Calcofluor white-cholesteryl hydrogen succinate conjugate mediated liposomes for enhanced targeted delivery of voriconazole into Candida albicans.

Fungal infections gradually lead to a high mortality rate due to difficulties in diagnosis, the limited number of antifungal drugs available, and the appearance of resistant isolates. Here, we developed a calcofluor white-cholesteryl hydrogen succinate conjugate (CFW-CHSc) as a novel nanomaterial that specifically binds to chitin chains in the cell wall. We showed that fluorescent-dye loaded CFW-CHSc-liposomes entered the cytoplasm of Candida albicans cells with increased efficacy. Voriconazole-loaded CFW-CHSc-liposomes displayed an increased antifungal activity against C. albicans yeast cells in an in vitro assay. Animal infection models and animal imaging analysis showed that fluorescent-dye loaded CFW-CHSc-liposomes maintained prolonged residence in rodent tissues. In mouse liver and kidney tissue, voriconazole-loaded CFW-CHSc-liposomes showed significantly enhanced antifungal activity when administered intravenously. Taken together, our studies confirm that CFW-CHSc increases the drug delivery efficacy of nanoparticles in vitro by interacting with chitin chains in the C. albicans cell wall. The fungi-targeting nanoparticles improve the drug delivery efficacy in vivo by enriching the nanoparticles at the site of fungal infection via the blood circulation system. Fungi-targeting nanomaterials have a promising future in the treatment of nosomycosis.

Cell penetrating peptide TAT-functionalized liposomes for efficient ophthalmic delivery of flurbiprofen: Penetration and its underlying mechanism, retention, anti-inflammation and biocompatibility.

In treating eye diseases, topical administration on the ocular surface is the most convenient and acceptable route. However, the intraocular efficiency of non-invasive drug delivery systems is still considerably hampered by the eye's defense barriers. In this work, cell-penetrating peptide TAT-functionalized, flurbiprofen-loaded liposomes (TAT-FB-Lip) were designed to enable transcorneal drug delivery and prolong ocular surface retention. The corneal penetration-promoting properties of TAT-functionalized liposomes (TAT-Lip) were confirmed in vitro using a corneal permeability assay and the HCE-T cell sphere model and in vivo by aqueous humor pharmacokinetics assessment. TAT-Lip induced an increase in intracellular calcium ion concentration and membrane potential depolarization. F-actin images of HCE-T cells treated with TAT-Lip show the tight junctions between cells partly opened. The cellular internalization pathway mainly depended on the electrostatic interaction between TAT-Lip and the cell membrane, and there is a certain degree of energy dependence. The pharmacokinetics of flurbiprofen in tears demonstrated TAT-Lip could reduce the drug loss rate. Moreover, the anti-inflammatory effect of TAT-FB-Lip was enhanced by markedly suppressing PGE2, IL-6, and TNF-α production in tears and aqueous humor in a rabbit conjunctivitis model. In conclusion, this work demonstrates that TAT-Lip is an effective ocular drug carrier system that facilitates transcorneal delivery.

Tripartite motif­containing 11 regulates the proliferation and apoptosis of breast cancer cells.

Breast cancer, an increasing health problem worldwide, is the second major cause of cancer­associated mortality in females. Studies have focused on the pathogenesis of breast cancer for decades, but the underlying mechanisms have not been fully elucidated. Tripartite motif­containing 11 (TRIM11), a novel oncogene that was recently identified, was reported to function in various types of cancer, including ovarian and lung cancer. In the present study, high expression levels of TRIM11 were detected in breast cancer tissues by reverse transcription­quantitative polymerase chain reaction and western blot analysis, which suggested that TRIM11 was likely to function in the progression of breast cancer. Downregulation of TRIM11 in MCF­7 and MDA­MB­231 cells inhibited cell proliferation and promoted cell apoptosis, accompanied by increased phosphatase and tensin homolog deleted on chromosome 10 (PTEN), p53 and Bcl­2­associated X protein, and decreased B­cell lymphoma 2, phosphorylated c­Jun N­terminal kinase 1/2 (p­JNK1/2) and phosphorylated extracellular signal­regulated kinases 1/2 (p­ERK1/2), whereas the overexpression of TRIM11 completely reversed these effects. Furthermore, TRIM11 downregulation enhanced the pro­apoptotic effect of chemotherapy drugs on breast cancer cells, and high levels of TRIM11 expression were observed in cisplatin­ and paclitaxel­resistant breast cancer tissues. These data indicated that TRIM11 is crucial to the development of breast cancer, and TRIM11 downregulation may benefit the treatment of breast cancer by regulating ERK1/2 and JNK1/2 signaling and the expression of apoptosis­associated genes.

Rho GTPase Activating Protein 24 (ARHGAP24) Regulates the Anti-Cancer Activity of Sorafenib Against Breast Cancer MDA-MB-231 Cells via the Signal Transducer and Activator of Transcription 3 (STAT3) Signaling Pathway.

