease (IBD) is one of the intractable diseases. Nutritional components associated with IBD have been identified, and it is known that excessive methionine intake exacerbates inflammation, and that tryptophan metabolism is involved in inflammation. Analysis of the gut microbiota has also progressed, where Lactobacillus regulate immune cells in the intestine and suppress inflammation. However, whether the methionine and tryptophan metabolic pathways affect the growth of intestinal Lactobacillus is unknown. Here we show how transient methionine, tryptophan, and niacin deficiency affects the host and gut microbiota in mouse models of colitis (induced by dextran sodium sulfate) fed a methionine‐deficient diet (1K), tryptophan and niacin‐deficient diet (2K), or methionine, tryptophan, and niacin‐deficient diet (3K). These diets induced body weight decrease and 16S rRNA analysis of mouse feces revealed the alterations in the gut microbiota, leading to a dramatic increase in the proportion of Lactobacillus in mice. Intestinal RNA sequencing data confirmed that the expression of several serine proteases and fat‐metabolizing enzymes were elevated in mice fed with methionine, tryptophan, and niacin (MTN) deficient diet. In addition, one‐carbon metabolism and peroxisome proliferator‐activated receptor (PPAR) pathway activation were also induced with MTN deficiency. Furthermore, changes in the expression of various immune‐related cytokines were observed. These results indicate that methionine, tryptophan, and niacin metabolisms are important for the composition of intestinal bacteria and host immunity. Taken together, MTN deficiencies may serve as a Great Reset of gut microbiota and host gene expression to return to good health. [ABSTRACT FROM AUTHOR]

Glioblastoma, a formidable brain tumor characterized by dysregulated NAD metabolism, poses a significant therapeutic challenge. The NAMPT inhibitor FK866, which induces NAD depletion, has shown promise in controlling tumor proliferation and modifying the tumor microenvironment. However, the clinical efficacy of FK866 as a single drug therapy for glioma is limited. In this study, we aim to disrupt NAD metabolism using fluorinated NAD precursors and explore their synergistic effect with FK866 in inducing cytotoxicity in glioblastoma cells. The synthesized analogue of nicotinamide riboside (NR), ara-F nicotinamide riboside (F-NR), inhibits nicotinamide ribose kinase (NRK) activity in vitro, reduces cellular NAD levels, and enhances FK866’s cytotoxicity in U251 glioblastoma cells, indicating a collaborative impact on cell death. Metabolic analyses reveal that F-NR undergoes conversion to fluorinated nicotinamide mononucleotide (F-NMN) and other metabolites, highlighting the intact NAD metabolic pathway in glioma cells. The activation of SARM1 by F-NMN, a potent NAD-consuming enzyme, is supported by the synergistic effect of CZ-48, a cell-permeable SARM1 activator. Temporal analysis underscores the sequential nature of events, establishing NAD depletion as a precursor to ATP depletion and eventual massive cell death. This study not only elucidates the molecular intricacies of glioblastoma cell death but also proposes a promising strategy to enhance FK866 efficacy through fluorinated NAD precursors, offering potential avenues for innovative therapeutic interventions in the challenging landscape of glioblastoma treatment.

Nuclear factor I B (NFIB) plays an important role in tumors. Our previous study found that NFIB can promote colorectal cancer (CRC) cell proliferation in acidic environments. However, its biological functions and the underlying mechanism in CRC are incompletely understood. Nicotinamide adenine dinucleotide (NAD+) effectively affects cancer cell proliferation. Nevertheless, the regulatory mechanism of NAD+ synthesis in cancer remains to be elucidated. Here we show NFIB promotes CRC proliferation in vitro and growth in vivo, and down-regulation of NFIB can reduce the level of NAD+. In addition, supplementation of NAD+ precursor NMN can recapture cell proliferation in CRC cells with NFIB knockdown. Mechanistically, we identified that NFIB promotes CRC cell proliferation by inhibiting miRNA-182-5p targeting and binding to NAMPT, the NAD+ salvage synthetic rate-limiting enzyme. Our results delineate a combination of high expression of NFIB and NAMPT predicted a clinical poorest prognosis. This work provides potential therapeutic targets for CRC treatment. Nuclear factor I B promotes colorectal cancer cell proliferation in vitro and growth in vivo by increasing intracellular NAD+ levels through downregulation of the NAMPT-targeting micro-RNA, miR-182-5p. [ABSTRACT FROM AUTHOR]

