Dendritic cell combination therapy reduces the toxicity of triptolide and ameliorates colitis in murine models

Triptolide (TP) exerts a promising effect in the treatment of ulcerative colitis (UC). However, its toxicity seriously hinders its application in the clinic. Previous studies indicated that dendritic cells (DCs) are the main target through which TP exerts its immunoregulatory effect. Thus, we designed an approach to target DCs in vitro to avoid the direct exposure of organs to TP. Our results revealed that DCs pretreated with TP (DCTP) exerted satisfactory therapeutic effects in mice with colitis, resulting in improved colonic inflammation and alleviated local lesion damage. In addition, no obvious toxicity was observed. DCTP also reshaped the immune milieu by decreasing CD4⁺ T cell numbers and increasing regulatory T cell numbers in the spleen, mesenteric lymph nodes, peripheral blood and colon; these effects were further confirmed in vitro. Downregulation of CD80/86, ICAM-1, MHCI, TLR2/4, TNF-α, and IL-6 expression and upregulation of programmed cell death ligand 1 (PDL1) and IL-10 expression were observed, indicating that DCs were converted into tolerogenic DCs. In conclusion, DCTP can effectively reduce toxicity and alleviate colonic inflammation and local lesion damage in mice with colitis. The immune mechanism underlying the effects of DCTP included the conversion of DCs into tolerogenic DCs and the alteration of T cell differentiation to produce immunoinhibitory rather than immunostimulatory T cells.     

Controllable release of pirfenidone by polyvinyl alcohol film embedded soft contact lenses in vitro and in vivo

To increase the amount of pirfenidone (PFD) loaded in polyvinyl alcohol (PVA) film embedded soft contact lens (SCL), and evaluate its function of sustaining delivery of drug in vitro and in vivo. Drug loading efficiency within PVA film and SCLs, drug release from SCLs in vitro, and the effects of parameters of SCLs and external environment on drug release in vitro were evaluated by ultraviolet–visible spectrophotometer at 312 nm. Safety of SCLs was evaluated in vitro by transformed human corneal epithelial cell. Safety in vivo was determined by optical coherence tomography and histology of anterior segment of rabbits. Drug release study in tear fluid and aqueous humor were measured by ultra-performance liquid chromatography. SCLs had smooth surface and were fit for experimental rabbits. Amount of PFD in PVA film and SCLs were 153.515 μg ± 12.508 and 127.438 μg ± 19.674, respectively, PFD in PVA film was significantly higher than SCLs (p=.006) and closed to 150 μg (targeting amount of PFD to be loaded). Thickness of SCLs, molecular weight of PVA, and amount of PVA used in SCLs affected drug release in vitro significantly. Thickness of PVA film and amount of drug in SCLs had no effect on drug release rate in vitro. SCLs were safe in vitro and in vivo, PFD released from SCLs could be detected around 12 hours in tears and aqueous humor, and the concentration of drug was higher than eye drop at all detected time points while amount of PFD in SCLs was lower than eye drop. Drug loaded PVA film embedded SCLs may be a promising ocular drug delivery system.     

Schizandrin A ameliorates cognitive functions via modulating microglial polarisation in Alzheimer’s disease mice

