Proanthocyanidin alleviates doxorubicin‐induced cardiac injury by inhibiting NF‐kB pathway and modulating oxidative stress, cell cycle, and fibrogenesis

Abstract

This study investigated the potential mechanism(s) and the signaling pathway(s) underlying the prophylactic effect of proanthocyanidin extract (PE) against doxorubicin (DOX)‐induced cardiotoxicity in rats. A total of 32 male albino rats were randomly allocated into four groups. Control rats were orally administrated normal saline. Rats in the second group were orally administrated PE (50 mg/kg bw/once daily) for 4 weeks. Rats in the third group were intraperitoneally injected with DOX (10 mg/kg on Days 3, 9, 15, and 21 of the experiment). Rats in the fourth group were injected with DOX and PE simultaneously for 4 weeks. DOX significantly augmented the levels of serum heart damage biomarkers. In addition, histopathology indicated that DOX‐induced cardiac tissue injury upregulated the expression of fibrogenic factors, alpha smooth muscle actin (α‐SMA), transforming growth factor β1 (TGF‐ β1), and p16INK4A. Downregulation of cell proliferation markers, cyclin‐dependent kinase‐4 (CDK4), and retinoblastoma (Rb) was also observed. Furthermore, DOX‐induced oxidative and inflammatory stress resulted in increased cardiac malondialdehyde (MDA), protein carbonyl (PC), interleukin‐2 (IL‐2), interleukin‐6 (IL‐6), and tumor necrosis factor‐alpha (TNF‐α). Decreased cardiac glutathione (GSH) levels and enzyme activity of catalase (CAT), superoxide dismutase (SOD), and glutathione S‐transferase (GST) were observed. Treatment of DOX‐induced rat cardiotoxicity with PE normalized serum parameters for the aforementioned parameters and alleviated cardiac tissue structure. Furthermore, reduced cardiac tissue α‐SMA and TGF‐β1, and increased CDK4 and Rb protein expression, along with the amelioration of oxidative and inflammatory effects were observed. PE attenuates DOX‐induced cardiomyocyte inflammation possibly by attenuating the nuclear factor kappa‐B (NF‐ kB) signaling pathway. These results indicate that PE may be useful as a preventative agent against DOX‐induced cardiac toxicity.

Evaluation of biomarkers for doxorubicin‑induced cardiac injury in rats

“…In the report of nishimura's, following repeated administration of isoprenaline in rats (0.5 mg/kg), the relative expression of miR-208a in plasma increases significantly after 2 days and decreases after 4 days ( 29 ). Sadek et al ( 57 ) showed that fibrogenic factors, such as α smooth muscle actin, TGF-β1 and p16 INK4A , are upregulated following DOX-induced cardiac injury. TGF-β1 binds to type II TGF-β receptor, subsequently activating type I TGF-β receptor.…”

Antioxidant, anti-inflammatory, and anti-apoptotic effects of crocin against doxorubicin-induced myocardial toxicity in rats

“…Protection of the heart by strengthening the cardiac antioxidant defense system against DOX-induced cardiac injury caused by ROS formation plays an important role in protection against DOX-induced myocardial damage (Arafa et al 2014, Oner et al 2019. Previous studies reported that DOX application caused impairment in antioxidant defense such as SOD, CAT and GSH (Qi et al 2020, Sadek et al 2021. As antioxidant enzymes, SOD and CAT scavenge superoxide anion and hydrogen peroxide.…”

Kaempferol 3‐O‐gentiobioside, an ALK5 inhibitor, affects the proliferation, migration, and invasion of tumor cells via blockade of the TGF‐β/ALK5/Smad signaling pathway

“…TGF‐β/ALK5/Smad signaling plays opposite roles in cancer progression (Connolly et al, 2011; Gu & Feng, 2018; M. Zhang et al, 2011). Acting as a tumor suppressor, TGF‐β/ALK5/Smad signaling inhibits proliferation and enhances differentiation by activating cyclin‐dependent kinase inhibitors, such as p16INK4a, p21cip1, and p27Kip1, and downregulating transcription factors, such as Myc, Id1, and Id2, in normal epithelial cells and premalignant lesion cells (S. H. Choi, Barker, Gerber, Letterio, & Kim, 2020; Sadek, Mahmoud, Zeweil, & Abouzed, 2021; Visram, Dasari, Anderson, Kumar, & Kourelis, 2021). In contrast, when malignant tumor reaches an advanced stage, TGF‐β/ALK5/Smad promotes tumor progression prominently by inducing EMT, reinforcing tumor–stroma interaction, and leading to escaping immune system surveillance.…”