Hepatic ischemia–reperfusion (IR) injury remains a common issue lacking effective strategy and validated pharmacological targets. Here, using an unbiased metabolomics screen, this study finds that following murine hepatic IR, liver 3‐hydroxyanthranilic acid (3‐HAA) and quinolinic acid (QA) decline while kynurenine and kynurenic acid (KYNA) increase. Kynurenine aminotransferases 2, functioning at the key branching point of the kynurenine pathway (KP), is markedly upregulated in hepatocytes during ischemia, shifting the kynurenine metabolic route from 3‐HAA and QA to KYNA synthesis. Defects in QA synthesis impair de novo nicotinamide adenine dinucleotide (NAD) biosynthesis, rendering the hepatocytes relying on the salvage pathway for maintenance of NAD and cellular antioxidant defense. Blocking the salvage pathway following IR by the nicotinamide phosphoribosyltransferase inhibitor FK866 exacerbates liver oxidative damage and enhanced IR susceptibility, which can be rescued by the lipid peroxidation inhibitor Liproxstatin‐1. Notably, nicotinamide mononucleotide administration once following IR effectively boosts NAD and attenuated IR‐induced oxidative stress, inflammation, and cell death in the murine model. Collectively, the findings reveal that metabolic rewiring of the KP partitions it away from NAD synthesis in hepatic IR pathophysiology, and provide proof of concept that NAD augmentation is a promising therapeutic measure for IR‐induced liver injury. [ABSTRACT FROM AUTHOR]

As longevity companies emerge with new products and the fields of anti‐aging research develop new cutting‐edge therapies, three distinct classes of longevity methodologies emerge. This discussion finds that there are three clear classes (Tiers) of longevity systems that are currently under development, and all three will be paramount to achieve biological escape velocity (where tissues can be repaired faster than aging can damage them). These classes are referred to as Tier 1, Tier 2, and Tier 3 treatments and are described in detail below. These three Tiers are required for easy identification for pharmaceutical companies and research companies to determine the type of therapy they may choose to deliver being noninvasive, invasive, time consuming, or simple end user products. Specific targets and goals need to be defined clearly from an early perspective in the development of these technologies for future precision medicines. This allows consumers of future anti‐aging technologies to consider which Tier a particular therapy may be, delivering a more informed choice. [ABSTRACT FROM AUTHOR]

Crohn's disease (CD), as one of the principal form of inflammatory bowel disease (IBD), is characterized by the chronic and recurring inflammatory conditions in the intestine resulting from the over-activation of intestinal immunity. Hyposplenism is strongly associated with CD, while the effect of human spleen on the differentiation and development of immune cell subsets in CD patients remains unclear. Isolated congenital asplenia (ICA) is an extremely rare condition characterized by the absence of a spleen at birth without any other developmental defects. Here, we describe the first case of a patient with both ICA and CD, and follow the progression of CD from remission to active stage. Using cytometry by time of flight (CyTOF) analysis, we draw the first single-cell mapping of peripheral blood mononuclear cells (PBMC) from this unique patient, tracing back to the innate or adaptive immune cell subsets and cell surface markers affected by the spleen. Based on our analysis, it is speculated that the spleen contributes to maintaining immune homeostasis, alleviating intestinal inflammation and improving prognosis by influencing the differentiation and development of peripheral immune cell subsets and the expression of cell surface markers in patients with CD. [ABSTRACT FROM AUTHOR]

Nicotinamide adenine dinucleotide (NAD) is the core of cellular energy metabolism. NAMPT, Sirtuins, PARP, CD38, and other molecules in this classic metabolic pathway affect many key cellular functions and are closely related to the occurrence and development of many diseases. In recent years, several studies have found that these molecules can regulate cell energy metabolism, promote the release of related cytokines, induce the expression of neoantigens, change the tumor immune microenvironment (TIME), and then play an anticancer role. Drugs targeting these molecules are under development or approved for clinical use. Although there are some side effects and drug resistance, the discovery of novel drugs, the development of combination therapies, and the application of new technologies provide solutions to these challenges and improve efficacy. This review presents the mechanisms of action of NAD pathway-related molecules in tumor immunity, advances in drug research, combination therapies, and some new technology-related therapies. [ABSTRACT FROM AUTHOR]

