[Show abstract][Hide abstract] ABSTRACT: Recently, coamorphous systems composed of a drug and a guest molecule, have gained increasing interest, due to their ability to overcome limitations associated with amorphous drug alone. In this study, a single-phase coamorphous form of lurasidone hydrochloride (LH) (a water-insoluble atypical antipsychotic agent with pH-dependent solubility) with saccharin (SAC) in a 1:1 molar ratio was obtained, and characterised by DSC and XPRD. Peak shifts in the FTIR spectra indicated the formation of charge-assisted hydrogen bond between the N+-H group of LH and the C=O group of SAC. In comparison to crystalline LH, amorphous LH showed similar solubility and temporary improvement in the intrinsic dissolution rate and supersaturated dissolution, while coamorphous LH-SAC exhibited greatly improved solubility with pH-independent solubility behavior in pH range of 2 to 5.5, as well as persistent enhanced intrinsic dissolution rate and supersaturated dissolution. In addition, coamorphous LH-SAC showed superior physical stability than amorphous LH under long-term storage condition. The coamorphization effect and charge-assisted hydrogen bond in coamorphous LH-SAC were speculated to be responsible for the above phenomena by prohibiting the recrystallization of LH.
[Show abstract][Hide abstract] ABSTRACT: Phenylethanoid glycosides (PhGs), a class of polyphenolic compounds, are considered one of major bioactive constituents of Cistanche deserticola Y.C. Ma (CD), whose extract is orally used in traditional Chinese medicine. Although previous pharmacological studies have reported that PhGs exert many activities, their intestinal transport profiles have not been clarified. In this study, we investigated the intestinal permeability of a PhG-rich extract (PRE) from CD as an integrated system in the Caco-2 cell monolayer model using a bioassay system. The results showed that PRE is primarily transported via poorly absorbed passive diffusion down a concentration gradient without efflux, which provides the pharmacokinetic basis for the clinical application of PhGs in CD. We also determined the intestinal permeability of three major PhGs [acteoside (AC), isoacteoside (IS) and echinacoside (EC)] by HLPC. Furthermore, we developed a novel HPLC-fluorescence detection method to accurately determine the flux amount of AC and IS. As expected, the transport characteristics of the three PhGs are consistent with those of PRE, indicating that the present bioassay system is appropriate and reliable for the evaluation of the transport characteristics of active ingredient groups (AIG) in PRE. Moreover, this system may also be suitable for other plant extracts given appropriate bioactivity.
PLoS ONE 02/2015; 10(2):e0116490. DOI:10.1371/journal.pone.0116490 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Shuang-Huang-Lian (SHL) is a common traditional Chinese preparation extracted from Lonicerae Japonicae Flos, Scutellariae Radix, and Fructus Forsythiae. In this study, we demonstrate the anti-inflammatory and antioxidative effects of SHL on lipopolysaccharide- (LPS-) induced acute lung injury (ALI) in mice. SHL reduced the lung wet/dry weight ratio, lowered the number of total cells in the bronchoalveolar lavage fluid, and decreased the myeloperoxidase activity in lung tissues 6 h after LPS treatment. It also inhibited the overproduction of proinflammatory cytokines (TNF-α, IL-1β, and IL-6) in the bronchoalveolar lavage fluid. Histological studies demonstrated that SHL attenuated LPS-induced interstitial edema, hemorrhage, and the infiltration of neutrophils into the lung tissue. Moreover, SHL could also enhance the superoxide dismutase and catalase activities, increase the reduced glutathione content, and decrease the malondialdehyde content. The present results suggest that SHL possesses anti-inflammatory and antioxidative properties that may protect mice against LPS-induced ALI.
Evidence-based Complementary and Alternative Medicine 01/2015; 2015:1-9. DOI:10.1155/2015/283939 · 1.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Excess or inappropriate angiogenesis occurs in the pathogenesis process of many diseases, such as cancer, wound healing and eye disease, especially angiogenesis stimulated by inflammatory factors contributes to the development of inflammation and cancer. In this study, we investigated the inhibitory effect of LL202, a newly synthesized flavonoid, on LPS-induced angiogenesis and further probed the potential molecular mechanisms by detecting MAPK and NF-κB pathways. We found that LL202 inhibited LPS-induced migration, tube formation of human umbilical vein endothelial cells (HUVECs), and microvessel sprouting from rat aotric ring in vivo. The result of matrigel plug assay and chicken chorioallantoic membrane (CAM) model also revealed that LL202 could inhibit LPS-induced angiogensis in vivo. Western Blot analysis indicated that LL202 could inhibit the expression of LPS acceptor toll-like receptor 4 (TLR4) and its downstream protein kinases, including the phosphorylation of JNK, p38, ERK, IKK and IκBα. Moreover, LL202 inhibited the nuclear translocation of NF-κB and its binding to DNA. Accordingly, the expression of vascular endothelial growth factor (VEGF) was down-regulated at the level of gene transcription, which is a crucial mediator in angiogenesis. Taken together, LL202 could suppress LPS-induced angiogenesis with the intervention of LPS/TLR4 signaling.
