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Diester diterpenoid alkaloids (DDAs) are the main active ingredients of herbaceous perennial plants Aconitum. DDAs possess cardiotoxic and neurotoxic properties. Although most deaths caused by DDA poisoning are accidental, a few instances of suicide and homicide have been reported. Presented is a case of an acute aconitine (AC) poisoning following the ingestion of approximately 50 mL of homemade medicinal liquor. We described the clinical manifestations after poisoning and detailed postmortem changes, and detected the concentrations of AC and hypaconitine (HA) by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The decedent experienced a burning sensation in the gastrointestinal tract after poisoning, followed by flushing and paralysis of the face and limbs, and severe cardiac arrhythmia. An autopsy revealed cyanosis of the lips and nail beds; conjunctival hemorrhage in both eyes; pulmonary edema; tissue hemorrhage and congestion in multiple organs; and inflammatory cell infiltration in the stomach, duodenum, pancreas, and cardiac muscle. The concentrations of AC and HA were as follows: cardiac blood, 38.4 ng/mL and 7.1 ng/mL; pericardial fluid, 7.3 ng/mL and 41 ng/mL; urine, 28.1 ng/mL and 574 ng/mL; bile, 38.5 ng/mL and 108 ng/mL; gastric contents, 0.06 mg and 0.56 mg; liver tissue, 10.7 ng/g and 109.6 ng/g; and medicinal liquor, 0.568 mg/mL and 0.664 mg/mL, respectively. The clinical manifestations, anatomy findings, and quantitative data on the concentrations of AC and HA in body fluids and tissues will aid forensic investigations of deaths caused by acute AC poisoning.

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Aconite poisoning refers to toxicity resulting from plants belonging to the Aconitum genus, which comprises over 350 different species of perennial flowering plants that grow in temperate mountainous areas of the northern hemisphere (North America, Europe, Asia). These plants contain a group of toxins known as aconite alkaloids, which encompass numerous closely related toxic compounds. Conventional teaching from toxicology textbooks has broadly classified these alkaloids based on their mechanism of action, often simplifying them as substances that prevent sodium channel inactivation. However, this is an oversimplified and sometimes inaccurate description, as some aconite alkaloids can act as sodium channel blockers. Aconite alkaloids have a long history of use as poisonous substances and have been historically employed for hunting, assassinations, traditional medicine, and self-inflicted harm. Toxicity can occur due to the consumption of traditional medicines derived from aconitum plants or the ingestion of aconite plants and their derivatives. The clinical manifestations of aconite poisoning may encompass gastrointestinal symptoms, sensory alterations, seizures, and life-threatening dysrhythmias that may not respond to standard treatments. Treatment is primarily supportive however evaluation and management of these patients should be personalized and carried out in collaboration with a toxicologist.

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Aconitine is the main active component of Aconitum plants. Although aconitine has effects that include strengthening the heart, analgesia, anti-tumor, and immune-regulating effects, aconitine has both efficacy and toxicity, especially cardiotoxicity. Severe effects can include arrhythmia and cardiac arrest, which limits the clinical application of aconitine-containing traditional Chinese medicine. Ginsenoside Rb1(Rb1) is mainly found in plants, such as ginseng and Panax notoginseng, and has cardiovascular-protective and anti-arrhythmia effects. This study aimed to investigate the detoxifying effects of Rb1 on aconitine cardiotoxicity and the electrophysiological effect of Rb1 on aconitine-induced arrhythmia in rats. Pathological analysis, myocardial enzymatic indexes, and Western blotting were used to investigate the ameliorating effect of Rb1 on aconitine cardiotoxicity. Optical mapping was used to evaluate the effect of Rb1 on action potential and calcium signaling after aconitine-induced arrhythmia. Rb1 inhibited pathological damage caused by aconitine, decreased myocardial enzyme levels, and restored the balance of apoptotic protein expression by reducing the expression of Bax and cleaved caspase 3 and increasing the expression of Bcl-2, thereby reducing myocardial damage caused by aconitine. Rb1 also reduced the increase in heart rate caused by aconitine, accelerated action potential conduction and calcium signaling, and reduced the dispersion of action potential and calcium signal conduction. Rb1 reduced the cardiotoxicity of aconitine by attenuating aconitine-induced myocardial injury and inhibiting the aconitine-induced retardation of ventricular action potential and calcium signaling in rats.

