Difference in liver injury induced by dictamnine between males and females: based on untargeted metabolomics / 中国中药杂志

In recent years, reports of adverse reactions related to traditional Chinese medicine(TCM) have been on the rise, especially some traditionally considered "non-toxic" TCM(such as Dictamni Cortex). This has aroused the concern of scholars. This study aims to explore the metabolomic mechanism underlying the difference in liver injury induced by dictamnine between males and females through the experiment on 4-week-old mice. The results showed that the serum biochemical indexes of liver function and organ coefficients were significantly increased by dictamnine(P<0.05), and hepatic alveolar steatosis was mainly observed in female mice. However, no histopathological changes were observed in the male mice. Furthermore, a total of 48 differential metabolites(such as tryptophan, corticosterone, and indole) related to the difference in liver injury between males and females were screened out by untargeted metabolomics and multivariate statistical analysis. According to the receiver operating characteristic(ROC) curve, 14 metabolites were highly correlated with the difference. Finally, pathway enrichment analysis indicated that disorders of metabolic pathways, such as tryptophan metabolism, steroid hormone biosynthesis, and ferroptosis(linoleic acid metabolism and arachidonic acid metabolism), may be the potential mechanism of the difference. Liver injury induced by dictamnine is significantly different between males and females, which may be caused by the disorders of tryptophan metabolism, steroid hormone biosynthesis, and ferroptosis pathways.

Species Differences of Bakuchiol-induced Liver Injury in Mice Based on Transcriptomics / 中国实验方剂学杂志

ObjectiveTo explore the differences in response to bakuchiol-induced hepatotoxicity between Institute of Cancer Research （ICR） mice and Kunming （KM） mice. MethodThe objective manifestations of bakuchiol-induced hepatotoxicity in mice were confirmed by acute and subacute toxicity animal experiments， and enrichment pathways of differential genes between normal ICR mice and KM mice were compared by transcriptomics. The real-time quantitative polymerase chain reaction （real-time qPCR） assay was used to verify the mRNA expression of key genes in the related pathways to confirm the species differences of bakuchiol-induced liver injury. ResultIn the subacute toxicity experiment， compared with the normal mice， the ICR mice showed increased serum content of alkaline phosphatase （ALP）， and 5′-nucleotidase （5′-NT）， without significant difference， and no manifest change was observed in KM mice. Pathological results showed that hepatocyte hypertrophy was the main pathological feature in ICR mice and hepatocyte steatosis in KM mice. In the acute toxicity experiment， KM mice showed erect hair， mental malaise， and near-death 3 days after administration. The levels of serum alanine aminotransferase （ALT） and aspartate aminotransferase （AST） in KM mice （400 mg·kg-1） significantly increased（P<0.01）， and the activity of total reactive oxygen species （SOD） in liver significantly decreased（P<0.01）compared with those in normal mice， while the serum content of 5′-NT and cholinesterase （CHE） in ICR mice （400 mg·kg-1） were significantly elevated （P<0.01）. The liver/brain ratio in ICR mice increased by 20.34% and that in KM mice increased by 29.14% （P<0.01）. The main pathological manifestation of the liver in ICR mice was hepatocyte hypertrophy， while those in KM mice were focal inflammation， hepatocyte hypertrophy， and hepatocyte steatosis. Kyoto Encyclopedia of Genes and Genomes（KEGG）and Reactome pathway enrichment analyses showed that the differential gene expression between ICR mice and KM mice was mainly involved in oxidative phosphorylation， bile secretion， bile acid and bile salts synthesis， and metabolism pathway. CYP7A1 was up-regulated in all groups with drug intervention （P<0.01） and MRP2 was reduced in all groups with drug intervention of KM mice （P<0.01） and elevated in all groups with drug intervention of ICR mice （P<0.01） compared with those in the normal group. The expression of BSEP was lowered in ICR mice with acute liver injury （400 mg·kg-1） （P<0.05）. SHP1 was highly expressed in KM mice with acute liver injury （400 mg·kg-1）. The expression of FXR was diminished in ICR mice with subacute liver injury （200 mg·kg-1） （P<0.01）. SOD1， CAT， and NFR2 significantly decreased in KM mice with acute liver injury （400 mg·kg-1）， and CAT dwindled in KM mice with subacute liver injury （200 mg·kg-1） （P<0.01）. GSTA1 and GPX1 significantly increased in KM mice with acute liver injury （400 mg·kg-1） （P<0.01） and SOD1， CAT， NRF2， and GSTA1 significantly increased in ICR mice with subacute liver injury （200 mg·kg-1） （P<0.01）. CAT and NRF2 significantly increased in ICR mice with acute liver injury （400 mg·kg-1） （P<0.01）. ConclusionWith the increase in the dosage of bakuchiol， the liver injury induced by oxidative stress in KM mice was gradually aggravated， and ICR mice showed stronger antioxidant capacity. The comparison of responses to bakuchiol-induced hepatotoxicity between ICR mice and KM mice reveals that ICR mice are more suitable for the investigation of the mechanisms related to bile secretion and bile acid metabolism in the research on bakuchiol-induced hepatotoxicity in mice. KM mice are more prone to liver injury caused by oxidative stress.

