Macrophage migration inhibitory factor (MIF) is a classical pro-inflammatory cytokine that plays an important role in the innate and adaptive immune regulation. In recent years, a large number of studies have demonstrated that the expression level of MIF is significantly increased in a variety of tumor tissues and MIF promotes the occurrence and development of tumors. MIF participates in the regulation of tumor growth, metastasis, angiogenesis, as well as induces and maintains the tumor microenvironment. Targeting MIF has been considered as a candidate strategy against cancer. In this review, the structural features, the signaling pathway, the biological functions of MIF are briefly outlined. Moreover, approaches that target MIF in the treatment of cancer are also summarized.

Free fatty acid receptor 1 (FFAR1), also known as G protein-coupled receptor 40 (GPR40), is a receptor for diverse free fatty acids. This review aims at summarizing effects and mechanisms of FFAR1 on insulin secretion and related blood glucose and lipids metabolism. FFAR1 is involved in the occurrence and development of type 2 diabetes, but its specific mechanism has not been clarified. FFAR1 is expressed in the wide variety of issues, especially β-cells in the pancreatic islets, as well as α-cells in islets, central nervous tissue, subcutaneous fat, skeletal muscle, gastrointestinal tract, etc. FFAR1 can act on islet β-cells to promote the secretion of insulin, promote α-cells on glucagon secretion, and regulate the secretion of endocrine cells in the gastrointestinal tract to balance the level of glucose and lipids. Existing research found that FFAR1 agonists have significant advantages. They promote insulin release, reduce weight and protect pancreatic β-cells, and have no risk of hypoglycemia. To in-depth understand the role of FFAR1 as a drug target in the treatment of diabetes, further pharmacological studies are still needed in order to obtain safer and more effective drugs against type 2 diabetes.

Pulmonary hypertension (PH) is a progressive cardiopulmonary disease with high mortality and increased prevalence. The target therapy of pulmonary hypertension is mainly dependent on vasodilation, but how to improve vascular remodeling with stem cell therapy has not been fully understood. Over the past ten years, the researches on endothelial progenitor cells, mesenchymal stem cells and pluripotent cells have brought the hope to patients with pulmonary hypertension. This article mainly introduces the latest progress of stem cell technology in the intervention of pulmonary hypertension, and discusses the problems in the application.

Indoleamine 2, 3-dioxygenase 1 (IDO1) is a key enzyme of L-tryptophan metabolic oxidation pathway, in which the L-tryptophan is transformed into N-formyl kynurenine by oxidative cleavage. IDO1 is considered as a potential target for the development of cancer immunotherapeutic molecules. Up to now, at least 10 drug candidates have been advanced into clinical research. In this review, the binding mode and structure-activity relationships of the representative IDO1 small molecule inhibitors were summarized according the characteristics of chemical structures. Hopefully, this review could provide some insights for further development of novel IDO1 inhibitors.

Multidrug resistance (MDR) seriously affects the clinical efficacy of chemotherapeutic drugs. One of the main mechanisms of MDR is the overexpression of P-glycoprotein (P-gp) in tumor cells that reduces the intracellular drug concentrations and limits the effective use of chemotherapeutic drugs. Accordingly, application of P-gp inhibitors that can reverse tumor MDR is an effective strategy to enhance the anti-tumor effect of chemotherapeutic drugs. In recent years, D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) has been widely applied as the potential P-gp inhibitor for its excellent P-gp inhibition effect as well as good safety. In this paper, we reviewed the P-gp inhibitors, the mechanisms of TPGS in reversing P-gp-mediated MDR and the application of TPGS-based nano-drug delivery system.

