Natural polyphenols are organic chemicals which contain phenol units in their structures and possess antitumor properties. However, a key problem is their short half-life and low bioavailability under in vivo conditions. Pterostilbene (3,5-dimethoxy-4′-hydroxystilbene; PT) is a phytoalexin originally isolated from the heartwood of red sandalwood. As recently reported by our group, PT was shown to be effective in the treatment of melanoma. Counterintuitively, PT is not effective (cytotoxic) against melanoma in vitro, and only under in vivo conditions does PT display its anticancer activity. This study elucidated that PT can be effective against melanoma through the inhibition of adrenocorticotropic hormone production in the brain of a mouse, which weakens the Nrf2-dependent antioxidant defenses of melanoma and also pancreatic cancers. This results in both the inhibition of tumor growth and sensitization of the tumor to oxidative stress. Moreover, PT can promote cancer cell death via a mechanism involving lysosomal membrane permeabilization. Different grades of susceptibility were observed among the different cancer cells depending on their lysosomal heat shock protein 70 content, a known stabilizer of lysosomal membranes. In addition, the safety of PT administered i.v. has been evaluated in mice. PT was found to be pharmacologically safe because it showed no organ-specific or systemic toxicity (including tissue histopathologic examination and regular hematology and clinical chemistry data) even when administered i.v. at a high dose (30 mg/kg per day × 23 days). Moreover, new pharmacological advances are being developed to increase its bioavailability and, thereby, its bioefficacy. Therefore, although applications of PT in cancer therapy are just beginning to be explored, it represents a potential (and effective) adjuvant/sensitizing therapy which may improve the results of various oncotherapies. The aim of this review is to present and discuss the results that in our opinion best support the usefulness of PT in cancer therapy, making special emphasis on the in vivo evidence.

Dietary vitamin B3 components, such as nicotinamide and nicotinic acid, are precursors to the ubiquitous redox cofactor nicotinamide adenine dinucleotide (NAD⁺). NAD⁺ levels are thought to decline with age and disease. While the drivers of this decline remain under intense investigation, strategies have emerged seeking to functionally maintain NAD⁺ levels through supplementation with NAD⁺ biosynthetic intermediates. These include marketed products, such as nicotinamide riboside (NR) and its phosphorylated form (NMN). More recent developments have shown that NRH (the reduced form of NR) and its phosphorylated form NMNH also increases NAD⁺ levels upon administration, although they initially generate NADH (the reduced form of NAD⁺). Other means to increase the combined levels of NAD⁺ and NADH, NAD(H), include the inhibition of NAD⁺-consuming enzymes or activation of biosynthetic pathways. Multiple studies have shown that supplementation with an NAD(H) precursor changes the profile of NAD(H) catabolism. Yet, the pharmacological significance of NAD(H) catabolites is rarely considered although the distribution and abundance of these catabolites differ depending on the NAD(H) precursor used, the species in which the study is conducted, and the tissues used for the quantification. Significantly, some of these metabolites have emerged as biomarkers in physiological disorders and might not be innocuous. Herein, we review the known and emerging catabolites of the NAD(H) metabolome and highlight their biochemical and physiological function as well as key chemical and biochemical reactions leading to their formation. Furthermore, we emphasize the need for analytical methods that inform on the full NAD(H) metabolome since the relative abundance of NAD(H) catabolites informs how NAD(H) precursors are used, recycled, and eliminated.

Charcot first described amyotrophic lateral sclerosis (ALS) between 1865 and 1874 as a sporadic adult disease resulting from the idiopathic progressive degeneration of the motor neuronal system, resulting in rapid, progressive, and generalized muscle weakness and atrophy. There is no cure for ALS and no proven therapy to prevent it or reverse its course. There are two drugs specifically approved for the treatment of ALS, riluzol and edaravone, and many others have already been tested or are following clinical trials. However, at the present moment, we still cannot glimpse a true breakthrough in the treatment of this devastating disease. Nevertheless, our understanding of the pathophysiology of ALS is constantly growing. Based on this background, we know that oxidative stress, alterations in the NAD⁺-dependent metabolism and redox status, and abnormal mitochondrial dynamics and function in the motor neurons are at the core of the problem. Thus, different antioxidant molecules or NAD⁺ generators have been proposed for the therapy of ALS. This review analyzes these options not only in light of their use as individual molecules, but with special emphasis on their potential association, and even as part of broader combined multi-therapies.

