TMT-Based Proteomics Reveal the Mechanism of Action of Amygdalin against Rheumatoid Arthritis in a Rat Model through Regulation of Complement and Coagulation Cascades.

The limitations of current medications for treating rheumatoid arthritis (RA) emphasize the urgent need for the development of new drugs. This study aimed to investigate the potential anti-RA mechanism of amygdalin using tandem mass tag (TMT)-based quantitative proteomics technology. First, the anti-RA activity of amygdalin was evaluated in a Complete Freund's adjuvant (CFA)-induced rat model. Then, the roles and importance of proteins in the extracted rat joint tissue were evaluated using TMT-based quantitative proteomics technology. A bioinformatics analysis was used to analyze differentially abundant proteins (DAPs). A proteomics analysis identified 297 DAPs in the amygdalin group compared with the model group, of which 53 upregulated proteins and 51 downregulated proteins showed opposite regulatory trends to the DAPs produced after modeling. According to enrichment analyses of the DAPs, the signaling pathways with a high correlation degree were determined to be the complement and coagulation cascades. Furthermore, western blotting and molecular docking were used to further validate the key node proteins, e.g., complement C1s subcomponent (C1s), component C3 (C3) and kininogen 1 (Kng1). These results suggest that amygdalin may be a promising agent for treating RA by regulating the complement and coagulation cascades.

Reversible structural transformations and color-tunable emissions in organic manganese halides.

Herein, we for the first time report a reversible conversion between green-emissive [DMPZ]MnCl4 and red-emissive [DMPZ]4(MnCl6)(MnCl4)2·(H2O)2 (DMPZ = 1,4-dimethylpiperazine) using kinetic and thermodynamic controlling strategies. Significantly, the synchronous structural and emission transformations in single-component organic manganese halides with adjustable emission colors are highlighted.

Insight of "Yin-Jing" medical property ofLigusticum chuanxiong Hort. via pharmacokinetics and tissue distributions by ultra-performance liquid chromatography-triple quadrupole mass spectrometry.

ETHNOPHARMACOLOGICAL RELEVANCE: Ligusticum chuanxiong Hort. (Chuanxiong, LC), as an important traditional Chinese medicine (TCM), can not only be used as a monarch herb but also be used as a classic "Yin-Jing" () medicine in compound prescriptions, e.g., Buyang Huanwu Decoction (BHD). Although LC has the effect of guiding components into the brain in BHD, there is still a lack of scientific evidence on this "Yin-Jing" effects. Herein, we used pharmacokinetics and tissue distributions to investigate "Yin-Jing" effects of LC. To simplify the study, four major constituents in BHD, i.e., Calycosin (CA), astragaloside IV (AI), paeoniflorin (PA), and amygdalin (AM) were combined to form a simple compound (abbreviated as CAPA here) to replace the original BHD in this paper. The Yin-Jing medical property of LC was confirmed by the compatibility of CAPA with LC or its different fractions (Fr. A âˆ¼ Fr. F). AIM OF THE STUDY: To explore the "Yin-Jing" medical property of LC via pharmacokinetics and tissue distributions by ultra-performance liquid chromatography-triple quadrupole mass spectrometry (UPLC-QQQ-MS). MATERIALS AND METHODS: The contents of CA, AI, PA, and AM were simultaneously determined by the established and validated UPLC-QQQ-MS method in different rat tissues and plasma after administration of CAPA with the combination of LC or Fr. A âˆ¼ Fr. F. The pharmacokinetic parameters, e.g., Tmax, Cmax, AUC0-t and MRT0-t, were calculated to evaluate the efficiency of "Yin-Jing". RESULTS: The Cmax and AUC0-t of CA, AI, PA, and AM were remarkably increased in rat brain tissues compared with those of the control group after compatibility of LC. This demonstrated that LC has the Yin-Jing effects on brain tissues. Additionally, Fr. B or Fr. C might be the material basis by specifically studying the distributions of CA, AI, PA, and AM in brain tissue based on mutual compatibility. The effects of Fr. B and Fr. C on distributions of these constituents in other tissues or plasma was also studied to verify the effects of Yin-Jing of LC. The results showed that the same upward trend is found in heart, liver and plasma, but the intensity is insignificant as that in brain tissue. Furthermore, the Cmax and AUC0-t of some analytes in the rat spleen, lung, and kidney were significantly decreased compared with the control group (P < 0.05 or 0.01). CONCLUSIONS: LC has the function of Yin-Jing, especially guiding the components into the brain tissue. Moreover, Fr. B and Fr. C is suggested to be the pharmacodynamic material basis for the effect of Yin-Jing of LC. These finding explained that it was recommended to add LC into some prescriptions for treating cardiovascular and cerebrovascular diseases caused by Qi deficiency and blood stasis. This has laid a certain foundation for the research on the Yin-Jing efficacy of LC to better clarify the theory of TCM and guide the clinical application of Yin-Jing drugs.

