Berberine Alleviates Doxorubicin-Induced Myocardial Injury and Fibrosis by Eliminating Oxidative Stress and Mitochondrial Damage via Promoting Nrf-2 Pathway Activation

Abstract

Doxorubicin (DOX)-related cardiotoxicity has been recognized as a serious complication of cancer chemotherapy. Effective targeted strategies for myocardial protection in addition to DOX treatment are urgently needed. The purpose of this paper was to determine the therapeutic effect of berberine (Ber) on DOX-triggered cardiomyopathy and explore the underlying mechanism. Our data showed that Ber markedly prevented cardiac diastolic dysfunction and fibrosis, reduced cardiac malondialdehyde (MDA) level and increased antioxidant superoxide dismutase (SOD) activity in DOX-treated rats. Moreover, Ber effectively rescued the DOX-induced production of reactive oxygen species (ROS) and MDA, mitochondrial morphological damage and membrane potential loss in neonatal rat cardiac myocytes and fibroblasts. This effect was mediated by increases in the nuclear accumulation of nuclear erythroid factor 2-related factor 2 (Nrf2) and levels of heme oxygenase-1 (HO-1) and mitochondrial transcription factor A (TFAM). We also found that Ber suppressed the differentiation of cardiac fibroblasts (CFs) into myofibroblasts, as indicated by decreased expression of α-smooth muscle actin (α-SMA), collagen I and collagen III in DOX-treated CFs. Pretreatment with Ber inhibited ROS and MDA production and increased SOD activity and the mitochondrial membrane potential in DOX-challenged CFs. Further investigation indicated that the Nrf2 inhibitor trigonelline reversed the protective effect of Ber on both cardiomyocytes and CFs after DOX stimulation. Taken together, these findings demonstrated that Ber effectively alleviated DOX-induced oxidative stress and mitochondrial damage by activating the Nrf2-mediated pathway, thereby leading to the prevention of myocardial injury and fibrosis. The current study suggests that Ber is a potential therapeutic agent for DOX-induced cardiotoxicity that exerts its effects by activating Nrf2.

Anti‐inflammatory, antioxidant, and immunomodulatory effects of Berberis vulgaris and its constituent berberine, experimental and clinical, a review

“…In mouse embryonic fibroblast cells (NIH‐3 T3) pretreated with LPS (1 μg/mL) for 1 h, treatment with berberine‐modified ZnO nano‐colloids hydrogel ZnO‐Ber (1 mg/mL) for 4 h significantly up‐regulated antioxidant stress factors (Nrf2, HO‐1, NQO1), reduced MDA, and increased SOD (Yin et al, 2022). Pretreatment with berberine (1 μM) for 24 h inhibited ROS and MDA production and increased SOD activity and the mitochondrial membrane potential in doxorubicin‐challenged cardiac fibroblasts by activating the nuclear erythroid factor 2‐related factor 2 (Nrf2)‐mediated pathway (Wang et al, 2023).…”

“…Pretreatment with berberine (1 μM) for 24 h inhibited ROS and MDA production and increased SOD activity and the mitochondrial membrane potential in doxorubicin-challenged cardiac fibroblasts by activating the nuclear erythroid factor 2-related factor 2 (Nrf2)-mediated pathway (Wang et al, 2023).…”

“…Berberine (60 mg/kg; i.g.) markedly prevented cardiac diastolic dysfunction and fibrosis, reduced cardiac MDA level, and increased SOD activity in doxorubicin-treated rats (Yiyang Wang et al, 2023).…”

Mixtures of Doxorubicin-Loaded Micelles and Berberine and Mifepristone Co-Loaded Liposomes Inhibit Breast Cancer Metastasis Based on Regulation of Tumor Microenvironments

“…Many natural product components extracted from medicinal plants have been proven to inhibit CAF activation. Berberine (Ber), an isoquinoline quaternary alkaloid derived from rhizoma coptidis, could exert anti-inflammation, anti-oxidative, and anti-cancer activities. , Recent research showed that Ber could inhibit α-SMA expression of quiescent fibroblasts and CAF-mediated ECM deposition. , Moreover, Ber also was proven to down-regulate the expression level of ZEB1 and Snail as well as block TGF-β/Smad2/3-mediated tumor metastasis. , Hence, Ber might be a potential component to modulate TME by inhibiting CAF-induced tumor development. Furthermore, the hormone receptor modulators (tamoxifen, letrozole, etc.)…”

“…9,10 Recent research showed that Ber could inhibit α-SMA expression of quiescent fibroblasts and CAF-mediated ECM deposition. 11,12 Moreover, Ber also was proven to down-regulate the expression level of ZEB1 and Snail as well as block TGF-β/Smad2/3-mediated tumor metastasis. 13,14 Hence, Ber might be a potential component to modulate TME by inhibiting CAF-induced tumor development.…”