[Effect and mechanism of aqueous extract of Strychni Semen on bone destruction in rats with type â ¡ collagen-induced rheumatoid arthritis].

To investigate the mechanism of action of aqueous extract of Strychni Semen(SA) on bone destruction in rats with type Ⅱ collagen-induced arthritis(CIA), the SD rats were randomly divided into normal group, model group, low, medium, and high dose(2.85, 5.70, and 11.40 mg·kg~(-1)) groups of SA, and methotrexate group. Except for the normal group, the CIA model was prepared for the other groups. After the second immunization, different doses of SA were given to the low, medium, and high dose groups of SA once a day, and the methotrexate group was given once every three days. 0.3% sodium hydroxymethylcellulose(CMC-Na) was given once a day to the normal and model groups for 28 d. The clinical score of arthritis was evaluated every three days. Micro computed tomography(Micro-CT) method was used to evaluate the degree of bone destruction. Histopathological changes in the joint tissue and the number of osteoclasts in CIA rats were evaluated by hematoxylin-eosin(HE) staining and tartrate-resistant acid phosphatase(TRAP) staining. The expression of interleukin-1ß(IL-1ß) in the joint tissue of rats was detected by immunohistochemistry. Western blot was used to detect key protein expression in mitogen-activated protein kinase(MAPK) and phosphatidylinositol 3-kinase/protein kinase B(PI3K/Akt) signaling pathways in the joint tissue of rats. The results showed that different doses of SA were able to improve the red and swollen inflammatory joint and joint deformity in CIA rats to varying degrees, reduce the clinical score, inhibit synovial inflammation, vascular opacification, cartilage erosion, and bone destruction, and reduce the number of TRAP-positive cells in bone tissue. Micro-CT results showed that the SA was able to increase bone mineral density, bone volume fraction, trabecular reduce, and trabecular number and reduce bone surface/bone volume and trabecular separation/spacing. Different doses of SA could down-regulate the protein expression of IL-1ß, p-JNK, p-ERK, p-p38, PI3K, and p-Akt to varying degrees. In conclusion, SA can improve disease severity, attenuate histopathological and imaging changes in joints, and have osteoprotective effects in CIA rats, and its mechanism of action may be related to the inhibition of the overactivation of MAPK and PI3K/Akt signaling pathways.

[Mechanism of aqueous extract of Strychni Semen in improving pain in rats with rheumatoid arthritis based on TLR4/TNF-α/MMP-9 signaling pathway].

This study aims to explore the mechanism of aqueous extract of Strychni Semen(SA) in relieving pain in the rat model of rheumatoid arthritis(RA) via Toll-like receptor 4(TLR4)/tumor necrosis factor-α(TNF-α)/matrix metalloproteinase-9(MMP-9) signaling pathway. Firstly, the main chemical components of Strychni Semen were searched against TCMSP, TCMID, ETCM, and related literature, and the main targets of the chemical components were retrieved from TargetNet and SwissTargetPrediction. The main targets of RA and pain were searched against GeneCards, Online Mendelian Inheritance in Man(OMIM), and Therapeutic Target Database(TTD). Venny 2.1.0 was used to obtain the common targets shared by Strychni Semen, RA, and pain, and STRING and Cytoscape 3.6.1 were used to build the protein-protein interaction network. Then, molecular docking was carried out in AutoDock Vina. Finally, the rat model of type Ⅱ collagen-induced arthritis(CIA) was established. The up-down method and acetone method were employed to examine the mechanical pain threshold and cold pain threshold of rats, and the pain-relieving effect of SA on CIA rats was evaluated comprehensively. Hematoxylin-eosin(HE) staining was employed to evaluate the histopathological changes of joints in CIA rats. The expression levels of key target proteins was determined by immunohistochemistry and Western blot, and the mRNA levels of key targets were determined by real-time fluorescence quantitative polymerase chain reaction(real-time PCR). The results of network prediction showed that Strychni Semen may act on the TLR4/TNF-α/MMP-9 signaling pathway to exert the pain-relieving effect. The results of molecular docking showed that brucine, the main active component of SA, had strong binding ability to TLR4, TNF-α, and MMP-9. The results of animal experiments showed that SA improved the mechanical and cold pain sensitivity(P<0.05, P<0.01) and reduced the joint histopathological score of CIA rats(P<0.01). In addition, medium and high doses of SA down-regulated the protein and mRNA levels of TNF-α, TLR4, and MMP-9(P<0.05,P<0.01). In conclusion, SA alleviated the mechanical pain sensitivity, cold pain sensitivity, and joint histopathological changes in CIA rats by inhibiting the over activation of TLR4/TNF-α/MMP-9 signaling pathway.

