Celastrol targets adenylyl cyclase-associated protein 1 to reduce macrophages-mediated inflammation and ameliorates high fat diet-induced metabolic syndrome in mice

Zhu, Yuyu; Wan, Ning; Shan, Xinni; Deng, Guoliang; Xu, Qiang; Ye, Hui; Sun, Yang

doi:10.1016/j.apsb.2020.12.008

Cited by 38 publications

(32 citation statements)

References 45 publications

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“…A waterfall effect will form through positive feedback, which in turn cause the release of toxic substances and destroy the functions of cells and tissues (19)(20)(21). Macrophages play an important role in the inflammatory response of sepsis; they are activated to express a large number of pro-inflammatory factors and further promote the inflammatory response of sepsis (22). Meanwhile, the phagocytosis and sterilization of macrophages could not be ignored when pathogens invaded, while the functions were inhibited in sepsis (23).…”

Section: Introductionmentioning

confidence: 99%

The Clinical Value of GDF15 and Its Prospective Mechanism in Sepsis

Tang

Chen

et al. 2021

Front. Immunol.

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Growth differentiation factor 15 (GDF15) is involved in the occurrence and development of many diseases, and there are few studies on its relationship with sepsis. This article aims to explore the clinical value of GDF15 in sepsis and to preliminarily explore its prospective regulatory effect on macrophage inflammation and its functions. We recruited 320 subjects (132 cases in sepsis group, 93 cases in nonsepsis group, and 95 cases in control group), then detected the serum GDF15 levels and laboratory indicators, and further investigated the correlation between GDF15 and laboratory indicators, and also analyzed the clinical value of GDF15 in sepsis diagnosis, severity assessment, and prognosis. In vitro, we used LPS to stimulate THP-1 and RAW264.7 cells to establish the inflammatory model, and detected the expression of GDF15 in the culture medium and cells under the inflammatory state. After that, we added GDF15 recombinant protein (rGDF15) pretreatment to explore its prospective regulatory effect on macrophage inflammation and its functions. The results showed that the serum GDF15 levels were significantly increased in the sepsis group, which was correlated with laboratory indexes of organ damage, coagulation indexes, inflammatory factors, and SOFA score. GDF15 also has a high AUC in the diagnosis of sepsis, which can be further improved by combining with other indicators. The dynamic monitoring of GDF15 levels can play an important role in the judgment and prognosis of sepsis. In the inflammatory state, the expression of intracellular and extracellular GDF15 increased. GDF15 can reduce the levels of cytokines, inhibit M1 polarization induced by LPS, and promote M2 polarization. Moreover, GDF15 also enhances the phagocytosis and bactericidal function of macrophages. Finally, we observed a decreased level of the phosphorylation of JAK1/STAT3 signaling pathway and the nuclear translocation of NF-κB p65 with the pretreatment of rGDF15. In summary, our study found that GDF15 has good clinical application value in sepsis and plays a protective role in the development of sepsis by regulating the functions of macrophages and inhibiting the activation of JAK1/STAT3 pathway and nuclear translocation of NF-κB p65.

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Section: Introductionmentioning

confidence: 99%

The Clinical Value of GDF15 and Its Prospective Mechanism in Sepsis

Tang

Chen

et al. 2021

Front. Immunol.

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“…Our findings demonstrated that celastrol was able to reduce both SARS-CoV-2 viral load and IL-6 production in two human cell lines, suggesting that this compound exerts anti-SARS-CoV-2 effects of clinical relevance to face the current pandemic. Several pharmacological applications of celastrol are associated with Covid-19 severity, including comorbidities such as obesity, diabetes, hypertension, and metabolic syndrome [95][96][97][98] , and pathological events such as non-homeostatic production of pro-inflammatory cytokines, thrombus generation, and formation of neutrophil extracellular traps [99][100][101] . Celastrol is currently under clinical trials to treat a variety of diseases, including different types of cancer, neurodegenerative disorders, and inflammatory conditions such as rheumatoid arthritis, psoriasis, and Crohn's disease [102][103][104][105][106] .…”

Section: Discussionmentioning

confidence: 99%

Drug repurposing to face Covid-19: Celastrol, a potential leading drug capable of inhibiting SARS-CoV-2 replication and induced inflammation

Fuzo

Martins

Fraga-Silva

et al. 2021

Preprint

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The global emergence of Covid-19 has caused huge human casualties. Clinical manifestations of the disease vary from asymptomatic to lethal, and the symptomatic form can be associated with cytokine storm and non-homeostatic inflammatory response. In face of the urgent demand for effective drugs to treat Covid-19, we have searched for candidate compounds using a drug repurposing approach based on in silico analysis followed by biological validation. Here we identified celastrol, a pentacyclic triterpene isolated from Tripterygium wilfordii Hook F – a plant used in traditional Chinese medicine – as one of the best compounds out of 39 repurposed drug candidates. Celastrol reverted gene expression signature from SARS-CoV-2-infected cells; bound with high-affinity energy to viral molecular targets such as main protease (Mpro) and receptor-biding domain (RBD); inhibited SARS-CoV-2 replication in monkey (Vero and Vero-ACE2) and human (Caco-2 and Calu-3) cell lines; and decreased interleukin-6 (IL-6) secretion in SARS-CoV-2-infected human cell lines. Interestingly, celastrol acted in a concentration-dependent manner, with undetectable signs of cytotoxicity. Therefore, celastrol is a promising lead drug candidate to treat Covid-19 due to its ability to suppress SARS-CoV-2 replication and IL-6 production in infected cells, two critical events in the pathophysiology of this disease.

