Therapeutic Potential of ACMSD Inhibitors in NAD+ Deficient Diseases

Liu Y.J., Kimura M., Li X., Sulc J., Wang Q., Rodríguez-López S., Scantlebery A.M., Strotjohann K., Gallart-Ayala H., Vijayakumar A., Myers R.P., Ivanisevic J., Houtkooper R.H., Subramanian G.M., Takebe T., et. al.

Recent findings reveal the importance of tryptophan-initiated de novo nicotinamide adenine dinucleotide (NAD

Alexandris A., Koliatsos V.E.

Dou Z., Yao H., Xie Y., Liu Y., Gao Y., Yang J.

Diabetic liver injury is a complication of diabetes without any specific medicine approved for its effective treatment or prevention. In this research, the effect of camel whey protein (CWP) on diabetic liver injury in T2DM rats (T2DM induced by a high-fat diet) and streptozotocin along with its possible mechanism were investigated by means of transcriptome and proteomics. The results demonstrated that CWP lowered fasting blood glucose and improved abnormal blood lipid profiles in T2DM rats. CWP reduced lipid accumulation, diminished oxidative stress, and effectively improved the pathological changes in the liver of T2DM rats. Further experiments indicated that CWP intake had adjusted mitochondrial dysfunction in the livers of T2DM rats and L-O2 cells induced by high glucose (HG)/palmitic acid (PA) by inhibiting α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) expression. In conclusion, CWP can ameliorate diabetic liver injury in T2DM rats by inhibiting the expression of ACMSD, promote de novo NAD+ synthesis and enhance mitochondrial function.

Bhasin S., Seals D., Migaud M., Musi N., Baur J.A.

Abstract Recent research has unveiled an expansive role of NAD+ in cellular energy generation, redox reactions, and as a substrate or co-substrate in signaling pathways that regulate health-span and aging. This review provides a critical appraisal of the clinical pharmacology and the pre-clinical and clinical evidence for therapeutic effects of NAD+ precursors for age-related conditions, with a particular focus on cardiometabolic disorders, and discusses gaps in current knowledge. NAD+ levels decrease throughout life; age-related decline in NAD+ bioavailability has been postulated to be a contributor to many age-related diseases. Raising NAD+ levels in model organisms by administration of NAD+ precursors improves glucose and lipid metabolism; attenuates diet-induced weight-gain, diabetes, diabetic kidney disease, and hepatic steatosis; reduces endothelial dysfunction; protects heart from ischemic injury; improves left ventricular function in models of heart failure; attenuates cerebrovascular and neurodegenerative disorders; and increases health-span. Early human studies show that NAD+ levels can be raised safely in blood and some tissues by oral NAD+ precursors and suggest benefit in preventing nonmelanotic skin cancer, modestly reducing blood pressure and improving lipid profile in older adults with obesity or overweight; preventing kidney injury in at-risk patients; and suppressing inflammation in Parkinson's disease and SARS-CoV-2 infection. Clinical pharmacology, metabolism, and therapeutic mechanisms of NAD+ precursors remain incompletely understood. We suggest that these early findings provide the rationale for adequately-powered randomized trials to evaluate the efficacy of NAD+ augmentation as a therapeutic strategy to prevent and treat metabolic disorders and age-related conditions.

McGuinness H.Y., Gu W., Shi Y., Kobe B., Ve T.

Axons are an essential component of the nervous system, and axon degeneration is an early feature of many neurodegenerative disorders. The NAD+ metabolome plays an essential role in regulating axonal integrity. Axonal levels of NAD+ and its precursor NMN are controlled in large part by the NAD+ synthesizing survival factor NMNAT2 and the pro-neurodegenerative NADase SARM1, whose activation triggers axon destruction. SARM1 has emerged as a promising axon-specific target for therapeutic intervention, and its function, regulation, structure, and role in neurodegenerative diseases have been extensively characterized in recent years. In this review, we first introduce the key molecular players involved in the SARM1-dependent axon degeneration program. Next, we summarize recent major advances in our understanding of how SARM1 is kept inactive in healthy neurons and how it becomes activated in injured or diseased neurons, which has involved important insights from structural biology. Finally, we discuss the role of SARM1 in neurodegenerative disorders and environmental neurotoxicity and its potential as a therapeutic target.