Chinese material medica (CMM) is the foundation for treating disease using traditional Chinese medicine (TCM), which is not only guided by the basic theory of TCM but also follows the general rules of drug action. There are both toxicity and efficacy in TCM. For TCM the integrated regularities of its toxicity and efficacy were demonstrated in their prescription, which were qualitatively characterized by compatible experiences such as "seven emotions", "Yin" and "Yang" compatibility, etc. When the toxicity is still produced by oral administration according to the prescription of TCM theory or administration is not abided by original requirement, the integral regularities of toxicity and efficacy that depends on experience appears to be at a loss what to do. Especially in recent years, with the modernization of TCM and the continuous advantages in new medicinal innovation, the CMM safety incidents occurred frequently. It is very urgent for us how to establish a set of integrated methods that are adequately situated to multiple components for TCM. With the combination of the biological supramolecular chemistry and the basic theory of TCM, an integrated model of toxicity and efficacy based on TCM supramolecular "imprinting template" has begun to take shape. The CMM and the human body are both biological supramolecular bodies that follow the autonomic action rules of their "imprinting template". The integrated trends of toxicity and efficacy are able to build on systematical results of single components in CMM based on the theory of TCM to treat diseases by prescription on syndromes. It is also the systematic actions resulting from single effective components in CMM by the supramolecular "imprinting template" self-acted regularities. Through the qualitative and quantitative analysis of supramolecular "imprinting templates" characteristics and actions and their network chromatotoxicometrology (chromatopharmacometrology), a toxic and effective integrated analysis methods will be established on an integrated "therapeutic window" for components in the CMM. This effort will finally permit the description of the components of the pharmacokinetic overlaid law of "therapeutic window", plotted to lower-overflow, entering and higher-overflow profiles.

This study is aimed to investigate the potential mechanisms of herceptin-acquired resistance and curcumin to reverse resistance in NCI N87/R gastric cancer cells. Western blot was used to evaluate the effect of curcumin on the expression of IκBα, NF-κBp65, HER-2, caspase-3, Bcl-2 and Bax in herceptin resistant cells; Annexin V-FITC/PI was exploited to analyze the effect of curcumin on cell apoptosis; Caspase kit was used to evaluate the effect of curcumin on the enzymatic activity of caspase-3, 8 and 9. The results showed a low expression of IκBα in the cytoplasm and a high expression of NF-κBp65 in the nucleus of NCI N87/R cells. Correspondingly, inhibition of NF-κB pathway by EVP4593, a specific NF-κB inhibitor, preferentially reduced cell viability of NCI N87/R cells, indicating the activation of NF-κB pathway in NCI N87/R cells. Curcumin preferentially reduced cell proliferation and inhibited NF-κB signaling pathway of NCI N87/R cells, downregulated the expression of HER-2 and Bcl-2, upregulated the expression of Bax, increased the activity of caspase-3, 8 and 9. Taken together, our study demonstrates the correlation between herceptin resistance acquirement of NCI N87 cells and the activation of NF-κB pathway. Moreover, curcumin reverses herceptin resistance of NCI N87 cells possibly by inhibiting NF-κB pathway and inducing cell apoptosis.

Rabdosia japonica(Burm.f.) Hara var.glaucocalyx(Maxim.) Hara is a traditional Chinese medicine, and is known to have anti-tumor effects. This study aims to investigate the effect of glaucocalyxin A (GLA), a diterpenoids extracted from Glaucocalyx Hara, on apoptosis of glioma cells and its mechanism. This study investigated the molecular signaling mechanism of GLA-induced glioma cell apoptosis by analyzing survival rate of C6 rat glioma cells, cell morphology, colony formation ability, interference ribonucleic acid, polymerase chain reaction, and Western blot. The result showed that in the presentce of GLA, the survival rate of C6 rat glioma cells decreased significantly, while the expression of guanine nucleotide-exchange factor-H1 was up-regulated, causing phosphorylation of extracellular regulated protein kinases proteins and apoptosis. Hence, the mechanism of GLA-induced glioma cell apoptosis was the GEF-H1/ERK pathway.

Forsythia suspensa is a herbal medicine that widely used for heat-clearing and detoxification in clinical practice. However, the molecular mechanism of its heat-clearing and detoxifying effect is still unclear. Based on the theory and methods of network pharmacology, the efficacy of the heat-clearing and detoxification of Forsythia suspensa was analyzed in this study. A total of 114 of compounds in Forsythia suspensa were collected, and 15 of effective compounds were obtained by analyzing the bioavailability (OB) and drug-like properties (DL). Then 26 corresponding targets were obtained using reverse pharmacophore-docking method. Using the BioGPS database, the organ location of the target initially was revealed. The compound-targetdisease network model of Forsythia suspensa was constructed by using the Cytoscape, which showed that the material basis of the heat-clearing and detoxification of Forsythia suspensa was to synthesize and synergize the effects by combining various active ingredients of multiple targets, simultaneously. This study explains the scientific mechanism of the heat-clearing and detoxification of Forsythia suspensa, and provides a theoretical foundation for clinical rational usage of Forsythia suspensa.

