Melatonin alleviates cadmium‐induced liver injury by inhibiting the TXNIP‐NLRP3 inflammasome

Cao, Zhengwang; Fang, Yiliang; Lu, Yonghui; Tan, Dun‐Xian; Du, Changhong; Li, Yuming; Ma, Qibin; Yu, Junmei; Chen, Mengyan; Zhou, Chao; Pei, Liping; Zhang, Lei; Ran, Haiying; He, Mindi; Yu, Zhengping; Zhou, Zhou

doi:10.1111/jpi.12389

Cited by 170 publications

(109 citation statements)

References 58 publications

(108 reference statements)

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“…These effects of melatonin against sepsis in mice lead to an increased survival rate of animals . The beneficial effects due the inhibition of the NLRP3 inflammasome by melatonin are receiving increased attention because it is related to the improvement of diseases such as cadmium‐induced liver injury, acute lung injury, and subarachnoid hemorrhage‐induced brain injury . However, the specific interaction of melatonin with the NLRP3 inflammasome during sepsis in cardiac tissue remains to be identified.…”

Section: Discussionmentioning

confidence: 99%

Melatonin administration to wild‐type mice and nontreated NLRP3 mutant mice share similar inhibition of the inflammatory response during sepsis

Rahim

Djerdjouri

Sayed

et al. 2017

Journal of Pineal Research

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The NLRP3 inflammasome is involved in the innate immune response during inflammation. Moreover, melatonin blunts the NF-κB/NLRP3 connection during sepsis. Thus, we compared the roles of the NLRP3 inflammasome and/or melatonin treatment in the septic response of wild-type and NLRP3 mice. Mouse myocardial tissue was used for this purpose. The nuclear turnover of NF-κB was enhanced during sepsis, with an increase in TNFα, iNOS, and pro-IL-1β. The lack of inflammasome in NLRP3 mice significantly reduced that response and blunted IL-1β maturation due to the lack of caspase-1. Clock and Bmal1 did not change in both mouse strains, enhancing Chrono expression in mutants. RORα, which positively regulates Bmal1, was enhanced at a similar extend in both mouse strains, whereas the expression of the Bmal1 repressor, Rev-Erbα, increased in WT but was depressed in NLRP3 mice. Nampt, transcriptionally controlled by Bmal1, increased in WT mice together with Sirt1, whereas they remained unchanged in NLRP3 mice. Melatonin treatment reduced the septic response in a comparable manner as did the lack of NLRP3, but unlike the latter, it normalized the clock genes turnover through the induction of RORα and repression of Rev-Erbα and Per2, leading to enhanced Nampt and Sirt1. The lack of NLRP3 inflammasome converts sepsis to a moderate inflammatory disease and identifies NLRP3 as a main target for the treatment of sepsis. The efficacy of melatonin in counteracting the NLRP3 inflammasome activation further confirms the indoleamine as a useful therapeutic drug against this serious condition.

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Section: Discussionmentioning

confidence: 99%

Melatonin administration to wild‐type mice and nontreated NLRP3 mutant mice share similar inhibition of the inflammatory response during sepsis

Rahim

Djerdjouri

Sayed

et al. 2017

Journal of Pineal Research

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“…Melatonin reduced liver injury and inflammation through decreasing serum ALT/AST levels, inhibiting pro-inflammatory cytokine production, preventing NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome activation, ameliorating oxidative stress, and attenuating hepatocyte death. In vivo and in vitro, Cd-induced TXNIP overexpression was markedly abrogated and the interaction between TXNIP and NLRP3 was decreased by melatonin [29]. In addition, melatonin increased hepatic GSH levels and improved histopathological changes after Cd 2+ exposure.…”

Section: Protective Effects Of Melatonin On Liver Injuriesmentioning

confidence: 99%

Effects of Melatonin on Liver Injuries and Diseases

Zhang

Meng

et al. 2017

IJMS

101

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Liver injuries and diseases are serious health problems worldwide. Various factors, such as chemical pollutants, drugs, and alcohol, could induce liver injuries. Liver diseases involve a wide range of liver pathologies, including hepatic steatosis, fatty liver, hepatitis, fibrosis, cirrhosis, and hepatocarcinoma. Despite all the studies performed up to now, therapy choices for liver injuries and diseases are very few. Therefore, the search for a new treatment that could safely and effectively block or reverse liver injuries and diseases remains a priority. Melatonin is a well-known natural antioxidant, and has many bioactivities. There are numerous studies investigating the effects of melatonin on liver injuries and diseases, and melatonin could regulate various molecular pathways, such as inflammation, proliferation, apoptosis, metastasis, and autophagy in different pathophysiological situations. Melatonin could be used for preventing and treating liver injuries and diseases. Herein, we conduct a review summarizing the potential roles of melatonin in liver injuries and diseases, paying special attention to the mechanisms of action.

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“…15,16 It was reported that the reduction in inflammasome activation could significantly decrease the level of inflammatory responses in neurons as a result of decreased caspase-1 activity and reduced production of IL-1. [20][21][22] In this study, we established a rat model of SCI and treated SCI rats with MT to explore the molecular mechanisms underlying the therapeutic effect of MT in the treatment of SCI. 18 Although the reduction in inflammatory responses is transient in nature, it can lead to significant improvements in terms of functional and histopathological properties of neurons.…”

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confidence: 99%

Melatonin ameliorates spinal cord injury by suppressing the activation of inflammasomes in rats

Shi

Zhi

et al. 2018

J of Cellular Biochemistry

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Background The activation of inflammasomes plays an important role in the pathogenesis of spinal cord injury (SCI). In addition, the administration of melatonin (MT) has been shown to suppress the activation of inflammasomes. In this study, we aimed to investigate the molecular mechanisms underlying the therapeutic effect of MT in the treatment of SCI. Methods Basso‐Beattie‐Bresnahan (BBB) locomotion scaling was conducted to evaluate the therapeutic effect of MT on post‐SCI locomotion recovery. In addition, the measurement of spinal cord water content was performed together with Nissl staining to evaluate the protective effect of MT against SCI. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, immunohistochemistry (IHC) assay, Western blot analysis, and real‐time polymerase chain reaction (PCR) were also conducted to clarify the molecular mechanisms underlying the therapeutic effect of MT in the treatment of SCI. Results BBB scores of SCI + MT rats were increased compared with the BBB scores of SCI rats, thus confirming the beneficial role of MT treatment in post‐SCI functional recovery. Meanwhile, the administration of MT could alleviate SCI by reducing spinal cord water content and by exerting a neuroprotective effect on motor neurons. Furthermore, in the treatment of SCI, MT also attenuated cell apoptosis. Moreover, the relative expression of NLRP3, interleukin‐1β (IL‐1β), and caspase‐1 were markedly elevated in the SCI group compared with that in the sham group, while the administration of MT reduced the expression of NLRP3 in SCI rats. Conclusions MT treatment accelerated the recovery of SCI by suppressing the activation of inflammasomes.

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Melatonin alleviates cadmium‐induced liver injury by inhibiting the TXNIP‐NLRP3 inflammasome

Cited by 170 publications

References 58 publications

Melatonin administration to wild‐type mice and nontreated NLRP3 mutant mice share similar inhibition of the inflammatory response during sepsis

Melatonin administration to wild‐type mice and nontreated NLRP3 mutant mice share similar inhibition of the inflammatory response during sepsis

Effects of Melatonin on Liver Injuries and Diseases

Melatonin ameliorates spinal cord injury by suppressing the activation of inflammasomes in rats

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