Nicotinamide-nucleotide adenylyl transferase (Rv2421c) was selected as a potential drug target, because it has been shown, in vitro, to be essential for Mycobacterium tuberculosis growth. It is conserved between mycobacterium species, is up-regulated during dormancy, has a known 3D crystal structure and has no known human homologs. A model of Rv2421c in complex with nicotinic acid adenine dinucleotide and magnesium ion was constructed and subject tovirtual ligand screening against the Prestwick Chemical Library and the ZINC database, which yielded 155 potential hit molecules. Of the 155 compounds identified five were pursued further using an IC50 based 3D-QSAR study. The 3D-QSAR model validated the inhibition properties of the five compounds based on R2 value of 0.895 and Q2 value of 0.944 compared to known inhibitors of Rv2421c. Higher binding affinities was observed for the novel ZINC13544129 and two FDA approved compounds (Novobiocin sodium salt, Sulfasalazine). Similarly, the total interaction energy was found to be the highest for Cromolyn disodium system (-418.88 kJ/mol) followed by Novobiocin (-379.19 kJ/mol) and Sulfasalazine with (-330.13 kJ/mol) compared to substrate DND having (-185.52 kJ/mol). Subsequent in vitro testing of the five compounds identified Novobiocin sodium salt with activity against Mycobacterium tuberculosis at 50 μM, 25μM and weakly at 10μM concentrations. Novobiocin salt interacts with a MG ion and active site residues His20, Thr86, Gly107 and Leu164 similar to substrate DND of Mycobacterium tuberculosis Rv2421c. Additional in silico structural analysis of known Novobiocin sodium salt derivatives against Rv2421c suggest Coumermycin as a promising alternative for the treatment of Mycobacterium tuberculosis based on large number of hydrogen bond interactions with Rv2421c similar in comparison to Novobiocin salt and substrate DND. [ABSTRACT FROM AUTHOR]

The majority of patients with systemic lupus erythematosus (SLE) have high expression of type I IFN-stimulated genes. Mitochondrial abnormalities have also been reported, but the contribution of type I IFN exposure to these changes is unknown. Here, we show downregulation of mitochondria-derived genes and mitochondria-associated metabolic pathways in IFN-High patients from transcriptomic analysis of CD4+ and CD8+ T cells. CD8+ T cells from these patients have enlarged mitochondria and lower spare respiratory capacity associated with increased cell death upon rechallenge with TCR stimulation. These mitochondrial abnormalities can be phenocopied by exposing CD8+ T cells from healthy volunteers to type I IFN and TCR stimulation. Mechanistically these 'SLE-like' conditions increase CD8+ T cell NAD+ consumption resulting in impaired mitochondrial respiration and reduced cell viability, both of which can be rectified by NAD+ supplementation. Our data suggest that type I IFN exposure contributes to SLE pathogenesis by promoting CD8+ T cell death via metabolic rewiring. Lupus pathogenesis is associated with high type 1 interferon stimulated gene (ISG) expression. Here, the authors correlate ISG expression in CD8+ T cells from lupus nephritis patients with abnormal mitochondrial function, implicating increased NAD consumption and reduced cell viability in the pathogenesis. [ABSTRACT FROM AUTHOR]

Reprogrammed metabolism is a hallmark of cancer. However, the metabolic dependency of cancer, from tumour initiation through disease progression and therapy resistance, requires a spectrum of distinct reprogrammed cellular metabolic pathways. These pathways include aerobic glycolysis, oxidative phosphorylation, reactive oxygen species generation, de novo lipid synthesis, fatty acid β-oxidation, amino acid (notably glutamine) metabolism and mitochondrial metabolism. This Review highlights the central roles of signal transducer and activator of transcription (STAT) proteins, notably STAT3, STAT5, STAT6 and STAT1, in orchestrating the highly dynamic metabolism not only of cancer cells but also of immune cells and adipocytes in the tumour microenvironment. STAT proteins are able to shape distinct metabolic processes that regulate tumour progression and therapy resistance by transducing signals from metabolites, cytokines, growth factors and their receptors; defining genetic programmes that regulate a wide range of molecules involved in orchestration of metabolism in cancer and immune cells; and regulating mitochondrial activity at multiple levels, including energy metabolism and lipid-mediated mitochondrial integrity. Given the central role of STAT proteins in regulation of metabolic states, they are potential therapeutic targets for altering metabolic reprogramming in cancer., (© 2023. Springer Nature Limited.)