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“…Brain leptin promoted hepatic lipid flux and reduced lipogenesis in the liver ( Hackl et al, 2019 ). Celastrol as a leptin sensitizer exhibited significant weight loss and food consumption reduction in HFD-obesity animals ( Wang et al, 2014 ; Liu et al, 2015 ; Ma et al, 2015 ; Zhang et al, 2017a ; Hu et al, 2017 ; Luo et al, 2017 ; Kyriakou et al, 2018 ; Pfuhlmann et al, 2018 ; Zhang et al, 2018 ; Feng et al, 2019a ; Zhao et al, 2019a ; Feng et al, 2019b ; Chellappa et al, 2019 ; Fang et al, 2019 ; Saito et al, 2019 ; Abu Bakar et al, 2020 ; Hu et al, 2020 ; Zhu C. et al, 2021 ; Zhu Y. et al, 2021 ; Hua et al, 2021 ; Ouyang et al, 2021 ; Yang et al, 2021 ) ( Table 1 ).…”

Section: Celastrol and Liver Diseasesmentioning

confidence: 99%

“…Numerous evidences supported that obesity is strongly associated with MAFLD development ( Fabbrini et al, 2010 ). The liver protective effect and molecular mechanism of celastrol on high fat diet (HFD) induced MAFLD animal models have been well-investigated ( Wang et al, 2014 ; Ma et al, 2015 ; Zhang et al, 2017a ; Hu et al, 2017 ; Luo et al, 2017 ; Kyriakou et al, 2018 ; Pfuhlmann et al, 2018 ; Zhang et al, 2018 ; Feng et al, 2019a ; Zhao et al, 2019a ; Feng et al, 2019b ; Chellappa et al, 2019 ; Fang et al, 2019 ; Abu Bakar et al, 2020 ; Hu et al, 2020 ; Zhu C. et al, 2021 ; Zhu Y. et al, 2021 ; Hua et al, 2021 ; Ouyang et al, 2021 ; Yang et al, 2021 ).…”

Section: Celastrol and Liver Diseasesmentioning

confidence: 99%

“…Different animal experiments have elucidated that the inflammation in fatty liver mice treated with celastrol are remarkably attenuated ( Table 1 ). Macrophage infiltration and inflammatory factors (IL-1β, IL-18, MCP-1α, and TNF-α) were reduced in liver of HFD induced C57BL/6J or C57BL/6N mice by celastrol treated for 3 weeks ( Hu et al, 2017 ; Luo et al, 2017 ; Zhang et al, 2018 ; Ouyang et al, 2021 ; Zhu Y. et al, 2021 ). In addition, adipose tissue inflammation and mitochondrial dysfunction in skeletal muscle ameliorated in HFD-induced SD rats treated with 3 mg/kg/day celastrol for 8 weeks ( Abu Bakar et al, 2020 ).…”

Section: Celastrol and Liver Diseasesmentioning

confidence: 99%

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Celastrol: An Update on Its Hepatoprotective Properties and the Linked Molecular Mechanisms

Xie

Wang

et al. 2022

Front. Pharmacol.

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The liver plays an important role in glucose and lipid homeostasis, drug metabolism, and bile synthesis. Metabolic disorder and inflammation synergistically contribute to the pathogenesis of numerous liver diseases, such as metabolic-associated fatty liver disease (MAFLD), liver injury, and liver cancer. Celastrol, a triterpene derived from Tripterygium wilfordii Hook.f., has been extensively studied in metabolic and inflammatory diseases during the last several decades. Here we comprehensively review the pharmacological activities and the underlying mechanisms of celastrol in the prevention and treatment of liver diseases including MAFLD, liver injury, and liver cancer. In addition, we also discuss the importance of novel methodologies and perspectives for the drug development of celastrol. Although celastrol has been claimed as a promising agent against several metabolic diseases, both preclinical and clinical studies are highly required to accelerate the clinical transformation of celastrol in treating different liver illness. It is foreseeable that celastrol-derived therapeutics is evolving in the field of liver ailments.

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Celastrol targets adenylyl cyclase-associated protein 1 to reduce macrophages-mediated inflammation and ameliorates high fat diet-induced metabolic syndrome in mice

Cited by 38 publications

References 45 publications

The Clinical Value of GDF15 and Its Prospective Mechanism in Sepsis

The Clinical Value of GDF15 and Its Prospective Mechanism in Sepsis

Drug repurposing to face Covid-19: Celastrol, a potential leading drug capable of inhibiting SARS-CoV-2 replication and induced inflammation

Celastrol: An Update on Its Hepatoprotective Properties and the Linked Molecular Mechanisms

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