Implications of the NADase CD38 in COVID pathophysiology.

During the COVID-19 pandemic, efforts have been made worldwide to develop effective therapies to address the devastating immune-mediated effects of SARS-CoV-2. With the exception of monoclonal antibody-mediated therapeutics and preventive approaches such as mass immunization, most experimental or repurposed drugs have failed in large randomized clinical trials (https://www.who.int/publications/i/item/therapeutics-and-covid-19-living-guideline). The worldwide spread of SARS-CoV-2 virus revealed specific susceptibilities to the virus among the elderly and individuals with age-related syndromes. These populations were more likely to experience a hyperimmune response characterized by a treatment-resistant acute lung pathology accompanied by multiple organ failure. These observations underscore the interplay between the virus, the biology of aging, and outcomes observed in the most severe cases of SARS-CoV-2 infection. The ectoenzyme CD38 has been implicated in the process of "inflammaging" in aged tissues. In a current publication, Horenstein et al. present evidence to support the hypothesis that CD38 plays a central role in altered immunometabolism resulting from COVID-19 infection. The authors discuss a critical but underappreciated trifecta of CD38-mediated NAD+ metabolism, aging, and COVID-19 immune response and speculate that the CD38/NAD+ axis is a promising therapeutic target for this disease.

The CD38 glycohydrolase and the NAD sink: implications for pathological conditions.

Nicotinamide adenine dinucleotide (NAD) acts as a cofactor in several oxidation-reduction (redox) reactions and is a substrate for a number of nonredox enzymes. NAD is fundamental to a variety of cellular processes including energy metabolism, cell signaling, and epigenetics. NAD homeostasis appears to be of paramount importance to health span and longevity, and its dysregulation is associated with multiple diseases. NAD metabolism is dynamic and maintained by synthesis and degradation. The enzyme CD38, one of the main NAD-consuming enzymes, is a key component of NAD homeostasis. The majority of CD38 is localized in the plasma membrane with its catalytic domain facing the extracellular environment, likely for the purpose of controlling systemic levels of NAD. Several cell types express CD38, but its expression predominates on endothelial cells and immune cells capable of infiltrating organs and tissues. Here we review potential roles of CD38 in health and disease and postulate ways in which CD38 dysregulation causes changes in NAD homeostasis and contributes to the pathophysiology of multiple conditions. Indeed, in animal models the development of infectious diseases, autoimmune disorders, fibrosis, metabolic diseases, and age-associated diseases including cancer, heart disease, and neurodegeneration are associated with altered CD38 enzymatic activity. Many of these conditions are modified in CD38-deficient mice or by blocking CD38 NADase activity. In diseases in which CD38 appears to play a role, CD38-dependent NAD decline is often a common denominator of pathophysiology. Thus, understanding dysregulation of NAD homeostasis by CD38 may open new avenues for the treatment of human diseases.

The NADase enzyme CD38: an emerging pharmacological target for systemic sclerosis, systemic lupus erythematosus and rheumatoid arthritis.

PURPOSE OF REVIEW: Here we review recent literature on the emerging role of nicotinamide adenine dinucleotide (NAD) metabolism and its dysfunction via the enzyme CD38 in the pathogenesis of rheumatologic diseases. We evaluate the potential of targeting CD38 to ameliorate NAD-related metabolic imbalance and tissue dysfunction in the treatment of systemic sclerosis (SSc), systemic lupus erythematous (SLE), and rheumatoid arthritis (RA). RECENT FINDINGS: In this review, we will discuss emerging basic, preclinical, and human data that point to the novel role of CD38 in dysregulated NAD-homeostasis in SSc, SLE, and RA. In particular, recent studies implicate increased activity of CD38, one of the main enzymes in NAD catabolism, in the pathogenesis of persistent systemic fibrosis in SSc, and increased susceptibility of SLE patients to infections. We will also discuss recent studies that demonstrate that a cytotoxic CD38 antibody can promote clearance of plasma cells involved in the generation of RA antibodies. SUMMARY: Recent studies identify potential therapeutic approaches for boosting NAD to treat rheumatologic diseases including SSc, RA, and SLE, with particular attention to inhibition of CD38 enzymatic activity as a target. Key future directions in the field include the determination of the cell-type specificity and role of CD38 enzymatic activity versus CD38 structural roles in human diseases, as well as the indicators and potential side effects of CD38-targeted treatments.

NAD metabolism: Role in senescence regulation and aging.