The Chinese herbal Radix Scrophulariae is the main medicine for nourishing yin and reducing fire. It can be used to treat hyperthyroidism due to yin deficiency and fire hyperactivity, but its mechanism is not clear. The present study was aimed to explore the mechanism of Radix Scrophulariae treatment of hyperthyroidism due to yin deficiency and fire hyperactivity. The urine metabolomic approach was conducted using the method of UPLC-TOF-MS. The results showed that Radix Scrophulariae has good therapeutic effects on hyperthyroidism rat model of yin deficiency. After treatment with Radix Scrophulariae, through metabolic profiling and protocol analysis, 6 potential metabolic markers may be closely related with the treatment mechanism of Radix Scrophulariae on this disease, including proline betaine, estrone, thymidine, 5-hydroxyindoleacetic acid, cyclic AMP and L-dopa. The strongest metabolic pathways were associated with tryptophan metabolism, pyrimidine metabolism, tyrosine metabolism, purine metabolism and steroid hormone biosynthesis. The urine metabolomic approach can be applied to clarify the therapeutic mechanism of Radix Scrophulariae on hyperthyroidism rat of yin deficiency, and provide the theoretical basis for the clinical practice of Radix Scrophulariae on nourishing yin to reduce pathogenic fire.

In this study, twenty containing ethylenediamine groups derivatives of oleanolic acid (OA) were synthesized, their structures were determined by ¹H NMR, ¹³C NMR and HR-MS. The anti-tumor activities in HepG2 and SGC7901 cells were evaluated by MTT assay. The results showed that all compounds exhibited anti-tumor activity, compounds Ⅰ₆, Ⅰ₈ and Ⅰ₉ exhibited significant anti-tumor activities with IC₅₀ values of 16.7, 9.8 and 6.3 μmol·L^-1, respectively. Molecular docking studies showed that compounds Ⅰ₆-Ⅰ₉ produce higher combining ability with VEGFR. Compound Ⅰ₆-Ⅰ₉ were further evaluated for the inhibitory activity against VEGFR-2, the result showed Ⅰ₉ had a strong inhibitory effect on VEGFR with IC₅₀ values of 0.56 μmol·L^-1.

Chemical investigation on the rice culture of an endophytic fungus Colletotrichum fioriniae F18, inhabiting in the stems of the medicinal plant Mahonia fortunei, led to the isolation of nine compounds. They included a new indole alkaloid, makomotindoline B (1), and two known indole derivatives, 3-indoleacetic acid methyl ester (2) and N-acetyltryptamine (3), together with six known aromatic compounds, 2-(4-hydroxyphenyl) acetic acid (4), 4-(2-hydroxyethyl)phenol (5), 2-(4-methoxyphenyl)acetic acid (6), 4-hydroxyphenethyl 2-(4-hydroxyphenyl)acetate (7), regiolone (8) and N-phenethylacetamide (9). The structures of these compounds were elucidated based on the analysis of spectroscopic data including MS and NMR. The absolute configuretion of compound 1 was determined by electronic circular dichroism (ECD) calculation. Antibacterial activity assay indicated that compounds 1-9 had no antibacterial activities against Bacillus subtilis, Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa, as well as no quorum sensing inhibitory (QSI) activity for Chromobacterium violaceum.

Tripterygium glycosides tablets (TGT) have good immunosuppressive activity, but they can also significantly injure the liver and kidney and its mechanism is unclear. In this study, delayed-type hypersensitivity (DTH) Balb/c mouse were administrated with different doses of TGT. Then the changes of sphingolipids levels in live, kidney and plasma as well as the mRNA expression levels of their metabolic enzymes were studied by the integrated targeted sphingolipidomics and transcriptomics methods to reveal the mechanism of efficacy and toxicity of TGT. It was found that low dose of TGT could significantly decrease levels of total ceramide in the plasma, long chain sphingolipids and saturate sphingolipids in the liver and kidney, but increase them in the plasma, which were related to the efficacy mechanism of TGT. High dose of TGT can significantly increase levels of total ceramide, Cer(d18:1/18:0)-1-P, long chain sphingolipids and decrease saturation sphingolipids mechanism. TGT can also cause significant changes of mRNA expression levels of various sphingolipid metabolic enzymes in the liver and kidney, which were correspond to the changes of sphingolipid levels. The efficacy and toxicity of TGT were related to the regulation of these key enzyme expression levels. In conclusion, the efficacy and toxic mechanism of TGT were closely related to the sphingolipids metabolism. A variety of potential biomarkers were found and they can provide valuable information for the evaluation of the efficacy and toxicity of TGT.