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Fuzi, an effective common herb, is often combined with Gancao to treat disease in clinical practice with enhancing its efficacy and alleviating its toxicity. The major toxic and bioactive compounds in Fuzi and Gancao are aconitine (AC) and glycyrrhizic acid (GL), respectively. This study aims to elucidate detoxification mechanism between AC and GL from pharmacokinetic perspective using physiologically based pharmacokinetic (PBPK) model. In vitro experiments exhibited that AC was mainly metabolized by CYP3A1/2 in rat liver microsomes and transported by P-glycoprotein (P-gp) in Caco-2 cells. Kinetics assays showed that the Km and Vmax of AC towards CYP3A1/2 were 2.38 µM and 57.3 pmol/min/mg, respectively, whereas that of AC towards P-gp was 11.26 µM and 147.1 pmol/min/mg, respectively. GL markedly induced the mRNA expressions of CYP3A1/2 and MDR1a/b in rat primary hepatocytes. In vivo studies suggested that the intragastric and intravenous administration of GL significantly reduced systemic exposure of AC by 27% and 33%, respectively. Drug-drug interaction (DDI) model of PBPK predicted that co-administration of GL would decrease the exposure of AC by 39% and 45% in intragastric and intravenous dosing group, respectively. The consistency between predicted data and observed data confirmed that the upregulation of CYP3A1/2 and P-gp was the crucial detoxification mechanism between AC and GL. Thus, this study provides a demonstration for elucidating the compatibility mechanisms of herbal formula using PBPK modeling and gives support for the clinical co-medication of Fuzi and Gancao.

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The root of Aconitum carmichaelii Debx. (Fuzi) is an herbal medicine used in China that exerts significant efficacy in rescuing patients from severe diseases. A key toxic compound in Fuzi, aconitine (AC), could trigger unpredictable cardiotoxicities with high-individualization, thus hinders safe application of Fuzi. In this study we investigated the individual differences of AC-induced cardiotoxicities, the biomarkers and underlying mechanisms. Diversity Outbred (DO) mice were used as a genetically heterogeneous model for mimicking individualization clinically. The mice were orally administered AC (0.3, 0.6, 0.9 mg· kg-1 ·d-1) for 7 d. We found that AC-triggered cardiotoxicities in DO mice shared similar characteristics to those observed in clinic patients. Most importantly, significant individual differences were found in DO mice (variation coefficients: 34.08%-53.17%). RNA-sequencing in AC-tolerant and AC-sensitive mice revealed that hemoglobin subunit beta (HBB), a toxic-responsive protein in blood with 89% homology to human, was specifically enriched in AC-sensitive mice. Moreover, we found that HBB overexpression could significantly exacerbate AC-induced cardiotoxicity while HBB knockdown markedly attenuated cell death of cardiomyocytes. We revealed that AC could trigger hemolysis, and specifically bind to HBB in cell-free hemoglobin (cf-Hb), which could excessively promote NO scavenge and decrease cardioprotective S-nitrosylation. Meanwhile, AC bound to HBB enhanced the binding of HBB to ABHD5 and AMPK, which correspondingly decreased HDAC-NT generation and led to cardiomyocytes death. This study not only demonstrates HBB achievement a novel target of AC in blood, but provides the first clue for HBB as a novel biomarker in determining the individual differences of Fuzi-triggered cardiotoxicity.

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Aconitine (AC), which is the primary bioactive diterpene alkaloid derived from Aconitum L plants, have attracted considerable interest due to its unique structural feature. Additionally, AC demonstrates a range of biological activities, such as its ability to enhance cardiac function, inhibit tumor growth, reduce inflammation, and provide analgesic effects. However, the structure-activity relationships of AC are remain unclear. A clear understanding of these relationships is indeed critical in developing effective biomedical applications with AC. In line with these challenges, this paper summarized the structural characteristics of AC and relevant functional and bioactive properties and the structure-activity relationships presented in biomedical applications. The primary temporal scope of this review was established as the period spanning from 2010 to 2023. Subsequently, the objective of this review was to provide a comprehensive understanding of the specific action mechanism of AC, while also exploring potential novel applications of AC derivatives in the biomedical field, drawing upon their structural characteristics. In conclusion, this review has provided a comprehensive analysis of the challenges and prospects associated with AC in the elucidation of structure-bioactivity relationships. Furthermore, the importance of exploring modern biotechnology approaches to enhance the potential biomedical applications of AC has been emphasized.