The geroscience hypothesis proposes that addressing the biology of aging could directly prevent the onset or mitigate the severity of multiple chronic diseases. Understanding the interplay between key aspects of the biological hallmarks of aging is essential in delivering the promises of the geroscience hypothesis. Notably, the nucleotide nicotinamide adenine dinucleotide (NAD) interfaces with several biological hallmarks of aging, including cellular senescence, and changes in NAD metabolism have been shown to be involved in the aging process. The relationship between NAD metabolism and cellular senescence appears to be complex. On the one hand, the accumulation of DNA damage and mitochondrial dysfunction induced by low NAD+ can promote the development of senescence. On the other hand, the low NAD+ state that occurs during aging may inhibit SASP development as this secretory phenotype and the development of cellular senescence are both highly metabolically demanding. However, to date, the impact of NAD+ metabolism on the progression of the cellular senescence phenotype has not been fully characterized. Therefore, to explore the implications of NAD metabolism and NAD replacement therapies, it is essential to consider their interactions with other hallmarks of aging, including cellular senescence. We propose that a comprehensive understanding of the interplay between NAD boosting strategies and senolytic agents is necessary to advance the field.

Ecto-CD38-NADase inhibition modulates cardiac metabolism and protects mice against doxorubicin-induced cardiotoxicity.

AIMS: Doxorubicin (DXR) is a chemotherapeutic agent that causes dose-dependent cardiotoxicity. Recently, it has been proposed that the NADase CD38 may play a role in doxorubicin-induced cardiotoxicity (DIC). CD38 is the main NAD+-catabolizing enzyme in mammalian tissues. Interestingly, in the heart, CD38 is mostly expressed as an ecto-enzyme that can be targeted by specific inhibitory antibodies. The goal of the present study is to characterize the role of CD38 ecto-enzymatic activity in cardiac metabolism and the development of DIC. METHODS AND RESULTS: Using both a transgenic animal model and a non-cytotoxic enzymatic anti-CD38 antibody, we investigated the role of CD38 and its ecto-NADase activity in DIC in pre-clinical models. First, we observed that DIC was prevented in the CD38 catalytically inactive (CD38-CI) transgenic mice. Both left ventricular systolic function and exercise capacity were decreased in wild-type but not in CD38-CI mice treated with DXR. Second, blocking CD38-NADase activity with the specific antibody 68 (Ab68) likewise protected mice against DIC and decreased DXR-related mortality by 50%. A reduction of DXR-induced mitochondrial dysfunction, energy deficiency, and inflammation gene expression were identified as the main mechanisms mediating the protective effects. CONCLUSION: NAD+-preserving strategies by inactivation of CD38 via a genetic or a pharmacological-based approach improve cardiac energetics and reduce cardiac inflammation and dysfunction otherwise seen in an acute DXR cardiotoxicity model.

Endogenous metabolism in endothelial and immune cells generates most of the tissue vitamin B3 (nicotinamide).

In mammals, nicotinamide (NAM) is the primary NAD precursor available in circulation, a signaling molecule, and a precursor for methyl-nicotinamide (M-NAM) synthesis. However, our knowledge about how the body regulates tissue NAM levels is still limited. Here we demonstrate that dietary vitamin B3 partially regulates plasma NAM and NAM-derived metabolites, but not their tissue levels. We found that NAD de novo synthesis from tryptophan contributes to plasma and tissue NAM, likely by providing substrates for NAD-degrading enzymes. We also demonstrate that tissue NAM is mainly generated by endogenous metabolism and that the NADase CD38 is the main enzyme that produces tissue NAM. Tissue-specific CD38-floxed mice revealed that CD38 activity on endothelial and immune cells is the major contributor to tissue steady-state levels of NAM in tissues like spleen and heart. Our findings uncover the presence of different pools of NAM in the body and a central role for CD38 in regulating tissue NAM levels.

Evolving concepts in NAD+ metabolism.

NAD(H) and NADP(H) have traditionally been viewed as co-factors (or co-enzymes) involved in a myriad of oxidation-reduction reactions including the electron transport in the mitochondria. However, NAD pathway metabolites have many other important functions, including roles in signaling pathways, post-translational modifications, epigenetic changes, and regulation of RNA stability and function via NAD-capping of RNA. Non-oxidative reactions ultimately lead to the net catabolism of these nucleotides, indicating that NAD metabolism is an extremely dynamic process. In fact, recent studies have clearly demonstrated that NAD has a half-life in the order of minutes in some tissues. Several evolving concepts on the metabolism, transport, and roles of these NAD pathway metabolites in disease states such as cancer, neurodegeneration, and aging have emerged in just the last few years. In this perspective, we discuss key recent discoveries and changing concepts in NAD metabolism and biology that are reshaping the field. In addition, we will pose some open questions in NAD biology, including why NAD metabolism is so fast and dynamic in some tissues, how NAD and its precursors are transported to cells and organelles, and how NAD metabolism is integrated with inflammation and senescence. Resolving these questions will lead to significant advancements in the field.