The toxicity of heavy metals and harmful elements is close related to their speciation. In the present study, the methods for mercury and arsenic speciation analysis based on high-performance liquid chromatography conjunction with inductively coupled plasma mass spectrometry (HPLC-ICP-MS) were established and applied to the determination of 31 kinds of animal drugs, 29 of which were included in the Chinese Pharmacopeia (2015 edition). The results showed that the LODs for all the speciation were within 0.1-0.65 μg·kg^-1, and the recoveries were within 86.9%-116.6% with the RSD of 1.49%-4.23%. Inorganic mercury (Hg²⁺) was detected in all the 87 batches of samples that came from 31 kinds of animal drugs, and the contents were 2.39-6567 μg·kg^-1. Methylmercury (MeHg) was detected in 33 batches of samples that came from 12 kinds of animal drugs, and the contents were 2.83-319.7 μg·kg^-1. Ethylmercury (EtHg) were detected in none of the samples. The detection rates of As(Ⅲ), As(Ⅴ), monomethylarsononous acid (MMA), dimethylarsinic acid (DMA), arsenobetaine (AsB) and arsenocholine (AsC) in the 31 batches of animal drugs was 96.77%, 100%, 45.16%, 90.32%, 93.55% and 22.58%, respectively. According to the toxic level of different speciation, the animal drugs with high risks of mercury were Agkistrodon, Bungarus Parvus, Zaocys, and Scolopendra; the animal drugs with high risks were Pheretima, Agkistrodon, Zaocys, and Aspongopus. This study can provide important evidence for the risk assessment, setting and revision of the limit standards of heavy metals and harmful elements.

An HPLC method was established for the simultaneous determination of saikosaponin a, b₂, c, d, e, f of Bupleurum chinense DC. in order to study the content difference of saikosaponins in different producing areas, different harvest time and different processed products of Bupleurum chinense DC. The Agela Venusil MP C₁₈ (4.6 mm×250 mm, 5 μm) column was used with a gradient elution of acetonitrile-water at the wavelength of 210 and 254 nm with the flow rate of 1.0 mL·min^-1 and the column temperature at 30℃. Based on the content of six kinds of saikosaponins, the differences of saikosaponins in four producing areas, eight harvest periods and 11 processing methods of Bupleurum chinense DC. were systematically studied. The results showed that the content of saikosaponins in Bupleurum chinense DC. was higher in May and August of Liaoning, Shaanxi and Gansu, but only in August from Shanxi in the four producing areas. The content of saikosaponins in 11 processed products was as follows:raw product > bran-stir-fried product > stir-fried product > wine-moistened product > turtle blood-stir-fried product > bran-wine-stir-fried product > wine-stir-fried product > vinegar-moistened product > turtle blood-wine-stir-fried product > vinegar-stir-fried product > honey-stir-fried product > honeymoistened product.

Timolol maleate cubic nanoparticles (TM-LCNPs) were prepared via fragmentation of a bulk GMO/poloxamer 407 cubic phase gel by high-pressure homogenization. The optimal prescription was selected based on particle size and entrapment efficiency by orthogonal design method. Malvern particle sizer, polarized light microscopy, and differential scanning calorimetry were used to characterize the cubic nanoparticles. Commercial eye drops were used as a control for the release and corneal permeation experiment in vitro. Fluorescence imaging was used to observe the retention of Rhodamine B cubic nanoparticles (RhB-LCNPs) in rabbit cornea. The results indicated that the optimal prescription and preparation of TM-LCNPs was oil-water ratio (7:3), homogenous pressure (900 bar), the number of homogenizations (6) and drug loading (1%). Corneal permeability of TM-LCNPs was significantly higher than that of commercially available eye drops. The residence time in eyes was longer which suggested a sustained release behavior. The pathology result of rabbit corneal after multiple administration of TM-LCNPs showed that there was no apparent damage.

