Dunnione ameliorates cisplatin-induced small intestinal damage by modulating NAD+ metabolism

Pandit, Arpana; Kim, Hyungjin; Oh, Gi‐Su; Shen, AiHua; Lee, Su-Bin; Khadka, Dipendra; Lee, Seung‐Hoon; Shim, Hyeok; Yang, Sei‐Hoon; Cho, Eunyoung; Kwon, Kang‐Beom; Kwak, Tae Hwan; Choe, Seong-Kyu; Park, Raekil; So, Hong-Seob

doi:10.1016/j.bbrc.2015.10.081

Cited by 22 publications

(21 citation statements)

References 29 publications

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“…Cisplatin activates NLRP3 inflammasome expression and releases proinflammatory cytokines, thereby resulting in acute injury to the liver and kidneys in rats [22]. Several cytokines, such as IL-1β, are elevated in the small intestinal tissue and serum in response to cisplatin, resulting in distinct histopathological changes in the gastrointestinal tract [54]. us, we suggest that there is an NLRP3 inflammasome-dependent inflammatory response mediating cisplatin-induced side effects in the gastrointestinal tract.…”

Section: Gapdh Normentioning

confidence: 72%

The Antiemetic Effect of Xiao‐Ban‐Xia‐Tang Formula against Cisplatin‐Induced Emesis is Mediated through Inhibition of NLRP3 Inflammasome Activation in a Rat Pica Model

Meng

Cheng

Feng

et al. 2020

Evidence-Based Complementary and Alternative Medicine

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Xiao-Ban-Xia-Tang (XBXT), a traditional Chinese medicine formula, has been used for the treatment of emesis for nearly 2000 years, but its underlying mechanism is not yet fully clarified. The purpose of this study is to reveal the antiemetic mechanisms of XBXT by focusing on the NLRP3 inflammasome pathway in a chemotherapy-induced rat pica model. The pica model was generated by a single intraperitoneal injection of cisplatin in this study. Consumption of kaolin (a type of clay) and food and body weight were recorded every 24 hours. Cisplatin-induced increase in kaolin consumption (pica) was used to quantify chemotherapy-induced nausea and vomiting (CINV). Tissue from the ileum and antrum was stained with hematoxylin eosin (HE) to observe pathological changes. The levels of reactive oxygen species (ROS) and inflammatory cytokines, including IL-1β and IL-18 in serum, were detected by ELISA. In addition, changes in the NLRP3 inflammasome activation in the ileum and antrum were investigated using western blot and immunofluorescence microscopy. The results showed that oral administration of XBXT and ondansetron inhibited acute and delayed pica and significantly protected against the gastrointestinal pathological injury induced by cisplatin. The levels of ROS, IL-1β, and IL-18 in the serum of cisplatin-treated rats were also remarkably decreased by XBXT and ondansetron. Moreover, we found that XBXT can inhibit cisplatin-induced NLRP3 inflammasome activation. The present study indicates that the inhibition of the NLRP3 inflammasome activation might be one of the potential mechanisms for the therapeutic effects of XBXT against CINV.

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Section: Gapdh Normentioning

confidence: 72%

The Antiemetic Effect of Xiao‐Ban‐Xia‐Tang Formula against Cisplatin‐Induced Emesis is Mediated through Inhibition of NLRP3 Inflammasome Activation in a Rat Pica Model

Meng

Cheng

Feng

et al. 2020

Evidence-Based Complementary and Alternative Medicine

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“…In addition, NF-κB activity is regulated via post-translational modifications, namely phosphorylation and acetylation. Current studies have suggested that the incapability of reduced SIRT1 activity to deacetylate the NF-κB subunit p65 at lysine-310 aggravates the inflammatory mediators [12,17,28]. Interestingly, the level of acetylated NF-κB p65 was strongly increased in the cardiac tissue of ADR-treated WT mice compared with control, and this effect was significantly suppressed by dunnione (Fig.…”

Section: Dunnione Inhibits Acetylation Of Nf-κb P65 and Production Ofmentioning

confidence: 87%

“…The role of NAD + acts as a rate-limiting co-substrate and a central metabolic cofactor for various enzymes involved in energy metabolism and cellular homeostasis. Modulation of exogenous NAD + biosynthesis shows therapeutic benefits against tissue damage in animal models of ischemia, cardiomyopathy [8], hearing impairment [12], and small intestine injury [17]. Interestingly, intracellular NAD + /NADH ratio can be easily controlled by NQO1 that carry out redox reactions by transferring electrons from NADH to its substrates [19,42,43].…”

Section: Discussionmentioning

confidence: 99%

“…5B). Dunnione is a potent NQO1 substrate that oxidizes NADH to NAD + , thus increasing the cellular NAD + /NADH ratio [17,25]. Thus, we next examined the effect of dunnione on NQO1 activity and cellular NAD + /NADH ratio in the cardiac tissue of ADR-treated WT mice or NQO1 −/− mice.…”