ContextSchizandrin A (Sch A) is a major phytochemical from Schisandra chinensis (Turcz.) Baill. (Schisandraceae), which exerts a neuroprotective effect in Alzheimer''s disease (AD).ObjectiveTo investigate the mechanism of Sch A in AD.Materials and methodsAD group: APP/PS1 transgenic mice served as AD models; AD + SCH group: APP/PS1 received 2 mg/kg Sch A by intragastric administration; WT: C57BL/6 mice were used as control. For in vitro assay, mouse microglial BV2 cells were treated with 0.5 µg/mL lipopolysaccharide or combined with 10 μmol/L Sch A for 24 h. The cognitive function and apoptosis in the mice was estimated. Microglial polarisation in the mice and cells was analysed.ResultsSch A treatment effectively improved spatial learning and memory ability and suppressed apoptosis in the brain tissues of APP/PS1 mice. APP/PS1 mice exhibited an increase in the levels of Aβ1-42 (2367.9 ± 431.1 pg/mg) and Aβ1-40 (1753.3 ± 253.4 pg/mg), which was abolished by Sch A treatment. Moreover, Sch A treatment repressed the proportions of iNOS⁺/Iba-1⁺ cells and IL-6 expression, while enhanced the proportions of Arg-1⁺/Iba-1⁺ cells and IL-10 expression in APP/PS1 mice. In vitro, Sch A treatment reduced the proportions of CD16/32⁺ cells, iNOS expression and IL-6 levels (25.7 ± 5.3 pg/mL) repressed M1 polarisation, and enhanced the proportions of CD206 cells, Arg-1 expression and IL-10 levels (75.9 ± 12.8 pg/mL) in BV2 cells.ConclusionsThis research confirms the neuroprotective effect of Sch A in AD, suggesting that Sch A may become a potential anti-AD agent.     

Intranasal administration of dauricine loaded on graphene oxide: multi-target therapy for Alzheimer's disease

Alzheimer''s disease (AD) is a degenerative disease of the central nervous system characterized by progressive cognitive and memory-related impairment. However, current therapeutic treatments have not proved sufficiently effective, mainly due to the complicated pathogenesis of the disease. In this study, a nano-formulation of graphene oxide (GO) loaded with dauricine (Dau) was investigated in terms of the combined anti-inflammatory and anti-oxidative stress effects of Dau and the inhibition of misfolding and aggregation of the amyloid-β (Aβ) protein by GO. Both in vivo and in vitro models were induced using Aβ_1-42, and the formulation was administered nasally in mice. The results showed that GO loaded with Dau greatly reduced oxidative stress through increasing superoxide dismutase levels and decreasing reactive oxygen species and malondialdehyde levels in vitro; it also alleviated the cognitive memory deficits and brain glial cell activation in mice with Aβ_1-42-induced AD. This proved that GO loaded with Dau could protect against Aβ_1-42-induced oxidative damage and apoptosis in both in vitro and in vivo AD models; therefore, GO loaded with Dau has the potential to be an effective and agent for the rapid treatment of AD.     

Cyanidin attenuates the apoptosis of rat nucleus pulposus cells and the degeneration of intervertebral disc via the JAK2/STAT3 signal pathway in vitro and in vivo

ContextCyanidin has been shown to have therapeutic potential in osteoarthritis. However, it is unclear whether cyanidin prevents the progression of intervertebral disc degeneration (IVDD).ObjectiveThis study evaluates the effects of cyanidin on IVDD in vitro and in vivo.Materials and methodsNucleus pulposus cells (NPCs) isolated from lumbar IVD of 4-week-old male Sprague-Dawley (SD) rats were exposed to 20 ng/mL IL-1β, and then treated with different doses (0-120 µM) of cyanidin for 24 h. SD rats were classified into three groups (n = 8) and treated as follows: control (normal saline), IVDD (vehicle), IVDD + cyanidin (50 mg/kg). Cyanidin was administered intraperitoneally for 8 weeks.ResultsThe IC₅₀ of cyanidin for NPCs was 94.78 µM, and cyanidin had no toxicity at concentrations up to 500 mg/kg in SD rats. Cyanidin inhibited the apoptosis of NPCs induced by IL-1β (12.73 ± 0.61% vs. 18.54 ± 0.60%), promoted collagen II (0.82-fold) and aggrecan (0.81-fold) expression, while reducing MMP-13 (1.02-fold) and ADAMTS-5 (1.40-fold) expression. Cyanidin increased the formation of autophagosomes in IL-1β-induced NPCs, and promoted LC3II/LC3I (0.83-fold) and beclin-1 (0.85-fold) expression, which could be reversed by chloroquine. Cyanidin inhibited the phosphorylation of JAK2 (0.47-fold) and STAT3 (0.53-fold) in IL-1β-induced NPCs. The effects of cyanidin could be enhanced by AG490. Furthermore, cyanidin mitigated disc degeneration in IVDD rats in vivo.Discussion and conclusionsCyanidin improved the function of NPCs in IVDD by regulating the JAK2/STAT3 pathway, which may provide a novel alternative strategy for IVDD. The mechanism of cyanidin improving IVDD still needs further work for in-depth investigation.     

