The difference in pH between apical and basolateral side of intestinal epithelial and pH dependence character of the combination of FcRn (neonatal Fc receptor) and ligand might improve the delivery of hydrophobic drugs by facilitating the transcytosis of nanocarriers. Here we designed FcBP (IgG Fc domain-binding peptides) decorated coumarin 6 (C6) loaded poly(ethyl ethylene phosphate)-co-poly(ε-caprolactone) (PEG-PCL) micelles with different ligand densities to study the effect of pH and ligand density on the endocytosis and exocytosis process of micelles on human colon adenanocaricinoma cell lines (Caco-2). Active micelles with different ligand densities and passive micelles were prepared using the thin-film hydration method. The size of the micelles was characterized by dynamic light scattering analysis and the morphology was observed by transmission electron microscope. The endocytosis and exocytosis of the micelles at pH 7.4 and pH 6.0, as well as the effect of FcRn on the endocytosis, were investigated by flow cytometry. The results showed that the size of micelles was about 30 nm, which was not affected by FcBP decoration. We found that pH and ligand density could both influence the endocytosis. The uptake of active micelles was higher at pH 6.0 than at pH 7.4, and an optimal ligand density of endocytosis was appeared in both pH environment. Then we proved that FcBP decorated micelles could be endocytosed at pH 6.0 and exocytosed at pH 7.4, and the exocytosis process was also related to ligand density. Micelles with 10% ligand density had the largest exocytosis, showing the potentiality to deliver drugs through the intestinal epithelial. In addition, the competitive inhibition experiments illustrated that the interaction between FcRn and FcBP were essential to endocytosis. The results will enhance the understanding on the FcBP decorated PEG-PCL micelles for transmemberane drug delivery.

In order to find highly active antidiabetic agents, the 3-amino group of skeletal structure of thiazolidine-2, 4-diones (TZDs) was modified to generate the new molecules TM1 and TM2 in the present research. The new molecules TM3-TM6 containing rhodanine structural units were designed based upon the bioisostere and combination principles. The target molecules TM7, which is similar to the traditional TZDs structurally, were designed by connecting the phenolic hydroxyl of the above target molecules to carbazole through a linker. All of these target compounds were synthesized successfully by selecting suitable synthetic routes with optimized procedures. The assay results of peroxisome proliferator activated receptor response element (PPRE) agonist activity revealed that the PPAR agonist activity was decreased due to the change of TZD ring. The assay of α-glucosidase inhibitory activity and protein tyrosine phosphatase-1B (PTP-1B) inhibitory activity showed that most of the seven serials target molecules have weak activities in vitro. However, 3 of the compounds exhibited strong PTP-1B inhibitory activities. TM2-6 exhibited the highest inhibitory activities, which reached 96.71% with IC₅₀ 1.48 mg·L^-1. In addition, the toxicity prediction disclosed that the highly active compounds were almost non-toxic. These results provide a hint for the development of new antidiabetic

This study was designed to investigate the effect of minocycline on microglia activation of M1/M2 phenotypes. The model was induced by lipopolysaccharide (LPS) in BV-2 microglia cells, and was used to evaluate the effect and mechanism of minocycline. We measured nitric oxide (NO), prostaglandin E₂ (PGE₂), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6) and interleukin-1 beta (IL-1β) in M1 type microglia, and interleukin-10 (IL-10) and transforming growth factor beta (TGF-β) in M2 type microglia through enzyme linked immunosorbent assay (ELISA). We used flow cytometry to detect the expression of M1 marker CD16/32 and M2 marker CD206 in order to evaluate the influence of minocycline on microglia activation of M1/M2 polarization. Finally, we explored the mechanism of minocycline through detection of the protein expression in response to activation of toll like receptor 4 (TLR4)-mediated myeloid differentiation factor 88 (MyD88) dependent pathway, mitogen activated protein kinase (MAPK) signaling and nuclear factor-κB (NF-κB). The results suggest that minocycline obviously inhibited the production of NO, PGE₂, TNF-α and IL-6, and increased the production of IL-10, TGF-β in LPS-stimulated BV-2 cells. Minocycline significantly down-regulated the expression of M1 marker CD16/32 and up-regulated the expression of M2 marker CD206. These results suggest that minocycline can inhibit the activation of microglia to M1 phenotype and promote the transformation of M2 phenotype through down-regulation of p38 and NF-κB signaling pathways.

