Combination ofSophora flavescensalkaloids and Panax quinquefolium saponins modulates different stages of experimental autoimmune myocarditis via the NF‑κB and TGF‑β1 pathways

Abstract

Chronic cardiac inflammation and fibrosis can progress into severe forms of cardiomyopathy. Sophora flavescens alkaloids (KuShen) have been previously reported to exert anti-inflammatory effects, whereas Panax quinquefolium saponins (XiYangShen) has been shown to alleviate cardiac fibrosis. Therefore, the potential effects of their combination (KX) on different stages of autoimmune myocarditis were investigated in the present study. Mice were randomly divided into the following four groups: Control; experimental autoimmune myocarditis (EAM); KX-High (275 mg/kg); and KX-Low (138 mg/kg). A 21-day and a 60-day EAM model was established through multi-site subcutaneous injections of cardiac myosin mixed with complete Freund's adjuvant on days 0, 7, 21 and 42. Mice in the High and Low KX groups were treated by gavage (10 ml/kg) daily from day 0 (1 day before treatment) until sacrifice (day 21 or 60). Mice in the control and EAM groups received an equivalent volume of distilled water. The levels of lactate dehydrogenase (LDH), creatine kinase-myocardial band (CK-MB), cardiac troponin I (cTn-I), IL-1β, IL-6, TNF-α, TGF-β1, collagen type I (Col Ⅰ) and collagen type III (Col Ⅲ) were measured by ELISA in the mouse myocardial tissues or serum. Myocardial tissue structure and extent of fibrosis were visualized using H&E and Masson's staining. Western blotting and immunohistochemistry were used to measure the expression levels NF-κB and TGF-β1 pathway proteins in the myocardial tissues. The degree of inflammation in the 21-day EAM model was found to be significantly higher compared with that in the 60-day EAM model. KX significantly reduced the inflammatory response at 21 days by decreasing the expression levels of CK-MB, LDH, cTn-I, IL-1β, IL-6, TNF-α and TGF-β-activated kinase 1-binding protein 1/NF-κB pathway proteins. Myocardial fibrosis in the 60-day EAM model was also significantly worse compared with that in the 21-day EAM model. However, fibrosis was significantly delayed by treatment with KX. In addition, KX significantly decreased the expression levels of TGF-β1, Smad2, Smad4, Col I and Col III. Therefore, these data suggest that KX is beneficial for treating myocarditis by targeting multiple pathways.

A combination of Sophora flavescens alkaloids and Panax quinquefolium saponins attenuates coxsackievirus B3‑induced acute myocarditis in mice via NF‑κB signaling

“…VMC is characterized by an acute onset, and complex and no specificity symptoms such as asthenia and shortness of breath ( 17 ). According to the TCM theory of treatment, the combination of Sophora flavescens alkaloids and Panax quinquefolium saponins shows good curative effects in the treatment of VMC, which displays the characteristic of TCM, including synergistic effects and advantages of drug combinations ( 14 ). KX has recently been shown to be effective in alleviating chronic inflammation and the degree of myocardial fibrosis in myocarditis ( 14 , 18 ).…”

“…According to the TCM theory of treatment, the combination of Sophora flavescens alkaloids and Panax quinquefolium saponins shows good curative effects in the treatment of VMC, which displays the characteristic of TCM, including synergistic effects and advantages of drug combinations ( 14 ). KX has recently been shown to be effective in alleviating chronic inflammation and the degree of myocardial fibrosis in myocarditis ( 14 , 18 ). To clarify whether the impact of KX treatment on VMC extends throughout the entire pathological development process, the present study established a CVB3-induced acute VMC model and explored the effect of KX on acute inflammation in VMC.…”

“…These drugs were obtained from the new drug center of the Jilin Academy of TCM. The optimal total matrine to total saponin ratio from American ginseng was 1.1:1, as determined using an experimental model of autoimmune myocarditis and the optimal concentrations corresponding to high and low doses of KX were 275 and 138 mg/kg, respectively ( 14 ).…”

“…The main pharmacodynamic agents in Sophora flavescens are Sophora flavescens alkaloids, while the main pharmacodynamic agents in Panax quinquefolium are Panax quinquefolium saponins, which were combined in the present study to investigate the characteristics of this Chinese herbal medicine. KX, the drug obtained by combining Sophora flavescens alkaloids and Panax quinquefolium saponins, was previously shown to ameliorate cardiac inflammation and myocarditis-induced fibrosis in mice with autoimmune myocarditis ( 14 ). However, its role in the acute inflammatory phase of VMC remains unclear.…”

Determination of Antioxidant, Cytotoxicity, and Acetylcholinesterase Inhibitory Activities of Alkaloids Isolated from Sophora flavescens Ait. Grown in Dak Nong, Vietnam

“…Ethnologically, the local people use SF root, which has a strong, bitter taste, and cold properties, in folk remedies such as Ninh Tam Vuong, which helps in tachycardia and in the treatment of gynecological infections. Clinically, SF has been scientifically proven to possess numerous therapeutic effects [5], including cytotoxicity [6], anti-inflammation [7], anti-asthma [8], anti-anaphylaxis [9], anti-microbial [10], anti-viral [11], anti-arrhythmic [12], and anti-myocardial fibrosis [13]. Commercially, SF roots have been employed in various functional products, such as Kushen food supplement of Nature's Health, Palm Springs, CA, USA.…”