Aconitine (AC) is well‐known as the main toxic ingredient and active compound of Aconitum species, of which several aconites are essential herbal medicines of Traditional Chinese Medicine (TCM) and widely applied to treat diverse diseases for their excellent anti‐inflammatory, analgesic, and cardiotonic effects. However, the cardiotoxicity and neurotoxicity of AC attracted a lot of attention and made it a favorite botanic poison in history. Nowadays, the narrow therapeutic window of AC limits the clinical application of AC‐containing herbal medicines; overdosing on AC always induces ventricular tachyarrhythmia and heart arrest, both of which are potentially lethal. But the underlying cardiotoxic mechanisms remained chaos. Recently, beyond its cardiotoxic effects, emerging evidence shows that low doses of AC or its metabolites could generate cardioprotective effects and are necessary to aconite's clinical efficacy. Consistent with TCM's theory that even toxic substances are powerful medicines, AC thus could not be simply identified as a toxicant or a drug. To prevent cardiotoxicity while digging the unique value of AC in cardiac pharmacology, there exists a huge urge to better know the characteristic of AC being a cardiotoxic agent or a potential heart drug. Here, this article reviews the advances of AC metabolism and focuses on the latest mechanistic findings of cardiac efficacy and toxicity of this aconite alkaloid or its metabolites. We also discuss how to prevent AC‐related cardiotoxicity, as well as the issues before the development of AC‐based medicines that should be solved, to provide new insight into the paradoxical nature of this ancient poison.

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Phytoestrogens were widely used as natural alternatives to estrogen for treating cardiovascular diseases. They have been reported to have cardioprotective and anti-inflammatory response, but the mechanisms remain unclear. In this study, we found cryptotanshinone and wogonin exhibited phytoestrogenic property in an estrogen-responsive reporter assay. In EA.hy926 cells, treatment of cryptotanshinone and wogonin led to significant increase in NO production levels, which were inhibited by co-incubation of estrogen receptor (ER)α antagonist methyl-piperidino-pyrazole (MPP). The expression of endothelial NO synthase (eNOS) and ERα were up-regulated with the same treatment, indicating they stimulate NO and eNOS expression via ERα-dependent pathway in endothelial cells. While in lipopolysaccharide activated vascular smooth muscle cell line A7r5, cryptotanshinone and wogonin exerted anti-inflammatory effects by inhibiting NO and inducible NO synthase expression via ERβ-dependent pathway. The reduction of NO synthesis was not affected by MPP, and was abrogated by ERβ antagonist R,R-tetrahydrochrysene. Our findings provide the potential molecular mechanism of cryptotanshinone and wogonin as phytoestrogens for their cardioprotective effects, which exerted regulatory effects on NO synthesis through differential regulation of estrogen receptors. It can be employed as a basis for evaluating the beneficial effects of phytoestrogens in the treatment of patients at risk of cardiovascular disease.

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Cassiae Semen is a widely used herbal medicine and a popular edible variety in many dietary or health beverage. Emerging evidence disclosed that improper administration of Cassiae Semen could induce obvious liver injury, which is possibly attributed to emodin, one of the bioactive anthraquinone compounds in Cassiae Semen, which caused hepatotoxicity, but the underlying mechanisms are not completely understood. Hence, the present study firstly explored the possible role of oxidative stress-mediated mitochondrial dysfunction and ER stress in emodin-cause apoptosis of L02 cells, aiming to elaborate possible toxic mechanisms involved in emodin-induced hepatotoxicity. Our results showed that emodin-induced ROS activated ER stress and the UPR via the BiP/IRE1α/CHOP signaling pathway, followed by ER Ca2+ release and cytoplasmic Ca2+ overloading. At the same time, emodin-caused redox imbalance increased mtROS while decreased MMP and mitochondrial function, resulting in the leaks of mitochondrial-related proapoptotic factors. Interestingly, blocking Ca2+ release from ER by 2-APB could inhibit emodin-induced apoptosis of L02, but the restored mitochondrial function did not reduce the apoptosis rates of emodin-treated cells. Besides, tunicamycin (TM) and doxorubicin (DOX) were used to activate ER stress and mitochondrial injury at a dosage where obvious apoptosis was not observed, respectively. We found that cotreatment with TM and DOX significantly induced apoptosis of L02 cells. Thus, all the results indicated that emodin-induced excessive ROS generation and redox imbalance promoted apoptosis, which was mainly associated with BiP/IRE1α/CHOP signaling-mediated ER stress and would be enhanced by oxidative stress-mediated mitochondrial dysfunction. Altogether, this finding has implicated that redox imbalance-mediated ER stress could be an alternative target for the treatment of Cassiae Semen or other medicine-food homologous varieties containing emodin-induced liver injury.

