Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence

Rajman, Luis A.; Chwalek, Karolina; Sinclair, David A.

doi:10.1016/j.cmet.2018.02.011

Cited by 670 publications

(641 citation statements)

References 267 publications

(346 reference statements)

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“…For example, Nicotinamide adenine dinucleotide (NAD), the hydrogen carrier for redox enzymes, is known for its important roles in redox reactions. NAD + levels are closely associated with energy metabolism and disease susceptibility [36]. Increasing cellular NAD + levels by treatment of the NAD + precursor, nicotinamide riboside can protect against liver injury in a SIRT1-dependent fashion [37].…”

Section: Discussionmentioning

confidence: 99%

Cangju Qinggan Jiangzhi Decoction Reduces the Development of NonAlcoholic Steatohepatitis and Activation of Kupffer Cells

Cheng

Chen

Jian

et al. 2018

Cell Physiol Biochem

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Background/Aims: Nonalcoholic steatohepatitis (NASH) is defined as lipid accumulation with hepatic injury, inflammation and early to moderate fibrosis. Kupffer cells play a crucial role in promoting hepatic inflammation, which further facilitates the development of NASH. Here we investigated the effects of Cangju Qinggan Jiangzhi decoction (CQJD) on high fat diet (HFD) and methionine-choline deficient (MCD) induced mouse NASH pathogenesis. Methods: Mouse NASH models were developed by HFD and MCD diet. The treated mice were divided into three groups: the control group (n = 10), the low-dose CQJD treatment group (n = 10) and the high-dose CQJD treatment group (n = 10). The hepatic injury, inflammation, and apoptotic molecules were evaluated by H&E staining, immunohistochemistry and real-time PCR. Kupffer cells were isolated from control mice and CQJD-treated mice after stimulation by lipopolysaccharide (LPS) and/or palmitic acid. The level of the inflammatory cytokines TNFα, IL1β, and CCL2 was measured by ELISA. Results: The HFD-fed mice displayed significant metabolic, inflammatory, and oxidative stress-related alterations due to hepatic lipid accumulation. CQJD treatment largely normalized the hepatic injury, lowered the ALT/AST level, and reduced the severity of liver inflammation, as revealed by the decreased inflammatory cytokines levels. In vitro, CQJD blocked the activation of LPS- or palmitic acid-primed Kupffer cells in a dose-dependent manner. In the MCD diet-induced NASH mice, similar therapeutic effects of CQJD were also observed. Conclusion: CQJD ameliorates mouse nonalcoholic steatohepatitis. The reduction in liver injury and inflammation induced by CQJD is associated with reduced activation of Kupffer cells. Our results suggest that CQJD is a promising therapeutic strategy in clinical steatohepatitis.

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Section: Discussionmentioning

confidence: 99%

Cangju Qinggan Jiangzhi Decoction Reduces the Development of NonAlcoholic Steatohepatitis and Activation of Kupffer Cells

Cheng

Chen

Jian

et al. 2018

Cell Physiol Biochem

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“…By 2050, $1 trillion will be spent yearly on those 65 years of age or older due to neurodegenerative diseases like dementia. [13] A current and rather controversial question regarding the cofactor is whether one's healthspan or lifespan depends heavily on one's NAD + levels. Since NAD + is the rate limiting cofactor of sirtuin enzymes, the decline of the cofactor with age has been linked to steady declines in sirtuin activity.…”

Section: Introductionmentioning

confidence: 99%

“…[15] The inevitable decline of NAD + is being combated through the use of oral supplements of the vitamin B 3 complex such as nicotinamide, nicotinic acid (niacin), nicotinamide mononucleo-tide (NMN), and NR, Figure 1, as well as sirtuin activating compounds like resveratrol. [11,13] NR, as well as NMN (i. e., the phosphorylated form), may be consumed daily from vegetables, fruits, and meat. [16] Niacin was generally used as an NAD + booster until severe flushing and itching caused by the supplement deterred users.…”

