β-Nicotinamide mononucleotide activates NAD+/SIRT1 pathway and attenuates inflammatory and oxidative responses in the hippocampus regions of septic mice

Li, Hui-ru; Liu, Qiang; Zhu, Chenglong; Sun, Xiaoyang; Sun, Cathy; Yu, Chang-meng; Li, Peng; Deng, Xiaoming; Wang, Jiafeng

doi:10.1016/j.redox.2023.102745

Cited by 14 publications

(8 citation statements)

References 88 publications

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“…NAD + -induced ROS abrogation has been demonstrated to be dependent on SIRT1 in a model of chronic cerebral hypoperfusion . Similarly, NMN was shown to prevent ROS generation via SIRT1 in the hippocampi of septic mice . Direct chemical antioxidant activity is another possible mechanism for the observed effects of our N-PAMs on HT-22 cells.…”

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confidence: 71%

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Nicotinamide Phosphoribosyltransferase Positive Allosteric Modulators Attenuate Neuronal Oxidative Stress

Gordon-Blake,

Ratia,

Weidig

et al. 2024

ACS Med. Chem. Lett.

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Evidence supports boosting nicotinamide adenine dinucleotide (NAD + ) to counteract oxidative stress in aging and neurodegenerative disease. One approach is to enhance the activity of nicotinamide phosphoribosyltransferase (NAMPT). Novel NAMPT positive allosteric modulators (N-PAMs) were identified. A cocrystal structure confirmed N-PAM binding to the NAMPT rear channel. Early hit-to-lead efforts led to a 1.88-fold maximum increase in the level of NAD + in human THP-1 cells. Select N-PAMs were assessed for mitigation of reactive oxygen species (ROS) in HT-22 neuronal cells subject to inflammatory stress using tumor necrosis factor alpha (TNFα). N-PAMs that increased NAD + more effectively in THP-1 cells attenuated TNFα-induced ROS more effectively in HT-22 cells. The most efficacious N-PAM completely attenuated ROS elevation in glutamate-stressed HT-22 cells, a model of neuronal excitotoxicity. This work demonstrates for the first time that N-PAMs are capable of mitigating elevated ROS in neurons stressed with TNFα and glutamate and provides support for further N-PAM optimization for treatment of neurodegenerative diseases.

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confidence: 71%

“… 40 Similarly, NMN was shown to prevent ROS generation via SIRT1 in the hippocampi of septic mice. 46 Direct chemical antioxidant activity is another possible mechanism for the observed effects of our N-PAMs on HT-22 cells. However, JGB-1-127 and JGB-1-134 contain the same potential antioxidant groups and did not inhibit ROS generation.…”

mentioning

confidence: 95%

Nicotinamide Phosphoribosyltransferase Positive Allosteric Modulators Attenuate Neuronal Oxidative Stress

Gordon-Blake,

Ratia,

Weidig

et al. 2024

ACS Med. Chem. Lett.

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“…Ten μg of EX-527 (Selleck, USA) was injected into the ventricle through the lateral ventricle, and its dosage concentration was based on the previous dosage. 21 , 22 …”

Section: Methodsmentioning

confidence: 99%

NAD-Dependent Protein Deacetylase Sirtuin-1 Mediated Mitophagy Regulates Early Brain Injury After Subarachnoid Hemorrhage

Wang,

Lin

2024

JIR

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Background This study focuses on the role of SIRT1 in neuroinflammation caused by early brain injury (EBI) after subarachnoid hemorrhage (SAH), and explores its mechanism in mitophagy after SAH. Methods C57BL/6J mice and primary microglia SAH in vivo and in vitro models were constructed to explore the expression level of SIRT1 in neuroinflammation after SAH. Subsequently, the brain edema content, blood–brain barrier (BBB) damage and neurological function scores of the mice were observed after using the SIRT1 inhibitor EX-527. q-PCR and Western blot were used to detect relevant genes and proteins, and enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of IL-6, IL-1β, and TNF-α inflammatory factors. Immunofluorescence staining was used to observe the positive level of SIRT1 and the degree of mitochondria-lysosome fusion, and transmission electron microscopy was used to observe mitochondrial damage and autophagosome levels. Results In in vivo and in vitro experiments, we found that SIRT1 expression increased after SAH, and neurological deficits, brain edema, and blood–brain barrier damage after SAH were aggravated. Inhibiting SIRT1 further aggravates the aforementioned damage. In addition, EX-527 can also inhibit the level of mitophagy and aggravate neuroinflammation after SAH. Conclusion Our results indicated that SIRT1 promotes mitophagy and alleviates neuroinflammation after SAH.

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“…found that NMN reversed the weakened NAD+/SIRT1/PGC-1α axis in sepsis rats and improved hippocampal apoptosis, inflammation, oxidative stress. These NMN benefits above mentioned were negated by EX-527 ( 173 ). In LPS-induced AKI, NAD+ level significantly decreases and is negatively correlated with renal dysfunction.…”

Section: Drugs Targeting the Sirts In Sepsis-induced Modsmentioning

confidence: 98%

The role and therapeutic potential of SIRTs in sepsis

You,

Li,

Chong

2024

Front. Immunol.

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Sepsis is a life-threatening organ dysfunction caused by the host’s dysfunctional response to infection. Abnormal activation of the immune system and disturbance of energy metabolism play a key role in the development of sepsis. In recent years, the Sirtuins (SIRTs) family has been found to play an important role in the pathogenesis of sepsis. SIRTs, as a class of histone deacetylases (HDACs), are widely involved in cellular inflammation regulation, energy metabolism and oxidative stress. The effects of SIRTs on immune cells are mainly reflected in the regulation of inflammatory pathways. This regulation helps balance the inflammatory response and may lessen cell damage and organ dysfunction in sepsis. In terms of energy metabolism, SIRTs can play a role in immunophenotypic transformation by regulating cell metabolism, improve mitochondrial function, increase energy production, and maintain cell energy balance. SIRTs also regulate the production of reactive oxygen species (ROS), protecting cells from oxidative stress damage by activating antioxidant defense pathways and maintaining a balance between oxidants and reducing agents. Current studies have shown that several potential drugs, such as Resveratrol and melatonin, can enhance the activity of SIRT. It can help to reduce inflammatory response, improve energy metabolism and reduce oxidative stress, showing potential clinical application prospects for the treatment of sepsis. This review focuses on the regulation of SIRT on inflammatory response, energy metabolism and oxidative stress of immune cells, as well as its important influence on multiple organ dysfunction in sepsis, and discusses and summarizes the effects of related drugs and compounds on reducing multiple organ damage in sepsis through the pathway involving SIRTs. SIRTs may become a new target for the treatment of sepsis and its resulting organ dysfunction, providing new ideas and possibilities for the treatment of this life-threatening disease.

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β-Nicotinamide mononucleotide activates NAD+/SIRT1 pathway and attenuates inflammatory and oxidative responses in the hippocampus regions of septic mice

Cited by 14 publications

References 88 publications

Nicotinamide Phosphoribosyltransferase Positive Allosteric Modulators Attenuate Neuronal Oxidative Stress

Nicotinamide Phosphoribosyltransferase Positive Allosteric Modulators Attenuate Neuronal Oxidative Stress

NAD-Dependent Protein Deacetylase Sirtuin-1 Mediated Mitophagy Regulates Early Brain Injury After Subarachnoid Hemorrhage

The role and therapeutic potential of SIRTs in sepsis

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