8-Gingerol Ameliorates Myocardial Fibrosis by Attenuating Reactive Oxygen Species, Apoptosis, and Autophagy via the PI3K/Akt/mTOR Signaling Pathway

Abstract

8-gingerol (8-Gin) is the series of phenolic substance that is extracted from ginger. Although many studies have revealed that 8-Gin has multiple pharmacological properties, the possible underlying mechanisms of 8-Gin against myocardial fibrosis (MF) remains unclear. The study examined the exact role and potential mechanisms of 8-Gin against isoproterenol (ISO)-induced MF. Male mice were intraperitoneally injected with 8-Gin (10 and 20 mg/kg/d) and concurrently subcutaneously injected with ISO (10 mg/kg/d) for 2 weeks. Electrocardiography, pathological heart morphology, myocardial enzymes, reactive oxygen species (ROS) generation, degree of apoptosis, and autophagy pathway-related proteins were measured. Our study observed 8-Gin significantly reduced J-point elevation and heart rate. Besides, 8-Gin caused a marked decrease in cardiac weight index and left ventricle weight index, serum levels of creatine kinase and lactate dehydrogenase (CK and LDH, respectively), ROS generation, and attenuated ISO-induced pathological heart damage. Moreover, treatment with 8-Gin resulted in a marked decrease in the levels of collagen types I and III and TGF-β in the heart tissue. Our results showed 8-Gin exposure significantly suppressed ISO-induced autophagosome formation. 8-Gin also could lead to down-regulation of the activities of matrix metalloproteinases-9 (MMP-9), Caspase-9, and Bax protein, up-regulation of the activity of Bcl-2 protein, and alleviation of cardiomyocyte apoptosis. Furthermore, 8-Gin produced an obvious increase in the expressions of the PI3K/Akt/mTOR signaling pathway-related proteins. Our data showed that 8-Gin exerted cardioprotective effects on ISO-induced MF, which possibly occurred in connection with inhibition of ROS generation, apoptosis, and autophagy via modulation of the PI3K/Akt/mTOR signaling pathway.

Elucidating the Beneficial Effects of Ginger (Zingiber officinale Roscoe) in Parkinson’s Disease

“…72 8-Gingerol has also been shown to inhibit myocardial fibrosis by decreasing oxidative stress, autophagy, and apoptosis by regulating the PI3K/Akt/mammalian target of rapamycin (mTOR) signaling pathway. 73 Since PI3/Akt/mTOR axis is critically implicated in PD, 74 this pathway may also underlie the effects of ginger in apoptosis in PD.…”

“…Furthermore, 6-gingerol has been shown to protect against cerebral ischemia/reperfusion injury via the inhibition of apoptosis and through transient receptor potential cation channel subfamily V member 1 (TRPV1)/Fas Associated Factor 1 (FAF1) complex dissociation . 8-Gingerol has also been shown to inhibit myocardial fibrosis by decreasing oxidative stress, autophagy, and apoptosis by regulating the PI3K/Akt/mammalian target of rapamycin (mTOR) signaling pathway . Since PI3/Akt/mTOR axis is critically implicated in PD, this pathway may also underlie the effects of ginger in apoptosis in PD.…”

Ginger- A Potential Source of Therapeutic and Pharmaceutical Compounds

“…It is an antineoplastic agent. It is rich in antioxidants, cardiotonics, and cardioprotective agents, including [8]-gingerol (Xue, et al, 2021b). Inhibition of leukotriene A (4) hydrolase expression and induction of G2/M arrest have been shown to be biochemical mechanisms by which 6-gingerol plays an anti-colorectal cancer role (Kumara et al, 2017).…”

“…Another study investigated the possible mechanisms by which 8-Gin (10 and 20 mg/kg/d) reduced J-point elevation and heart rate in mice induced with isoproterenol (ISO-10mg/kg/d) for 2 weeks. It was found that 8-Gin exerted cardioprotective effects on ISO-induced MF, which is likely associated with its inhibition of ROS generation, apoptosis, and autophagy by modulating the PI3K/Akt/mTOR signaling pathway (Xue et al, 2021b).…”

Research progress on drugs targeting the TGF-β signaling pathway in fibrotic diseases

“…On the other hand, TGF-β can also regulate the activity of RhoA, promoting the activation of Rho-related kinase (ROCK) and inhibiting cofilin (CFL) [24]. Rac and Cdc42 are also involved in the non-Smad signaling pathway mediated by TGF-β signaling [25][26][27][28][29]. Most notably, TGF-β1 is the strongest profibrotic cytokine discovered to date [30][31][32][33][34]; many studies have shown that blocking the TGF-β1 pathway can improve organ fibrosis [32,35].…”