[Knowledge map analysis of research progress of Strychni Semen based on CiteSpace].

To analyze the study advance of Strychni Semen, a kind of traditional Chinese medicine, this study systematically retrieved the related Chinese literatures about Strychni Semen from CNKI database platforms and the core database of Web of Science, and used bibliometrics and CiteSpace 5.6.R5 software to visually display the authors, research institutions, keywords and other contents. A total of 1 895 Chinese literatures and 1 599 English literatures were included in the study. The analysis of Chinese and English literature authors showed that CAI Bao-chang and CHEN Jun had the most publications on Strychni Semen, and CAI Bao-chang's team was the core research team. According to the analysis of publishing institutions, Nanjing University of Traditional Chinese Medicine and Chinese Academy of Science were the research institutions with the largest number of Chinese and English literatures, respectively. But there was less cooperation between Chinese and English study institutions. The analysis of keywords in Chinese and English literatures showed that the research contents of Strychni Semen mainly focused on component analysis, research methods, receptor targets, clinical application, synergistic and attenuation measures. Break analysis showed that the apoptosis induced by Strychni Semen was a hot research topic, and research on components, toxicity and pharmacokinetics will be the research hotspot in future. The research on Strychni Semen is still in the developing period. This study has provided reference for the rapid grasp of the research contents and the judgment of research hotspots.

A discovery in traditional Chinese medicine compatibility: Cinnabaris suppresses the Strychni Semen-induced neurotoxicity in Shang-Ke-Jie-Gu tablet.

BACKGROUND: Cinnabaris, as a commonly used mineral drugs, is a classic sedative medicine. Shang-Ke-Jie-Gu tablet is a famous Chinese patent medicine with Cinnabaris, However, the function of Cin in the prescription hasn't been clarified. PURPOSE: Our study evaluated the toxicity of Shang-Ke-Jie-Gu tablet (SK) with or without Cinnabaris, and illuminate the related mechanisms that why cinnabaris is necessary. METHODS: The toxicity of SK and Cin free Shang-Ke-Jie-Gu tablet (CFSK) was evaluated by physical and behavioral tests and histological examinations. The detoxificaion mechanism of Cin on Strychni Semen (SS)-induced neurotoxicity in SK was performed based on the analysis of intestinal absorption, liver metabolism, serum metabolomics, and gut microbiota. The mercury accumulation of SK was assayed using human hair by ICP-MS. RESULTS: Cin was found to inhibit the neurotoxicity of SS in SK. Our study shows that Cin could inhibit SS's absorption in small intestine and promote its metabolism in the liver. A serum metabolomics study showed that taurine and hypotaurine metabolism and retrograde endocannabinoid signaling pathway were associated with Cin attenuation. Association analysis with gut microbiota suggested that Cin could downregulate four key metabolites, including 12­hydroxy arachidonic acid, GM4(d18:1/18:0), C16 sphinganine, and LysoPC(18:1(11Z)/0:0), by downregulating Lachnospiraceae_NK4A136 and upregulating Prevotella to inhibit the toxic effects of SS. In addition, the danger of mercury poisoning in a longer time administration of SK was evaluated using human hair, and no visible increase in mercury was observed. CONCLUSION: As a new discovery in compatibility, Cin was proved to be capable of inhibiting the neurotoxicity not only in SK but also in Cin-SS combination, displaying vital roles in Traditional Chinese Medicines.