[Show abstract][Hide abstract] ABSTRACT: The aim of this study is to characterize the in-vitro physicochemical and in-vivo pharmacokinetic properties of the scutellarin-loaded bovine serum albumin nanoparticles (STA-BSA-NPs). STA existed as amorphous form in the nanoparticles. Reconstituted STA-BSA-NPs had an average particle size of 283.4nm and a zeta potential of +17.95mV. The in-vitro sustained release profile was well fitted with Weibull distribution model. In comparison to STA solution, STA-BSA-NPs exhibited a significantly higher plasma concentration from 20min to 6h after intravenous administration to rats. In addition, significantly higher AUC0-inf (2.8-fold), prolonged elimination half-life (4.2-fold) and lower clearance (2.7-fold) were achieved.
International Journal of Pharmaceutics 09/2014; 476(1-2). DOI:10.1016/j.ijpharm.2014.09.038 · 3.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Abstract Context: Venous irritation is the most common side effect of intravenous therapy. Although many in vitro models have been developed to evaluate intravenous drug irritation, these models are not widely accepted. Objectives: The aim of this paper is to determine whether delayed or immediate cytotoxicity better reflects the in vivo venous irritation ranking. Materials and methods: We compared the endothelial toxicity induced by high-concentrations of amiodarone and diazepam after short-term exposure (20 min) in a human umbilical vein endothelial cell line (EVC304) by using five in vitro models: lactate dehydrogenase (LDH), glucose-6-phosphate dehydrogenase (G6PD), glutathione (GSH), adenosine triphosphate (ATP), and MTT assays. Results: In the 24-h MTT assay, the IC50 of diazepam and amiodarone was 1.08 and 1.96 mM, respectively. In the 48-h MTT assay, the IC50 of diazepam and amiodarone was 1.114 and 1.128 mM, respectively. In the intracellular LDH and G6PD assays, the EC50 of diazepam was found to be 3.307 and 1.53 mM, while the values of amiodarone were 0.853 and 0.325 mM, respectively. In the intracellular ATP and GSH assays, the EC50 of diazepam was 0.905 and 1.283 mM, while the values of amiodarone were 0.040 and 0.326 mM, respectively. Conclusion: Both the results of intracellular macromolecule activities and micromolecule concentrations were similar to that observed in in vivo venous irritation studies. However, the delayed cytotoxicity rank from the MTT assay is inconsistent with the in vivo venous irritation rank, suggesting that initial toxicity, but not the delayed toxicity, is related to venous irritation.
[Show abstract][Hide abstract] ABSTRACT: Genkwanin is one of the major non-glycosylated flavonoids in many herbs with anti-inflammatory activities. Although its anti-inflammatory activity in vivo has been reported, the potential molecular mechanisms remain obscure. In this study, by pharmacological and genetic approaches, we explore the anti-inflammatory effects of genkwanin in LPS-activated RAW264.7 macrophages. Genkwanin potently decreases the proinflammatory mediators, such as iNOS, TNF-α, IL-1β and IL-6, at the transcriptional and translational levels without cytotoxicity, indicating the excellent anti-inflammatory potency of genkwanin in vitro. Mechanism study shows that genkwanin significantly suppresses the p38- and JNK-mediated AP-1 signaling pathway and increases the mitogen-activated protein kinase (MAPK) phosphatase 1 (MKP-1) expression at the posttranscriptional level. We also confirmed that microRNA-101 (miR-101) is a negative regulator of MKP-1 expression. Moreover, regardless of miR-101-deficient cells or miR-101-abundant cells, the suppression effects of genkwanin on supernatant proinflammatory mediators' levels are far less than that in respective negative control cells, suggesting that genkwanin exerts anti-inflammatory effect mainly through reducing miR-101 production. However, genkwanin can't affect the level of phospho-Akt (p-Akt), indicating that the phosphorylation of Akt may be not responsible for the effect of genkwanin on miR-101 production. We conclude that genkwanin exerts its anti-inflammatory effect mainly through the regulation of the miR-101/MKP-1/MAPK pathway.
