Sphingosine kinase (SphK), sphingosine-1-phosphate (S1P) and S1P receptor (S1PR) are involved in the tumor biological processes such as tumor cell proliferation and migration, and play an important role in the development of cancer. In recent years, researchers have increasingly focused on the interaction between cancer cells and the tumor microenvironment. The tumor microenvironment is genetically stable and can be induced to an antitumor phenotype, which has significant therapeutic advantages. Studies have shown that SphK/S1P/S1PR can regulate multiple aspects of the tumor microenvironment. This review summarizes the effects of SphK and S1P/S1PR signaling on the tumor microenvironment from four perspectives: tumor immune microenvironment, cancer associated fibroblasts, tumor angiogenesis and tumor hypoxic microenvironment, and also outlines potential drug research related to these signal molecules, aiming to elucidate the role of SphK/S1P/S1PR in tumor occurrence and development and provide new ideas for the research of anti-tumor drugs.

The cis-emodin-emodin dianthrone (compound 1) and trans-emodin-emodin dianthrone (compound 2) were extracted from Polygonum multiflorum Thunb. The protective effect and mechanism of compound 1 and compound 2 (emodin-emodin dianthrones) on acute liver injury induced by concanavalin A (ConA) in ICR mice was first investigated. The results indicated that emodin-emodin dianthrones at 1 mg·kg^-1 significantly reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) level (P < 0.05). Emodin-emodin dianthrones also improved liver histopathological damage in liver-injured mice. The level of Bcl-2-associated X protein (Bax) mRNA in liver was significantly reduced by 1 mg·kg^-1 of emodin-emodin dianthrones, while the level of B-cell lymphoma-2 (Bcl-2) mRNA expression was significantly increased (P < 0.05). The protective activity of compounds 1 and 2 against hepatocyte injury was further evaluated by hydrogen peroxide (H₂O₂)-induced hepatocyte injury. Compounds 1 and 2 significantly inhibited H₂O₂-induced hepatocyte injury and reduced the levels of ALT, AST, alkaline phosphatase (ALP), and lactate dehydrogenase (LDH) in cell culture. Compounds 1 and 2 also significantly improved the cell survival rate and decreased H₂O₂-induced oxidative stress in hepatocytes. Compound 1 (0.5 µmol·L^-1) significantly increased the enzymatic activity of superoxide dismutase (SOD) in hepatocytes (P < 0.01), and 0.5 µmol·L^-1 of compound 2 significantly decreased the intracellular reactive oxygen species (ROS), increased SOD enzyme activity, and glutathione (GSH) content (P < 0.01). Compounds 1 and 2 at 0.5 µmol·L^-1 also inhibited hepatocyte apoptosis by increasing the protein expression ratio of Bcl-2/Bax (P < 0.05) and decreasing the protein expression ratio of cleaved caspase-3 and pro caspase-3 (P < 0.05). This study indicates that the emodin-emodin dianthrones from Polygonum multiflorum Thunb. have liver-protective activity. Compounds 1 and 2 exerted hepatoprotective effects by inhibiting apoptosis and oxidative stress. The study provides an important material basis for the hepatoprotective effect of commonly used amounts of Polygonum multiflorum Thunb.

The last essential enzyme in the biosynthetic pathway of trilobatin, phloretin-4'-O glycosyltransferase (P4'-OGT), catalyzes the conversion of trilobatin to phloretin in vitro. However, only a few P4'-OGTs have been found in plants. This study used Malus domestica phloretin-4'-O glycosyltransferase (MdPh-4'-OGT) as a query to identify and clone two UDP-glucuronosyltransferase (UGT) genes, designated UGT74L2 and UGT74L3, from the transcriptome of Andrographis paniculata. According to a phylogenetic tree analysis, UGT74L2 and UGT74L3 belonged to the UGT74 family, which has been linked to several activities in other species. The in vitro enzymatic reaction demonstrated that UGT74L2 could particularly catalyze the formation of trilobatin from phloretin, but UGT74L3 had no effects. By using Ni-NTA affinity chromatography to extract the soluble UGT74L2 recombinant protein, the enzymatic kinetics of the activity was investigated using phloretin as the substrate. The results showed that the optimal temperature and pH for UGT74L2 enzymatic reaction were 40 ℃ and 8.0 (Tris-HCl system), respectively. Three metal ions (Ca²⁺, Mn²⁺ and Co²⁺) showed inhibitory effect on the activity of UGT74L2, while Mg²⁺ could improve the activity of UGT74L2. Other tested metal ions have no significant effect on UGT74L2. The results of enzymatic kinetic parameters that the K_m value was 29.84 μmol·L^-1, the k_cat was 0.02 s^-1, and the k_cat·K_m^-1 was 572.6 mol^-1·s^-1. By homology modeling, molecular docking and mutation experiments, we found that multiple amino acids residues around the substrate binding pocket play quite an important role during catalytic process, In summary, we identified a novel P4'-OGT gene from medicinal plant Andrographis paniculata and provided a new efficient catalyst to synthesize trilobatin. Meanwhile, this study provides a reference for mining new efficient glycosylation modules from plants.