Strychni Semen Combined with Atractylodes Macrocephala Koidz Attenuates Rheumatoid Arthritis by Regulating Apoptosis.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disease that can lead to joint pain and disability, and seriously impact patients' quality of life. Strychni Semen combined with Atractylodes Macrocephala koidz (SA) have pronounced curative effect on RA, and there is no poisoning of Strychni Semen (SS). However, its pharmacological mechanisms are still unclear. OBJECTIVE: In this study, we aimed to investigate the pharmacological mechanisms of Strychni Semen combined with Atractylodes Macrocephala Koidz (SA) for the treatment of RA. METHODS: We used network pharmacology to screen the active components of SA and predict the targets and pathways involved. Results originating from network pharmacology were then verified by animal experiments. RESULTS: Network pharmacology identified 81 active ingredients and 141 targets of SA; 2640 disease-related genes were also identified. The core targets of SA for the treatment of RA included ALB, IL-6, TNF and IL-1ß. A total of 354 gene ontology terms were identified by Gene ontology (GO) enrichment analysis. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis results showed that SA was closely associated with TNF signaling pathways in the treatment of RA. Furthermore, according to the predicted results of network pharmacology, we established a rat model of Adjuvant arthritis (AA) for in vivo experiments. Analysis showed that each treatment group led to an improvement in paw swelling, immune organ coefficient and synovial tissue morphology in AA rats to different degrees, inhibit the expression levels of IL-1ß, TNF-α and IL-6, upregulated the levels of Fas, Bax and Caspase 3, down-regulated the expression levels of Fas-L, Bcl-2 and p53. CONCLUSION: SA has an anti-RA effect, the mechanism underlying the therapeutic action of SA in AA rats was related to the regulation of apoptosis signaling pathways.

Mechanism of Action of Strychni Semen for Treating Rheumatoid Arthritis and Methods for Attenuating the Toxicity.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disease, which affects the joints and causes significant pain, impairing patient's quality of life. Strychni semen showed promising results to treat RA. However, there are increasing safety concerns in using strychni semen due to its severe toxicity. AIM AND OBJECTIVE: The purpose of this review is to provide insight into using Strychni semen as an alternative medicine to treat RA, as well as to offer a method for the safe application of Strychni semen through processing and compatibility studies. METHODS: Publications were retrieved and surveyed from CNKI and PubMed relevant to Strychni semen for a literature review. RESULTS: This article summarized the mechanism of function of strychni semen in treating RA with its anti-inflammatory, analgesic, and immunomodulatory effect. Commonly used methods to attenuate the toxicity of Strychni semen were also discussed in this article. CONCLUSION: Strychni semen has a good therapeutic effect on RA, mainly by the modulation of immunity with anti-inflammatory and analgesic effects. Also, the reported toxicity of strychni semen can be effectively reduced by processing and compatibility methods. Hence, as an alternative medicine for RA treatment, strychni semen has a broad prospect.

Strychnine poisoning due to traditional Chinese medicine: a case series.

Background: Strychnine poisoning is rare but possibly fatal. The most reported sources of strychnine poisoning include rodenticides and adulterated street heroin. Here we report a case series of an unusual cause of strychnine poisoning - Strychnisemen, a herb known as "maqianzi" in traditional Chinese medicine (TCM). Methods: All cases of strychnine poisoning confirmed by the Hospital Authority Toxicology Reference Laboratory (HATRL, the highest-level clinical toxicology laboratory in Hong Kong) between May 2005 and May 2018 were reviewed. Results: Twelve cases of strychnine poisoning were recorded, and Strychni semen was the exclusive source. Ten (83.3%) patients presented with muscle spasms, and four (33.3%) developed typical conscious convulsions. The poisoning was severe in two (16.7%) patients, moderate in three (25%) and mild in eight (58.3%). No case fatality was recorded. Three (25%) patients were TCM practitioners and two (16.7%) were laymen who bought the herb themselves without a proper prescription. Conclusion: The practice of TCM is becoming popular in different parts of the world amid the COVID-19 pandemic. The spectrum of clinical features of strychnine poisoning secondary to Strychni semen are similar to those arising from different origins. Eliciting a history of TCM use, apart from exposure to rodenticides and drugs of abuse, may allow timely diagnosis in patients with compatible clinical features. Enhancement of TCM safety could minimize the hazard.