[Retrospective analysis and discussion on 74 cases of adverse reactions of traditional Chinese medicine injection].

As a modern dosage form drug with rapid effect, traditional Chinese medicine (TCM) injection has been more and more used in clinical practice. Meanwhile the safety of TCM injection has attracted more and more attention. The retrospective analysis on 74 cases of adverse reaction of TCM injections collected from 2007 to 2016 in the Third Affiliated Hospital of Beijing University of Chinese Medicine showed that the proportion of men and women with adverse reactions was 0.54:1; the average age was 62.5 years old; 21 kinds of TCM injections were involved. Among them, the most reported were blood-regulating agents. The top four kinds of TCM injections with highest adverse drug reactions (ADRs) were Tanreqing injection, Danhong Injection, Shuxuening Injection and Xuesaitong for injection. The top three clinical manifestations of adverse reactions were lesions of skin and its appendages, damage of circulatory system and damage of nervous system. The potential causes of the adverse reactions of TCM injections were analyzed, and it was believed that individual difference, medicine, pharmaceutical excipients, solvent and TCM syndrome differentiation may be the main five causes for the adverse reactions of TCM injections. In order to reduce the adverse reactions of TCM injections, it is suggested that the clinical pharmacists should participate in the application management of TCM injections in the hospital; the production enterprises shall strengthen the whole life cycle management of the drugs; and at the same time, the drug control and administration authorities should improve the drug management methods constantly and encourage the development of TCM injections to the high quality level.

Reagent-Controlled Tandem Reactions of Vinyl Epoxides: Access to Functionalized γ-Butenolides.

A new approach to functionalized γ-butenolides based on reagent-controlled tandem reaction sequences of Morita-Baylis-Hillman-type vinyl epoxides is described. The nucleophilic addition of a tertiary phosphine to the electron-deficient alkene led to ring-opening of the epoxide followed by lactonization to produce phosphonium ylides, which could undergo Wittig olefination with aryl trifluoromethyl ketones and aryl aldehydes to give 3-alkenyl γ-butenolides in moderate to good yields and high E/Z selectivity. Tertiary amine promoted the Michael-type addition of carbon- and nitrogen-based nucleophiles to the vinyl epoxides followed by lactonization to provide diverse 3-substituted γ-butenolides.

[Safety grade of application of traditional Chinese medicines during pregnancy].

The efficacy and safety of application of traditional Chinese medicines (TCMs) during the pregnancy is a hotspot among scholars. However, the traditional pregnancy contraindication content has certain historical limitations, and cannot meet the needs of the current pregnant women for rational drug use. We need to refine and interpret it with modern medical science. In this paper, we summarized the ancient and modern knowledge about pregnancy contradiction and tried to establish a grading safety system, based on the actual clinical practices and thte medication grading concept of western medicines. Specifically speaking, in this paper, we compared the connotations of forbidden/contradiction and cautious use, and focused on the safe herbs that included in the prescriptions for dietary therapy. Meanwhile, in this paper, we summarized the core content of the famous theories of ″You Gu Wu Yun (pregnancy disease)″ and ″Shuai Qi Da Ban Er Zhi (therapy during pregnancy)″, and studied the dangerous and unknown risk of TCMs during pregnancy. At last, a five-grade safety system of TCMs applied on the pregnant women was established, including forbidden, contraindicated, cautious, uncertain and available medicines. We classified medicines with the embryotoxicity (e.g. teratogenic, mutagenic, ageneisa), the traditional toxicity (e.g. abortion), the fierce herbal property (e.g. removing blood stasis, promoting Qi circulation) and reliable edible medicinal herbs. We also place an ″uncertain″ category based on objective reality. Meanwhile, 33 sample TCMs were preliminarily determined. This paper proposed the preference and ideas for the rational herbal use in pregnancy.

[Construction and practice on rational medication model of Chinese patent medicine for orthopedics based on ″symdrome-dosage-toxicity differentiation″ theory].

