The therapeutic promises of NAD+ boosters

Montllor-Albalate, Claudia; Song, Zehan; Chen, Danica

doi:10.1016/j.cmet.2021.06.008

Cited by 7 publications

(3 citation statements)

References 10 publications

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“…NAD + levels have been shown to decrease with aging ( Fang et al, 2017 ; Imai and Guarente, 2014 ), during pregnancy ( Shi et al, 2017 ), and upon viral infection ( Mesquita et al, 2016 ) and are dysregulated in some cancers ( Chiarugi et al, 2012 ; Yaku et al, 2018 ). Augmenting NAD + through pharmacological means has been of increasing interest ( Giroud-Gerbetant et al, 2019 ; Montllor-Albalate et al, 2021 ). Dihydronicotinamide riboside (NRH) is a reduced form of nicotinamide riboside (NR) and is uniquely metabolized, rapidly leading to enhanced levels of intracellular NAD + ( Giroud-Gerbetant et al, 2019 ; Yang et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Temporal dynamics of base excision/single-strand break repair protein complex assembly/disassembly are modulated by the PARP/NAD+/SIRT6 axis

et al. 2021

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Section: Introductionmentioning

confidence: 99%

Temporal dynamics of base excision/single-strand break repair protein complex assembly/disassembly are modulated by the PARP/NAD+/SIRT6 axis

et al. 2021

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“…Because we identified a global impairment of NAD + metabolism and a depletion of NAD + levels, which were directly associated with an active and inflammatory status, our next goal was to test mechanistically the capacity of several NAD + boosters (NR, NAM, and NMN) (41) to increase NAD + levels in PBMCs from active RA patients and modulate their activated status.…”

Section: Discussionmentioning

confidence: 99%

Preclinical Characterization of Pharmacologic NAD⁺ Boosting as a Promising Therapeutic Approach in Rheumatoid Arthritis

Pérez-Sánchez

Escudero‐Contreras

Cerdó

et al. 2023

Arthritis & Rheumatology

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ObjectiveWe analyzed NAD+ metabolism in patients with rheumatoid arthritis (RA), its association with disease activity and clinical outcomes of RA, and the therapeutic potential of pharmacologic NAD+ boosting.MethodsOur study included 253 participants. In the first cohort, comprising 153 RA patients and 56 healthy donors, we assessed NAD+ levels and NAD+‐related gene pathways. We analyzed 92 inflammatory molecules by proximity extension assay. In the second cohort, comprising 44 RA patients starting anti–tumor necrosis factor (anti‐TNF) drugs, we evaluated changes in NAD+ levels and their association with clinical response after 3 months. Mechanistic studies were performed ex vivo on peripheral blood mononuclear cells (PBMCs) from patients with RA to test the beneficial effects of NAD+ boosters, such as nicotinamide and nicotinamide riboside.ResultsReduced NAD+ levels were found in RA samples, in line with altered activity and expression of genes involved in NAD+ consumption (sirtuins, poly[ADP‐ribose] polymerase, CD38), transport (connexin 43), and biosynthesis (NAMPT, NMNATs). Unsupervised clustering analysis identified a group of RA patients with the highest inflammatory profile, the lowest NAD+ levels, and the highest disease activity (as shown by the Disease Activity Score in 28 joints). NAD+ levels were modulated by anti‐TNF therapy in parallel with the clinical response. In vitro studies using PBMCs from RA patients showed that nicotinamide riboside and nicotinamide increased NAD+ levels via NAMPT and NMNAT and reduced their prooxidative, proapoptotic, and proinflammatory status.ConclusionRA patients display altered NAD+ metabolism, directly linked to their inflammatory and disease activity status, which was reverted by anti‐TNF therapy. The preclinical beneficial effects of NAD+ boosters, as shown in leukocytes from RA patients, along with their proven clinical safety, might pave the way for the development of clinical trials using these compounds.