Of Mice and Men: NAD+ Boosting with Niacin Provides Hope for Mitochondrial Myopathy Patients.

In this issue of Cell Metabolism, Pirinen et al. (2020) show that disruption in NAD+ homeostasis is a key component of the pathogenesis of mitochondrial myopathy in humans that can be targeted by the administration of the NAD+ precursor niacin, identifying NAD+ boosting as a potential treatment for this devastating disease.

Implications of the PAPP-A-IGFBP-IGF-1 pathway in the pathogenesis and treatment of polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common genetic diseases implicated in the development of end stage renal disease (ESRD). Although FDA has recently approved a drug against ADPKD, there is still a great need for development of alternative management strategies for ADPKD. Understanding the different mechanisms that lead to cystogenesis and cyst expansion in ADPKD is imperative to develop new therapies against ADPKD. Recently, we demonstrated that caloric restriction can prevent the development of cystic disease in animal models of ADPKD and through these studies identified a new role for pregnancy associated plasma protein-A (PAPP-A), a component of the insulin-like growth factors (IGF) pathway, in the pathogenesis of this disease. The PAPP-A-IGF pathway plays an important role in regulation of cell growth, differentiation, and transformation and dysregulation of this pathway has been implicated in many diseases. Several indirect studies support the involvement of IGF-1 in the pathogenesis of ADPKD. However, it was only recently that we described a direct role for a component of this pathway in pathogenesis of ADPKD, opening a new avenue for the therapeutic approaches for this cystic disease. The present literature review will critically discuss the evidence that supports the role of components of IGF pathway in the pathogenesis of ADPKD and discuss the pharmacological implications of PAPP-A-IGF axis in this disease.

The enzyme CD38 (a NAD glycohydrolase, EC 3.2.2.5) is necessary for the development of diet-induced obesity.

Obesity is one of the major health problems of our times. Elucidating the signaling mechanisms by which high-fat caloric diet induces obesity is critical for the understanding of this condition and for the development of therapeutic strategies for its treatment. Here, we demonstrate a novel role for protein CD38 as a regulator of body weight during a high-fat diet. CD38 is a ubiquitous enzyme that catalyzes the synthesis of second messengers and has been implicated in the regulation of a wide variety of signaling pathways. We report that CD38-deficient mice are protected against high-fat diet-induced obesity owing to enhanced energy expenditure. In fact, calorimetric studies indicate that CD38-deficient animals have a higher metabolic rate compared to control mice. Analysis of the mechanism revealed that this resistance to diet-induced obesity is mediated at least in part via a NAD-dependent activation of SIRT-PGC1alpha axis, a well-established cascade, involved in the regulation of mitochondrial biogenesis and energy homeostasis. Thus, together these results identify a novel pathway regulating body weight and clearly show that CD38 is a nearly obligatory component of the cellular cascade that led to diet-induced obesity.

Complications after unintentional intra-arterial injection of drugs: risks, outcomes, and management strategies.

Unintentional intra-arterial injection of medication, either iatrogenic or self-administered, is a source of considerable morbidity. Normal vascular anatomical proximity, aberrant vasculature, procedurally difficult situations, and medical personnel error all contribute to unintentional cannulation of arteries in an attempt to achieve intravenous access. Delivery of certain medications via arterial access has led to clinically important sequelae, including paresthesias, severe pain, motor dysfunction, compartment syndrome, gangrene, and limb loss. We comprehensively review the current literature, highlighting available information on risk factors, symptoms, pathogenesis, sequelae, and management strategies for unintentional intra-arterial injection. We believe that all physicians and ancillary personnel who administer Intravenous therapies should be aware of this serious problem.

Deleted in breast cancer-1 (DBC-1) in the interface between metabolism, aging and cancer.

DBC1 (deleted in breast cancer-1) is a nuclear protein that regulates cellular metabolism. Since alteration in cellular metabolism have been proposed to be the emerging 'hallmark' of cancer, it is possible that DBC1 may be implicated in the regulation of cancer cell energy metabolism. However, at this point any role of DBC1 in cancer is only speculative. In this review, we will discuss the new developments in DBC1 research, its molecular structure, regulatory roles and implication in metabolism, aging and cancer.

