Metformin ameliorates doxorubicin-induced cardiotoxicity targeting HMGB1/TLR4/NLRP3 signaling pathway in mice

Alzokaky, Amany A.; Al‐Karmalawy, Ahmed A.; Saleh, Mohamed A.; Abdo, Walied; Farage, Amira E.; Belal, Amany; Abourehab, Mohammed A.S.; Antar, Samar A.

doi:10.1016/j.lfs.2023.121390

Cited by 15 publications

(16 citation statements)

References 21 publications

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“…In recent years, there has been growing interest in understanding the involvement of NLRP3 in ammasome and Myd-88 myddosome activation in various pathological conditions, including cardiotoxicity induced by DOXO [46,47]. In line with literature, DOXO therapy increased myocardial levels of NLRP3 and MyD-88 compared to Saline (Fig.…”

Section: Dapa Attenuates Myocardial Nlrp3 and Myd-88 Expression In Do...mentioning

confidence: 52%

Sodium-glucose cotransporter 2 inhibitor Dapagliflozin prevents ejection fraction reduction, reduces myocardial and renal NF-κB expression and systemic pro-inflammatory biomarkers in models of short-term doxorubicin cardiotoxicity

Quagliariello

Canale

Bisceglia

et al. 2023

Preprint

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Background Anthracycline-mediated adverse cardiovascular events are among the leading causes of morbidity and mortality in cancer patients. Cardioprotective strategies in primary and secondary prevention are still needed in clinical practice to improve cancer patient survival and to avoid drug therapy discontinuation. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) exerts multiple cardiometabolic benefits in patients with/without type 2 diabetes, chronic kidney disease and heart failure with reduced and preserved ejection fraction. We hypothesized that Dapagliflozin, an SGLT2i. administered before and during doxorubicin therapy, could improve cardiac function and reduce pro-inflammatory pathways in preclinical models.Methods Female C57Bl/6 mice were treated with a saline solution (Saline, n = 6) or treated for 10 days with doxorubicin i.p at 2.17 mg/kg (DOXO, n = 6), DAPA at 10 mg/kg (DAPA, n = 6) or doxorubicin combined to DAPA (DOXO-DAPA, n = 6). Ejection fraction, radial and longitudinal strain were analysed through transthoracic echocardiography (Vevo 2100). Cardiac troponin, BNP and NT-pro-BNP were quantified. Myocardial expression of NLRP-3 inflammasome and MyD-88 were quantified through selective ELISA methods. Systemic levels of ferroptosis-related biomarkers (MDA and 4-HNA), Galectin-3, hs-CRP and pro-inflammatory chemokines/growth factors (IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12, IL17-α, IL-18, IFN-γ, TNF-α, G-CSF, and GM-CSF) were quantified through selective ELISA methods. After treatments, immunohistochemical (IHC) staining of myocardial and renal p65/NF-kB was performed.Results DAPA prevented the reduction of radial and longitudinal strain and ejection fraction after 10 days of treatment with doxorubicin. A reduced myocardial expression of NLRP-3 and MyD-88 was seen in DOXO-DAPA group compared to DOXO mice (p < 0.001). Systemic levels of IL-1β, IL-6, TNF-α, G-CSF and GM-CSF were significantly reduced after treatment with DAPA, indicating anti-inflammatory properties. Serum levels of galectine-3 and hs-CRP were strongly enhanced in DOXO group; contrary, their expression were reduced in DAPA-DOXO group (p < 0.005). Biomarkers of cardiotoxicity, troponin-T, BNP and NT-pro-BNP were strongly reduced in DOXO-DAPA group, revealing cardioprotective properties of SGLT2-i. The myocardial and renal p65/NF-kB expression of Saline and DOXO mice were distinctly different, and DAPA treatment was associated with larger reductions in tissue p65/NF-kB than DOXO.Conclusion DAPA is able to improve cardiac function and reduce systemic biomarkers involved in heart failure and inflammation. IHC analysis clearly indicates anti-inflammatory properties of DAPA in cardiac and renal tissues during DOXO therapy. The overall picture of the study encourages the use of DAPA in primary prevention of cardiomyopathies induced by anthracyclines in cancer patients.

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Section: Dapa Attenuates Myocardial Nlrp3 and Myd-88 Expression In Do...mentioning

confidence: 52%

Sodium-glucose cotransporter 2 inhibitor Dapagliflozin prevents ejection fraction reduction, reduces myocardial and renal NF-κB expression and systemic pro-inflammatory biomarkers in models of short-term doxorubicin cardiotoxicity

Quagliariello

Canale

Bisceglia

et al. 2023

Preprint

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“…K. Jha et al, 2021), and TGFβ (Seki et al, 2007). In addition, HMGB1, a direct target of metformin, is an endogenous ligand of TLR4 (Alzokaky et al, 2023;Horiuchi et al, 2017). These results are suggesting the relationship between metformin and TLR4 signaling pathway via downstream factors.…”