PLoS ONE 05/2014; 9(5):e96741. DOI:10.1371/journal.pone.0096741 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Irisflorentin, a naturally occurring isoflavone, is an abundant active constituent in Rhizoma Belamcandae. Although some chemical studies have been reported, pharmacological actions of irisflorentin are not well studied. In this study, we demonstrate the anti-inflammatory activity of irisflorentin in lipopolysaccharides (LPS)-stimulated RAW 264.7 macrophages. Irisflorentin markedly reduces the transcriptional and translational levels of inducible nitric oxide synthase (iNOS) as well as the production of NO. Furthermore, it also significantly inhibits TNF-α, IL-1β and IL-6 at both the transcriptional and translational levels. These effects mainly act via ERK1/2 - and p38-mediated the activator protein-1 (AP-1) rather than the nuclear factor-κB (NF-κB) pathway. Thus, our study elucidates the anti-inflammatory mechanism of irisflorentin in LPS-activated RAW 264.7 macrophages.
Experimental Biology and Medicine 04/2014; 239(8). DOI:10.1177/1535370214530081 · 2.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Since steroids and cyclooxygenase inhibitors may cause serious side effects, the IκB kinase (IKK) β/nuclear factor-κB (NF-κB) system becomes an intriguing candidate anti-inflammatory target. Rhein, the active metabolite of diacerein, possesses anti-inflammatory ability with gastrointestinal protective effect. However, in our preliminary study，we accidentally found that rhein showed both anti- and pro-inflammatory activities in lipopolysaccharide (LPS)-activated macrophages. Thus, in this study, we explored the underlying molecular mechanisms of the dual effect of rhein. In LPS-activated macrophages, rhein inhibits NF-κB activation and sequentially suppresses its downstream inducible nitric oxide synthase (iNOS), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) transcriptions and supernatant nitric oxide (NO) and IL-6 levels by inhibiting IKKβ (IC50≈11.79μM). But in the meantime, rhein enhances the activity of caspase-1 through inhibiting intracellular (in situ) IKKβ, in turn increasing the IL-1β and high mobility group box 1 (HMGB1) release, which can be amplified by rhein's reductive effect on intracellular superoxide anion (O2(-)). Unexpectedly, it is because of IKKβ inhibition that rhein significantly enhances TNF-α secretion and phagocytosis in macrophages with or without LPS. These results indicate that rhein exerts anti- and pro-inflammatory activities by targeting IKKβ inhibition, providing a molecular mechanism for the unanticipated role of rhein in macrophages. Furthermore, our study also highlights the potential complications of IKKβ inhibitors (e.g. rhein and diacerein, etc.) application in inflammation disorders, for the overall effects of IKKβ inhibition in different organ systems and disease processes are not easily predictable under all circumstances.
Free Radical Biology and Medicine 04/2014; 72. DOI:10.1016/j.freeradbiomed.2014.04.001 · 5.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In this paper, a lipid material glycerol monooleate was used as the starting material to synthesize the oxidized glycerol monooleate (OGMO). OGMO was subsequently linked to chitosan (CS) via imine bonds (CN) to obtain a new chitosan-based polymer (OGMO-CS), which can form hydrogels rapidly in aqueous media. Scanning electron microscopy, swelling behavior studies and degradation kinetics studies were performed to demonstrate the effect of this synthetic modification on the hydrogels formation of chitosan network and in vitro drug release. The effects of OGMO-CS type, dry hydrogels percentage, release media and drug loading on the sustained release of the model drug trimetazidine hydrochloride were evaluated. The release profiles of the hydrogels could be described by the Peppas-Sahlin mechanism, a combination of Fickian diffusion and Case-II relaxation. Based on the fact that numerous pharmaceutical lipids are available, the present study may pave the way for other lipids to be employed as modifiers of chitosan for more innovative chitosan derivatives with versatile properties and pharmaceutical applications.