Comparative Study on Hepatotoxicity of Psoraleae Fructus in Rats and Mice / 中国实验方剂学杂志

Objective:Arrange long-term toxicity experiments by a uniform design method， so as to explore the effect of different extracts of Psoraleae Fructus on liver toxicity in rats and mice， and find the drug factors that cause psoralen liver toxicity. Method:Based on the factors of processing， extraction technology， dosage and treatment course， each experimental group was arranged by uniform design method. A total of 220 SD rats and 220 Kunming mice with half male and half female were divided into normal groups and drug groups 1 to 8. The corresponding drugs （50% alcohol extract of salt Psoraleae Fructus in rats 2.57 g·kg-1， mice 5.14 g·kg-1， 95% alcohol extract of Psoraleae Fructus in rats 0.51 g·kg-1， mice 1.02 g·kg-1， 70% alcohol extract of salt Psoraleae Fructus in rats 1.71 g·kg-1， mice 3.42 g·kg-1， water extract of Psoraleae Fructus in rats 1.03 g·kg-1， mice 2.06 g·kg-1， water extract of salt Psoraleae Fructus in rats 1.03 g·kg-1， mice 2.06 g·kg-1， 70% alcohol extract of Psoraleae Fructus in rats 1.71 g·kg-1， mice 3.42 g·kg-1， 95% alcohol extract of salt Psoraleae Fructus in rats 0.51 g·kg-1， mice 1.02 g·kg-1， 50% alcohol extract of Psoraleae Fructus in rats 2.57 g·kg-1， mice 5.14 g·kg-1） were administered by gavage daily. The body weight and food intake of the rats and mice were measured once a week. After the treatment course， the rats were anesthetized with sodium pentobarbital， and blood was taken from the abdominal aorta， and the mice were sacrificed by removing the eyeballs， and the liver and brain were taken to calculate the organ coefficients. Serum was taken to determine liver function-related indicators， and the liver was taken for histopathological examination by hematoxylin-eosin （HE） staining. Result:The liver visceral-brain ratio of female rats in group 3 were significantly increased （P<0.05）. The liver quality， visceral-body ratio and visceral-brain ratio of male mice in groups 1 to 3 were significantly increased （P<0.05， P<0.01）. Histopathological manifestations in mice were more obvious than those in rats. Histopathology showed hepatocyte hypertrophy in the central area of liver lobules in mice， in particular in group 3. According to the multiple regression equation， there were interactions between extraction technology， processing， dosage and treatment course， and the extraction technology was positively correlated with the pathological score of liver injury. Based on the results of visual analysis and other indicators， it is concluded that the extraction technology factor is most relevant to psoralen liver toxicity of Psoraleae Fructus. Conclusion:Psoraleae Fructus has the hepatotoxicity， which is related to ethanol extraction technology； alcohol extraction is more toxic than water extraction， and 70% ethanol extraction is the most toxic. Besides， there are species differences， with a more significant hepatotoxicity in mice than that in rats.

Study of macrophage polarization on pulmonary fibrosis and signaling pathway / 中国中药杂志

Macrophages are a group of immune cells with pluripotency and plasticity that can differentiate into different phenotypes under different microenvironments in vitro and in vivo. In the development of pulmonary fibrosis, there are alveolar macrophages and interstitial macrophages, which are polarized to different cell phenotypes at different stages of development. And their polarized phenotypes include M1 macrophages and M2 macrophages. In the inflammation early stages of pulmonary fibrosis, the increase of classical activated macrophages are helpful to clear pathogenic microorganisms and promote the progress of inflammation. In the fibrosis stage, the alternatively activated macrophages increased, which inhibiting the inflammatory reaction or directly promoting tissue fibrosis, on the other hand, it also promoting the fibrosis degradation. To clarify the polarization and polarization mechanisms of macrophages in pulmonary fibrosis will be conducive to the treatment of pulmonary fibrosis. In IPF, the polarization mechanism of M1 and M2 is closely related to TGF-β1/Smad. TGF-β1/Smad pathway plays an important regulatory role in liver fibrosis, renal fibrosis, myocardial fibrosis, scars, tumors and other diseases. Blocking the signaling of TGF-β1 by Smad3 and Smad4 is beneficial to inhibit the polarization of AM, which in turn helps to inhibit the progression of IPF.