Background: Recently eosin B was shown to have an effect on the asexual stage of Plasmodium falciparum and in this study, its activity against gametocytes and changes in the culture medium metabolites were investigated using an¹HNMRbased metabolomics approach. Methods: In the Biochemistry Department of Pasteur Institute of Iran in 2017, parasites were cultured and gametocytogenesis induced by heparin and 5% hematocrit. Sexual stage parasites were tested by eosin B in 90 well plates and IC50 determined using Lactate Dehydrogenase assay. Gametocytes were treated by IC50 dose of eosin B and the medium collected in the two groups: with eosin B and controls and sent for 1HNMR spectroscopy. The spectra were analyzed on MATLAB interface and the altered metabolites in the culture medium and eosin-affected biochemical pathways were identified by Human Metabolome Database and Metaboanalyst website. Results: The results revealed eosin B had an effective gametocytocidal activity against P. falciparum. The significant metabolites changed in the medium were thiamine, Asp, Asn, Tyr, Lys, Ala, Phenylpyruvic acid, NAD+ and lipids. The main pathways identified were aminoacyl-tRNA biosynthesis, Phenylalanine, tyrosine and tryptophan biosynthesis, Alanine, aspartate and glutamate metabolism, Phenylalanine metabolism, Nicotinate and nicotinamide metabolism, and lysine degradation. Conclusion: Eosin B exhibited substantial gametocytocidal activity and affected important drug targets in the Plasmodium. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) affects many ICU patients and is responsible for increased morbidity and mortality. Although lifesaving in many situations, renal replacement therapy (RRT) may be associated with complications, and the appropriate timing of its initiation is still the subject of intense debate. An early initiation strategy can prevent some metabolic complications, whereas a delayed one may allow for renal function recovery in some patients without need for this costly and potentially dangerous technique. For years, most of the knowledge on this issue stemmed from observational studies or small randomized controlled trials. Recent randomized controlled trials have indicated that a watchful waiting strategy (in the absence of life-threatening conditions such as severe hyperkalemia or pulmonary edema) during severe AKI allowed many patients to escape RRT and did not seem to adversely affect survival compared with a strategy of immediate RRT. In addition, data suggest that a delayed strategy may reduce the rate of complications (such as catheter infection) and favor renal function recovery. Ongoing studies will have to both confirm these conclusions and clarify to what extent the delay in initiating RRT can be prolonged. Pending those results, the bulk of evidence suggests that, in the absence of potential severe complications of AKI, delaying RRT is a valid and safe strategy that may also allow for considerable cost savings. [ABSTRACT FROM AUTHOR]

NAD+ plays essential roles in cellular energy homoeostasis and redox state, functioning as a cofactor along the glycolysis and citric acid cycle pathways. Recent discoveries indicated that, through the NAD+ -consuming enzymes, this molecule may also be involved in many other cellular and biological outcomes such as chromatin remodelling, gene transcription, genomic integrity, cell division, calcium signalling, circadian clock and pluripotency. Poly(ADP-ribose) polymerase 1 (PARP1) is such an enzyme and dysfunctional PARP1 has been linked with the onset and development of various human diseases, including cancer, aging, traumatic brain injury, atherosclerosis, diabetes and inflammation. In the present study, we showed that overexpressed acyl-CoAbinding domain containing 3 (ACBD3), a Golgi-bound protein, significantly reduced cellular NAD+ content via enhancing PARP1's polymerase activity and enhancing auto-modification of the enzyme in a DNA damage-independent manner. We identified that extracellular signal-regulated kinase (ERK)1/2 as well as de novo fatty acid biosynthesis pathways are involved in ACBD3- mediated activation of PARP1. Importantly, oxidative stressinduced PARP1 activation is greatly attenuated by knocking down the ACBD3 gene. Taken together, these findings suggest that ACBD3 has prominent impacts on cellular NAD+ metabolism via regulating PARP1 activation-dependent auto-modification and thus cell metabolism and function. [ABSTRACT FROM AUTHOR]