This study was designed to explore the "multi-components, multi-targets and multi-pathways" intervention mechanism of Huanglian Jiedu decoction (HLJDD) in the treatment of Alzheimer's disease (AD) by pharmacological network technology, which may establish a foundation for drug development and innovative research. Seventeen active constituents of HLJDD with anti-AD activities were submitted to PharmMapper and Molecule Annotation System (MAS 3.0) bioinformatics softwares to predict the target proteins and carry out related KEGG pathways annotation respectively. The network of "active compound-target-pathway" was constructed and analyzed using the Cytoscape 3.4.0 software. The results suggest that 47 pathways are affected by the 17 active components through 59 target proteins, in which 4 target proteins are related to AD and 2 pathways related to neuroinflammation, respectively. The effect of HLJDD on AD may be dependent on clearing/reducing β-amyloid protein, inhibiting Tau hyperphosphorylation, anti-inflammation and immunoregulation.

Idiosyncratic drug-induced liver injury(IDILI)is an adverse drug reaction that occurs only in a minority of the population. IDILI also has many characteristics such as unpredictable and low morbidity, its occurrence has often not been clearly correlated with the dose, route, or duration of drug administration. Several studies have shown that IDILI is a synergistic effect which was caused by body diathesis, environment and drugs. In addition, evidence also suggests that most IDILIs are mediated by immunity. Chemical medicines-related IDILIs have been extensively studied, and a variety of immunological mechanism hypotheses have also emerged to explain the pathogenesis and characteristics of chemical medicines-related IDILIs. However, the traditional Chinese medicine(TCM)-related IDILI has always been neglected due to the complexity and specificity of TCM. In recent years, TCM-related IDILI has been gradually confirmed by researchers, and formed a new hypothesis, a immunological stress-mediated tri-elements synergetic mechanism hypothesis, which can reveal the pathogenesis and clinical characteristics of TCM-related IDILI. This paper is prepared to summarize the immunological mechanism hypotheses of chemical medicine-related IDILI and TCM-related IDILI to provide a scientific basis for guiding IDILI research and establishing its clinical risk prevention and control measures.

To study the chemical constituents of the fruits of Fructus carotae, silica gel column chromatography and preparative HPLC were used to isolate and purify the extract of Fructus carotae. The structures of obtained compounds were elucidated on the basis of physicochemical property and spectral data. Nine guaiane-type sesquiterpenes were isolated and identified as 8β-angeloyloxy-11-hydroxy-4-guaien-3-one(1), 11-acetoxy-4-guaien-3-one(2), 11-acetoxy-8β-isobutyryl-4-guaien-3-one(3), 11-acetoxy-8β-propionyl-4-guaien-3-one(4), 11-hydroxy-4-guaien-3-one(5), 11-acetoxy-8β-angeloyloxy-1β-hydroxy-4-guaien-3-one(6), 11-acetoxy-8β-angeloyloxy-4-guaien-3-one(7), 11-acetoxy-8β-hydroxy-4-guaien-3-one(8)and 8β, 11-dihydroxy-4-guaien-3-one(9). Compound 1 is a new compound, compound 5 is a new natural product, and compounds 2-4 were isolated from this genus for the first time.

This study was designed to investigate the effect of 2, 3, 5, 4'-tetrahydroxystilbene-2-O-β-D-glycoside(TSG)on hypoxia/reoxygenation(H/R)-induced oxidative stress injury and its potential mechanism in human bronchial epithelial cell(BEAS-2B)cells. BEAS-2B cells were exposed to H/R treatment. Level of intracellular ROS was detected using DCFH-DA probe and fluorescence microplate reader. Production of MDA and activity of SOD were evaluated with MDA and SOD kits. Nucleus was shaped by DAPI staining. Translocation of Bax to mitochondria was observed in MCF-7/GFP-Bax cells. Change in mitochondrial membrane potential was detected by JC-1 staining. Release of cytochrome C from mitochondria was detected by immunofluorescence. Expressions of mitochondrial/cytoplasmic Bax and cytochrome C, caspase-9, caspase-3, phosphorylated MAPK, HIF-1α and phosphorylated p53(p-p53) were determined by Western blotting. TSG significantly improved cell viability and reduced H/R-induced ROS production in BEAS-2B cells, while significantly decreased MDA production. It inhibited Bax translocation and nucleus fracture, reversed the decrease in mitochondrial membrane potential and inhibited the release of cytochrome C and following activation of caspase-9/caspase-3. Simultaneously, TSG down-regulated the signals of SAPK JNK1/2 and p38 MAPK without an impact in ERK1/2. It attenuated expression of HIF-1α and phosphorylation of p53. This study suggests that TSG could protect BEAS-2B against H/R-induced apoptosis, perhaps through the MAPK, HIF-1α and p53 pathways.

