Aconitum (Ranunculaceae) has a long-standing history in traditional Chinese medicine (TCM), where it has been widely used to treat conditions such as rheumatoid arthritis (RA), myocardial infarction, and heart failure. However, the potency of Aconitum alkaloids, the primary active components of Aconitum, also confers substantial toxicity. Therefore, assessing the efficacy and toxicity of these Aconitum alkaloids is crucial for ensuring clinical effectiveness and safety. Metabolomics, a quantitative method for analyzing low-molecular-weight metabolites involved in metabolic pathways, provides a comprehensive view of the metabolic state across multiple systems in vivo. This approach has become a vital investigative tool for facilitating the evaluation of their efficacy and toxicity, identifying potential sensitive biomarkers, and offering a promising avenue for elucidating the pharmacological and toxicological mechanisms underlying TCM. This review focuses on the applications of metabolomics in pharmacological and toxicological studies of Aconitum alkaloids in recent years and highlights the significant role of metabolomics in exploring compatibility detoxification and the mechanisms of TCM processing, aiming to identify more viable methods for characterizing toxic medicinal plants.
Aconitum/metabolism* ; Metabolomics/methods* ; Alkaloids/metabolism* ; Humans ; Animals ; Drugs, Chinese Herbal/pharmacology* ; Medicine, Chinese Traditional

Bovine neosporosis,a significant disease affecting the livestock industry,is caused by the protozoan parasite Neospora caninum(N.caninum).The current absence of efficacious vaccines and therapeutics necessitates the exploration of novel interventions.Cordycepin,a bioactive nucleo-side derived from Cordyceps militaris,has garnered attention for its diverse pharmacological properties.This study endeavors to elucidate the inhibitory effects of cordycepin on N.caninum in-fection.The cytotoxicity of cordycepin to bovine macrophages was assessed using the CCK-8 assay to ascertain a non-toxic concentration range.The impact of cordycepin on the N.caninum burden within bovine macrophages was evaluated using qPCR analysis and immunofluorescence assays.Additionally,the modulation of cytokine,interferon,and defensin expression induced by N.cani-num in the presence of cordycepin was examined through qRT-PCR analysis.The results showed that cordycepin exhibited negligible cytotoxicity to bovine macrophages at concentrations ranging from 2.812 5 to 180.000 0 μmol/L,compared to the control group.At concentrations of 5.625 0,11.250 0,and 22.500 0 μmol/L,cordycepin significantly reduced the intracellular N.caninum loads and diminished the intensity of intracellular parasite fluorescence.While N.caninum infection downregulated the expression of pro-inflammatory cytokines such as TNF-α,IL-1β,and IL-6,cordycepin treatment robustly induced their expression.Furthermore,although cordycepin treatment reduced the expression levels of IFN-α,IFN-β,and IFN-γ that were upregulated by N.caninum infection,it maintained substantial expression levels.In conclusion,cordycepin demon-strates a promising resistance against N.caninum infection,suggesting its potential as a therapeu-tic agent for the treatment of bovine neosporosis.

Bovine neosporosis,a significant disease affecting the livestock industry,is caused by the protozoan parasite Neospora caninum(N.caninum).The current absence of efficacious vaccines and therapeutics necessitates the exploration of novel interventions.Cordycepin,a bioactive nucleo-side derived from Cordyceps militaris,has garnered attention for its diverse pharmacological properties.This study endeavors to elucidate the inhibitory effects of cordycepin on N.caninum in-fection.The cytotoxicity of cordycepin to bovine macrophages was assessed using the CCK-8 assay to ascertain a non-toxic concentration range.The impact of cordycepin on the N.caninum burden within bovine macrophages was evaluated using qPCR analysis and immunofluorescence assays.Additionally,the modulation of cytokine,interferon,and defensin expression induced by N.cani-num in the presence of cordycepin was examined through qRT-PCR analysis.The results showed that cordycepin exhibited negligible cytotoxicity to bovine macrophages at concentrations ranging from 2.812 5 to 180.000 0 μmol/L,compared to the control group.At concentrations of 5.625 0,11.250 0,and 22.500 0 μmol/L,cordycepin significantly reduced the intracellular N.caninum loads and diminished the intensity of intracellular parasite fluorescence.While N.caninum infection downregulated the expression of pro-inflammatory cytokines such as TNF-α,IL-1β,and IL-6,cordycepin treatment robustly induced their expression.Furthermore,although cordycepin treatment reduced the expression levels of IFN-α,IFN-β,and IFN-γ that were upregulated by N.caninum infection,it maintained substantial expression levels.In conclusion,cordycepin demon-strates a promising resistance against N.caninum infection,suggesting its potential as a therapeu-tic agent for the treatment of bovine neosporosis.