Aconitine is attracting increasing attention for its unique positive inotropic effect on the cardiovascular system, but underlying molecular mechanisms are still not fully understood. The cardiotonic effect always requires abundant energy supplement, which is mainly related to mitochondrial function. And OPA1 has been documented to play a critical role in mitochondrial morphology and energy metabolism in cardiomyocytes. Hence, this study was designed to investigate the potential role of OPA1-mediated regulation of energy metabolism in the positive inotropic effect caused by repeated aconitine treatment and the possible mechanism involved. Our results showed that repeated treatment with low-doses (0–10 μM) of aconitine for 7 days did not induce detectable cytotoxicity and enhanced myocardial contraction in Neonatal Rat Ventricular Myocytes (NRVMs). Also, we first identified that no more than 5 μM of aconitine triggered an obvious perturbation of mitochondrial homeostasis in cardiomyocytes by accelerating mitochondrial fusion, biogenesis, and Parkin-mediated mitophagy, followed by the increase in mitochondrial function and the cellular ATP content, both of which were identified to be related to the upregulation of ATP synthase α-subunit (ATP5A1). Besides, with compound C (CC), an inhibitor of AMPK, could reverse aconitine-increased the content of phosphor-AMPK, OPA1, and ATP5A1, and the following mitochondrial function. In conclusion, this study first demonstrated that repeated aconitine treatment could cause the remodeling of mitochondrial function via the AMPK–OPA1–ATP5A1 pathway and provide a possible explanation for the energy metabolism associated with cardiotonic effect induced by medicinal plants containing aconitine.

1) These compounds might contribute to the anti-hypertensive effect collectively. However, the anti-hypertensive effect of Eucommia ulmoides OLIV. bark remains largely unclear.Pharmacological studies have revealed that Eucommia ulmoides OLIV. bark extract induce endothelium and NO-cyclic guanosine monophosphate (cGMP) dependent relaxation in the rat thoracic aorta.2) Another report demonstrated that the endothelium-dependent vascular relaxation induced by the bark extract is mediated by NO and endothelium-derived hyperpolarizing factor in small vessels.3) However, the vasorelaxing components have been unclear. Recently, we found oroxylin A and wogonin isolated from Eucommia ulmoides OLIV. bark could significantly lower the perfusion pressure.4) In the previous study, we had reported that oroxylin A could relax rat thoracic aorta and it was endothelium and NO dependent.5)The present study was undertaken to investigate vasodilatory effect of wogonin and its mechanism.Wogonin ( Fig. 1) is a flavone and has a variety of cardiovascular protective effect. It could regulate migration, proliferation and apoptosis of vascular smooth muscle cells. [6][7][8] Besides, wogonin could inhibit angiogenesis, suppress collagen deposition in cardiac fibroblasts and inhibit ischemic brain injury. [9][10][11][12] There is no evidence for vascular relaxation effect of wogonin. We describe here that wogonin, unlike oroxylin A, is an endothelium-and NO-independent vasodilatory flavonoid. One report demonstrated that wogonin offered a wide margin of safety.13) It has therapeutic potential for the treatment of cardiovascular and cerebrovascular diseases.