Altered behavioral and metabolic circadian rhythms in mice with disrupted NAD+ oscillation.

The Intracellular levels of nicotinamide adenine dinucleotide (NAD(+)) are rhythmic and controlled by the circadian clock. However, whether NAD(+) oscillation in turn contributes to circadian physiology is not fully understood. To address this question we analyzed mice mutated for the NAD(+) hydrolase CD38. We found that rhythmicity of NAD(+) was altered in the CD38-deficient mice. The high, chronic levels of NAD(+) results in several anomalies in circadian behavior and metabolism. CD38-null mice display a shortened period length of locomotor activity and alteration in the rest-activity rhythm. Several clock genes and, interestingly, genes involved in amino acid metabolism were deregulated in CD38-null livers. Metabolomic analysis identified alterations in the circadian levels of several amino acids, specifically tryptophan levels were reduced in the CD38-null mice at a circadian time paralleling with elevated NAD(+) levels. Thus, CD38 contributes to behavioral and metabolic circadian rhythms and altered NAD(+) levels influence the circadian clock.

Deleted in breast cancer-1 regulates SIRT1 activity and contributes to high-fat diet-induced liver steatosis in mice.

The enzyme sirtuin 1 (SIRT1) is a critical regulator of many cellular functions, including energy metabolism. However, the precise mechanisms that modulate SIRT1 activity remain unknown. As SIRT1 activity in vitro was recently found to be negatively regulated by interaction with the deleted in breast cancer-1 (DBC1) protein, we set out to investigate whether DBC1 regulates SIRT1 activity in vivo. We found that DBC1 and SIRT1 colocalized and interacted, and that DBC1 modulated SIRT1 activity, in multiple cell lines and tissues. In mouse liver, increased SIRT1 activity, concomitant with decreased DBC1-SIRT1 interaction, was detected after 24 hours of starvation, whereas decreased SIRT1 activity and increased interaction with DBC1 was observed with high-fat diet (HFD) feeding. Consistent with the hypothesis that DBC1 is crucial for HFD-induced inhibition of SIRT1 and for the development of experimental liver steatosis, genetic deletion of Dbc1 in mice led to increased SIRT1 activity in several tissues, including liver. Furthermore, DBC1-deficient mice were protected from HFD-induced liver steatosis and inflammation, despite the development of obesity. These observations define what we believe to be a new role for DBC1 as an in vivo regulator of SIRT1 activity and liver steatosis. We therefore propose that the DBC1-SIRT1 interaction may serve as a new target for therapies aimed at nonalcoholic liver steatosis.

CD38 as a regulator of cellular NAD: a novel potential pharmacological target for metabolic conditions.

CD38 is a multifunctional enzyme that uses nicotinamide adenine dinucleotide (NAD) as a substrate to generate second messengers. Recently, CD38 was also identified as one of the main cellular NADases in mammalian tissues and appears to regulate cellular levels of NAD in multiple tissues and cells. Due to the emerging role of NAD as a key molecule in multiple signaling pathways, and metabolic conditions it is imperative to determine the cellular mechanisms that regulate the synthesis and degradation of this nucleotide. In fact, recently it has been shown that NAD participates in multiple physiological processes such as insulin secretion, control of energy metabolism, neuronal and cardiac cell survival, airway constriction, asthma, aging and longevity. The discovery of CD38 as the main cellular NADase in mammalian tissues, and the characterization of its role on the control of cellular NAD levels indicate that CD38 may serve as a pharmacological target for multiple conditions.

To be or not to be ... nicotinic acid adenine dinucleotide phosphate (NAADP): a new intracellular second messenger?

Nicotinic acid adenine dinucleotide phosphate (NAADP) is a potent activator of intracellular Ca2+ release in several vertebrate and invertebrate systems. The role of the NAADP system in physiological processes is being extensively investigated at the present time. The NAADP receptor and its associated Ca2+ pool have been hypothesized to be important in several physiological processes including fertilization, T cell activation, and pancreatic secretion. However, whether NAADP is a new second messenger or a tool for the discovery of a new Ca2+ channel is still an unanswered question. Research developed over the last two years has provided some important clues to whether NAADP is or not a physiological cellular messenger. In this short review, I will discuss some of these new findings that are helping us to find an answer to the important question: Is NAADP a second messenger or not?