Auranofin Attenuates Non-Alcoholic Fatty Liver Disease by Suppressing Lipid Accumulation and NLRP3 Inflammasome-Mediated Hepatic Inflammation In Vivo and In Vitro

Hwangbo, Hyun; Kim, Min Yeong; Ji, Seon Yeong; Kim, So Young; Lee, Hyesook; Kim, Gi‐Young; Park, Cheol; Keum, Young‐Sam; Hong, Su Hyun; Cheong, JaeHun; Choi, Yung Hyun

doi:10.3390/antiox9111040

Cited by 31 publications

(25 citation statements)

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“…Previous studies have shown that the activation of NLRP3 is the main cause of STSLS [ 29 ]. It has been proved that auranofin can play an anti-inflammatory role by inhibiting NLRP3 [ 31 , 32 ]. Our results show that for some severely infected patients, auranofin alone or in combination with first-line drugs may be a better choice.…”

Section: Discussionmentioning

confidence: 99%

Auranofin Has Advantages over First-Line Drugs in the Treatment of Severe Streptococcus suis Infections

Lü

Zhu

et al. 2020

Antibiotics

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Streptococcal toxic shock-like syndrome (STSLS) likely occurs when an individual is infected with the Streptococcus suis (S. suis) epidemic strain and is characterized by a cytokine storm, multiple organ dysfunction syndrome (MODS) and a high incidence of mortality despite adequate treatment. A number of antibiotics exhibit excellent bactericidal effects in vivo, such as fluoroquinolones, aminoglycosides (gentamicin) and β-lactams (penicillin G, ceftiofur, or amoxicillin), but are less effective for treating STSLS. Therefore, there is an urgent need to identify new compounds that can reduce the damage caused by STSLS. In the present study, we identified auranofin, an orally bioavailable FDA-approved anti-rheumatic drug as a candidate repurposed drug to treat severe S. suis infections. Our results showed that auranofin can bind to the functional domain of bacterial thioredoxin reductase, decreasing the reducing redox-responsive capacity of target bacteria and allowing for the killing of S. suis cells. We also observed that auranofin has antibacterial activity against other gram-positive bacteria, such as multidrug resistant Streptococcus pneumoniae (MDRSP), Streptococcus agalactiae, and vancomycin-resistant strains of Staphylococcus aureus. Additionally, auranofin is capable of eradicating intracellular S.suis present inside infected macrophage cells. Mouse model experimental results showed that auranofin could effectively reduce the mortality of mice infected with S. suis. Compared to the ampicillin treatment group, the survival rate of mice in the auranofin treatment group in severely infected model mice was significantly improved. These results suggest that auranofin has the potential for use as an effective antibiotic against S. suis.

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Section: Discussionmentioning

confidence: 99%

Auranofin Has Advantages over First-Line Drugs in the Treatment of Severe Streptococcus suis Infections

Lü

Zhu

et al. 2020

Antibiotics

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“…In another study, Liou et al (2018) reported that fisetin, a naturally abundant flavonoid isolated from various vegetables and fruits, could alleviate hepatic lipid metabolism and improve NAFLD in mice via the activation of the FAO pathway. Recently, Hwangbo et al (2020) showed that auranofin might have potential as a candidate for improving NAFLD symptoms. Auranofin significantly suppressed lipid peroxidation, inflammatory activity, and hepatic steatosis of liver tissues in NAFLD mice induced by a high-fat diet, which attributed to the decreased expression of NADPH oxidase 4 and PPARγ.…”

Section: Implications Of Carnitine Palmitoyltransferase System In Inflammatory Diseases and Cancersmentioning

confidence: 99%

“…In view of the present research, FA metabolism has been attracting considerable interest in hepatic IR injury ( Hwangbo et al, 2020 ), and the role of FAO in the disease is an important research topic (Wang et al, 2020). Luo et al (2021) reported that CPT1A deficiency mitigated inflammation and oxidative stress in carbon tetrachloride-induced liver injury of mice.…”

Section: Implications Of Carnitine Palmitoyltransferase System In Inflammatory Diseases and Cancersmentioning

confidence: 99%

Carnitine Palmitoyltransferase System: A New Target for Anti-Inflammatory and Anticancer Therapy?

Wang

Liao

et al. 2021

Front. Pharmacol.