Heat shock protein 90(HSP90), as an essential molecular chaperone, regulates the folding, assembly and maturation of a wide range of oncogenic client proteins. The process of adenosine triphosphate(ATP)binding and adenosine diphosphate(ADP)/ATP exchange act as a conformational switch to regulate the chaperone function of HSP90. Furthermore, this process is controlled by a range of accessory proteins(as referred to co-chaperones), such as Hop, CDC37, p23, AHA1, PP5, etc. This article describes the structure and function of several co-chaperones, and their roles in tumor progress.

This study was designed to investigate the correlation between idiosyncratic liver injury and content of cis-2, 3, 5, 4'-tetrahydroxystilbene-2-O-β-D-glucoside(cis-SG)in radix Polygoni multiflori Preparata(RPMP). In order to compare the effect of hepatotoxicity of different cis-SG contents in RPMP, rats were administered with 50% alcohol extracts of RPMP(7.56 g·kg^-1, via intragastric administration)alone or co-treated with lipopolysaccharide(LPS, 2.8 mg·kg^-1, via tail vein injection). The results showed that no significant alterations of plasma ALT and AST activities were observed in the normal rats. In the LPS treated rats, the group without light treatment and the group with 0.10% cis-SG after light treatment did not exhibit obvious injury in liver. The group with 0.35% cis-SG after light treatment and the group with 0.70% cis-SG after light treatment showed significant increases in ALT, AST, TNF-α, IL-6, NF-κB p65 and apoptosis rate(P < 0.05), causing pathological changes in the liver tissue. Through the content analysis of drug in patients with liver injury, we found that the content of cis-SG( > 0.40%)was generally higher than that of pieces collected from different origins( < 0.10%). The comparative analysis of experiments and clinical data showed that there was a relationship between the content of cis-SG and idiosyncratic liver injury. In order to reduce the risk of clinical medication, the content of cis-SG of 0.10% should be a limit of quality control in the production processing of Polygonum multiflorum.

On basis of the idiosyncratic lipopolysaccharide(LPS)-mediated hepatotoxicity model, liver injury induced by Zhuangguguanjie wan(ZGW)was evaluated, and the mechanism was explored. Idiosyncratic hepatotoxicity model was established in rats by injecting LPS at a dosage of 2.8 mg·kg^-1. Rats were randomly divided into the normal control group, LPS group, ZGW group and LPS+ZGW group. Alanine aminotransferase(ALT)and aspartate aminotransferase(AST)activities were analyzed in serum; pathological changes(HE staining)and the content of cytokines of liver were tested; and immune cell subpopulation ration were determined in blood and liver. Compared with the control group, the ZGW group and LPS group had no significant changes in ALT, AST and liver pathology(P > 0.05); while the ZGW+LPS group exhibited an elevation in ALT and AST(P < 0.05). Disorder of liver lobular arrangement and irregular island-like or massive necrosis of liver cells were observed in the group. Several cytokines in the liver were increased in LPS group and ZGW+LPS group(P < 0.05 or P < 0.01), and the level in ZGW+LPS group was higher than that of LPS group. Compared with the control group, the ratio of CD3⁺ T cell/lymphocyte of blood in LPS group was significantly decreased(P < 0.01); while the percentage of CD3⁺ T cells in the liver were significantly increased(P < 0.05). The contents of immune cells of blood had no significant changes between LPS group and ZGW+LPS group(P > 0.05). CD3⁺ T cell in the liver of ZGW+LPS group was significantly increased over the LPS group(P < 0.05). Aggregation or activity of CD3⁺ T cell was increased by ZGW combined with LPS. These results suggest that ZGW could promote T lymphocyte recruitment to liver under the immune activation state leading to inflammatory response, which may contribute to idiosyncratic liver injury.