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BACKGROUND: Monkshood, a toxic plant containing a potent cardio- and neurotoxin called aconitine, can lead to a range of symptoms, including nausea, vomiting, dizziness, seizures, and cardiac arrhythmias. Mortality associated with this intoxication are due to ventricular tachyarrhythmias which are difficult to treat and often refractory in nature. CASE PRESENTATION: We present a case of a 17-year-old female patient who presented to the emergency department after intentionally ingesting a monkshood plant and developed atrioventricular dissociation and frequent ventricular ectopy. The patient was successfully treated with activated charcoal, supportive care, and cardiac monitoring. CONCLUSION: This case highlights the importance of early recognition of aconitine poisoning and the need for prompt supportive care, cardiac rhythm monitoring, and preemptive antiarrhythmic treatment planning.

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BACKGROUND: Most species of aconite contain highly toxic aconitines, the oral ingestion of which can be fatal, primarily because they cause ventricular arrhythmias. We describe a case of severe aconite poisoning that was successfully treated through veno-arterial extracorporeal membrane oxygenation (VA-ECMO) and in which detailed toxicological analyses of the aconite roots and biological samples were performed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). CASE SUMMARY: A 23-year-old male presented to the emergency room with circulatory collapse and ventricular arrhythmia after ingesting approximately half of a root labeled, "Aconitum japonicum Thunb". Two hours after arrival, VA-ECMO was initiated as circulatory collapse became refractory to antiarrhythmics and vasopressors. Nine hours after arrival, an electrocardiogram revealed a return to sinus rhythm. The patient was weaned off VA-ECMO and the ventilator on hospital days 3 and 5, respectively. On hospital day 15, he was transferred to a psychiatric hospital. The other half of the root and his biological samples were toxicologically analyzed using LC-MS/MS, revealing 244.3 mg/kg of aconitine and 24.7 mg/kg of mesaconitine in the root. Serum on admission contained 1.50 ng/mL of aconitine. Beyond hospital day 2, neither were detected. Urine on admission showed 149.09 ng/mL of aconitine and 3.59 ng/mL of mesaconitine, but these rapidly decreased after hospital day 3. CONCLUSION: The key to saving the life of a patient with severe aconite poisoning is to introduce VA-ECMO as soon as possible.

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Aconitum spp. are important medicinal plants mentioned in Ayurveda as Ativisa or Vatsanabha. The present study aims to evaluate anti-rheumatic potential in seven Aconitum species and correlation with aconitine and hypaconitine content. Anti-rheumatic potential was analyzed through in vitro xanthine oxidase inhibition, anti-inflammatory and ROS scavenging assays; and quantification of aconitine and hypaconitine with RP-HPLC method validated as per ICH guidelines. The findings reveal that A. palmatum possessed the most promising response (IC50 =12.68±0.15 µg/ml) followed by A. ferox (IC50 =12.912±1.87 µg/ml) for xanthin oxidase inhibition. We observed a wide variation in aconitine and hypaconitine content ranging from 0.018 %-1.37 % and 0.0051 %-0.077 % respectively on dry weight basis. Aconitine and hypaconitine showed moderate positive correlation (r=0.68 and 0.59 respectively) with anti-rheumatic potential. The study identifies potential alternative species of Aconitum that can help in sustainable availability of quality raw material.