Enrofloxacin/florfenicol loaded cyclodextrin metal-organic-framework for drug delivery and controlled release

We presented an antibiotic-loaded γ-cyclodextrin metal-organic framework that delivered antibiotics suitable for the treatment of bacterial infections. The γ-cyclodextrin metal-organic framework was developed using γ-cyclodextrin and potassium ion via the ultrasonic method. The antibiotic (florfenicol and enrofloxacin) was primarily encapsulated into the pore structures of γ-CD-MOF, which allowed the sustained release of antibiotics over an extended period of time in vitro and in vivo. Notably, antibiotics-loaded γ-CD-MOF showed much superior activity against bacteria than free antibiotics (lower MIC value) and displayed better long-lasting activity (longer antibacterial time). The antibiotics-loaded γ-CD-MOF showed nontoxic and perfect biocompatibility to mammalian cells and tissues both in vitro and in vivo. These materials thus represent a novel drug-delivery device suitable for antibiotic therapy. This research is of great significance for reducing the generation of bacterial resistance and providing new ideas for the application of γ-CD-MOF.     

Caudatin blocks the proliferation,stemness and glycolysis of non-small cell lung cancer cells through the Raf/MEK/ERK pathway

ContextThe antitumor effects of caudatin have been explored in multiple cancers, but the research on lung cancer has not been fully understood.ObjectiveWe explored the effects of caudatin on non-small cell lung cancer (NSCLC) in vitro and in vivo.Materials and methodsIn the in vitro experiments, 0, 25, 50 and 100 μM of caudatin were selected to examine the effects on stemness and glycolysis. Subcutaneous tumour xenografts were constructed by injecting the nude mice (BALB/C) with 5 × 10⁶ H1299 cells. In the in vivo experiments, all nude mice were divided into the caudatin group (50 mg/kg/day, n = 5) and the sham group (equal amount of DMSO, n = 5).ResultsThe IC₅₀ of caudatin for H1299 and H520 cells was 44.68 μM and 69.37 μM, respectively. Compared with caudatin 0 μM group, cell apoptosis rate was increased about 10 times and cell stemness was decreased by 75–85% in caudatin 100 μM group. Glucose uptake (65–80% reduction), lactic acid production (75–80% reduction), ATP level (70–80% reduction) and the expression of HK2 and LDHA (75–85% reduction) were decreased in caudatin 100 μM group. The expression of Raf/MEK/ERK pathway related proteins was decreased to 20–25% by caudatin. Tumour weight (about 70% reduction) and the expression of stemness, glycolysis and Raf/MEK/ERK pathway related proteins (about 50–75% reduction) were suppressed by caudatin in vivo.Discussion and conclusionsWe revealed that caudatin blocked stemness and glycolysis in NSCLC for the first time. More experiments about exact dosage of caudatin in vivo should be conducted.     

A novel dendritic mesoporous silica based sustained hydrogen sulfide donor for the alleviation of adjuvant-induced inflammation in rats