Li W., Liang L., Liao Q., Li Y., Zhou Y.

Cluster of differentiation 38 (CD38) is a multifunctional extracellular enzyme on the cell surface with NADase and cyclase activities. CD38 is not only expressed in human immune cells, such as lymphocytes and plasma cells, but also is abnormally expressed in a variety of tumor cells, which is closely related to the occurrence and development of tumors. T cells are one of the important immune cells in the body. As NAD consuming enzymes, CD38, ART2, SIRT1 and PARP1 are closely related to the number and function of T cells. CD38 may also influence the activity of ART2, SIRT1 and PARP1 through the CD38-NAD+ axis to indirectly affect the number and function of T cells. Thus, CD38-NAD+ axis has a profound effect on T cell activity. In this paper, we reviewed the role and mechanism of CD38+ CD4+ T cells / CD38+ CD8+ T cells in cellular immunity and the effects of the CD38-NAD+ axis on T cell activity. We also summarized the relationship between the CD38 expression level on T cell surface and disease prediction and prognosis, the effects of anti-CD38 monoclonal antibodies on T cell activity and function, and the role of anti-CD38 chimeric antigen receptor (CAR) T cell therapy in tumor immunity. This will provide an important theoretical basis for a comprehensive understanding of the relationship between CD38 and T cells.

Cianci M., Giacchè N., Cialabrini L., Carotti A., Liscio P., Rosatelli E., De Franco F., Gasparrini M., Robertson J., Amici A., Raffaelli N., Pellicciari R.

Human α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) stands at a branch point of the de novo NAD+ synthesis pathway and plays an important role in maintaining NAD+ homeostasis. It has been recently identified as a novel therapeutic target for a wide range of diseases, including inflammatory, metabolic disorders, and aging. So far, in absence of potent and selective enzyme inhibitors, only a crystal structure of the complex of human dimeric ACMSD with pseudo-substrate dipicolinic acid has been resolved. In this study, we report the crystal structure of the complex of human dimeric ACMSD with TES-1025, the first nanomolar inhibitor of this target, which shows a binding conformation different from the previously published predicted binding mode obtained by docking experiments. The inhibitor has a Ki value of 0.85 ± 0.22 nM and binds in the catalytic site, interacting with the Zn2+ metal ion and with residues belonging to both chains of the dimer. The results provide new structural information about the mechanism of inhibition exerted by a novel class of compounds on the ACMSD enzyme, a novel therapeutic target for liver and kidney diseases.

Dou Z., Liu C., Feng X., Xie Y., Yue H., Dong J., Zhao Z., Chen G., Yang J.

CWP8, an active protein component isolated from camel milk, ameliorates liver injury in T2DM rats by activating the PI3K/Akt signaling pathway and stimulates glycogen synthesis to improve lipid accumulation in insulin-resistant HepG2 cells.

Abdellatif M., Sedej S., Kroemer G.

Nicotinamide adenine dinucleotide (NAD + ) is a central metabolite involved in energy and redox homeostasis as well as in DNA repair and protein deacetylation reactions. Pharmacological or genetic inhibition of NAD + -degrading enzymes, external supplementation of NAD + precursors, and transgenic overexpression of NAD + -generating enzymes have wide positive effects on metabolic health and age-associated diseases. NAD + pools tend to decline with normal aging, obesity, and hypertension, which are all major risk factors for cardiovascular disease, and NAD + replenishment extends healthspan, avoids metabolic syndrome, and reduces blood pressure in preclinical models. In addition, experimental elevation of NAD + improves atherosclerosis, ischemic, diabetic, arrhythmogenic, hypertrophic, or dilated cardiomyopathies, as well as different modalities of heart failure. Here, we critically discuss cardiomyocyte-specific circuitries of NAD + metabolism, comparatively evaluate distinct NAD + precursors for their preclinical efficacy, and raise outstanding questions on the optimal design of clinical trials in which NAD + replenishment or supraphysiological NAD + elevations are assessed for the prevention or treatment of major cardiac diseases. We surmise that patients with hitherto intractable cardiac diseases such as heart failure with preserved ejection fraction may profit from the administration of NAD + precursors. The development of such NAD + -centered treatments will rely on technological and conceptual progress on the fine regulation of NAD + metabolism.

