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.
The present study investigated the anti-cholestatic effect of melatonin (MT) against α-naphthyl isothiocyanate (ANIT)-induced liver injury in rats and screened for potential biomarkers of cholestasis. Rats were administered ANIT by intraperitoneal injection and then sacrificed 36 h later. Serum biochemical parameters were measured and liver tissue samples were subjected to histological analysis. Active components in the serum were identified by gas chromatography-mass spectrometry, while biomarkers and biochemical pathways were identified by multivariate data analysis. The results revealed that the serum levels of alanine aminotransferase, aspartate aminotransferase, total bilirubin, direct bilirubin, γ-glutamyl transpeptidase, and alkaline phosphatase were reduced in rats with ANIT-induced cholestasis that were treated with MT. The histological observations indicated that MT had a protective effect against ANIT-induced hepatic tissue damage. Metabolomics analysis revealed that this effect was likely to be associated with the regulation of compounds related to MT synthesis and catabolism, and amino acid metabolism, including 5-aminopentanoate, 5-methoxytryptamine, L-tryptophan, threonine, glutathione, L-methionine, and indolelactate. In addition, principal component analysis demonstrated that the levels of these metabolites differed significantly between the MT and control groups, providing further evidence that they may be responsible for the effects induced by MT. These results provide an insight into the mechanisms underlying cholestasis development and highlight potential biomarkers for disease diagnosis.
Cholestasis is a devastating liver condition which is increasing in prevalence worldwide; however, its underlying pathogenic mechanisms remain to be fully elucidated. It was hypothesised that melatonin may alleviate the hepatic injury associated with cholestasis due to its established antioxidant effects. Therefore, the effect and potential anticholestatic properties of melatonin were investigated in rats with α-naphthylisothiocyanate (ANIT)-induced liver injury, a common animal model that mimics the cholestasis-associated liver injury in humans. The rats received intraperitoneal injection of ANIT with or without subsequent treatment with melatonin, and were sacrificed 24 h later. The serum biochemistry parameters of the liver were measured using conventional laboratory assays, and the liver tissue was subjected to conventional histological examination, reverse transcription-quantitative polymerase chain reaction analysis and western blotting. The levels of alanine transaminase, aspartate transaminase, total bilirubin, direct bilirubin, total bile acids, alkaline phosphatase, γ-glutamyl transferase and glutathione were restored in rats treated with melatonin. Histological examination provided further evidence supporting the protective effect of melatonin against ANIT-induced cholestasis. In addition, the mRNA and protein expression levels of glutamate cysteine ligase, phosphorylated Akt and nuclear factor-erythroid 2-related factor-2 were restored in rats treated with melatonin. These findings indicate that melatonin is a natural agent that appears to be promising for the treatment of cholestasis, and that the anticholestatic effects of melatonin involve the alleviation of oxidative stress.
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.
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