The aim of this study is to apply 3D printing technology to hospital drug dosing operations, and explore its feasibility and scalability. Drugs often dosed in hospitals are selected as models. The commercially available drug was ground into powder, diluted with medicinal excipients and then mixed with 75% ethanol and binder to prepare a paste for 3D printing. The dose and physicochemical properties of divided tablets were controlled by setting print parameters and printing models in computer software. Different 3D printers were employed to evaluate the impact of the device on the dosing tablet. Two drugs were dosed in this study to explore the scalability of 3D printing technology between different drugs. The drug content of the three divided dose tablets (warfarin sodium 1 mg, 2 mg, hydrochlorothiazide 5 mg) was 1.02±0.03, 1.96±0.01, 5.19±0.06 mg. The content uniformity was 1.0, 5.3, 2.6, respectively. The drug dissolution rate was (99.3±1.2)%, (101.5±0.3)%, (98.1±0.8)% in 45, 45 and 30 min. The mechanical properties of the three sub-doses and the stability within 30 days were in line with the Chinese Pharmacopoeia (2015) requirements. At the same time, it was found that the printing parameters and prescriptions can affect the properties of the divided dose tablets. By controlling the dilution ratio of commercial drug and printing parameters, the drug release rate can be customized to achieve individualized treatment. Both different modes of 3D printers can produce qualified sub-doses, and 3D print dispensing technology was also versatile between the two drugs. 3D printing can prepare small-volume, high-precision, high-repetition dosing tablets, with all properties in compliance with pharmacopoeia regulations. Thus, this method can be used as a new and scalable sub-dosing method.

Anthraquinones are not only the main active constituents but also the index components for the quality control of Rhei Radix et Rhizoma. To study the anthraquinone biosynthesis, Rheum palmatum L. seedlings were subjected to a high-throughput transcriptomic sequencing analysis by Illumina HiSeq^TM 2000 150PE. The Illumina sequencing generated a total of 11.04 G clean data resulting in 736 309 74 clean reads, deposited in the sequence read archive (SRA accession SRP160030). Trinity do novo assembly yielded 93 646 unigenes, with an average of 1 108 nt. Functional annotation revealed that all unigenes were successfully annotated in the NR, NT, Swiss-port, PFAM, and KOG databases. GO enrichments showed that 57 subgroups were involved in biological process, cellular component, and molecular function. KEGG analysis indicated that 1 107 unigenes were implicated in 19 standard secondary metabolic pathways. 172 unigenes were analyzed to encode 28 key enzymes during the MVA, MEP, shikimic acid, and polyketide pathways related to anthraquinone biosynthesis. 125 CYP450 and 73 UGTs unigenes were related the modification of secondary metabolites in R. palmatum L. Furthermore, seven unigenes with full length cDNAs were successfully verified by RT-PCR and sequencing analyses. Then, MISA prediction produced a number of 18 885 simple sequence repeats (SSRs). Herein, the transcriptomic gene expression profiles of R. palmatum L. and candidate genes during the anthraquinone biosynthesis pathway were obtained for the first time. The results provided basic information for subsequent gene function characterization, secondary metabolic pathway analysis, and anthraquinone biosynthesis and regulation elucidation in R. palmatum L.

Traditional Chinese medicine Baitouweng have a long history of application. The pharmacopoeia included dry roots of Pulsatilla chinensis (Bge.) Regel of Ranunculaceae. There are easily confused species in the market circulation, such as P. cernua (Thunb.) Bercht. et Opiz., P. dahurica (Fisch.) Spreng., P. turczaninovii Kryl. et Serg., and P. chinensis (Bge.) Regel var. kissii (Mandl) S. H. Li et Y. H. Huang, etc. In this study, using the method of metagenomics, based on high-throughput sequencing technology, the ITS2 sequence of mixed samples of five species of Baitouweng medicinal materials was sequenced. First, the total DNA extraction of medicinal materials mixing powder, and the ITS2 fragment of total DNA was amplified by PCR. Second, the Illumina MiSeq platform was used to carry out Paired-end sequencing for DNA fragments. Last, using FLASH, QⅡME and GraPhlAn software to arrange and analyze, and clustering analysis with the sequences of uploaded to GenBank by our group in the early stage. The results showed that a total of 53 024 sequences of ITS2 were obtained from the mixed samples, there are 52 295 effective sequences, there are a total of 49 079 of five species of medicinal materials of P. Miller. After the representative sequences and the sequence of uploaded to GenBank by our group in the early stage were clustering analysis, 5 species of Baitouweng medicinal materials were clustered into one branch separately, presenting monophyletic. The results showed that using the high-throughput sequencing technology, using ITS2 sequence as DNA barcode, the mix powder of 5 species of Baitouweng medicinal materials could be effectively identified. It provides a new method and thought for the origin identification of mixed Chinese medicinal materials.