In this study, we established a novel bioassay to determine the activity of polyethylene glycolated recombinant human growth hormone (PEG-rhGH) using Nb2-11 cells. We performed experimental condition optimization and methodological verification, and then detected the relative potency of PEG-rhGH products using this method. We demonstrated that the bioactivity of PEG-rhGH in promoting Nb2-11 cell proliferation displays a dose-response relationship, which conformed to the four-parameter model. Using PEG-rhGH reference as a control, we analyzed the relative potency of six batches of PEG-rhGH products, as well as linearity, regression and parallelism of the obtained curves. The relative potency of six batches of PEG-rhGH products was 95% to 105%. These results implied that the new bioassay established may be employed in quality control of PEG-rhGH products.

An open reading frame (ORF) of isopentenyl-diphosphate delta isomerase gene (FuIPI) was cloned from Fritillaria unibracteata Hsiao et K. C. Hsia. (F. unibracteata). Furthermore, the bioinformatics and functional analyses of FuIPI were performed in this study. The result showed that, the ORF of FuIPI gene was 825 bp, encoding a polypeptide of 274 amino acids in length, with a relative molecular mass of about 31 kD and a theoretical isoelectric point of 5.61. Sequence analysis showed that FuIPI contained conserved structural domains and key residues involved in the catalyzing process. The phylogenetic analysis exhibited that FuIPI was closely related to IPIs of Dendrobium officinale and Musa acuminate. Real-time PCR analysis showed that FuIPI was distributed in different tissues of F. unibracteata, but had the highest transcriptional level in leaves, followed by stems, bulbs, and flowers. Furthermore, the FuIPI protein was successfully expressed in Escherichia coli BL21(DE3). The purified FuIPI protein successfully catalyzed the conversion from isopentenyl diphosphate (IPP) to dimethylallyl pyrophosphate (DMAPP). The above results provided a theoretical basis for further investigation of the molecular role of FuIPI in the biosynthesis of alkaloids.

In this study, a series of 18 histone deacetylases inhibitors (HDACis), derived from our in-house anti-cancer trans-β-arylacryl 1, 2, 3, 4-tetrahydroisoquinoline-based scaffold, were designed, synthesized, and antitumor evaluated. HDAC1 inhibitory activity assay showed that compounds 13d-13f and 13m-13o demonstrated attractive enzymatic activity with IC₅₀ at single-digit nanomolar or subnanomolar level.In addition, 13o exerted superior anti-proliferative activity (A549, IC₅₀ = 0.89 μmol·L^-1; HCT116, IC₅₀ = 0.49 μmol·L^-1) to that of vorinostat (SAHA).Besides, 13e, with the most potent HDAC1 enzymatic activity (IC₅₀ = 3.8 nmol·L^-1), also displayed attractive cellular activity (A549, IC₅₀ = 1.74 μmol·L^-1; HCT116, IC₅₀ = 2.43 μmol·L^-1). The Western blot analysis illustrated that 13e treatment increased the acetylation of H3 and α-tubulin in a dose-dependent manner in A549 cells. In summary, 13e and 13o deserve further functional investigation.

Seven compounds were isolated from Onychium japonicum by macroporous resin, silica gel, ODS, Sephadex LH-20 column chromatography and semi-preparative HPLC. Their structures were identified by NMR, MS and other spectroscopic methods as onychone A (1), quercetin (2), quercetin-3-O-α-L-rhamnoside (3), kaempferol-7-O-β-D-glucopyranoside (4), kaempferol-3-O-α-L-rhamnopyranoside (5), (-)-prunin (6), and norathyriol (7). Compound 1 is a novel macrocyclic flavonoid, and all the others are reported from this plant for the first time. In vitro cytotoxic activities of compounds 1-7 were evaluated by MTS testing with five cancer cell lines. Compound 7 exhibited weak cytotoxicity against tumor cell lines A549, SMMC-7721, and SW480.