PurposeS-propargyl-cysteine (SPRC), an excellent endogenous hydrogen sulfide (H₂S) donor, could elevate H₂S levels via the cystathionine γ-lyase (CSE)/H₂S pathway both in vitro and in vivo. However, the immediate release of H₂S in vivo and daily administration of SPRC potentially limited its clinical use.MethodsTo solve the fore-mentioned problem, in this study, the dendritic mesoporous silica nanoparticles (DMSN) was firstly prepared, and a sustained H₂S delivery system consisted of SPRC and DMSN (SPRC@DMSN) was then constructed. Their release profiles, both in vitro and in vivo, were investigated, and their therapeutical effect toward adjuvant-induced arthritis (AIA) rats was also studied.ResultsThe spherical morphology of DMSN could be observed under scanning Electron Microscope (SEM), and the transmission electron microscope (TEM) images showed a central-radiational pore channel structure of DMSN. DMSN showed excellent SPRC loading capacity and attaining a sustained releasing ability than SPRC both in vitro and in vivo, and the prolonged SPRC releasing could further promote the release of H₂S in a sustained manner through CSE/H₂S pathway both in vitro and in vivo. Importantly, the SPRC@DMSN showed promising anti-inflammation effect against AIA in rats was also observed.ConclusionsA sustained H₂S releasing donor consisting of SPRC and DMSN was constructed in this study, and this sustained H₂S releasing donor might be of good use for the treatment of AIA.     

In vivo dissolution of poorly water-soluble drugs: Proof of concept based on fluorescence bioimaging

In vitro‒in vivo correlation (IVIVC) of solid dosage forms should be established basically between in vitro and in vivo dissolution of active pharmaceutical ingredients. Nevertheless, in vivo dissolution profiles have never been accurately portrayed. The current practice of IVIVC has to resort to in vivo absorption fractions (F_a). In this proof-of-concept study, in vivo dissolution of a model poorly water-soluble drug fenofibrate (FNB) was investigated by fluorescence bioimaging. FNB crystals were first labeled by near-infrared fluorophores with aggregation-caused quenching properties. The dyes illuminated FNB crystals but quenched immediately and absolutely once been released into aqueous media, enabling accurate monitoring of residual drug crystals. The linearity established between fluorescence and crystal concentration justified reliable quantification of FNB crystals. In vitro dissolution was first measured following pharmacopoeia monograph protocols with well-documented IVIVC. The synchronicity between fluorescence and in vitro dissolution of FNB supported using fluorescence as a measure for determination of dissolution. In vitro dissolution correlated well with in vivo dissolution, acquired by either live or ex vivo imaging. The newly established IVIVC was further validated by correlating both in vitro and in vivo dissolution with F_a obtained from pharmacokinetic data.KEY WORDS: In vivo dissolution, Fenofibrate, Fluorescence, Aggregation-caused quenching, Bioimaging, IVIVC     

Discovery of novel diarylamides as orally active diuretics targeting urea transporters

Urea transporters (UT) play a vital role in the mechanism of urine concentration and are recognized as novel targets for the development of salt-sparing diuretics. Thus, UT inhibitors are promising for development as novel diuretics. In the present study, a novel UT inhibitor with a diarylamide scaffold was discovered by high-throughput screening. Optimization of the inhibitor led to the identification of a promising preclinical candidate, N-[4-(acetylamino)phenyl]-5-nitrofuran-2-carboxamide (1H), with excellent in vitro UT inhibitory activity at the submicromolar level. The half maximal inhibitory concentrations of 1H against UT-B in mouse, rat, and human erythrocyte were 1.60, 0.64, and 0.13 μmol/L, respectively. Further investigation suggested that 8 μmol/L 1H more powerfully inhibited UT-A1 at a rate of 86.8% than UT-B at a rate of 73.9% in MDCK cell models. Most interestingly, we found for the first time that oral administration of 1H at a dose of 100 mg/kg showed superior diuretic effect in vivo without causing electrolyte imbalance in rats. Additionally, 1H did not exhibit apparent toxicity in vivo and in vitro, and possessed favorable pharmacokinetic characteristics. 1H shows promise as a novel diuretic to treat hyponatremia accompanied with volume expansion and may cause few side effects.     