Effects of Shenqi Xingnao Prescription on Learning and Memory Ability, Contents of Choline Acetyltransferase and Acetylcholine Esterase in Brain Tissue of Mice Models with Alzheimer Disease / 中国中医药信息杂志

Objective To observe the effects of Shenqi Xingnao Prescription on learning and memory ability, contents of choline acetyltransferase (ChAT) and acetylcholine esterase (AChE) in brain tissue in mice models with scopolamine-induced Alzheimer disease (AD); To investigate its mechanism for prevention and treatment for AD. Methods Totally 110 ICR mice were randomly divided into control group, control+Shenqi Xingnao Prescription high-dose group,model group,donepezil group,model+Shenqi Xingnao Prescription high-,medium-,and low-dose groups. The control and model group were given distilled water for gavage, and the other groups were given the corresponding medicine for gavage, once a day, for 14 days. On the 15th day, Morris water maze test and object recognition test were used to evaluate the learning and memory ability of each group. The model mice of memory impairment induced by intraperitoneal injection of scopolamine was established 20 minutes before the behavioral test. The expressions of ChAT and AChE in cortex and hippocampus were detected by Western blot. Results The results of Morris water maze test showed that compared with the control group, the model group had significant longer escape latency(P<0.05);Compared with the model group,Shenqi Xingnao Prescription medium-and high-dose groups could shorten the escape latency (P<0.05). The results of the object recognition test showed that compared with the control group, the ability of the model group to explore new things decreased and the discrimination index (DI) decreased (P<0.001);Compared with the model group,Shenqi Xingnao Prescription groups could increase the DI of model mice (P<0.05, P<0.01, P<0.001). The results of Western blot showed that the expression of AChE protein in the cortex and hippocampus of the model group was significantly higher than the control group (P<0.01); Compared with the model group, Shenqi Xingnao Prescription low- and medium-dose groups could decrease the expression of AChE in the cortex in different degrees(P<0.01);Shenqi Xingnao Prescription groups could decreaed the expression of AChE in the hippocampus (P<0.001); There was no significant statistical significance in the expression of ChAT in the cortex and hippocampus in each group.Conclusion Shenqi Xingnao Prescription can significantly improve the learning and memory ability of AD model mice induced by scopolamine, which may be related to the descent expression of AChE protein in the cortex and hippocampus of the model mice.

Origin of lifting and lowering theory and its herb pair study / 中国中药杂志

Lifting and lowering theory is one of the important basis for guiding clinical medication. Through the study of ancient books and literature, we learned that lifting and lowering theory was originated in Huangdi Neijing, practiced more in the Shanghan Zabing Lun, established in Yixue Qiyuan, and developed in Compendium of Materia Medica and now. However, lifting and lowering theory is now mostly stagnated in the theoretical stage, with few experimental research. In the clinical study, the guiding role of lifting and lowering theory to prescriptions?mainly includes opposite?role?of lift and lower medicine property, mutual promotion of lift and lower medicine property, main role of lift medicine property and main role of lower medicine property. Under the guidance of lifting and lowering theory, the herb pair compatibility include herb combination of lift medicine property, herb combination of lift and lower medicine property and herb combination of lower medicine property. Modern biological technology was used in this study to carry out experimental research on the lifting and lowering theory, revealing the scientific connotation of it, which will help to promote clinical rational drug use.

Analysis of historical origin and standardization system construction of Citri Grandis Exocarpium / 中国中药杂志

To understand the history development and changes of Citri Grandis Exocarpium and initially establish its standard system after exploring the historical origins and modern development of Citri Grandis Exocarpium. In CNKI, Wanfang database and other academic search platforms were searched for literature on Citri Grandis Exocarpium and Chinese medicine standard system； the books related to its modern cultivation techniques and processing technology were also accessed, and after combining with the actual situation analysis, the prospective design of the standard system of Citri Grandis Exocarpium was finally established with research conclusion. The earliest records of the Citri Grandis Exocarpium were documented in the Northern and Southern Dynasties, but its medicinal value was discovered in the Song Dynasty. Its drug use was developed on the basis of Jupi（orange peel） and Citri Exocarpium Rubrum. In 21st century, a number of large-scale, intensive Citri Grandis Exocarpium bases have been formed due to high price, good planting efficiency, and rapid growth of cultivation areas. The standard system includes the technical specifications of seed selection and seedling cultivation of Citri Grandis Exocarpium, technical norms of cultivation, technical specifications of fertilizing and weeding, technical specifications of irrigation and drainage, technical standard of pest and disease control, standard of medicinal materials grade, standard of processing technology of sliced pieces and the quality standard of slices, etc.

