Construction of a high-throughput screening model for mitochondrial function of Aconiti Lateralis Radix Praeparata by machine learning algorithm and mechanism analysis / 中国中药杂志

A high-throughput screening machine learning model for mitochondrial function was constructed, and compounds of Aco-niti Lateralis Radix Praeparata were predicted. Deoxyaconitine with the highest score and benzoylmesaconine with the lowest score among the compounds screened by the model were selected for mitochondrial mechanism analysis. Mitochondrial function data were collected from PubChem and Tox21 databases. Random forest and gradient boosted decision tree algorithms were separately used for mo-deling, and ECFP4(extended connectivity fingerprint, up to four bonds) and Mordred descriptors were employed for training, respectively. Cross-validation test was carried out, and balanced accuracy(BA) and overall accuracy were determined to evaluate the performance of different combinations of models and obtain the optimal algorithm and hyperparameters for modeling. The data of Aconiti Lateralis Radix Praeparata compounds in TCMSP database were collected, and after prediction and screening by the constructed high-throughput screening machine learning model, deoxyaconitine and benzoylmesaconine were selected to measure mitochondrial membrane potential, reactive oxygen species(ROS) level and protein expression of B-cell lymphoma 2(Bcl-2), Bcl-2-associated X protein(Bax) and peroxisome proliferator-activated receptor-γ-coactivator 1α(PGC-1α). The results showed that the model constructed using gradient boosted decision tree+Mordred algorithm performed better, with a cross-validation BA of 0.825 and a test set accuracy of 0.811. Deoxyaconitine and benzoylmesaconine changed the ROS level(P<0.001), mitochondrial membrane potential(P<0.001), and protein expression of Bcl-2(P<0.001, P<0.01) and Bax(P<0.001), and deoxyaconitine increased the expression of PGC-1α protein(P<0.01). The high-throughput screening model for mitochondrial function constructed by gradient boosted decision tree+Mordred algorithm was more accurate than that by random forest+ECFP4 algorithm, which could be used to build an algorithm model for subsequent research. Deoxyaconitine and benzoylmesaconine affected mitochondrial function. However, deoxyaconitine with higher score also affected mitochondrial biosynthesis by regulating PGC-1α protein.

Hydrolysis mechanism of aconitine and deoxyaconitine in Aconitum soongaricum / 中草药

Objective To determinate the hydrolysis products of two ingredients in Aconitum soongaricum under different heating conditions by liquid chromatography-mass spectrometry method, analyze its hydrolysis change rule, and verify it in A. soongaricum, analyze the changes of alkaloid before and after processing, and summarize the change rules and processing hydrolysis mechanism, so as to provide theoretical basis for the processing parameters of A. soongaricum. Methods Taking two kinds of main chemical constituents in A. soongaricum, aconitine and deoxyaconitine as the research object, the change rule of alkaloid monomer variation under different heating conditions was summarized combined with HPLC and HPLC-MS results, which was verified in different processed products in A. soongaricum. Results There was the significant change in the content of aconitine and deoxyaconitine after different heating time, the content of the mainly products from aconitine hydrolysis was increased with the increase of heating time, and aconitine and deoxyaconitine were gradually disappeared, eventually not detected. Conclusion The processing parameters of A. soongaricum were preliminarily determined as heating for 5-6 h, and the hydrolysis of aconitine and deoxyaconitine producing new hydrolysis products, thus achieving the effect of reducing toxicity and increasing efficiency.

ANTIINFLAMMATORY, ANALGESIC AND ANTIPYRETIC EFFECTS OF DEOXYACONITINE / 中国药理学通报

Deoxyaconitine (DAC), an extract from the tuber of Aconitum flavum Hand-Mazz, was assayed comparatively with the other previously studied alkaloid 3-Acetylaconitine(3AAC)with respect to their antiinflammatory, analgesic and anti-pyretic effects in laboratory animals. DACO.Smg /kg ip markedly inhibited the croton oil induced ear edema in micei 0.2 mg/kg ip or sc showed significant inhibiton on the hind-paw edema in rats induced by carrageenin or formalin,and on the increase of vascular permeability induced by intradermic injection of histam-ine in rats or acetic acid ip in mice. With the model of carrageenin induced hind-paw edema in rats, the antiinflammatory therapeutic index of DAC ip (6.38) was slightly higher than that of 3AAC (5.92 ) . The sc analgesic ED50 of DAC measured with acetic acid twisting test in mice was 0.22+ 0.06mg/kg and that measured with hotplate method by ip was 0.41+0.10 mg/kg.In the latter case, the analgesic therapeutic index of DAC (6.37) was higher than that of 3-AAC(4.60) . DAC 0.24mg/kg ip showed marked anti-pyretic effect on the rabbit fever induced by typho-paratyphoid vaccine.