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ObjectiveTo observe the effect of Yangyin Xifeng Tongluo Formula （养阴熄风通络方） and its core herbs combination on prevention of ventricular precontraction （PVC）. MethodsExperiment 1： Forty SD rats were randomly divided into model group， formula group， core herb-pairs medium-dose group and amiodarone group， with 10 rats in each group. Rats in the model group were given 10 ml/（kg·d） of pure water by gavage， rats in the formula group were given 1.125 g/（kg·d） of Yangyin Xifeng Tongluo Granules （养阴熄风通络方颗粒） by gavage， rats in the core herb-pairs medium-dose group were given 0.585 g/（kg·d） of granules of core herb-pairs by gavage， and rats in the amiodarone group were given 18 mg/（kg·d） of amiodarone hydrochloride tablets by gavage. The rats in each group were gavaged once a day for 14 consecutive days， and then a PVC model was established using rat tail vein injection of aconitine 25 μg/kg to compare the mortality and incidence of PVC， ventricular tachycardia （VT） and ventricular fibrillation （VF）， the time of the appearance of PVC， and the duration of PVC in the rats in each group. Experiment 2： Sixty SD rats were randomly divided into model group， the amiodarone group， and the core herb-pairs of low， medium and high dose groups， 12 rats in each group. Rats in the model group were gavaged with 10 ml/（kg·d） of purified water， rats in the low， medium， and high dose groups were gavaged with 0.2925， 0.585， and 1.17 g/（kg·d） of the core herb-pairs granules respectively， and rats in the amiodarone group were gavaged with 18 mg/（kg·d） of amiodarone hydrochloride tablets. All of them were gavaged once a day. After 14 days， rats in each group were injected intravenously into the tail vein with aconitine 25 μg/kg， and then the rats in each group were observed to show the mortality and incidence of PVC， VT and VF， and the time of appearance and duration of PVC. ResultsExperiment 1： Compared with the model group， The difference in the incidence of PVC in rats of all groups was not statistically signi-ficant （P＞0.05）， and the mortality and incidence of VT and VF in rats in the formula group， the core herb-pairs medium-dose group， and the amiodarone group significantly reduced， with delayed time of the occurrence of PVC and shorter duration of the PVC （P＜0.05 or P＜0.01） as compared with the model group， whereas the difference between each group with medication intervention was not statistically significant （P＞0.05）. Experiment 2： There was no statistically significant difference in the incidence of PVC in all groups （P＞0.05）， and the mortality and incidence of VT and VF reduced in the core herb-pairs of low-， medium-， and high-dose groups and in the amiodarone group， and the appearance of PVC delayed and its duration shortened （P＜0.05 or P＜0.01） as compared with the control group， whereas the differences were not statistically significant in the comparison among groups with medication （P＞0.05）. ConclusionBoth Yangyin Xifeng Tongluo Formula and its core herb-pairs could delay the time of occurrence and shorten the duration of PVC.

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BACKGROUND: We report a case of a clinical challenge lasting for 12 months, with severe and unresolved clinical features involving several medical disciplines. CASE PRESENTATION: A 53-year-old Caucasian male, who had been previously healthy apart from a moderate renal impairment, was hospitalized 12 times during a 1-year period for a recurrent complex of neurological, cardiovascular, and gastrointestinal symptoms and signs, without any apparent etiology. On two occasions, he suffered a cardiac arrest and was successfully resuscitated. Following the first cardiac arrest, a cardiac defibrillator was inserted. During the 12th admission to our hospital, aconitine poisoning was suspected after a comprehensive multidisciplinary evaluation and confirmed by serum and urine analyses. Later, aconitine was also detected in a hair segment, indicating exposure within the symptomatic period. After the diagnosis was made, no further episodes occurred. His cardiac defibrillator was later removed, and he returned to work. A former diagnosis of epilepsy was also abandoned. Criminal intent was suspected, and his wife was sentenced to 11 years in prison for attempted murder. To make standardized assessments of the probability for aconitine poisoning as the cause of the eleven prior admissions, an "aconitine score" was established. The score is based on neurological, cardiovascular, gastrointestinal, and other clinical features reported in the literature. We also make a case for the use of hair analysis to confirm suspected poisoning cases evaluated after the resolution of clinical features. CONCLUSION: This report illustrates the medical challenge raised by cases of covert poisoning. In patients presenting with symptoms and signs from several organ systems without apparent cause, poisoning should always be suspected. To solve such cases, insight into the effects of specific toxic agents is needed. We present an "aconitine score" that may be useful in cases of suspected aconitine poisoning.