National physician master Jin Shiyuan's dispensing technology of Rehmanniae Radix Praeparata based on Li Shizhen's pharmaceutical academic thought / 中国中药杂志

To collect the historical origin, processing methods and clinical application of Rehmanniae Radix Preparata in Compendium of Materia Medica, compare and analyze the theoretical knowledge and relevant practical operation of national physician master Jin Shiyuan, which is beneficial for the inheritance and development of Rehmanniae Radix Preparata's clinical dispensing technology. In the analysis process, CNKI was searched with "Rehmanniae Radix Preparata", "Processing method", "Clinical application" "Li Shizhen", "Jin Shiyuan", and "Dispensing technology" as keywords. In addition, Shennong's Herbal Classic, Bencao Tujing (illustrated Classics of Materia Medica), Compendium of Materia Medica, Jingyue Quanshu (Jingyue's Complete Works) and related ancient books were accessed systematically to summarize the historical change of processing methods and efficacy of Rehmanniae Radix Praeparata. Professor Jin Shiyuan emphasizes the clinical dispensing technology of Rehmanniae Radix Praeparata, including its nature identification technology, clinical processing technology, prescription audit technology, prescription coping technology, drug delivery technology, clinical decocting technology, purchasing management technology as well as storage, maintenance and supply technology. Through the collation and research, it was confirmed that historical origin, processing methods and clinical application of Rehmanniae Radix Preparata were recorded in details in Compendium of Materia Medica. Steaming method of Rehmanniae Radix Preparata was originated from Synopsis of Golden Chamber. Li Shizhen attached great importance to the processing method of "steaming and drying alternatively for nine times" for Rehmanniae Radix Preparata, and differentiated it from Radix Rehmanniae Recen and fresh rehmannia root in clinical applications. Professor Jin Shiyuan has developed and improved the clinical dispensing technology of Rehmanniae Radix Praeparata, and carried forward the essence of Li Shizhen's pharmaceutical academic thought with his own proficient knowledge structure in medicine, providing scientific pharmaceutical service for clinical application of Rehmanniae Radix Preparata in future.

National physician master Jin Shiyuan's dispensing technology of Aconiti Lateralis Radix Praeparata based on Li Shizhen's pharmaceutical academic thought / 中国中药杂志

To collect Li Shizhen's experience in Aconiti Lateralis Radix Praeparata identification and clinical application, compare and analyze national physician master Jin Shiyuan's practical operation and theoretical knowledge, which is beneficial for the inheritance and improvement of Aconiti Lateralis Radix Praeparata clinical dispensing technology. In the analysis process, CNKI, Wanfang and other databases were searched with "Aconiti Lateralis Radix Praeparata", "Li Shizhen", "pharmacological method state theory" "Jin Shiyuan" and "Chinese medicine dispensing technology" as the key words. In addition, Treatise on Febrile Disease, Compendium of Materia Medica, Chinese Pharmacopoeia(2015 edition), Notes to Medical Professions(Yi Zong Shuo Yue), and other medicine books were accessed to summarize the processing methods and decoction dosage of Aconiti Lateralis Radix Praeparata in both ancient and modern medicine, and in consideration of technical research and practice operation, Li Shizhen's description of Aconiti Lateralis Radix Praeparata and Professor Jin Shiyuan's research on Aconiti Lateralis Radix Praeparata dispensing technology were analyzed and collected. Li Shizhen recorded the nature identification and clinical application of Aconiti Lateralis Radix Praeparata by using pharmacological method state theory in Compendium of Materia Medica. National physician master Jin Shiyuan carries forward the essence of Li Shizhen's pharmaceutical academic thought with his own proficient knowledge structure in medicine, providing scientific pharmaceutical service for clinical application of Aconiti Lateralis Radix Praeparata Professor. Jin Shiyuan put forward the dispensing technology for the first time, including nature identification technology, clinical processing technology, clinical decocting technology, prescription coping technology, and class specifications of Aconiti Lateralis Radix Praeparata. In this paper, Aconiti Lateralis Radix Praeparata was used as an example to analyze the key dispensing technology of traditional Chinese medicine, and apply the key dispensing technology of traditional Chinese medicine in various commonly used Chinese medicines in the future.