Chinese patent medicines for orthopedics are among the hotspot and difficulty in the rational medication of traditional Chinese medicine (TCM), because they mostly contain toxic medicinal herbs and oriented to special patients. According to the hospital pharmacy practices and the therapeutic theories of TCM, this paper focused on a novel model of rational drug use of Chinese patent medicine for orthopedics based on the principles of ″syndrome-dosage-toxicity differentiation″. We also proposed relevant specifications for guiding their clinical use. Firstly, we proposed a list of the primary clinical application characteristics for rational drug use of orthopedic TCMs, including the syndromes of patient, the dosage of medicine and the toxic ingredients in medicine. Secondly, a database was established for recording the package inserts of all of the 81 orthopedic patent medicines in our hospital, and 2 000 retrospective recipes were analyzed for looking for the high-frequency medicines and common irrational factors. Then clinical case reports involving the adverse reactions and side effects of related drugs were searched from CNKI, VIP and WanFang databases. Then the key information for rational application of each medicine was extracted from these resources and some survey questionnaires. Finally, we established a guide named instructions for clinical use of orthopedic Chinese patient medicines (ICUOCPM) after the discusstion with experts. According to the effect after the practice in hospital for 2 months, the proposed principles of ″syndrome-dosage-toxicity differentiation″ in this paper were believed to be the core elements and the most important clinical monitoring points in TCM for orthopedic patents. It would provide innovative ideas, theoretical guarantee and data support for the development of TCM clinical pharmacy.

[Preliminary study on general safe medication regularity of Chinese patent orthopedic medicines based on adverse reaction/event literature analysis].

Chinese patent orthopedic medicines feature complex components, mainly including desperate and toxic herbal pieces, narrow safety window, more clinical contraindications and frequent adverse drug reaction/events (ADR/ADE). To study the general safe medication regularity of Chinese patent orthopedic medicines, define key points in the medication education and ensure rational clinical medication, the authors took 80 types of commonly used Chinese patent orthopedic medicines as the study objects, collect 237 cases from 164 ADR/ADE documents through a system retrieval strategy, make a multidimensional literature analysis to determine the common risk factors for safe and rational medication of Chinese patent orthopedic medicines and establish an ADR/ADE prevention regularity. First, in the aspect of clinical symptoms, skin allergy is the most common ADR/ADE and closely related to the toxic ingredients, particularly accumulated liver or kidney damage caused by some drugs. Second, there are three time nodes in the ADR/ADE occurrence; The ADR/ADE occurred in 30 minutes is closely related to the idiosyncrasy; the ADR/ADE occurred between several months and half a year is related to the drug-induced liver and kidney damages; The most common ADR/ADE was observed within 7 days and predictable according to the pharmacological actions; Third, toxicity is an important factor in the occurrence of ADR/ADE of Chinese patent orthopedic medicines. Fourth, emphasis shall be given to the special medication factors, such as the combination with western medicines and Chinese herbal decoctions, overdose and long-course medication and self-medical therapy. In conclusion, the general ADR/ADE prevention regularity for Chinese patent orthopedic medicines was summarized to provide supports for clinicians in safe and rational medication and give the guidance for pharmacist in medication education.

Antifibrotic effects of ZK14, a novel nitric oxide-donating biphenyldicarboxylate derivative, on rat HSC-T6 cells and CCl4-induced hepatic fibrosis.

AIM: To study the pharmacologic effect of ZK(14), a novel nitric oxide-donating biphenyldicarboxylate (DDB) derivative, on HSC-T6 cells and on CCl(4)-induced hepatic fibrosis. METHODS: Inhibition of HSC-T6 cell growth by ZK(14) was evaluated by MTT assay. The effect of ZK(14) on the percentage of HSC-T6 cells undergoing apoptosis was measured using Annexin-V/PI double-staining and TUNEL assay. Mitochondrial membrane potential (MMP) and caspase activities were tested. Hepatic fibrosis was induced in Sprague-Dawley rats by intraperitoneal injection with 14% CCl(4). Rats with hepatic fibrosis were randomly divided into four groups: model control, ZK(14) (20 mg/kg), ZK(14) (10 mg/kg) and DDB (5 mg/kg). Levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), hyaluronic acid (HA), type III collagen (PCIII), and nitric oxide (NO) were assessed, and liver samples were stained with hematoxylin-eosin. The NO level in cells treated with ZK(14) in vitro was also measured. RESULTS: The effect of ZK(14) on HSC-T6 cell apoptosis was concentration- and time-dependent, with up to 50% of cells becoming apoptotic when exposed to 100 mumol/L ZK(14) for 18 h. ZK(14) treatment resulted in mitochondrial membrane depolarization and activation of caspases 3 and 9. At a dose of 20 mg/kg, ZK(14) significantly decreased serum transaminase (AST, ALT) activities and fibrotic index (HA, PCIII) levels and significantly inhibited fibrogenesis. CONCLUSION: These data indicate that ZK(14), a novel NO-donating DDB derivative, promotes HSC-T6 apoptosis in vitro through a signaling mechanism involving mitochondria and caspase activation and it inhibits CCl(4)-induced hepatic fibrosis in vivo. The results suggest that ZK(14) has potential therapeutic value in the treatment of hepatic fibrosis.