The FAPα-activated prodrug Z-GP-DAVLBH inhibits the growth and pulmonary metastasis of osteosarcoma cells by suppressing the AXL pathway

Osteosarcoma is a kind of bone tumor with highly proliferative and invasive properties, a high incidence of pulmonary metastasis and a poor prognosis. Chemotherapy is the mainstay of treatment for osteosarcoma. Currently, there are no molecular targeted drugs approved for osteosarcoma treatment, particularly effective drugs for osteosarcoma with pulmonary metastases. It has been reported that fibroblast activation protein alpha (FAPα) is upregulated in osteosarcoma and critically associated with osteosarcoma progression and metastasis, demonstrating that FAPα-targeted agents might be a promising therapeutic strategy for osteosarcoma. In the present study, we reported that the FAPα-activated vinblastine prodrug Z-GP-DAVLBH exhibited potent antitumor activities against FAPα-positive osteosarcoma cells in vitro and in vivo. Z-GP-DAVLBH inhibited the growth and induced the apoptosis of osteosarcoma cells. Importantly, it also decreased the migration and invasion capacities and reversed epithelial–mesenchymal transition (EMT) of osteosarcoma cells in vitro and suppressed pulmonary metastasis of osteosarcoma xenografts in vivo. Mechanistically, Z-GP-DAVLBH suppressed the AXL/AKT/GSK-3β/β-catenin pathway, leading to inhibition of the growth and metastatic spread of osteosarcoma cells. These findings demonstrate that Z-GP-DAVLBH is a promising agent for the treatment of FAPα-positive osteosarcoma, particularly osteosarcoma with pulmonary metastases.KEY WORDS: Osteosarcoma, Fibroblast activation protein alpha, Growth, Pulmonary metastasis, Vinblastine prodrug, AXL, β-Catenin     

Green synthesis of gold nanoparticles from Dendrobium officinale and its anticancer effect on liver cancer

A novel gold nanoparticle (Do-AuNP) was successfully synthesized from water extracts of traditional Chinese medicine Dendrobium officinale (DO) without using any extra chemicals regents. The physicochemical properties of Do-AuNPs were analyzed by transmission electron microscopy, dynamic light scattering, energy-dispersive X-ray spectroscopy, Fourier transform infrared spectroscopy, and atomic force microscopy. The amount of DO extract on the AuNPs was about 13%. In order to evaluate the anti-tumor efficiency and biosafety, the inhibitory rate of HepG2 cells and survival rate of L02 cells were performed in vitro, and the immunohistochemical analysis of H&E, Ki-67, and TUNEL staining were conducted in vivo. Our results demonstrated that Do-AuNP had better anti-tumor efficiency compared with DO extraction alone without increasing toxicity in vivo and in vitro. The present study provides useful information for Do-AuNP as a new nanomedicine for liver cancer.     

In vitro and in vivo correlation for lipid-based formulations: Current status and future perspectives

Lipid-based formulations (LBFs) have demonstrated a great potential in enhancing the oral absorption of poorly water-soluble drugs. However, construction of in vitro and in vivo correlations (IVIVCs) for LBFs is quite challenging, owing to a complex in vivo processing of these formulations. In this paper, we start with a brief introduction on the gastrointestinal digestion of lipid/LBFs and its relation to enhanced oral drug absorption; based on the concept of IVIVCs, the current status of in vitro models to establish IVIVCs for LBFs is reviewed, while future perspectives in this field are discussed. In vitro tests, which facilitate the understanding and prediction of the in vivo performance of solid dosage forms, frequently fail to mimic the in vivo processing of LBFs, leading to inconsistent results. In vitro digestion models, which more closely simulate gastrointestinal physiology, are a more promising option. Despite some successes in IVIVC modeling, the accuracy and consistency of these models are yet to be validated, particularly for human data. A reliable IVIVC model can not only reduce the risk, time, and cost of formulation development but can also contribute to the formulation design and optimization, thus promoting the clinical translation of LBFs.KEY WORDS: Lipid-based formulation, In vitro and in vivo correlations, Lipolysis, Absorption, Oral delivery, Model, In silico prediction, Perspectives     

WIN-34B May Have Analgesic and Anti-Inflammatory Effects by Reducing the Production of Pro-Inflammatory Mediators in Cells via Inhibition of IκB Signaling Pathways