Kellum J.A., Romagnani P., Ashuntantang G., Ronco C., Zarbock A., Anders H.

Acute kidney injury (AKI) is defined by a sudden loss of excretory kidney function. AKI is part of a range of conditions summarized as acute kidney diseases and disorders (AKD), in which slow deterioration of kidney function or persistent kidney dysfunction is associated with an irreversible loss of kidney cells and nephrons, which can lead to chronic kidney disease (CKD). New biomarkers to identify injury before function loss await clinical implementation. AKI and AKD are a global concern. In low-income and middle-income countries, infections and hypovolaemic shock are the predominant causes of AKI. In high-income countries, AKI mostly occurs in elderly patients who are in hospital, and is related to sepsis, drugs or invasive procedures. Infection and trauma-related AKI and AKD are frequent in all regions. The large spectrum of AKI implies diverse pathophysiological mechanisms. AKI management in critical care settings is challenging, including appropriate volume control, nephrotoxic drug management, and the timing and type of kidney support. Fluid and electrolyte management are essential. As AKI can be lethal, kidney replacement therapy is frequently required. AKI has a poor prognosis in critically ill patients. Long-term consequences of AKI and AKD include CKD and cardiovascular morbidity. Thus, prevention and early detection of AKI are essential. Acute kidney injury (AKI) describes a sudden loss of excretory kidney function that can result in long-term kidney damage. This Primer describes AKI epidemiology and pathophysiology in different economic settings, discusses current diagnostic and management principles, and highlights long-term effects on quality of life and initiatives to improve patient care.

Zapata‐Pérez R., Wanders R.J., Karnebeek C.D., Houtkooper R.H.

Lin Q., Zuo W., Liu Y., Wu K., Liu Q.

• NAD + plays pivotal roles in controlling many biological processes in the organism. • NAD + and NAD + -related enzymes participate in several key processes in cardiovascular diseases. • Maintaining the level of NAD + is a best way to treat and prevent cardiovascular diseases. Nicotinamide adenine dinucleotide (NAD) plays pivotal roles in controlling many biochemical processes. ‘NAD’ refers to the chemical backbone irrespective of charge, whereas ‘NAD + ’ and ‘NADH’ refers to oxidized and reduced forms, respectively. NAD + /NADH ratio is essential for maintaining cellular reduction–oxidation (redox) homeostasis and for modulating energy metabolism. As a sensing or consuming enzyme of the poly (ADP-ribose) polymerase 1 (PARP1), the cyclic ADP-ribose (cADPR) synthases (CD38 and CD157), and sirtuin protein deacetylases (sirtuins, SIRTs), NAD + participates in several key processes in cardiovascular disease. For example, NAD + protects against metabolic syndrome, heart failure, ischemia–reperfusion (IR) injury, arrhythmia and hypertension. Accordingly, the subsequent loss of NAD + in aging or during stress results in altered metabolic status and potentially increased disease susceptibility. Therefore, it is essential to maintain NAD + or reduce loss in the heart. This review focuses on the involvement of NAD + in the pathogenesis of cardiovascular disease and explores the effects of NAD + boosting strategies in cardiovascular health.

Manrique-Caballero C.L., Kellum J.A., Gómez H., De Franco F., Giacchè N., Pellicciari R.