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“…Such dysregulated NAD + metabolism not only affects mitochondrial function but also fosters inflammatory conditions, ultimately causing organ dysfunction ( 15 , 19 – 22 ). As such, methods that help maintain NAD(H) homeostasis with NAD + boosting strategies, such as treating with vitamin B3 derivatives ( 71 ), presents an attractive therapeutic strategy for chronic inflammatory diseases ( 15 – 17 , 22 ). Our results showed that placentas from LPS treated pregnant rats exhibited a significant decrease in NAD + levels, and in the NAD + /NADH ratio, which correlated to a reduction in mitochondrial respiration at multiple complexes, as a marker of mitochondrial function ( Figures 4D-F ).…”

Section: Discussionmentioning

confidence: 99%

A comparison of rat models that best mimic immune-driven preeclampsia in humans

Jahan,

Vasam,

Cariaco

et al. 2023

Front. Endocrinol.

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Preeclampsia (PE), a hypertensive pregnancy disorder, can originate from varied etiology. Placenta malperfusion has long been considered the primary cause of PE. However, we and others have showed that this disorder can also result from heightened inflammation at the maternal-fetal interface. To advance our understanding of this understudied PE subtype, it is important to establish validated rodent models to study the pathophysiology and test therapies. We evaluated three previously described approaches to induce inflammation-mediated PE-like features in pregnant rats: 1) Tumor necrosis factor-α (TNF-α) infusion via osmotic pump from gestational day (GD) 14-19 at 50ng/day/animal; 2) Polyinosinic:polycytidylic acid (Poly I:C) intraperitoneal (IP) injections from GD 10-18 (alternate days) at 10mg/kg/day/animal; and, 3) Lipopolysaccharide (LPS) IP injections from GD 13-18 at 20ug-70ug/kg/day per animal. Maternal blood pressure was measured by tail-cuff. Upon sacrifice, fetal and placenta weights were recorded. Placenta histomorphology was assessed using H&E sections. Placenta inflammation was determined by quantifying TNF-α levels and inflammatory gene expression. Placenta metabolic and mitochondrial health were determined by measuring mitochondrial respiration rates and placenta NAD+/NADH content. Of the three rodent models tested, we found that Poly I:C and LPS decreased both fetal weight and survival; and correlated with a reduction in region specific placenta growth. As the least effective model characterized, TNF-α treatment resulted in a subtle decrease in fetal/placenta weight and placenta mitochondrial respiration. Only the LPS model was able to induce maternal hypertension and exhibited pronounced placenta metabolic and mitochondrial dysfunction, common features of PE. Thus, the rat LPS model was most effective for recapitulating features observed in cases of human inflammatory PE. Future mechanistic and/or therapeutic intervention studies focuses on this distinct PE patient population may benefit from the employment of this rodent model of PE.

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The therapeutic promises of NAD+ boosters

Cited by 7 publications

References 10 publications

Temporal dynamics of base excision/single-strand break repair protein complex assembly/disassembly are modulated by the PARP/NAD+/SIRT6 axis

Temporal dynamics of base excision/single-strand break repair protein complex assembly/disassembly are modulated by the PARP/NAD+/SIRT6 axis

Preclinical Characterization of Pharmacologic NAD⁺ Boosting as a Promising Therapeutic Approach in Rheumatoid Arthritis

A comparison of rat models that best mimic immune-driven preeclampsia in humans

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The therapeutic promises of NAD+ boosters

Cited by 7 publications

References 10 publications

Temporal dynamics of base excision/single-strand break repair protein complex assembly/disassembly are modulated by the PARP/NAD+/SIRT6 axis

Temporal dynamics of base excision/single-strand break repair protein complex assembly/disassembly are modulated by the PARP/NAD+/SIRT6 axis

Preclinical Characterization of Pharmacologic NAD+ Boosting as a Promising Therapeutic Approach in Rheumatoid Arthritis

A comparison of rat models that best mimic immune-driven preeclampsia in humans

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Preclinical Characterization of Pharmacologic NAD⁺ Boosting as a Promising Therapeutic Approach in Rheumatoid Arthritis