Along with the progress of pharmaceutical science in the past century, the theme of pharmacology has gone through pseudo agent scheme, to ligand-receptor model, and then to the theory of targeted therapy today. Due to the success of drug R&D, current drug research keeps its focus mainly on drugs with single target and precise treatment, in which the molecular mechanism is relatively clear but the therapeutic efficacy is often limited. Thus, there is a big space for exploration in the field of pharmacology. In the past 30 years, several novel chemical drugs, originated from traditional Chinese medicine, have been identified and then used in clinic, provoking a strong interest to explore new theory for pharmacology, of which the term of "Biao Ben Jian Zhi" (treating diseases by directing symptoms and root causes) has demonstrated a promising nature. We consider this concept useful for future drug discovery, drug design and clinical therapy. In this review, example drugs such as berberine, metformin and azvudine, are discussed, and "drug Cloud" (dCloud) model is introduced to elaborate the mechanism of treating diseases by directing symptoms and root causes of diseases.

Decoction is a classical dosage form of traditional Chinese medicines. In the process of decocting, various complex components produce physical interactions and chemical reactions, among which physical interactions include van der Waals force, hydrogen bond, electrostatic interaction, π-π stacking, etc., and chemical reactions include Maillard reaction, oxidation reaction, hydrolysis reaction, degradation reaction, polymerization reaction, etc. New substances and original ingredients from chemical reactions can be further activated. These effects form the basis of particle formation in the broth. The sizes of the particles in decoctions range from nanoscale to micron scale, mostly composed of polysaccharide, protein matrix, wrapped in water insoluble molecules, can increase the dispersion of insoluble components and the stability of unstable components, as well as reduce the volatile components and toxic components of volatile components, and ultimately achieve the purpose of efficient absorption and toxicity reduction. From the angle of physical change and chemical reaction in the process of decoction, this paper expounds the formation mechanism of particles in decoction, expounds the research method of particles, analyzes the components in particles and the interaction between components, and then explains the pharmacodynamic characteristics of traditional Chinese medicine decoction, which provides the foundation for the modernization of Chinese decoction.

The study aims to investigate the anti-hepatic fibrosis and anti-inflammatory activities of palbinone, and to explore the internal regulatory mechanism, so as to lay an active foundation for its development as an anti-non-alcoholic steatohepatitis (NASH) candidate. First, sulforhodamine B (SRB) method was used to detect the effect of palbinone on the proliferation of human hepatic stellate cells LX-2 and rat hepatic stellate cells HSC-T6. Following, in the in vitro hepatic fibrosis cell model that activated by transforming growth factor beta 1 (TGF-β1), quantitative real-time PCR (qRT-PCR) and Western blot were used to detect the inhibitory effect of different concentrations of palbinone on the transcription level and protein expression level of hepatic fibrosis markers. And the regulating mechanism of palbinone on fibrosis-related genes was analyzed at the same time. In addition, in the inflammatory cell model that induced by lipopolysaccharide (LPS) and nigericin, ELISA was used to detect the effect of palbinone on the released interleukin-1β (IL-1β) level. At the same time, Western blot was used to detect the effect of palbinone on the related proteins of inflammatory pathway. The results showed that palbinone could significantly inhibit the proliferation activity of LX-2 and HSC-T6, and their half maximal inhibitory concentration (IC₅₀) values were (375.11 ± 55.45) and (260.27 ± 36.81) nmol·L^-1, respectively. In addition, palbinone showed a dose-dependent inhibitory effect on the expression levels of TGF-β1-induced fibrosis-related genes, including collagen type Ⅰ α 1 (COL1A1), TGF-β1, α-smooth muscle actin (α-SMA) and tissue inhibitor of metalloproteinase 1 (TIMP1). Mechanism study showed that palbinone may decrease the expression level of Yes-associated protein (YAP), thereby weakening its activation effect on the downstream fibrosis pathway. In addition, palbinone also exerted an anti-inflammatory effect by inhibiting the activity of nuclear factor kappa-B (NF-κB) signaling pathway and reducing inflammatory factors cysteinyl aspartate specific proteinase-1 (caspase-1) and IL-1β release. In conclusion, palbinone can not only inhibit the proliferation and activation of hepatic stellate cells by inhibiting the expression of YAP, but also inhibit the expression and release of inflammatory factors at the same time. All these studies provide theoretical support for the development of palbinone as an anti-nonalcoholic steatohepatitis drug.