Nicotinamide adenine dinucleotide (NAD+) is an essential metabolite utilized as a redox cofactor and enzyme substrate in numerous cellular processes. Elevated NAD+ levels have been observed in red blood cells infected with the malaria parasite Plasmodium falciparum, but little is known regarding how the parasite generates NAD+. Here, we employed a mass spectrometry-based metabolomic approach to confirm that P. falciparum lacks the ability to synthesize NAD+de novo and is reliant on the uptake of exogenous niacin. We characterized several enzymes in the NAD+ pathway and demonstrate cytoplasmic localization for all except the parasite nicotinamidase, which concentrates in the nucleus. One of these enzymes, the P. falciparum nicotinate mononucleotide adenylyltransferase (PfNMNAT), is essential for NAD+ metabolism and is highly diverged from the human homolog, but genetically similar to bacterial NMNATs. Our results demonstrate the enzymatic activity of PfNMNAT in vitro and demonstrate its ability to genetically complement the closely related Escherichia coli NMNAT. Due to the similarity of PfNMNAT to the bacterial enzyme, we tested a panel of previously identified bacterial NMNAT inhibitors and synthesized and screened twenty new derivatives, which demonstrate a range of potency against live parasite culture. These results highlight the importance of the parasite NAD+ metabolic pathway and provide both novel therapeutic targets and promising lead antimalarial compounds. [ABSTRACT FROM AUTHOR]

Insulin resistance (IR) underlines aging and aging-associated medical (diabetes, obesity, dyslipidemia, hypertension) and psychiatric (depression, cognitive decline) disorders. Molecular mechanisms of IR in genetically or metabolically predisposed individuals remain uncertain. Current review of the literature and our data presents the evidences that dysregulation of tryptophan (TRP)-kynurenine (KYN) and KYN-nicotinamide adenine dinucleotide (NAD) metabolic pathways is one of the mechanisms of IR. The first and rate-limiting step of TRP-KYN pathway is regulated by enzymes inducible by pro-inflammatory factors and/or stress hormones. The key enzymes of KYN-NAD pathway require pyridoxal-5-phosphate (P5P), an active form of vitamin B, as a cofactor. Deficiency of P5P diverts KYN-NAD metabolism from production of NAD to the excessive formation of xanthurenic acid (XA). Human and experimental studies suggested that XA and some other KYN metabolites might impair production, release, and biological activity of insulin. We propose that one of the mechanisms of IR is inflammation- and/or stress-induced upregulation of TRP-KYN metabolism in combination with P5P deficiency-induced diversion of KYN-NAD metabolism towards formation of XA and other KYN derivatives affecting insulin activity. Monitoring of KYN/P5P status and formation of XA might help to identify subjects at risk for IR. Pharmacological regulation of the TRP-KYN and KYN-NAD pathways and maintaining of adequate vitamin B status might contribute to prevention and treatment of IR in conditions associated with inflammation/stress-induced excessive production of KYN and deficiency of vitamin B, e.g., type 2 diabetes, obesity, cardiovascular diseases, aging, menopause, pregnancy, and hepatitis C virus infection. [ABSTRACT FROM AUTHOR]

Studies to quantify the protein acetylome show that lysine-residue acetylation rivals phosphorylation in prevalence as a posttranslational modification. Interesting, this posttranslational modification is modified by nutrient flux and by redox stress and targets the vast majority of metabolic pathway proteins in the mitochondria. Furthermore, the mitochondrial deacetylase enzyme SIRT3 appears to be regulated by exercise in skeletal muscle and in response to pressure overload in the heart. The alteration of protein lysine residues by acetylation and the enzymes controlling deacetylation are beginning to be explored as important regulatory events in the control of mitochondrial function and homeostasis. This review focuses on the mitochondrial targets of SIRT3 that are functionally implicated in heart biology and pathology and on the direct cardiac consequences of the genetic manipulation of SIRT3. As therapeutic modulators of other SIRT isoforms have been identified, the longer-term objective of our understanding of this biology would be to identify SIRT3 modulators as putative cardiac therapeutic agents. [ABSTRACT FROM AUTHOR]