Metabolic alterations shared between the nervous system and skin fibroblasts have emerged in amyotrophic lateral sclerosis (ALS). Recently, we found that a subgroup of sporadic ALS (sALS) fibroblasts (sALS1) is characterized by metabolic profiles distinct from other sALS cases (sALS2) and controls, suggesting that metabolic therapies could be effective in sALS. The metabolic modulators nicotinamide riboside and pterostilbene (EH301) are under clinical development for the treatment of ALS. Here, we studied the transcriptome and metabolome of sALS cells to understand the molecular bases of sALS metabotypes and the impact of EH301. Metabolomics and transcriptomics were investigated at baseline and after EH301 treatment. Moreover, weighted gene coexpression network analysis (WGCNA) was used to investigate the association of the metabolic and clinical features. We found that the sALS1 transcriptome is distinct from sALS2 and that EH301 modifies gene expression differently in sALS1, sALS2 and the controls. Furthermore, EH301 had strong protective effects against metabolic stress, an effect linked to the antiinflammatory and antioxidant pathways. WGCNA revealed that the ALS functional rating scale and metabotypes are associated with gene modules enriched for the cell cycle, immunity, autophagy and metabolic genes, which are modified by EH301. The meta-analysis of publicly available transcriptomic data from induced motor neurons by Answer ALS confirmed the functional associations of genes correlated with disease traits. A subset of genes differentially expressed in sALS fibroblasts was used in a machine learning model to predict disease progression. In conclusion, multiomic analyses highlighted the differential metabolic and transcriptomic profiles in patient-derived fibroblast sALS, which translate into differential responses to the investigational drug EH301.

Introduction: Nicotinamide adenine dinucleotide (NAD+) is a metabolite of vitamin B3 necessary for the production of key hormones like estradiol. Both NAD+ and estradiol levels decrease with age. Reduced estradiol levels have been associated with undesirable symptoms of the menopause transition. Previous clinical trials have demonstrated that oral supplementation with NRPT, a combination of the NAD+ precursor nicotinamide riboside (NR) plus pterostilbene (PT), significantly increases NAD+ levels. In the present study, the effects of a 7-day supplementation of NRPT on undesirable symptoms of the menopause transition were examined. Methods: An open-label, pilot clinical trial ( ClinicalTrials.gov identifier NCT04841499) was conducted to assess the efficacy of NRPT supplementation (commercially known as Basis; a combination of nicotinamide riboside and pterostilbene) in 40 healthy women over 35 years of age, 32 of which self-reported symptoms associated with the menopause transition (MS group) and eight women who were not experiencing any (or minimal) symptoms associated with menopause (No-MS group). All 40 women were given the recommended dose of NRPT (250 mg NR and 50 mg PT) daily for 7 days. A menopausal symptom survey was taken at baseline and at the end of the 7-day intervention. Urine was also collected at baseline and after 7 days to assess levels of estrone (E1) and estradiol (E2) and the changes in the vitamin B3 catabolome stemming from NRPT supplementation. Results: At the end of the study, significant decreases in both the frequency and magnitude of bloating, hot flashes, and poor sleep were reported in the MS group as compared to baseline. This was accompanied by a significant increase in the E2/E1 ratio. The No-MS group did not report any significant changes in these endpoints. As anticipated NRPT intake significantly increased urinary levels of methyl-nicotinamide (Me-NAM) as well as the methylated pyridone carboxamides (Me-PYs) in all groups. A significant time x menopausal status interaction was observed for nicotinuric acid (NUA). No other significant changes occurred for the other nicotinamide catabolites, such as nicotinamide N-oxide (NAM-N-Oxide), and a newly characterized NAD ⁺ catabolite, N-methyl-nicotinuric acid (Me-NUA). Discussion: This study demonstrates that NRPT is effective in significantly decreasing the frequency and magnitude of undesirable symptoms of the menopause transition and significantly increases the E2/E1 ratio in menopausal women.