Atherosclerosis （AS） is a chronic inflammatory pathological process in which lipid and/or fibrous substances are deposited in the intima of arteries， and it is one of the pathological bases of many cardiovascular and cerebrovascular diseases. Endoplasmic reticulum stress （ERS） is a protective mechanism of cell adaptation. Moderate ERS can reduce abnormal protein aggregation and increase the degradation of misfolded proteins to repair and stabilize the internal environment， while excessive ERS can cause unfolded protein reaction， activate inflammation， oxidative stress， apoptosis， autophagy， and other downstream pathways， and lead to cell damage， or even apoptosis. A large number of studies have shown that ERS mediates a variety of pathological processes related to AS， affects endothelial cells， smooth muscle cells， macrophages， endothelial progenitor cells， and other cell components closely related to its occurrence and development， influences the progress of AS by regulating cell function， and promotes the formation of AS plaque， the transformation of stable plaque to unstable plaque， and the rupture of unstable plaque. Regulation of ERS may be a key target for the prevention and treatment of AS， and it is a research hotspot at present. Traditional Chinese medicine （TCM） believes that the origin of AS is the imbalance of Yin and Yang， the disharmony of Zangfu organs， and the abnormal operation of Qi， blood， and body fluid， which leads to the accumulation of phlegm， blood stasis， and other pathological products in the pulse channels， making the blood flow blocked or misfunction and causing the disease， which belongs to the syndrome of deficiency in origin and excess in superficiality. As the pathogenesis of AS is complex， and the symptoms are diverse， TCM has significant advantages in treating AS because of its multiple targets， multiple pathways， stable efficacy， strong individualization， and high safety. This paper systematically elaborated on the role of ERS in the occurrence and development of AS and summarized the mechanism research on the regulation and control of ERS by Chinese herbal monomer， Chinese herbal extract， Chinese herbal compound， and proprietary medicine， so as to provide a theoretical basis for clinical research and drug development in the prevention and treatment of AS.

Objective To investigate the relationship between the expression of Krüppel-like factor 5(KLF5)and lysine demethylase 2A(KDM2A)in cancer tissues of patients with oral cancer and clinicopatho-logical characteristics and prognosis.Methods Cancer tissues of 80 patients with oral cancer who underwent surgical treatment in the Zigong First People's Hospital from January 2015 to January 2018 were retrospec-tively collected as research objects,and normal adjacent tissues were selected as controls.The expression of KLF5 and KDM2A in cancer tissues and adjacent tissues of patients with oral cancer was detected by immuno-histochemical staining,and the correlation between KLF5 and KDM2A in cancer tissues was analyzed by Spearman correlation.Clinicopathological features of patients with oral cancer were collected,and the relation-ship between the expression of KLF5 and KDM2A in cancer tissues and clinicopathological features of patients was analyzed,as well as the prognostic factors of patients with oral cancer were analyzed by multivariate Cox regression.Kaplan-Meier method was used to analyze the relationship between the expression of KLF5 and KDM2A and the prognosis of patients with oral cancer.Results The high expression rates of KDM2A and KLF5 in oral cancer tissues were significantly higher than those in adjacent tissues,and the difference was sta-tistically significant(P＜0.05).Spearman correlation analysis showed that there was a positive correlation be-tween KLF5 and KDM2A expression in oral cancer patients(r=0.375,P＜0.05).The expressions of KLF5 and KDM2A in patients with oral cancer were correlated with TNM stage,clinical stage,lymph node metasta-sis,local invasion and differentiation degree(P＜0.05).Multivariate Cox regression analysis showed that the expression level of KLF5 and KDM2A,TNM stage,lymph node metastasis,local invasion and differentiation degree were independent risk factors for poor prognosis in patients with oral cancer(P＜0.05).The 5-year survival rates of patients with high expression of KLF5 and KDM2A in cancer tissues[38.88％(21/54),42.37％(25/59)]were lower than those of patients with low expression of KLF5 and KDM2A in cancer tis-sues[65.38％(17/26),61.90％(13/21)],the difference was statistically significant(x2=6.554,4.046,P＜0.05).Conclusion The expression of KLF5 and KDM2A in cancer tissues of patients with oral cancer is high and affects the prognosis of patients.