Nicotinamide adenine dinucleotide (NAD) is an essential redox cofactor, but it also acts as a substrate for NAD-consuming enzymes, regulating cellular events such as DNA repair and gene expression. Since such processes are fundamental to support cancer cell survival and proliferation, sustained NAD production is a hallmark of many types of neoplasms. Depleting intratumor NAD levels, mainly through interference with the NAD-biosynthetic machinery, has emerged as a promising anti-cancer strategy. NAD can be generated from tryptophan or nicotinic acid. In addition, the "salvage pathway" of NAD production, which uses nicotinamide, a byproduct of NAD degradation, as a substrate, is also widely active in mammalian cells and appears to be highly exploited by a subset of human cancers. In fact, research has mainly focused on inhibiting the key enzyme of the latter NAD production route, nicotinamide phosphoribosyltransferase (NAMPT), leading to the identification of numerous inhibitors, including FK866 and CHS-828. Unfortunately, the clinical activity of these agents proved limited, suggesting that the approaches for targeting NAD production in tumors need to be refined. In this contribution, we highlight the recent advancements in this field, including an overview of the NAD-lowering compounds that have been reported so far and the related in vitro and in vivo studies. We also describe the key NAD-producing pathways and their regulation in cancer cells. Finally, we summarize the approaches that have been explored to optimize the therapeutic response to NAMPT inhibitors in cancer. [ABSTRACT FROM AUTHOR]

Smoke from wildland fires has been shown to produce neuroinflammation in preclinical models, characterized by neural infiltrations of neutrophils and monocytes, as well as altered neurovascular endothelial phenotypes. To address the longevity of such outcomes, the present study examined the temporal dynamics of neuroinflammation and metabolomics after inhalation exposures from biomass-derived smoke. 2-month-old female C57BL/6 J mice were exposed to wood smoke every other day for 2 weeks at an average exposure concentration of 0.5 mg/m 3 . Subsequent serial euthanasia occurred at 1-, 3-, 7-, 14-, and 28-day post-exposure. Flow cytometry of right hemispheres revealed two endothelial populations of CD31 Hi and CD31 Med expressors, with wood smoke inhalation causing an increased proportion of CD31 Hi . These populations of CD31 Hi and CD31 Med were associated with an anti-inflammatory and pro-inflammatory response, respectively, and their inflammatory profiles were largely resolved by the 28-day mark. However, activated microglial populations (CD11b + /CD45 low ) remained higher in wood smoke-exposed mice than controls at day 28. Infiltrating neutrophil populations decreased to levels below controls by day 28. However, the MHC-II expression of the peripheral immune infiltrate remained high, and the population of neutrophils retained an increased expression of CD45, Ly6C, and MHC-II. Utilizing an unbiased approach examining the metabolomic alterations, we observed notable hippocampal perturbations in neurotransmitter and signaling molecules, such as glutamate, quinolinic acid, and 5-α-dihydroprogesterone. Utilizing a targeted panel designed to explore the aging-associated NAD + metabolic pathway, wood smoke exposure drove fluctuations and compensations across the 28-day time course, ending with decreased hippocampal NAD + abundance on day 28. Summarily, these results indicate a highly dynamic neuroinflammatory environment, with potential resolution extending past 28 days, the implications of which may include long-term behavioral changes, systemic and neurological sequalae directly associated with wildfire smoke exposure., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Mycobacterium tuberculosis is leading cause of death worldwide. NAD participates in a host of redox reactions in energy landscape of organisms. Several studies implicate surrogate energy pathways involving NAD pools as important in survival of active as well as dormant mycobacteria. One of the NAD metabolic pathway enzyme, nicotinate mononucleotide adenylyltransferase (NadD) is indispensable in mycobacterial NAD metabolism and is perceived as an attractive drug target in pathogen. In this study, we have employed in silico screening, simulation and MM-PBSA strategies to identify potentially important alkaloid compounds against mycobacterial NadD for structure-based inhibitor development. We have performed an exhaustive structure-based virtual screening of an alkaloid library, ADMET, DFT profiling followed by Molecular Dynamics (MD) simulation, and Molecular Mechanics-Poisson Boltzmann Surface Area (MM-PBSA) calculation to identify 10 compounds which exhibit favourable drug like properties and interactions. Interaction energies of these 10 alkaloid molecules range between -190 kJ/mol and -250 kJ/mol. These compounds could be promising starting point in the development of selective inhibitors against Mycobacterium tuberculosis., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Imbalances in NAD + homeostasis have been linked to aging and various diseases. Nicotine, a metabolite of the NAD + metabolic pathway, has been found to possess anti-inflammatory and neuroprotective properties, yet the underlying molecular mechanisms remained unknown. Here we find that, independent of nicotinic acetylcholine receptors, low-dose nicotine can restore the age-related decline of NAMPT activity through SIRT1 binding and subsequent deacetylation of NAMPT, thus increasing NAD + synthesis. 18 F-FDG PET imaging revealed that nicotine is also capable of efficiently inhibiting glucose hypermetabolism in aging male mice. Additionally, nicotine ameliorated cellular energy metabolism disorders and deferred age-related deterioration and cognitive decline by stimulating neurogenesis, inhibiting neuroinflammation, and protecting organs from oxidative stress and telomere shortening. Collectively, these findings provide evidence for a mechanism by which low-dose nicotine can activate NAD + salvage pathways and improve age-related symptoms., (© 2023. The Author(s).)