International Journal of Pharmaceutics 02/2014; 465(1-2). DOI:10.1016/j.ijpharm.2014.02.001 · 3.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Curcumol is one of the major components of the essential oil of Rhizoma Curcumae, a common traditional Chinese medicine with anti-inflammatory properties. However, the anti-inflammatory activity and the underlying molecular mechanisms of this compound remain unclear. In the present study, the anti-inflammation effect of curcumol on lipopolysaccharide (LPS)-induced RAW264.7 cells is demonstrated along with its underlying mechanisms. We show that curcumol inhibits LPS-induced NO production by suppressing iNOS mRNA expression and protein level but not iNOS activity. Moreover, curcumol inhibits LPS-induced production of TNF-α, IL-1β and IL-6 at both the transcriptional and translational levels. Further investigations reveal that these effects mainly act via suppressing JNK-mediated AP-1 rather than the NF-κB pathway; these effects include a decrease in the phosphorylation level of JNK and a direct inhibition of the activity of p-JNK. These data provide scientific molecular evidence that curcumol may be a potential lead compound for a novel anti-inflammatory drug because of its inhibitory activity on the production of various inflammatory mediators.
European journal of pharmacology 11/2013; 723(1). DOI:10.1016/j.ejphar.2013.11.007 · 2.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Shuang-Huang-Lian (SHL) is a traditional Chinese compound formula prepared from Lonicerae Japonicae Flos, Scutellariae Radix and Fructus Forsythiae. In this study, we demonstrate the anti-inflammatory and anti-oxidative activities of SHL in lipopolysaccharide (LPS)-stimulated murine alveolar macrophages (MH-S). SHL significantly reduces the transcriptional and translational levels of iNOS and COX-2 as well as the production of NO and prostaglandin E2 (PGE2). It also suppresses the transcription and translation of inflammatory cytokines production, such as TNF-α, IL-1β and IL-6. These inhibitory effects mainly act via ERK1/2- and p38-mediated AP-1 rather than the NF-κB pathway. In parallel with the anti-inflammatory activity, SHL suppresses LPS-induced intracellular total ROS levels by weakening NADPH oxidase activity, enhancing SOD activity and increasing GSH content. In addition, SHL directly scavenges OH and O2(-). Thus, our study elucidates the anti-inflammatory and anti-oxidative mechanisms of SHL in LPS-stimulated MH-S.
Phytomedicine: international journal of phytotherapy and phytopharmacology 11/2013; 21(4). DOI:10.1016/j.phymed.2013.09.022 · 2.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Nrf2-mediated activation of ARE regulates expression of cytoprotective enzymes against oxidative stress, inflammation and carcinogenesis. We have discovered a novel structure (1) as an ARE inducer via luciferase reporter assay to screen the in-house database of our laboratory. The potency of 1 was evaluated by the expression of NQO-1, HO-1 and nuclear translocation of Nrf2 in HCT116 cells. In vivo potency of 1 was studied using AOM-DSS models, showing that the development of colorectal adenomas was significantly inhibited. Administration with 1 lowered the expression of IL-6, IL-1β and promoted Nrf2 nuclear translocation. These results indicated that 1 is a potent Nrf2/ARE activator, both in vitro and in vivo. 41 derivatives were synthesized for SAR study, and a more potent compound 17 was identified. To our knowledge, this is a potent ARE activator. Besides, its novel structure makes it promising for further optimization.
[Show abstract][Hide abstract] ABSTRACT: When exposed to electrophiles, human colorectal cancer cells (HCT116) counteract oxidative stress through activating NF-E2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway. To identify new activators, luciferase reporter gene assay was used to screen in-house database of our laboratory, leading to a novel α-pyrone compound 1 as a hit. 2 with 2-fluoro phenyl group exhibited the strongest ARE inductive activity in the first round structure-activity relationship (SAR) study. Biological studies showed the compound induced nuclear translocation of Nrf2 preceded by phosphorylation of ERK1/2. The data encouraged us to use 2 as lead and 20 derivatives were synthesized to discuss a more detailed SAR, leading to a more potent compound 9, which can be the starting compound for further modification.
European Journal of Medicinal Chemistry 06/2013; 66C:364-371. DOI:10.1016/j.ejmech.2013.06.007 · 3.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recently, coamorphous systems composed of two drugs or a drug and a small molecule excipient, gained interests due to their ability in overcoming limitations associated with solid dispersions. In this study, coamorphous form of repaglinide (REP), a BCS class II anti-diabetic drug with low aqueous solubility and high permeability was achieved with saccharin (SAC) by solution crystallization and characterized. An accurate and precise HPLC method was established for the simultaneous determination of REP and SAC. Coamorphous REP-SAC with 1:1 stoichiometry had unique thermal behavior, obvious FTIR shifts and the absence of sharp diffraction peak, suggesting the formation of a coamorphous material and interaction of REP with SAC through hydrogen bonds formed between REP's secondary amine and SAC's carbonyl group. Coamorphous REP-SAC showed great improvement in solubility and dissolution under sink conditions in various media. In addition, It was conformed in supersaturated dissolution of coamorphous REP-SAC in distilled water that the coamorphous material had remarkably longer time length for REP to be remained at a supersaturated concentration and had better metastable solubility. This coamorphous system provides a feasible way to process drugs with low solubility into substances with enhanced dissolution and stabilized amorphous state that could be conducive to greater bioavailability than the crystalline drug.
