Dihydrotanshinone I Specifically Inhibits NLRP3 Inflammasome Activation and Protects Against Septic Shock In Vivo

Wei, Ziying; Zhan, Xiaoyan; Ding, Kaixin; Xu, Guang; Shi, Wei; Ren, Lutong; Fang, Zhie; Liu, Tingting; Hou, Xiaorong; Zhao, Jia; Li, Jiayi; Li, Zhiyong; Li, Qiang; Lin, Li; Yang, Yan; Xiao, Xiaohe; Bai, Zhaofang; Cao, Junling

doi:10.3389/fphar.2021.750815

Cited by 13 publications

(4 citation statements)

References 68 publications

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“…Previous studies revealed that tanshinones, the main component of Salvia miltiorrhiza , have been reported to have anti-inflammatory effects and may be the key component for its anti-inflammatory effects (Jiang et al 2019 ; Liu et al 2022 ; Wang et al 2020a ). In addition, Tanshinone IIA and Dihydrotanshinone I have been reported to inhibit the activation of NLRP3 inflammasome and protect against NLRP3-related diseases (Gao et al 2019 ; Li et al 2022c ; Wei et al 2021 ; Xu et al 2022 ). A recent study found that 15 tanshinones (isolated from Salvia miltiorrhiza ) including Tan I inhibited IL-1β secretion, but did not further demonstrate the specificity of the effect of Tan I on NLRP3 inflammasome activation or the mechanism of action.…”

Section: Discussionmentioning

confidence: 99%

Tanshinone I specifically suppresses NLRP3 inflammasome activation by disrupting the association of NLRP3 and ASC

Zhao

Hong

Luo

et al. 2023

Mol Med

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Background Abnormal activation of NLRP3 inflammasome is related to a series of inflammatory diseases, including type 2 diabetes, gouty arthritis, non-alcoholic steatohepatitis (NASH), and neurodegenerative disorders. Therefore, targeting NLRP3 inflammasome is regarded as a potential therapeutic strategy for many inflammatory diseases. A growing number of studies have identified tanshinone I (Tan I) as a potential anti-inflammatory agent because of its good anti-inflammatory activity. However, its specific anti-inflammatory mechanism and direct target are unclear and need further study. Methods IL-1β and caspase-1 were detected by immunoblotting and ELISA, and mtROS levels were measured by flow cytometry. Immunoprecipitation was used to explore the interaction between NLRP3, NEK7 and ASC. In a mouse model of LPS-induced septic shock, IL-1β levels in peritoneal lavage fluid and serum were measured by ELISA. Liver inflammation and fibrosis in the NASH model were analyzed by HE staining and immunohistochemistry. Results Tan I inhibited the activation of NLRP3 inflammasome in macrophages, but had no effect on the activation of AIM2 or NLRC4 inflammasome. Mechanistically, Tan I inhibited NLRP3 inflammasome assembly and activation by targeting NLRP3-ASC interaction. Furthermore, Tan I exhibited protective effects in mouse models of NLRP3 inflammasome-mediated diseases, including septic shock and NASH. Conclusions Tan I specifically suppresses NLRP3 inflammasome activation by disrupting the association of NLRP3 and ASC, and exhibits protective effects in mouse models of LPS-induced septic shock and NASH. These findings suggest that Tan I is a specific NLRP3 inhibitor and may be a promising candidate for treating NLRP3 inflammasome-related diseases. Graphical Abstract

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Section: Discussionmentioning

confidence: 99%

Tanshinone I specifically suppresses NLRP3 inflammasome activation by disrupting the association of NLRP3 and ASC

Zhao

Hong

Luo

et al. 2023

Mol Med

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“…Protein extraction and detection were carried out in accordance with the conventional protocol described previously (Z. Wei et al, 2021). The protein extract was lysed with 1× loading buffer.…”

Section: Methodsmentioning

confidence: 99%

Polysaccharide extract from Isatidis Radix inhibits multiple inflammasomes activation and alleviate gouty arthritis