WIN-34B showed analgesic and anti-inflammatory effects in various animal models of pain and osteoarthritis. However, the molecular mechanism by which WIN-34B inhibits pain and inflammation in vivo remains to be elucidated. We investigated the molecular mechanisms of the actions of WIN-34B using various in vitro models using fibroblast-like synoviocytes from patients with rheumatoid arthritis (RA FLSs), RAW264.7 cells and peritoneal macrophages. WIN-34B inhibited the level of IL-6, PGE₂, and MMP-13 in IL-1β-stimulated RA FLSs in a dose-dependent manner. The mRNA levels were also inhibited by WIN-34B. The level of PGE₂, NO, IL-1β, and TNF-α were inhibited by WIN-34B at different concentrations in LPS-stimulated RAW264.7 cells. The production of NO and PGE₂ was inhibited by WIN-34B in a dose-dependent manner in LPS-stimulated peritoneal macrophages. All of these effects were comparable to the positive control, celecoxib or indomethacin. IκB signaling pathways were inhibited by WIN-34B, and the migration of NF-κB into the nucleus was inhibited, which is consistent with the degradation of IκB-α. Taken together, the results suggest that WIN-34B has potential as a therapeutic drug to reduce pain and inflammation by inhibiting the production of pro-inflammatory mediators.     

L-EGCG-Mn nanoparticles as a pH-sensitive MRI contrast agent

This study aimed to synthesize and characterize L-epigallocatechin gallate (EGCG) complexed Mn²⁺ nanoparticle (L-EGCG-Mn), a proof-of-concept pH-sensitive manganese core nanoparticle (NP), and compare its magnetic resonance (MR) properties with those of Gd-DTPA, both in vitro and in vivo. Reverse microemulsion was used to obtain the L-EGCG-Mn NPs. The physicochemical properties of L-EGCG-Mn were characterized using dynamic light scattering, transmission electron microscopy, and near-infrared fluorescence small animal live imaging. The in vitro relaxivity of L-EGCG-Mn incubated with different pH buffer solutions (pH = 7.4, 6.8, 5.5) was evaluated. The T1-weighted MR imaging (MRI) properties were evaluated in vitro using hypoxic H22 cells as well as in H22 tumor-bearing mice. Cytotoxicity tests and histological analysis were performed to evaluate the safety of L-EGCG-Mn. L-EGCG-Mn showed good biocompatibility, stability, pH sensitivity, and tumor-targeting ability. Moreover, when the pH was decreased from 7.4 to 5.5, the r₁ relaxivity of L-EGCG-Mn was shown to gradually increase from 1.79 to 6.43 mM⁻¹·s⁻¹. Furthermore, after incubation with L-EGCG-Mn for 4 h, the T1 relaxation time of hypoxic H22 cells was significantly lower than that of normoxic H22 cells (1788 ± 89 vs. 1982 ± 68 ms, p=.041). The in vivo analysis showed that after injection, L-EGCG-Mn exhibited a higher MRI signal compared to Gd-DTPA in H22 tumor-bearing mice (p < .05). Furthermore, L-EGCG-Mn was found to have a good safety profile via cytotoxicity tests and histological analysis. L-EGCG-Mn has a good safety profile and pH sensitivity and may thus serve as a potential MRI contrast agent.     

The synergistic antitumor activity of 3-(2-nitrophenyl) propionic acid-paclitaxel nanoparticles (NPPA-PTX NPs) and anti-PD-L1 antibody inducing immunogenic cell death