Background: Age-related hearing loss (ARHL) is a common phenomenon observed during aging. On the other hand, the decrease in Nicotinamide adenine dinucleotide (NAD +) levels is reported to be closely related to the age-related declines in physiological functions such as ARHL in animal studies. Moreover, preclinical studies confirmed NAD + replenishment effectively prevents the onset of age-related diseases. However, there is a paucity of studies on the relationship between NAD + metabolism and ARHL in humans., Methods: This study was analyzed the baseline results of our previous clinical trial, in which nicotinamide mononucleotide or placebo was administered to 42 older men (Igarashi et al., NPJ Aging 8:5, 2022). The correlations between blood levels of NAD + -related metabolites at baseline and pure-tone hearing thresholds at different frequencies (125, 250, 500, 1000, 2000, 4000, and 8000 Hz) in 42 healthy Japanese men aged > 65 years were analyzed using Spearman's rank correlation. Multiple linear regression analysis was performed with hearing thresholds as the dependent variable and age and NAD + -related metabolite levels as independent variables., Results: Positive associations were observed between levels of nicotinic acid (NA, a NAD + precursor in the Preiss-Handler pathway) and right- or left-ear hearing thresholds at frequencies of 1000 Hz (right: r = 0.480, p = 0.001; left: r = 0.422, p = 0.003), 2000 Hz (right: r = 0.507, p < 0.001, left: r = 0.629, p < 0.001), and 4000 Hz (left: r = 0.366, p = 0.029). Age-adjusted multiple linear regression analysis revealed that NA was an independent predictor of elevated hearing thresholds (1000 Hz (right): p = 0.050, regression coefficient (β) = 1610; 1000 Hz (left): p = 0.026, β = 2179; 2000 Hz (right): p = 0.022, β = 2317; 2000 Hz (left): p = 0.002, β = 3257). Weak associations of nicotinic acid riboside (NAR) and nicotinamide (NAM) with hearing ability were observed., Conclusions: We identified negative correlations between blood concentrations of NA and hearing ability at 1000 and 2000 Hz. NAD + metabolic pathway might be associated with ARHL onset or progression. Further studies are warranted., Trial Registration: The study was registered at UMIN-CTR (UMIN000036321) on 1st June 2019., (© 2023. The Author(s).)

Rationale: Alteration of the NAD + metabolic pathway is proposed to be implicated in lipopolysaccharide (LPS)-induced neurotoxicity and mitochondrial dysfunction in neurodegenerative diseases. Apigenin, a naturally-occurring flavonoid, has been reported to maintain NAD + levels and to preserve various metabolic functions., Objectives: This study aimed to explore the effect of apigenin on mitochondrial SIRT3 activity as a mediator through which it could modulate mitochondrial quality control and to protect against intracerebrovascular ICV/LPS-induced neurotoxicity., Methods: Mice received apigenin (40 mg/kg; p.o) for 7 consecutive days. One hour after the last dose, LPS (12 µg/kg, icv) was administered., Results: Apigenin robustly guarded against neuronal degenerative changes and maintained a normal count of intact neurons in mice hippocampi. Consequently, it inhibited the deleterious effect of LPS on cognitive functions. Apigenin was effective in preserving the NAD + /NADH ratio to boost mitochondrial sirtuin-3 (SIRT3), activity, and ATP production. It conserved normal mitochondrial features via induction of the master regulator of mitochondrial biogenesis, peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α), along with mitochondrial transcription factor A (TFAM) and the fusion proteins, mitofusin 2 (MFN2), and optic atrophy-1 (OPA1). Furthermore, it increased phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1) and parkin expression as well as the microtubule-associated protein 1 light chain 3 II/I ratio (LC3II/I) to induce degradation of unhealthy mitochondria via mitophagy., Conclusions: These observations reveal the marked neuroprotective potential of apigenin against LPS-induced neurotoxicity through inhibition of NAD + depletion and activation of SIRT3 to maintain adequate mitochondrial homeostasis and function., (© 2022. The Author(s).)