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Lipid metabolism involves multiple biological processes. As one of the most important lipid metabolic pathways, fatty acid oxidation (FAO) and its key rate-limiting enzyme, the carnitine palmitoyltransferase (CPT) system, regulate host immune responses and thus are of great clinical significance. The effect of the CPT system on different tissues or organs is complex: the deficiency or over-activation of CPT disrupts the immune homeostasis by causing energy metabolism disorder and inflammatory oxidative damage and therefore contributes to the development of various acute and chronic inflammatory disorders and cancer. Accordingly, agonists or antagonists targeting the CPT system may become novel approaches for the treatment of diseases. In this review, we first briefly describe the structure, distribution, and physiological action of the CPT system. We then summarize the pathophysiological role of the CPT system in chronic obstructive pulmonary disease, bronchial asthma, acute lung injury, chronic granulomatous disease, nonalcoholic fatty liver disease, hepatic ischemia–reperfusion injury, kidney fibrosis, acute kidney injury, cardiovascular disorders, and cancer. We are also concerned with the current knowledge in either preclinical or clinical studies of various CPT activators/inhibitors for the management of diseases. These compounds range from traditional Chinese medicines to novel nanodevices. Although great efforts have been made in studying the different kinds of CPT agonists/antagonists, only a few pharmaceuticals have been applied for clinical uses. Nevertheless, research on CPT activation or inhibition highlights the pharmacological modulation of CPT-dependent FAO, especially on different CPT isoforms, as a promising anti-inflammatory/antitumor therapeutic strategy for numerous disorders.

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“…The arthritis drug auranofin has also been investigated in the treatment of non-alcoholic fatty liver disease ( Hwangbo et al., 2020 ). Through staining of liver tissue in a mouse model of fatty liver disease, it was shown that auranofin treatment reduced the number of circulating macrophages, which would decrease the amount of inflammatory cytokines secreted.…”

Section: The Il-1 Familymentioning

confidence: 99%

“…This was also shown to be due to the reduction of NLRP3 inflammasome following treatment. Auranofin likely interrupts the formation of the NLRP3 inflammasome in fibrotic liver tissue resulting in the activation of IL-1β by caspase-1 ( Hwangbo et al., 2020 ). The upstream target of auranofin encourages a widespread effect and increased the effectiveness of the drug.…”

Section: The Il-1 Familymentioning

confidence: 99%

Effects of cytokine signaling inhibition on inflammation-driven tissue remodeling

Bignold

Johnson

2021

Current Research in Pharmacology and Drug Discovery

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Fibrosis is a common condition that can affect all body tissues, driven by unresolved tissue inflammation and resulting in tissue dysfunction and organ failure that could ultimately lead to death. A myriad of factors are thought to contribute to fibrosis and, although it is relatively common, treatments focusing on reversing fibrosis are few and far between. The process of fibrosis involves a variety of cell types, including epithelial, endothelial, and mesenchymal cells, as well as immune cells, which have been shown to produce pro-fibrotic cytokines. Advances in our understanding of the molecular mechanisms of inflammation-driven tissue fibrosis and scar formation have led to the development of targeted therapeutics aiming to prevent, delay, or even reverse tissue fibrosis. In this review, we describe promising targets and agents in development, with a specific focus on cytokines that have been well-described to play a role in fibrosis: IL-1, TNF-α, IL-6, and TGF-β. An array of small molecule inhibitors, natural compounds, and biologics have been assessed in vivo, in vivo, and in the clinic, demonstrating the capacity to either directly interfere with pro-fibrotic pathways or to block intracellular enzymes that control fibrosis-related signaling pathways. Targeting pro-fibrotic cytokines, potentially via a multi-pronged approach, holds promise for the treatment of inflammation-driven fibrotic diseases in numerous organs. Despite the complexity of the interplay of cytokines in fibrotic tissues, the breadth of the currently ongoing research targeting cytokines suggests that these may hold the key to mitigating tissue fibrosis and reducing organ damage in the future.

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Auranofin Attenuates Non-Alcoholic Fatty Liver Disease by Suppressing Lipid Accumulation and NLRP3 Inflammasome-Mediated Hepatic Inflammation In Vivo and In Vitro

Cited by 31 publications

References 58 publications

Auranofin Has Advantages over First-Line Drugs in the Treatment of Severe Streptococcus suis Infections

Auranofin Has Advantages over First-Line Drugs in the Treatment of Severe Streptococcus suis Infections

Carnitine Palmitoyltransferase System: A New Target for Anti-Inflammatory and Anticancer Therapy?

Effects of cytokine signaling inhibition on inflammation-driven tissue remodeling

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