Section: Dunnione Attenuates Parp-1 Hyperactivation By Adr-induced Dnmentioning

confidence: 99%

“…Numerous NQO1 substrates have been recognized, including mitomycin C, RH1, AZQ, coenzyme Q10, idebenone, and β-lapachone [15,16]. Dunnione, an orange-red pigment extracted from Streptocarpus dunnii Mast, is usually recognized as an anti-fungal and anti-tumor agent, but has lately been shown to act as a powerful substrate of NQO1, leading to an increase in the intracellular NAD + /NADH ratio by NQO1 action, resulting in SIRT1 activation by using increased NAD + as a co-substrate [17]. Although the association between NAD + -dependent molecular and cellular events and various diseases is evident, it is unclear whether modulation of NAD + levels affects ADR-induced cardiomyopathy (AIC).…”

Section: Introductionmentioning

confidence: 99%

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Augmentation of NAD+ levels by enzymatic action of NAD(P)H quinone oxidoreductase 1 attenuates adriamycin-induced cardiac dysfunction in mice

Khadka¹,

Kim²,

Oh³

et al. 2018

Journal of Molecular and Cellular Cardiology

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Background: Adriamycin (ADR) is a powerful chemotherapeutic agent extensively used to treat various human neoplasms. However, its clinical utility is hampered due to severe adverse side effects i.e. cardiotoxicity and heart failure. ADR-induced cardiomyopathy (AIC) has been reported to be caused by myocardial damage and dysfunction through oxidative stress, DNA damage, and inflammatory responses. Nonetheless, the remedies for AIC are even not established. Therefore, we illustrate the role of NAD + /NADH modulation by NAD(P)H quinone oxidoreductase 1 (NQO1) enzymatic action on AIC. Methods and results: AIC was established by intraperitoneal injection of ADR in C57BL/6 wild-type (WT) and NQO1 knockout (NQO1 −/−) mice. All Mice were orally administered dunnione (named NQO1 substrate) before and after exposure to ADR. Cardiac biomarker levels in the plasma, cardiac dysfunction, oxidative biomarkers, and mRNA and protein levels of pro-inflammatory mediators were determined compared the cardiac toxicity of each experimental group. All biomarkers of Cardiac damage and oxidative stress, and mRNA levels of proinflammatory cytokines including cardiac dysfunction were increased in ADR-treated both WT and NQO1 −/− mice. However, this increase was significantly reduced by dunnione in WT, but not in NQO1 −/− mice. In addition, a decrease in SIRT1 activity due to a reduction in the NAD + /NADH ratio by PARP-1 hyperactivation was associated with AIC through increased nuclear factor (NF)-κB p65 and p53 acetylation in both WT and NQO1 −/− mice. While an elevation in NAD + /NADH ratio via NQO1 enzymatic action using dunnione recovered SIRT1 activity and subsequently deacetylated NF-κB p65 and p53, however not in NQO1 −/− mice, thereby attenuating AIC. Conclusion: Thus, modulation of NAD + /NADH by NQO1 may be a novel therapeutic approach to prevent chemotherapy-associated heart failure, including AIC.

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Targeting NAD Metabolism for the Therapy of Age-Related Neurodegenerative Diseases

Wang

2023

Neurosci. Bull.

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As the aging population continues to grow rapidly, age-related diseases are becoming an increasing burden on the healthcare system and a major concern for the well-being of elderly individuals. While aging is an inevitable process for all humans, it can be slowed down and age-related diseases can be treated or alleviated. Nicotinamide adenine dinucleotide (NAD) is a critical coenzyme or cofactor that plays a central role in metabolism and is involved in various cellular processes including the maintenance of metabolic homeostasis, post-translational protein modifications, DNA repair, and immune responses. As individuals age, their NAD levels decline, and this decrease has been suggested to be a contributing factor to the development of numerous age-related diseases, such as cancer, diabetes, cardiovascular diseases, and neurodegenerative diseases. In pursuit of healthy aging, researchers have investigated approaches to boost or maintain NAD levels. Here, we provide an overview of NAD metabolism and the role of NAD in age-related diseases and summarize recent progress in the development of strategies that target NAD metabolism for the treatment of age-related diseases, particularly neurodegenerative diseases.

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Dunnione ameliorates cisplatin-induced small intestinal damage by modulating NAD+ metabolism

Cited by 22 publications

References 29 publications

The Antiemetic Effect of Xiao‐Ban‐Xia‐Tang Formula against Cisplatin‐Induced Emesis is Mediated through Inhibition of NLRP3 Inflammasome Activation in a Rat Pica Model

The Antiemetic Effect of Xiao‐Ban‐Xia‐Tang Formula against Cisplatin‐Induced Emesis is Mediated through Inhibition of NLRP3 Inflammasome Activation in a Rat Pica Model

Augmentation of NAD+ levels by enzymatic action of NAD(P)H quinone oxidoreductase 1 attenuates adriamycin-induced cardiac dysfunction in mice

Targeting NAD Metabolism for the Therapy of Age-Related Neurodegenerative Diseases

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