ObjectiveTo study the effect and mechanism of Curculiginis Rhizoma in ameliorating kidney-Yang deficiency in castrated rats. MethodThe targets of Curculiginis Rhizoma and male reproductive diseases due to kidney-Yang deficiency were screened from relevant databases by network pharmacology， and key targets were screened out according to topological eigenvalues. After that， gene ontology （GO） and Kyoto Encyclopedia of Genes and Genomes （KEGG） enrichment analyses were performed to obtain the pathways of Curculiginis Rhizoma in treating kidney-Yang deficiency. The rat model of kidney-Yang deficiency was established by castration. The rats were assigned into model， testosterone propinate （2 mg·kg^-1）， and low-， medium-， high-dose （0.14， 0.28， 0.56 g·kg^-1， respectively） Curculiginis Rhizoma groups. Another 8 healthy male rats with first incising and then suturing were used as the sham group. The rats were administrated with corresponding agents by gavage once a day for 6 consecutive weeks. During the experiment， the general conditions of rats in each group were observed， and their body mass was recorded. At the end of the experiment， the indexes of accessory sex organs were calculated， and the pathological changes of the seminal vesicle glands and prostate glands were observed by hematoxylin-eosin （HE） staining. The serum levels of luteinizing hormone （LH）， follicle-stimulating hormone （FSH）， testosterone （T）， and interleukin-6 （IL-6） were determined by enzyme-linked immunosorbent assay. The results of the network pharmacological prediction were verified by animal experiments， and the expression levels of related genes and proteins were determined by real-time polymerase chain reaction and Western blot， respectively. ResultThe biological functions enriched mainly involved four overexpression modules including regulation of cell responses to various stimuli， metabolic responses， regulation of intracellular signal transduction， and regulation of reproduction. Phosphatidylinositol 3-kinase/protein kinase B （PI3K/Akt） signaling pathway was a significantly enriched pathway for the core target and also a pathway with the highest enrichment factor in the biological process of regulating cell responses to stimuli. The results of animal experiments showed that compared with the model group， low-dose Curculiginis Rhizoma group increased the body weight gain （P<0.05）. In addition， high-dose Curculiginis Rhizoma group increased the seminal vesicle gland index and epididymis index （P<0.05）. The administration with Curculiginis Rhizoma ameliorate epithelial cell hyperplasia of the seminal vesicle glands， did not attenuate the vacuolar degeneration， mitigated the enlarged vesicular lumen of the prostate gland， changing of epithelial cells of the glands from flattened to cubic and columnar shapes， and cellular disarrangement， and reduced the mesenchymal stroma thickness. Compared with the model group， all the intervention measures elevated the levels of FSH， LH， T， and IL-6 （P<0.05， P<0.01） and up-regulated the mRNA and protein levels of PI3K and the mRNA levels of Akt in the epididymis tissue （P<0.05）. ConclusionCurculiginis Rhizoma can alleviate the T level reduction and accessory sex organ atrophy in castrated rats by regulating the PI3K/Akt signaling pathway.

The basic pathological change of diabetic macroangiopathy is atherosclerosis （AS）， which is mainly associated with vascular endothelial cells （VECs） injury， oxidative stress， glucose and lipid metabolism disorders， hemorheological abnormalities， and endoplasmic reticulum stress. The injury and dysfunction of VECs are the initiating factors of diabetic macroangiopathy. Autophagy is a subcellular self-protection mechanism that regulates basic intracellular metabolism through lysosome-mediated degradation of proteins and damaged organelles to maintain homeostasis. Insufficient autophagy of VECs leads to enhanced inflammation， apoptosis， and oxidative stress of VECs， which promotes AS. According to the theory of traditional Chinese medicine （TCM）， diabetic macroangiopathy corresponds to the syndrome of internal deficiency and pathogen invasion， with Qi deficiency and stagnation as the key pathogenesis. Qi deficiency is the root cause， and Qi stagnation is the manifestation. The disease occurs with the initial cause of nutrient-defense disharmony and instability of vessels， the main cause of the deficiency of kidney Qi and the lack of source for generation and transformation， the internal cause of Qi and blood loss in the viscera and the stagnation of Qi， blood， and fluid， and the superficial cause of the stagnation of pathological products and the damage of vessels. Autophagy is a microscopic manifestation of Qi， which has the function of dispelling pathogens and maintaining homeostasis. Insufficient autophagy of VECs leads to Qi deficiency and stagnation， and the gradual deficiency and heavy stagnation of Qi lead to insufficient autophagy， which form a vicious cycle. Modern research has demonstrated that regulating the autophagy of VECs is the main way to prevent and treat AS， and TCM can exert the therapeutic effect in a multi-target and multi-pathway manner. Therefore， based on the theory of Qi deficiency and stagnation， the method of tonifying deficiency of and removing stagnation can be adopted to select prescriptions for regulating the autophagy of VECs and treating AS， which can slow down the procession of diabetic macroangiopathy.