Synthesis and biological evaluation of nitric oxide-donating thalidomide analogues as anticancer agents.

In search of more potent anticancer agents, 15 nitric oxide (NO)-donating thalidomide analogues, 6a, 6b, 8a-8e, and 13a-13h, were designed and synthesized. Cytotoxicity of these compounds was evaluated in vitro against three human tumor cell lines (HepG2, A549, and PC-3). The results indicated that 13a-13d exhibited notable anticancer activities comparable to or stronger than that of 5-fluorouracil (5-FU). Structure-activity relationships were also discussed, based on the experimental data obtained. Generally, the cytotoxic activity of target compounds is closely related to the type of NO donors, and the length of the spacers connecting to NO donors also appears important for the bioactivities.

Synthesis and cytotoxic evaluation of novel dimethyl [1,1'-biphenyl]-2,2'-dicarboxylates bearing 1,3,4-thiadiazole moieties.

In search of novel anticancer agents, two series of dimethyl [1,1'-biphenyl]-2,2'-dicarboxylate derivatives, 8a-8k and 9a-9k, containing both methylenedioxy and 1,3,4-thiadiazole moieties were designed and synthesized. Cytotoxicity of these compounds was evaluated in vitro against five human tumor cell lines, i.e., HepG2, KB, A549, K562, and MCF-7. The results indicated that 8h, 8j, 8k, 9d, 9g, 9h, 9j, and 9k showed notable anticancer activities comparable to or stronger than that of 5-fluorouracil, a canonical anticancer drug. Structure-activity relationships were also discussed based on the experimental data obtained.

A novel synthetic oleanolic acid derivative (CPU-II2) attenuates liver fibrosis in mice through regulating the function of hepatic stellate cells.

UNLABELLED: Regulation on the function of the hepatic stellate cells (HSCs) is one of the proposed therapeutic approaches to liver fibrosis. In the present study, we examined the in vitro and in vivo effects of CPU-II2, a novel synthetic oleanolic acid (OLA) derivative with nitrate, on hepatic fibrosis. This compound alleviated CCl4-induced hepatic fibrosis in mice with a decrease in hepatic hydroxyproline (Hyp) content and histological changes. CPU-II2 also attenuated the mRNA expression of alpha-smooth muscle actin (alpha-SMA) and tissue inhibitor of metalloproteinase type 1 (TIMP-1) induced by CCl4 in mice and reduced both mRNA and protein levels of alpha-SMA in HSC-T6 cells. Interestingly, CPU-II2 did not affect the survival of HSC-T6 cells but decreased the expression of procollagen-alpha1 (I) in HSC-T6 cells through down-regulating the phosphorylation of p38 MAPK. CONCLUSION: CPU-II2 attenuates the development of liver fibrosis rather by regulating the function of HSCs through p38 MAPK pathway than by damaging the stellate cells.

[Investigation and confirmatory factor analysis of information collected with the four diagnostic methods in patients with bronchial asthma].

OBJECTIVE: To investigate the information acquired through the four diagnostic methods of traditional Chinese medicine in patients with bronchial asthma, and to classify the syndrome types. METHODS: Four hundred and thirty patients with bronchial asthma were randomly investigated. The information acquired through the four diagnostic methods was recorded and the database was established by Amos software, and then the data were analyzed by confirmatory factor analysis (CFA). RESULTS: After analyzing the data with 4 factors, 5 factors and 6 factors, we found that the results of CFA with 6 factors were in accordance with clinical practical experience. CONCLUSION: According to the results of CFA with 6 factors and with the standard regression coefficient 0.4 as primary and secondary critical points, the syndromes in patients with bronchial asthma can be classified into 5 types, which are syndromes of cold fluid retained in lung, phlegm-heat obstructing lung, wind-phlegm blocking lung, qi deficiency of lung and kidney and qi deficiency of spleen.