Section: Introductionmentioning

confidence: 99%

Electrochemical Characterization of Nicotinamide Riboside

Goines

Dick

2019

ChemElectroChem

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To improve quality of life, nicotinamide riboside (NR) has become a go-to supplement to serve as a precursor to nicotinamide adenine dinucleotide (NAD + /NADH). NAD + is a cofactor used in various extra-and intra-cellular metabolic pathways by enzymes that maintain physiological functions like vision, hearing, and cognitive behavior. Unfortunately, innate NAD + levels decline over time giving rise to a need for NAD + boosters like NR to fight age-related diseases. To better understand redox pathways of NR in biological systems, we chose to study the electrochemistry of NR. Here, we electrochemically characterize NR in aqueous solutions using voltammetry, amperometry, bulk electrolysis, and mass spectrometry. We found the reduction of NR (E p,c = À 1.1 V vs. Ag/AgCl) is a diffusion-controlled reaction and calculated a diffusion coefficient of 4.6�0.1 × 10 À 6 cm 2 · s À 1 . Square wave voltammetry indicated NR is reduced by one electron, and cyclic voltammetry suggested a major kinetic product, oxidizable at E p,a = + 0.15 V vs. Ag/AgCl. Bulk electrolysis confirmed the species at + 0.15 V vs. Ag/AgCl was a kinetic product, and liquid chromatography-mass spectrometry of the bulk electrolysis products revealed the thermodynamic product was a dimer (NR 2 ). Finally, we studied the reduction of NR in whole cell lysate, which is shown to differ markedly from simple buffer solutions.[a] S.

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“…Thus, NAD is considered a nexus for metabolism and aging. Numbers of studies show that NAD levels decrease with aging in multiple organs and that declines in intracellular NAD concentrations are related to various aging‐associated phenotypes (Canto et al., 2015; Rajman, Chwalek, & Sinclair, 2018; Yoshino, Baur, & Imai, 2017). Therefore, increases in intracellular NAD levels may combat with aging‐associated diseases.…”

Section: Introductionmentioning

confidence: 99%

Overexpression of Nmnat3 efficiently increases NAD and NGD levels and ameliorates age‐associated insulin resistance

et al. 2018

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SummaryNicotinamide adenine dinucleotide (NAD) is an important cofactor that regulates various biological processes, including metabolism and gene expression. As a coenzyme, NAD controls mitochondrial respiration through enzymes of the tricarboxylic acid (TCA) cycle, β‐oxidation, and oxidative phosphorylation and also serves as a substrate for posttranslational protein modifications, such as deacetylation and ADP‐ribosylation by sirtuins and poly(ADP‐ribose) polymerase (PARP), respectively. Many studies have demonstrated that NAD levels decrease with aging and that these declines cause various aging‐associated diseases. In contrast, activation of NAD metabolism prevents declines in NAD levels during aging. In particular, dietary supplementation with NAD precursors has been associated with protection against age‐associated insulin resistance. However, it remains unclear which NAD synthesis pathway is important and/or efficient at increasing NAD levels in vivo. In this study, Nmnat3 overexpression in mice efficiently increased NAD levels in various tissues and prevented aging‐related declines in NAD levels. We also demonstrated that Nmnat3‐overexpressing (Nmnat3 Tg) mice were protected against diet‐induced and aging‐associated insulin resistance. Moreover, in skeletal muscles of Nmnat3 Tg mice, TCA cycle activity was significantly enhanced, and the energy source for oxidative phosphorylation was shifted toward fatty acid oxidation. Furthermore, reactive oxygen species (ROS) generation was significantly suppressed in aged Nmnat3 Tg mice. Interestingly, we also found that concentrations of the NAD analog nicotinamide guanine dinucleotide (NGD) were dramatically increased in Nmnat3 Tg mice. These results suggest that Nmnat3 overexpression improves metabolic health and that Nmnat3 is an attractive therapeutic target for metabolic disorders that are caused by aging.

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Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence

Cited by 670 publications

References 267 publications

Cangju Qinggan Jiangzhi Decoction Reduces the Development of NonAlcoholic Steatohepatitis and Activation of Kupffer Cells

Cangju Qinggan Jiangzhi Decoction Reduces the Development of NonAlcoholic Steatohepatitis and Activation of Kupffer Cells

Electrochemical Characterization of Nicotinamide Riboside

Overexpression of Nmnat3 efficiently increases NAD and NGD levels and ameliorates age‐associated insulin resistance

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