International Journal of Pharmaceutics 04/2013; 450(1). DOI:10.1016/j.ijpharm.2013.04.032 · 3.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of the study was to investigate the potential of nanocrystals to enhance the oral bioavailability of apigenin (AP), a bioactive flavonoid with various pharmacological activities but poor aqueous solubility. In the present investigation, the AP nanocrystals were prepared by the supercritical antisolvent process. In vitro characterization was performed by scanning electron microscopy, FT-IR, differential scanning calorimetry, X-ray powder diffractometry. In vitro dissolution of prepared nanocrystals was studied and compared with untreated coarse powder. In addition, the pharmacokinetic study of AP nanocrystals, in comparison to coarse powder, was also performed in rats after a single oral dose. The prepared AP nanocrystals, without change in crystalline structure, appeared in spherical shape with particle size of about 400-800 nm. The reduction of particle size resulted in a more rapid dissolution of AP from nanocrystals than from coarse powder. In comparison to coarse powder, AP nanocrystals exhibited a significantly decreased t(max), a 3.6-fold higher peak plasma concentration (C(max)) and 3.4-fold higher area under the curve (AUC).
European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences 01/2013; 48(4). DOI:10.1016/j.ejps.2012.12.026 · 3.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objectives The aim of the study was to prepare and to characterize two polymorphs of lornoxicam, a water-insoluble non-steroidal anti-inflammatory drug, which has thus far received no exploration of its polymorphs. Methods Form I and form II of lornoxicam were prepared by recrystallization and characterized by X-ray powder diffractometry (XRPD), thermal analysis, Fourier transform infrared spectroscopy and scanning electron microscopy. The solubility and dissolution of both polymorphs were also determined and compared to provide the basis for polymorph selection in formulation. Key findings The crystal structures of the two polymorphs were established by the experimental XRPD patterns. Form I was demonstrated to be triclinic with two kinds of intermolecular hydrogen bonds, while form II was orthorhombic with two kinds of intramolecular hydrogen bonds. The morphologies of form I and form II were observed to be rectangle and approximately oval, respectively. Conclusions Form II had the significantly higher solubility and dissolution and would be the suitable polymorph for the preparation of oral and injectable dosage forms of lornoxicam.
[Show abstract][Hide abstract] ABSTRACT: Using a newly developed strategy whose key step is the regioselective propargylation of hydroxyxanthone substrates, 99 structurally diverse Garcinia natural product-like xanthones based on gambogic acid were designed and synthesized and their in vitro antitumor activity was evaluated. A set of 40 related compounds was chosen for determination of their physicochemical properties including polar surface area, log D7.4, aqueous solubility and permeability at pH 7.4. In the light of the in vitro antitumor activity and the physicochemical properties, 2 compounds were advanced into in vivo efficacy experiments. The antitumor activity of compound 112, administered po, showed more potent in vivo oral antitumor activity than gambogic acid.
[Show abstract][Hide abstract] ABSTRACT: Gambogic acid (GA), a natural product, was identified as a promising antitumor agent. To further explore the structureactivity relationship of GA and discover novel GA derivatives as antitumor agents, 19 novel GA derivatives modified at C(34) were synthesized and evaluated against A549, BGC-823, U251, HepG2, and MB-231 cancer cell lines by cellular assays. Among them, 15 compounds were found to be more potent than GA against some cancer cell lines. Notably, compound 3 possessed potent inhibitory activities against five cell lines with IC(50) values ranging between 0.24 and 1.09 μM. Compounds 9 and 18 were seven to eightfold more active than GA against A549 cell line. Chemical modification at C(34) of GA by introducing of hydrophilic aliphatic amines resulted in increased activity and improved drug-like properties. These findings will enhance our understanding of the SAR of GA and can lead to the discovery of novel GA derivatives as potential antitumor agents.