Consumption of thermally oxidized oil is associated with metabolic disorders, but oxidized oil-elicited changes in the metabolome are not well defined. In this study, C57BL/6 mice were fed the diets containing either control soybean oil or heated soybean oil (HSO) for 4 weeks. HSO-responsive metabolic events were examined through untargeted metabolomics-guided biochemical analysis. HSO directly contributed to the presence of new HSO-derived metabolites in urine and the decrease of polyunsaturated fatty acid-containing phospholipids in serum and the liver. HSO disrupted redox balance by decreasing hepatic glutathione and ascorbic acid. HSO also activated peroxisome proliferator-activated receptors, leading to the decrease of serum triacylglycerols and the changes of cofactors and products in fatty acid oxidation pathways. Most importantly, multiple metabolic changes, including the decrease of tryptophan in serum; the increase of NAD + in the liver; the increases of kynurenic acid, nicotinamide and nicotinamide N-oxide in urine; and the decreases of the metabolites from pyridine nucleotide degradation in the liver indicated that HSO activated tryptophan-NAD + metabolic pathway, which was further confirmed by the upregulation of gene expression in this pathway. Because NAD + and its metabolites are essential cofactors in many HSO-induced metabolic events, the activation of tryptophan-NAD + pathway should be considered as a central metabolic response to the exposure of HSO., (Copyright © 2018 Elsevier Inc. All rights reserved.)

NMNAT-1 and PARP-1, two key enzymes in the NAD(+) metabolic pathway, localize to the nucleus where integration of their enzymatic activities has the potential to control a variety of nuclear processes. Using a variety of biochemical, molecular, cell-based, and genomic assays, we show that NMNAT-1 and PARP-1 physically and functionally interact at target gene promoters in MCF-7 cells. Specifically, we show that PARP-1 recruits NMNAT-1 to promoters where it produces NAD(+) to support PARP-1 catalytic activity, but also enhances the enzymatic activity of PARP-1 independently of NAD(+) production. Furthermore, using two-photon excitation microscopy, we show that NMNAT-1 catalyzes the production of NAD(+) in a nuclear pool that may be distinct from other cellular compartments. In expression microarray experiments, depletion of NMNAT-1 or PARP-1 alters the expression of about 200 protein-coding genes each, with about 10% overlap between the two gene sets. NMNAT-1 enzymatic activity is required for PARP-1-dependent poly(ADP-ribosyl)ation at the promoters of commonly regulated target genes, as well as the expression of those target genes. Collectively, our studies link the enzymatic activities of NMNAT-1 and PARP-1 to the regulation of a set of common target genes through functional interactions at target gene promoters.

We identified nicotinamide phosphoribosyltransferase (NAMPT), also known as pre-B cell colony enhancing factor (PBEF), as an essential enzyme mediating granulocyte colony-stimulating factor (G-CSF)-triggered granulopoiesis in healthy individuals and in individuals with severe congenital neutropenia. Intracellular NAMPT and NAD(+) amounts in myeloid cells, as well as plasma NAMPT and NAD(+) levels, were increased by G-CSF treatment of both healthy volunteers and individuals with congenital neutropenia. NAMPT administered both extracellularly and intracellularly induced granulocytic differentiation of CD34(+) hematopoietic progenitor cells and of the promyelocytic leukemia cell line HL-60. Treatment of healthy individuals with high doses of vitamin B3 (nicotinamide), a substrate of NAMPT, induced neutrophilic granulocyte differentiation. The molecular events triggered by NAMPT include NAD(+)-dependent sirtuin-1 activation, subsequent induction of CCAAT/enhancer binding protein-alpha and CCAAT/enhancer binding protein-beta, and, ultimately, upregulation of G-CSF synthesis and G-CSF receptor expression. G-CSF, in turn, further increases NAMPT levels. These results reveal a decisive role of the NAD(+) metabolic pathway in G-CSF-triggered myelopoiesis.