Section: Toll-like Receptormentioning

confidence: 91%

“…It was shown that metformin inhibited the activity of caspase-3 and -8 in LPS-induced inflammation model (Yuan et al, 2012) and the expression of caspase-3 in lymphocytes (Mxinwa et al, 2022). In addition, a computer prediction suggested that metformin directly binds caspase-3 (Alzokaky et al, 2023). Metformin's apoptosis regulation may have both pathways, caspase-dependent and -independent (J. H. Jang et al, 2020;Rosidi et al, 2023;Zheng et al, 2020).…”

Section: Caspasesmentioning

confidence: 99%

“…Several studies revealed that metformin targets NF‐κB pathway to inhibit inflammation (Chiang et al, 2017; Isoda et al, 2006). In addition, a recent study suggested that metformin directory binds NF‐κB (Alzokaky et al, 2023). As mentioned above, metformin regulates various inflammatory factors including NF‐κB regulated factors.…”

Section: Target Moleculesmentioning

confidence: 99%

“…Also, the extracellular HMGB1 is a ligand of TLR4 (mentioned in the following section). It has been revealed that metformin inhibits inflammation via HMGB1 in three ways: inhibition of expression (Huang et al, 2018), reduction of release from macrophage cells (Tsoyi et al, 2011), and direct binding to extracellular HMGB1 (Alzokaky et al, 2023; Horiuchi et al, 2017). HMGB1 is a sole extracellular factor that the direct binding is validated by biochemical analysis (Horiuchi et al, 2017).…”

Section: Target Moleculesmentioning

confidence: 99%

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The anti‐inflammatory effect of metformin: The molecular targets

Sakata

2024

Genes to Cells

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Metformin is an anti‐diabetic drug. Metformin mainly inhibits gluconeogenesis in the liver and reduces blood sugar. In addition to the anti‐diabetic effects, many studies have revealed that metformin has anti‐inflammatory effects. Various molecules were suggested to be the target of the metformin's anti‐inflammatory effects. However, the conclusion is not clear. Metformin is related to a number of molecules and the identification of the main target in anti‐inflammatory effects leads to the understanding of inflammation and metformin. In this article, I discuss each suggested molecule, involved mechanisms, and their relationship with various diseases.

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Protective effects of esculetin against doxorubicin‐induced toxicity correlated with oxidative stress in rat liver: In vivo and in silico studies

Köroğlu,

Kizir,

Karaman

et al. 2024

J Biochem & Molecular Tox

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Doxorubicin (DOX) is widely used in cancer treatment but the dose‐related toxicity of DOX on organs including the liver limit its use. Therefore, there is great interest in combining DOX with natural compounds with antioxidant properties to reduce toxicity and increase drug efficacy. Esculetin is a natural coumarin derivative with biological properties encompassing anti‐inflammatory and antioxidant activities. In light of these properties, this study was meticulously crafted to investigate the potential of esculetin in preventing doxorubicin (DOX)‐induced hepatotoxicity in Sprague‐Dawley rats. The rats were divided into a total of six groups: control group, DOX group (administered DOX at a cumulative dose of 5 mg/kg intraperitoneally every other day for 2 weeks), E50 group (administered 50 mg/kg of esculetin intraperitoneally every day), E100 group (administered 100 mg/kg of esculetin intraperitoneally every day) and combined groups (DOX + E50 and DOX + E100) in which esculetin was administered together with DOX. The treatments, both with DOX alone and in combination with E50, manifested a reduction in catalase (CAT mRNA) levels in comparison to the control group. Notably, the enzymatic activities of superoxide dismutase (SOD), CAT, and glutathione peroxidase (GPx) witnessed significant decreases in the liver of rats treated with DOX. Moreover, DOX treatment induced a statistically significant elevation in malondialdehyde (MDA) levels, coupled with a concurrent decrease in glutathione (GSH) levels. Additionally, molecular docking studies were conducted. However, further studies are needed to confirm the hepatoprotective properties of esculetin and to precisely elucidate its mechanisms of action.

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Metformin ameliorates doxorubicin-induced cardiotoxicity targeting HMGB1/TLR4/NLRP3 signaling pathway in mice

Cited by 15 publications

References 21 publications

Sodium-glucose cotransporter 2 inhibitor Dapagliflozin prevents ejection fraction reduction, reduces myocardial and renal NF-κB expression and systemic pro-inflammatory biomarkers in models of short-term doxorubicin cardiotoxicity

Sodium-glucose cotransporter 2 inhibitor Dapagliflozin prevents ejection fraction reduction, reduces myocardial and renal NF-κB expression and systemic pro-inflammatory biomarkers in models of short-term doxorubicin cardiotoxicity

The anti‐inflammatory effect of metformin: The molecular targets

Protective effects of esculetin against doxorubicin‐induced toxicity correlated with oxidative stress in rat liver: In vivo and in silico studies

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