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Aconitum species are commonly used in traditional Chinese medicine, and they have a narrow therapy window due to the possibility of aconitine poisoning. Aconitine poisoning deaths appear infrequently in forensic practice. It is important to collect valuable body samples in time due to the rapid absorption and excretion of aconitine. However, it is unknown whether postmortem samples have value for toxicological analysis if the deceased has experienced long-term treatment before death. Herein, we present a case of a woman who died after 12 days of failed active treatment for aconitine poisoning. Aconitine was detected in the liver tissue. To our knowledge, this is the first case report describing the detection of aconitine in a decedent after long-term active treatment. The findings indicated that the aconitine concentration in liver tissue can be maintained after long-term treatment; this information may therefore serve as a reference in forensic practice.

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Aconitine is a sodium channel opener, but its effects on the respiratory center are not well understood. We investigated the dose-dependent effects of aconitine on central respiratory activity in brainstem-spinal cord preparations isolated from newborn rats. Bath application of 0.5-5 µM aconitine caused an increase in respiratory rhythm and decrease in the inspiratory burst amplitude of the fourth cervical ventral root (C4). Separate application of aconitine revealed that medullary neurons were responsible for the respiratory rhythm increase, and neurons in both the medulla and spinal cord were involved in the decrease of C4 amplitude by aconitine. A local anesthetic, lidocaine (100 µM), or a voltage-dependent sodium channel blocker, tetrodotoxin (0.1 µM), partially antagonized the C4 amplitude decrease by aconitine. Tetrodotoxin treatment tentatively decreased the respiratory rhythm, but lidocaine tended to further increase the rhythm. Treatment with 100 µM riluzole or 100 µM flufenamic acid, which are known to inhibit respiratory pacemaker activity, did not reduce the respiratory rhythm enhanced by aconitine + lidocaine. The application of 1 µM aconitine depolarized the preinspiratory, expiratory, and inspiratory motor neurons. The facilitated burst rhythm of inspiratory neurons after aconitine disappeared in a low Ca2+/high Mg2+ synaptic blockade solution. We showed the dose-dependent effects of aconitine on respiratory activity. The antagonists reversed the depressive effects of aconitine in different manners, possibly due to their actions on different sites of sodium channels. The burst-generating pacemaker properties of neurons may not be involved in the generation of the facilitated rhythm after aconitine treatment.

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Riko Majima published seven papers in this journal, and seeing these papers and their surrounding contexts allows us to glance at the birth of a galaxy of scientists.

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Aconitine is a crucial toxic component in Chinese herbal medicines such as Aconitum, Aconitum coreanum, and Aconitum soongaricum. The poisoning symptoms of the central nervous system and cardiovascular system caused by it are relatively common in China, and there are many studies on cardiovascular system diseases caused by aconitine. However, the specific mechanism of neurotoxicity induced by aconitine is still unclear. This study explored the effect and mechanism of mitochondrial calcium uniporter on mitochondrial energy metabolism disorder in aconitine poisoning hippocampal neurons. The results showed that after treatment with 400µmol/L aconitine, mitochondrial energy metabolism was abnormal in rat hippocampal neuron cells, the expression of MCU in mitochondria was up-regulated, calcium overload in mitochondria, ATP production decreased, and mitochondrial membrane potential Changes, increased expression of the apoptosis gene Cleaved-Caspase-3. After treatment with the MCU agonist spermine, mitochondrial energy metabolism was significantly abnormal, and cell apoptosis was increased considerably. However, pretreatment with calcium ion channel inhibitor Ruthenium Red (RR) effectively promoted the generation of ATP, thereby improving mitochondrial energy metabolism disorders and reducing cell apoptosis. These results suggest that aconitine induces mitochondrial energy metabolism dysfunction in hippocampal neurons, which may be related to the increased expression of MCU.

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[This corrects the article DOI: 10.3389/fphar.2022.837810.].

