TFEB-NF-κB inflammatory signaling axis: a novel therapeutic pathway of Dihydrotanshinone I in doxorubicin-induced cardiotoxicity

Abstract

Background: Doxorubicin is effective in a variety of solid and hematological malignancies. Unfortunately, clinical application of doxorubicin is limited due to a cumulative dose-dependent cardiotoxicity. Dihydrotanshinone I (DHT) is a natural product from Salvia miltiorrhiza Bunge with multiple anti-tumor activity and anti-inflammation effects. However, its anti-doxorubicin-induced cardiotoxicity (DIC) effect, either in vivo or in vitro, has not been elucidated yet. This study aims to explore the anti-inflammation effects of DHT against DIC, and to elucidate the potential regulatory mechanism. Methods: Effects of DHT on DIC were assessed in zebrafish, C57BL/6 mice and H9C2 cardiomyocytes. Echocardiography, histological examination, flow cytometry, immunochemistry and immunofluorescence were utilized to evaluate cardio-protective effects and anti-inflammation effects. mTOR agonist and lentivirus vector carrying GFP-TFEB were applied to explore the regulatory signaling pathway. Results: DHT improved cardiac function via inhibiting the activation of M1 macrophages and the excessive release of pro-inflammatory cytokines both in vivo and in vitro. The activation and nuclear localization of NF-κB were suppressed by DHT, and the effect was abolished by mTOR agonist with concomitant reduced expression of nuclear TFEB. Furthermore, reduced expression of nuclear TFEB is accompanied by up-regulated phosphorylation of IKKα/β and NF-κB, while TFEB overexpression reversed these changes. Intriguingly, DHT could upregulate nuclear expression of TFEB and reduce expressions of p-IKKα/β and p-NF-κB. Conclusions: Our results demonstrated that DHT can be applied as a novel cardioprotective compound in the antiinflammation management of DIC via mTOR-TFEB-NF-κB signaling pathway. The current study implicates TFEB-IKK-NF-κB signaling axis as a previously undescribed, druggable pathway for DIC.

TFEB insufficiency promotes cardiac hypertrophy by blocking autophagic degradation of GATA4

“…For example, in Cry ABR 120G-induced cardiac proteinopathy, TFEB overexpression can upregulate HSPB8 to restore normal desmin location ( 39 ). While in doxorubicin-induced cardiotoxicity, TFEB offered protection for dihydrotanshinone I against doxorubicin-induced cardiotoxicity by downregulating phosphorylation of inhibitor of κb kinase α/β and NF-κB ( 53 ). TFEB overexpression has also been shown to attenuate autophagosome buildup and mitochondrial fission in monoamine oxidase-A–induced HF ( 54 ).…”

Date Palm Pollen Extract Avert Doxorubicin-Induced Cardiomyopathy Fibrosis and Associated Oxidative/Nitrosative Stress, Inflammatory Cascade, and Apoptosis-Targeting Bax/Bcl-2 and Caspase-3 Signaling Pathways

“…Mitochondrial damage can also initiate intracellular Ca 2+ imbalance [ 22 ], which further affects the apoptosis paths and causes myocardial cell death [ 23 ]. DOX also interferes with iron regulation [ 24 ], up-regulates NF-κB expression, which consequently causes the release of pro-inflammatory cytokines, i.e., tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6), and triggers vascular and cardiac inflammatory reaction [ 25 ] and exaggerates their downstream apoptotic pathways [ 26 ]. In addition, oxidative stress activates several pro-fibrogenic factors, which enhances the accumulation of extracellular matrix and development of cardiac fibrosis [ 27 ], remodeling [ 28 ], and eventual cardiac dysfunction [ 29 ].…”

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

“…Dihydrotanshinone I (DHT) is a natural compound extracted from Danshen. According to the reports, DHT has antitumor ( Allegri et al, 2021 ), anti-inflammatory ( Wang et al, 2020 ), and immunomodulatory effects ( Wang et al, 2020 ). Evidence has emerged that DHT attenuates crystalline silica–induced lung inflammation by regulating the immune response and inhibiting STAT1/STAT3 ( Wang et al, 2020 ).…”

“…According to the reports, DHT has antitumor ( Allegri et al, 2021 ), anti-inflammatory ( Wang et al, 2020 ), and immunomodulatory effects ( Wang et al, 2020 ). Evidence has emerged that DHT attenuates crystalline silica–induced lung inflammation by regulating the immune response and inhibiting STAT1/STAT3 ( Wang et al, 2020 ). It has been reported that DHT could inhibit the activation of NF-κB induced by TNF-α ( Weng et al, 2021 ).…”