Cancer immunotherapy is a strategy that is moving to the frontier of cancer treatment in the current decade. In this study, we show evidence that 3-(2-nitrophenyl) propionic acid-paclitaxel nanoparticles (NPPA-PTX NPs), act as immunogenic cell death (ICD) inducers, stimulating an antitumor response which results in synergistic antitumor activity by combining anti-PD-L1 antibody (aPD-L1) in vivo. To investigate the antitumor immunity induced by NPPA-PTX NPs, the expression of both ICD marker calreticulin (CRT) and high mobility group box 1 (HMGB1) were analyzed. In addition, the antitumor activity of NPPA-PTX NPs combined with aPD-L1 in vivo was also investigated. The immune response was also measured through quantitation of the infiltration of T cells and the secretion of pro-inflammatory cytokines. The results demonstrate that NPPA-PTX NPs induce ICD of MDA-MB-231 and 4T1 cells through upregulation of CRT and HMGB1, reactivating the antitumor immunity via recruitment of infiltrating CD3+, CD4+, CD8+ T cells, secreting IFN-γ, TNF-α, and the enhanced antitumor activity by combining with aPD-L1. These data suggest that the combined therapy has a synergistic antitumor activity and has the potential to be developed into a novel therapeutic regimen for cancer patients.     

The hydrogen sulfide donor,GYY4137, exhibits anti-atherosclerotic activity in high fat fed apolipoprotein E?/? mice

Background and Purpose

Atherosclerosis is associated with reduced vascular hydrogen sulfide (H₂S) biosynthesis. GYY4137 is a novel slow-releasing H₂S compound that may effectively mimic the time course of H₂S release in vivo. However, it is not known whether GYY4137 affects atherosclerosis.

Experimental Approach

RAW 264.7 cells and human blood monocyte-derived macrophages were incubated with oxidized low density lipoprotein (ox-LDL) with/without GYY4137. ApoE^−/− mice were fed a high-fat diet for 4 weeks and administered GYY4137 for 30 days. Lipid and atherosclerotic lesions were measured by oil red O staining. Endothelium-dependent relaxation was assessed in response to acetylcholine. Superoxide production was detected by dihydroethidium staining. Expression of mRNA and protein were evaluated by quantitative real-time PCR and Western blot.

Key Results

GYY4137 inhibited ox-LDL-induced foam cell formation and cholesterol esterification in cultured cells. GYY4137 decreased the expression of lectin-like ox-LDL receptor-1, iNOS, phosphorylated IκBα, NF-κB, ICAM-1, VCAM-1 and chemokines, including CXCL2, CXCR4, CXCL10 and CCL17, but increased the scavenger protein CD36, in ox-LDL-treated RAW 264.7 cells. In vivo, GYY4137 decreased aortic atherosclerotic plaque formation and partially restored aortic endothelium-dependent relaxation in apoE^−/− mice. GYY4137 decreased ICAM-1, TNF-α and IL-6 mRNA expression as well as superoxide (O₂⁻) generation in aorta. In addition, GYY4137 increased aortic eNOS phosphorylation and expression of PI3K, enhanced Akt Ser⁴⁷³ phosphorylation and down-regulated the expression of LOX-1.

Conclusion and Implications

GYY4137 inhibits lipid accumulation induced by ox-LDL in RAW 264.7 cells. In vivo, GYY4137 decreased vascular inflammation and oxidative stress, improved endothelial function and reduced atherosclerotic plaque formation in apoE^−/− mice.     

Β-Cyclodextrin-graft-poly(amidoamine) dendrons as the nitric oxide deliver system for the chronic rhinosinusitis therapy

Chronic rhinosinusitis (CRS) is a rather prevalent condition with a chronic inflammatory process, which is hard to cure. Herein, a new antibacterial drug, nitric oxide (NO), was used for the attempt on CRS therapy. To achieve this, a star copolymer (β-CD-PAMAM) consisting of the β-cyclodextrin (β-CD) core and seven PAMAM-G3 arms, which was designed as a low-cytotoxicity and high NO loading carrier, were synthesized and characterizied. The obtained β-CD-PAMAM/NONOate showed the effect in inhibiting and dispersing the biofilm of S. aureus, as well as the effective antibacterial performance, implying the promising application in CRS treatment. The in vivo assay confirmed that β-CD-PAMAM/NONOate displayed excellent therapy effect on CRS and significantly improved the symptoms of the experimental rats, which was no significant different in therapy effect with the clinical Rhinocort. Incorporated with its little toxicity in vitro and in vivo, the β-CD-PAMAM/NONOate was suggested a promising application in CRS therapy.