Ren

Zhan

et al. 2022

Phytotherapy Research

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The polysaccharide extract from Isatidis Radix exhibits potent antiinflammatory and antiviral activities, but the mechanism of Isatidis Radix polysaccharide (IRP) remains obscure. Herein, we reported that IRP blocked the activation of nod‐like receptor pyrin domain‐containing 3 (NLRP3) inflammasome, leading to the inhibiting of caspase‐1 cleavage and IL‐1β secretion. Mechanistically, IRP did not inhibit NLRP3 inflammasome through suppressing mitochondrial reactive oxygen species (mtROS) production. However, IRP can significantly suppress the oligomerization of apoptosis‐associated speck‐like protein (ASC) and subsequently block the formation of inflammasome. Next, we evaluate the role of IRP in monosodium urate (MSU)‐induced gout in vivo which is a NLRP3‐associated disease. We also observed that oral administration of IRP can reduce the increased ankle thickness and the secretion of IL‐1β, IL‐18, IL‐6, TNF‐α and MPO of the mouse ankle joints caused by MSU crystals. Furthermore, flow cytometry analysis highlighted a significant modulation of T helper 17 cells (Th17)/regulatory T cells (Treg) following IRP treatment in MSU induced gout. Overall, our findings suggest that IRP has comprehensive and potent antiinflammatory effects and provide a reasonable therapeutic strategy in preventing inflammasome‐associated diseases, such as inflammatory gouty arthritis.

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“…In addition to its ability to reverse multidrug resistance and promote vasorelaxation of coronary arteries in rats, DHT has shown promise as a tumor suppressor by inducing cytotoxicity and reducing angiogenesis. Furthermore, DHT has demonstrated anti-inflammatory properties both in vitro and in vivo 26 – 31 . Potential anti-inflammatory properties of DHT have been reported for acute kidney injury 27 , adipose tissue inflammation 30 and NLRP3 inflammasome 31 .…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, DHT has demonstrated anti-inflammatory properties both in vitro and in vivo 26 – 31 . Potential anti-inflammatory properties of DHT have been reported for acute kidney injury 27 , adipose tissue inflammation 30 and NLRP3 inflammasome 31 . Yuan et al 27 demonstrated that DHT exerted anti-inflammatory effects by inhibiting the secretions of inflammatory cytokines and the activation of the NF-κB pathway in vitro and by alleviating LPS-induced acute kidney injury in vitro.…”

Section: Introductionmentioning

confidence: 99%

Dihydrotanshinone I protects human chondrocytes and alleviates damage from spontaneous osteoarthritis in a guinea pig model

Zhang,

Wei,

et al. 2023

Sci Rep

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Osteoarthritis (OA) is the most common degenerative joint disease. Currently, no satisfactory pharmacological treatment exists for OA. The potential anti-inflammatory properties of Dihydrotanshinone I (DHT) have been reported, but its effects on OA are unclear. In this study, we assess the impact of DHT on the viability of human chondrocytes in vitro. We then use a guinea pig model to investigate the effects of DHT on knee osteoarthritis progression. Twelve-week-old Dunkin Hartley guinea pigs spontaneously developing OA were intraperitoneally injected with different doses of DHT for eight weeks. Micro-CT analysis was performed on the subchondral bone in the knee, and histological assessment of the knee joint was done using stained sections, the ratio of hyaline to calcified cartilage, and Mankin scores. DHT successfully restored IL-1β-induced decreases in cell viability in human primary chondrocytes. In the guinea pig model, intraperitoneal injections of DHT ameliorated age-induced OA, effectively reduced the expression level of two cartilage metabolism-related genes (ADAMTS4 and MMP13) and decreased the inflammatory biomarker IL-6 in the serum of guinea pigs developing spontaneous osteoarthritis. These findings demonstrate DHT’s protective effects on chondrocytes and suggest that it alleviates cartilage degradation and proteoglycan loss in OA.

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Dihydrotanshinone I Specifically Inhibits NLRP3 Inflammasome Activation and Protects Against Septic Shock In Vivo

Cited by 13 publications

References 68 publications

Tanshinone I specifically suppresses NLRP3 inflammasome activation by disrupting the association of NLRP3 and ASC

Tanshinone I specifically suppresses NLRP3 inflammasome activation by disrupting the association of NLRP3 and ASC

Polysaccharide extract from Isatidis Radix inhibits multiple inflammasomes activation and alleviate gouty arthritis

Dihydrotanshinone I protects human chondrocytes and alleviates damage from spontaneous osteoarthritis in a guinea pig model

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