Latest ArticlesPoly(2-ethyl-2-oxazoline) (PEOz), a hydrophilic long-chain polymer synthesized by living cationic ring-opening isomerization polymerization of 2-ethyl-2-oxazoline, has the characteristics of low toxicity, biocompatibility, flexible chain, and modified expediently. PEOz is a potential substitute of polyethylene glycol (PEG) to render the ability of long-circulation, enhance cellular uptake and endosomal escape behaviors to PEOz modified drug delivery system. In this review, we summarized recent literature for the research progress of physicochemical properties, synthetic methods and the application of PEOz in drug delivery system.
Increasing evidence suggests that hepatocellular carcinomas (HCCs) are sustained by a distinct subpopulation of self-renewing cells known as cancer stem cells (CSC). However, our understanding of their regulation is limited. Rapid reversible changes of CSC-like cells within tumors may result from the effect of biological mediators found in the tumor microenvironment. This paper aims to explore how nitrite, a key cellular modulator whose level is elevated in many tumors, affects CSC-like phenotypes of human hepatoma cells SMMC-7721 cells. The SMMC-7721 cell line was cultured under serum-free conditions to produce floating spheres. The distribution of cell cycle was analyzed by flow cytometry, the capability of cells self-renew was detected by colony-forming capabilities and spheroid-formation assay, the expression of stemness protein such as CD133, CD90 and EpCAM were determined by flow cytometry and Western blot, cell invasion was analyzed by transwell assay, and viability of SMMC-7721 parental cells and spheroids cancer cells was determined by the 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT) assay. Xenograft tumor models were established by subcutaneously injecting SMMC-7721 spheroids cancer cells, the transplanted tumor tissue ROS levels was detected by reactive oxygen species (ROS) test kits, the expression of HIF-1α was observed by immunofluorescence. Our results showed that the SMMC-7721 spheroid cells were enriched with CSCs properties, indicated by the ability to self-renew, increased expression of CSCs markers, and increased resistance to chemotherapeutic drugs. Additionally, SMMC-7721 parental cells and spheroids cancer cells were treated with 150 μmol·L-1 sodium nitrite for 6 days, compared with control cells, an increased accumulation of G0/G1 phase cells was observable in treatment cells. Indeed, our data demonstrated that in parent cells and spheres cells that were treated with sodium nitrite for different time, the cells' ability to chemoresistance and invasion, clone-forming efficiencies and the spheres forming ability were significantly higher than that of control cells. Exposure of sodium nitrite regulated CSC-like phenotype, indicated by increased expression of known CSC markers, CD133, CD90 and EpCAM in the exposed parental cells, as well as in dormant spheroids cancer cells. Compared with the parent cells, the above effects of nitrite on the spheres cells were significantly enhanced. In vivo data also presented a more significant promotion of tumor xenograft growth from the nitrite treatment than from either of the control. Mechanistic analysis indicated that nitrite induced the upregulation of HIF-1α as well as the downregulation of ROS in the tumor microenvironment. These results suggest that nitrite increases the invasiveness of SMMC-7721 cells through up-regulation of tumor stemness.
The impact of statins on airway inflammation has not yet been established and it may differ from their cholesterol-lowering effects. Oral administration of statins at large-doses may have adverse effects. It is possible to overcome the side effect to increase the clinical efficacy through the inhalation route. Female BALB/c mice were randomly divided into four groups including the control group (NS-vehicle), model group[ovalbumim (OVA)-vehicle], simvastatin (Sim) group and dexamethasone (DXM) group at 10 mice in each group. In this study, we hypothesize Sim as a potential anti-inflammatory drug with biological and pharmacokinetic properties suitable for delivery through the inhalation route. Mice were immunized with OVA and then challenged with OVA aerosol to induce the asthma reaction. Sim was inhaled at a dosage (5 mg ·mL-1, ih, 15 min) or administrated by intraperitoneal injection (40 mg·kg-1, ip) or gavage (40 mg·kg-1, ig) during the OVA-challenge. In the mouse model of asthma, Sim significantly attenuated the total inflammatory cell counts and eosinophil counts (P < 0.01 or P < 0.05) via the different routes. Pretreatment with Sim at 1, 5, 20 mg·mL-1, ih, significantly decreased the total inflammatory cell counts and eosinophil counts in alveolar lavage fluid (BALF) (P < 0.01) and the inhibitory effect was increased with the dosages of Sim via inhalation. Both of DXM and Sim at 5, 20 mg·mL-1, ih, were more potent than that of Sim at 1 mg·mL-1, ih. Sim significantly decreased IL-4 and IL-5 mRNA expression of lung at 5, 20 mg·mL-1, ih (P < 0.01 or P < 0.05). Sim (5, 20 mg·mL-1, ih) significantly decreased levels of IL-4 and IL-5 in BALF (P < 0.01 or P < 0.05). However, Sim (1 mg·mL-1) declined slightly on IL-4 level in BALF. Sim at 5, 20 mg·mL-1 had a greater rate of decline in IL-5 than at 1 mg·mL-1. These results suggest Sim with different doses as a potential anti-inflammatory drug for airway inflammatory diseases with properties suitable for delivery by inhalation, which probably overcome the side effects and low clinical efficacy of oral Sim.