ObjectiveTo investigate the effect of Loulianwan on the gut microbiota of db/db mice with type 2 diabetes mellitus （T2DM）. MethodMale db/m+ mice aged 4-5 weeks were assigned to the normal group， and male db/db model mice of the same age were randomly divided into model group， metformin group （0.25 g·kg^-1·d^-1）， and Loulianwan group （13 g·kg^-1·d^-1）， with six mice in each group. Drug intervention lasted five weeks. The body weight， water intake， and fasting blood glucose （FBG） of the mice were recorded every week. After five weeks， the FBG， liver triglyceride （TG）， liver total cholesterol （TC）， glycated serum protein （GSP）， and fasting serum insulin （FINS） were detected， and the insulin resistance index （HOMA-IR） was calculated. The feces in the mouse intestines were collected， and the 16S rRNA sequencing technology was used to detect the structural changes in the fecal gut microbiota of mice in each group. ResultCompared with the normal group， the model group showed increased body weight， water intake， FBG， liver TG， liver TC， GSP， FINS， and HOMA-IR （P<0.01）. Compared with the model group， the Loulianwan group showed reduced water intake， FBG， liver TG， liver TC， GSP， FINS， and HOMA-IR （P<0.01）. The gut microbiota in the Loulian Lills group changed from phylum to genus level. The relative abundance of beneficial bacteria increased and the relative abundance of harmful bacteria decreased. Among them， the abundance of Akkermansia muciniphila， Blautia， Ruminococcus， and Parabacteroides increased （P<0.01）. ConclusionLoulianwan can significantly improve glucose and lipid metabolism in db/db mice with T2DM， and its mechanism may be related to the increase in the abundance of Akkermansia muciniphila， Blautia， Ruminococcus， and Parabacteroides in the intestine.

Type 2 diabetes mellitus （T2DM） is a chronic metabolic disease characterized by insulin resistance， hyperinsulinemia， and disturbance of glucose and lipid metabolism， with elevated blood glucose as the main clinical manifestation. Due to its complex etiology and pathogenesis， there is no effective treatment， which critically threatens human health and places a heavy burden on society and families. Saponins are a class of glycosides with complex structures that have the advantage of a wide range of sources， elevated safety， and low adverse effects. As an essential active ingredient in Chinese medicine， Chinese medicine saponins have a variety of biological activities such as hypoglycemia， hypoglycaemia， anti-inflammation， antioxidation， anti-tumor， and immune modulation. In recent years， numerous studies have shown that Chinese medicine saponins are effective in preventing and treating T2DM. Although there have been numerous studies on the hypoglycemic effects and mechanisms of Chinese medicine saponins， there has been no systematic review of the mechanisms of Chinese medicine saponins in the treatment of T2DM. Therefore， to provide a theoretical basis for an in-depth study of the hypoglycemic effects of Chinese medicine saponins and a scientific basis for the development and clinical application of drugs， this paper systematically summarized the hypoglycemic mechanisms of Chinese medicine saponins， such as improving islet β-cell function， improving insulin resistance， inhibiting glycosidase activity， reducing the inflammatory response， anti-oxidative stress， and regulating intestinal flora， and analyzed the current research problems and development trends.

Diabetic nephropathy （DN） is one of the serious and common microvascular complications of diabetes mellitus （DM） and the main cause of end-stage renal disease （ESRD）. Endoplasmic reticulum stress （ERS） is a common stress defense mechanism in eukaryotic cells. In the ERS state， cells activate the unfolded protein response （UPR） to enhance the folding of unfolded proteins and the degradation of misfolded proteins， so as to restore the normal physiological function of the endoplasmic reticulum and avoid cell damage. However， excessive or chronic persistent ERS can induce apoptosis， inflammation， oxidative stress and other pathways to eventually cause cell damage. In recent years， a large number of studies have confirmed that ERS is closely associated with the occurrence and development of DN. In the case of DN， ERS is involved in the damage or protection of podocytes， glomerular mesangial cells， renal tubular epithelial cells， and glomerular endothelial cells. The regulation of ERS has become one of the hotspots in the prevention and treatment of DN and has received extensive attention in the field of traditional Chinese medicine. This paper systematically expounds the role of ERS in the occurrence and development of DN and summarizes the ERS-targeted regulation of DN by traditional Chinese medicine， with a view to providing certain research ideas for the prevention and control of DN with traditional Chinese medicine.