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Background: Herbs originating from the Aconitum L. (Ranunculaceae), such as Aconitum carmichaelii Debeaux. (Wutou), Aconitum pendulum Busch. (Tiebangchui), and Aconitum kusnezoffii Reichb. (Caowu), etc. are highly valued for their medicinal properties. The roots and tubers of these herbs are commonly used to treat an array of ailments, including joint pain and tumors. The alkaloids present in them are the primary active components, with aconitine being the most notable. Aconitine has gained attention for its exceptional anti-inflammatory and analgesic properties, as well as its potential as an anti-tumor and cardiotonic agent. However, the exact process through which aconitine hinders the growth of cancerous cells and triggers their programmed cell death remains unclear. Therefore, we have undertaken a comprehensive systematic review and meta-analysis of the current research on the potential antitumor properties of aconitine. Methods: We conducted a thorough search of relevant preclinical studies in databases including PubMed, Web of Science, VIP, WanFang Data, CNKI, Embase, Cochrane Library, and National Center for Biotechnology Information (NCBI). The search was conducted up until 15 September 2022, and the data were statistically analyzed using RevMan 5.4 software. The number of tumor cell value-added, tumor cell apoptosis rate, thymus index (TI), and Bcl-2 gene expression level were the main indicators to be analyzed. Results: After applying the final inclusion criteria, a total of thirty-seven studies, comprising both in vivo and in vitro research were analyzed. The results showed that treatment with aconitine led to a significant reduction in tumor cell proliferation, a noteworthy increase in the rate of apoptosis among tumor cells, a decrease in the thymus index, and a reduction in the expression level of Bcl-2. These results suggested that aconitine could inhibit the proliferation, invasion, and migration abilities of tumor cells by regulating Bcl-2 etc., thereby enhancing the anti-tumor effects. Conclusion: In summary, our present study demonstrated that aconitine effectively reduced tumor size and volume, indicating a strong anti-tumor effect. Additionally, aconitine could increase the expression levels of caspase-3, Bax and other targets. Mechanistically, it may regulate the expression levels of Bax and Bcl-2 through the NF-κB signaling pathway, ultimately inhibiting tumor cell proliferation through autophagy.

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As one of the most common malignancies in female dogs, no drugs have been developed specifically for the treatment of canine mammary carcinoma. In our previous study, a series of diterpenoid alkaloids derivatives were synthesized and exhibited good anti-proliferative activity in vitro against both normal and adriamycin-resistant human breast cancer cells lines. In this study, a series of structurally diverse aconitine-type alkaloids derivatives were also synthesized basing on the minimal modification principle, by modifying on A-ring, C-ring, D-ring, N-atom or salt formation on aconitine skeleton. Their anti-proliferative effects and mechanism on canine mammary cancer cells were investigated, exhibiting the importance of the substitution at A ring, the long chain ester at the C8, the hydroxyl group at the C13, the phenyl ring at the C14 and the N-ethyl group, while the methoxy group at the C1 and C16 showed little effect on the activity. The results of the proliferation, apoptosis and ultrastructure tests of the treated canine mammary carcinoma cells referred that the representative compound, aconitine linoleate (25) could block the cell cycle of canine mammary carcinoma cells in the G0/G1 phase, and exhibit the anti-proliferative effect by inducing apoptosis.

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Complicated chemical reactions occur in the decoction of traditional Chinese medicines(TCMs) which features complex components, influencing the safety, efficacy, and quality controllability of TCMs. Therefore, it is particularly important to clarify the chemical reaction mechanism of TCMs in the decoction. This study summarized eight typical chemical reactions in the decoction of TCMs, such as substitution reaction, redox reaction, isomerization/stereoselective reaction, complexation, and supramolecular reaction. With the "toxicity attenuation and efficiency enhancement" of aconitines and other examples, this study reviewed the reactions in decoction of TCMs, which was expected to clarify the variation mechanisms of key chemical components in this process and to help guide medicine preparation and safe and rational use of medicine in clinical settings. The current main research methods for chemical reaction mechanisms of decoction of TCMs were also summed up and compared. The novel real-time analysis device of decoction system for TCMs was found to be efficient and simple without the pre-treatment of samples. This device provides a promising solution, which has great potential in quantity evaluation and control of TCMs. Moreover, it is expected to become a foundational and exemplary research tool, which can advance the research in this field.

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