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 investigate the synergistic analgesic effect between choline (Cho) and acetaminophen (Ace). Mice were treated with 0.6% acetic acid solution by intraperitoneal injection to build acetate writhing model. The KM mice were randomly divided into four groups:control group (n=10), Cho group (n=50), Ace group (n=50), combination group (Cho+Ace group, n=40), then the writhing times were counted respectively. OriginPro8.5 was used to calculate ED 50. The isobolographic analysis was used to test the interaction of Cho and Ace. To explore the mechanism, forty KM mice were randomly divided into control group, Cho group, Ace group and Cho + Ace group. Blood was collected for detection of TNF-α, IL-6, PGE2 and NF-κB content using ELISA kits. The result ED 50 was calculated as followings. ED50 of Cho and Ace was 19.47 mg·kg-1 and 20.56 mg·kg-1. The concentrations were 2.94 mg·kg-1 for Cho and 3.15 mg·kg-1 for Ace in the combination test. The levels of TNF-α, IL-6, PGE2 and NF-κB in Cho group and Ace group were lower than those in the control group (P < 0.05). Compared to the Cho group and Ace group, the levels of TNF-α, IL-6, PGE2, NF-κB in Cho + Ace group were reduced further (P < 0.05). The results revealed that Cho and Ace have synergistic analgesic effects, which may associate with inhibition of the NF-κB signaling pathway.
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.
Hepatic disease is one of the high-prevalence diseases in China, of which gastrointestinal bleeding is a common complication treated by proton pump inhibitors. Vonoprazan is a novel proton pump inhibitor which acts better than lansoprazole in pharmacokinetics and pharmacodynamics. In this study, the pharmacokinetics of vonoprazan was compared between acute hepatic injury and normal condition in rats. Results showed that the exposure (AUC) of vonoprazan was significantly higher in rats with acute hepatic injury than in normal rats, and the metabolites formation rates of vonoprazan also slowed down, which might be due to the change of activity of enzymes and transporters. This find may provide a theoretical basis for the dose regulation of vonoprazan in patients with hepatic injury.
The glucose consumption activity of 9-substitued analogues of berberine was evaluated in L6 myotubes. It was found that the introduction of an ethoxy group on the 9-position of berberine was beneficial for the activity. 9-Ethoxy berberine analogue 2a exhibited superior activity to berberine in multiple dose levels, and the activity of 2a was 5.4 times as high as that of berberine at the dose of 1.25 μmol·L-1. At the meantime, the potency on AMPK activation of 2a was 2.8 times of that of berberine at the dose of 10 μmol·L-1. Therefore, the compound 2a is a promising scaffold for further modification.
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
The chemical constituents of Dioscorea opposite Thunb. were isolated and purified by Diaion HP-20, Sephadex LH-20, Toyopearl HW-40, MCI Gel CHP-20, ODS, silica gel column chromatography and semi-preparative-HPLC. Nine compounds were found and their structures were elucidated by spectral data and physicochemical properties, which were identified as 2-(1', 2', 3'-trihydroxybutyl-4'-O-α-D-glucopyranoside)-6-(2", 3", 4"-trihydroxybutyl)-pyrazine (1), uracil (2), xanthine (3), hypoxanthine (4), thymine (5), adenosine (6), uridine (7), inosine (8), and 5'-deoxy-5'-methylsulphinyladenosine (9). The compound 1 is a new pyrazine derivative, and the compound 3-5, 8, 9 are found in this plant for the first time.
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