Significance: Acute kidney injury (AKI) is a common and life-threatening complication in hospitalized and critically ill patients. It is defined by an abrupt deterioration in renal function, clinically manifested by increased serum creatinine levels, decreased urine output, or both. To execute all its functions, namely excretion of waste products, fluid/electrolyte balance, and hormone synthesis, the kidney requires incredible amounts of energy in the form of adenosine triphosphate. Recent Advances: Adequate mitochondrial functioning and nicotinamide adenine dinucleotide (NAD+) homeostasis are essential to meet these high energetic demands. NAD+ is a ubiquitous essential coenzyme to many cellular functions. NAD+ as an electron acceptor mediates metabolic pathways such as oxidative phosphorylation (OXPHOS) and glycolysis, serves as a cosubstrate of aging molecules (i.e., sirtuins), participates in DNA repair mechanisms, and mediates mitochondrial biogenesis. Critical Issues: In many forms of AKI and chronic kidney disease, renal function deterioration has been associated with mitochondrial dysfunction and NAD+ depletion. Based on this, therapies aiming to restore mitochondrial function and increase NAD+ availability have gained special attention in the last two decades. Future Directions: Experimental and clinical studies have shown that by restoring mitochondrial homeostasis and increasing renal tubulo-epithelial cells, NAD+ availability, AKI incidence, and chronic long-term complications are significantly decreased. This review covers some general epidemiological and pathophysiological concepts; describes the role of mitochondrial homeostasis and NAD+ metabolism; and analyzes the underlying rationale and role of NAD+ aiming therapies as promising preventive and therapeutic strategies for AKI. Antioxid. Redox Signal. 35, 1449-1466.

Yang Y., Borel T., de Azambuja F., Johnson D., Sorrentino J.P., Udokwu C., Davis I., Liu A., Altman R.A.

In the kynurenine pathway for tryptophan degradation, an unstable metabolic intermediate, α-amino-β-carboxymuconate-ε-semialdehyde (ACMS), can nonenzymatically cyclize to form quinolinic acid, the precursor for de novo biosynthesis of nicotinamide adenine dinucleotide (NAD+). In a competing reaction, ACMS is decarboxylated by ACMS decarboxylase (ACMSD) for further metabolism and energy production. Therefore, the inhibition of ACMSD increases NAD+ levels. In this study, an Food and Drug Administration (FDA)-approved drug, diflunisal, was found to competitively inhibit ACMSD. The complex structure of ACMSD with diflunisal revealed a previously unknown ligand-binding mode and was consistent with the results of inhibition assays, as well as a structure-activity relationship (SAR) study. Moreover, two synthesized diflunisal derivatives showed half-maximal inhibitory concentration (IC50) values 1 order of magnitude better than diflunisal at 1.32 ± 0.07 μM (22) and 3.10 ± 0.11 μM (20), respectively. The results suggest that diflunisal derivatives have the potential to modulate NAD+ levels. The ligand-binding mode revealed here provides a new direction for developing inhibitors of ACMSD.

Covarrubias A.J., Perrone R., Grozio A., Verdin E.

Nicotinamide adenine dinucleotide (NAD+) is a coenzyme for redox reactions, making it central to energy metabolism. NAD+ is also an essential cofactor for non-redox NAD+-dependent enzymes, including sirtuins, CD38 and poly(ADP-ribose) polymerases. NAD+ can directly and indirectly influence many key cellular functions, including metabolic pathways, DNA repair, chromatin remodelling, cellular senescence and immune cell function. These cellular processes and functions are critical for maintaining tissue and metabolic homeostasis and for healthy ageing. Remarkably, ageing is accompanied by a gradual decline in tissue and cellular NAD+ levels in multiple model organisms, including rodents and humans. This decline in NAD+ levels is linked causally to numerous ageing-associated diseases, including cognitive decline, cancer, metabolic disease, sarcopenia and frailty. Many of these ageing-associated diseases can be slowed down and even reversed by restoring NAD+ levels. Therefore, targeting NAD+ metabolism has emerged as a potential therapeutic approach to ameliorate ageing-related disease, and extend the human healthspan and lifespan. However, much remains to be learnt about how NAD+ influences human health and ageing biology. This includes a deeper understanding of the molecular mechanisms that regulate NAD+ levels, how to effectively restore NAD+ levels during ageing, whether doing so is safe and whether NAD+ repletion will have beneficial effects in ageing humans. Nicotinamide adenine dinucleotide (NAD+) is a central redox factor and enzymatic cofactor that functions in a plethora of cellular processes, including metabolic pathways and DNA metabolism, and affects cell fate and function. NAD+ levels gradually decline with age, and therapeutic elevation of NAD+ levels is being trialled for extending human healthspan and lifespan.