BACKGROUND STAT3 has emerged as a novel potential target for sorafenib, a multikinase inhibitor, in the context of cancer therapy. ARHGAP24 is a Rac-specific Rho GTPase-activating protein (Rho GAP), which can convert Rho GTPases to an inactive state. It has been proved to be an oncosuppressor protein in renal cancer. In the present study, we investigated its anti-cancer effect in breast cancer (BC). MATERIAL AND METHODS Quantitative real-time PCR (qRT-PCR) and Western blot analysis were performed to detect the expression of ARHGAP24 in clinical tissue samples. Then, BC MDA-MB-231 cells were virally transduced with ARHGAP24 silencing or overexpression lentiviral vectors in the absence or presence of sorafenib. Cell viability and metastatic ability were evaluated by using the Cell Counting Kit-8 (CCK-8) and Transwell assays. Proteins belonging to the STAT3 pathway were detected by Western blot. RESULTS ARHGAP24 decreased in BC tissues compared with the adjacent normal tissues. Forced expression of ARHGAP24 and sorafenib treatment significantly suppressed the viability, migration, and invasion of MDA-MB-231 cells. Conversely, elimination of the endogenous ARHGAP24 with shRNA promoted cell viability, migration, and invasion. The phosphorylation of STAT3 and the expression of MMP-2 and MMP-9 were attenuated by ARHGAP24 ectopic expression and sorafenib treatment. Furthermore, forced expression of ARHGAP24 significantly enhanced sorafenib-induced decrease of cell viability, migration, and invasion of MDA-MB-231 cells, while elimination of the endogenous ARHGAP24 with shRNA inhibited it. CONCLUSIONS ARHGAP24 can suppress the development of MDA-MB-231 cells via the STAT3 signaling pathway, and sorafenib inhibits cell viability, migration, invasion, and STAT3 activation in MDA-MB-231 cells through ARHGAP24.

Omega-3 Polyunsaturated Fatty Acids Eicosapentaenoic Acid and Docosahexaenoic Acid Enhance Dexamethasone Sensitivity in Multiple Myeloma Cells by the p53/miR-34a/Bcl-2 Axis.

Dexamethasone is widely used in multiple myeloma (MM) for its cytotoxic effects on lymphoid cells. However, many MM patients are resistant to dexamethasone, although some can benefit from dexamethasone treatment. In this study, we noted that ω-3 polyunsaturated fatty acids (PUFAs) enhanced the dexamethasone sensitivity of MM cells by inducing cell apoptosis. q-PCR analysis revealed that miR-34a could be significantly induced by PUFAs in U266 and primary MM cells. Transfection with miR-34a antagonist or miR-34a agomir could restore or suppress the dexamethasone sensitivity in U266 cells. Both luciferase reporter assay and Western blot showed that Bcl-2 is the direct target of miR-34a in MM cells. In addition, we observed that PUFAs induced p53 protein expression in MM cells under dexamethasone administration. Furthermore, suppressing p53 by its inhibitor, Pifithrin-α, regulated the miR-34a expression and modulated the sensitivity to dexamethasone in U266 cells. In summary, these results suggest that PUFAs enhance dexamethasone sensitivity to MM cells through the p53/miR-34a axis with a likely contribution of Bcl-2 suppression.

Flavonol glycosides from the leaves of Elaeagnus pungens.

The leaves of Elaeagnus pungens were extracted and successively purified by a set chromatographic techniques. The structures of the obtained constituents were elucidated on the basis of spectroscopic methods including 1D/2D NMR and high resolution-MS. One new flavonoid glycosides, kaempferol 3-O-ß-d-glucopyranosyl-(1 → 3)-α-l-rhamnopyranosyl-(1 → 6)-[α-l-rhamnopyranosyl(1 → 2)]-ß-d-galactopyranoside-7-O-ß-d-glucopyranoside (1), along with five known compounds (2-6) were isolated and identified. The MTT assay in vitro showed that the isolated flavonol glycosides have no proliferating activity, suggesting no aggravating impact on the increased airway smooth muscle cells.

Two new flavonol glycosides from the leaves of Elaeagnus pungens.

The leaves of Elaeagnus pungens were extracted with 70% ethanol and successively purified by column chromatography. Seven constituents were obtained and characterized, all of which belong to the class of flavonol glycosides. Their structures were elucidated on the basis of spectroscopic methods including 1D/2D NMR and MS analysis techniques. The seven flavonol glycosides were determined as kaempferol 3-O-ß-d-glucopyranosyl-(1 â†’ 3)-α-l-rhamnopyranosyl-(1 â†’ 6)-[α-l-rhamnopyranosyl(1 â†’ 2)]-ß-d-galactopyranoside (1), isorhamnetin 3-O-ß-d-glucopyranosyl-(1 â†’ 3)-α-l-rhamnopyranosyl-(1 â†’ 6)-ß-d-galactopyranoside (2), together with five known compounds, respectively. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliu-m bromide assay in vitro showed that the isolated flavonol glycosides showed no proliferation activity in the asthma airway smooth muscle cells, comparing with solvent as the control group.

[Water-soluble chemical constituents from Elaeagnus pungens leaves].

OBJECTIVE: To study water-soluble chemical constituents from the leaves of Elaeagnus pungens. METHOD: Chemical constituents of E. pungens leaves were separated by a combination of macroporous resin column chromatography, reverse phase silica gel column chromatography, Sephadex LH-20 column chromatography and semi-preparative HPLC. Their structures were identified on the basis of physicochemical properties using the spectral method. RESULT: The two compounds were separated from E. pungens leaves and identified as kaempferol 3-O-P-D-glucopyranosyl- (1-->3)-alpha-L-rhamn-opyranosyl-(1-->6) -/3-D-galactopyranoside (1), kaempferol 3-O-P-D-glucopyranosyl-(1-->3)-alpha-L-rhamnopyranosyl-(1-->6)-beta-D-glucopyranoside-7-O-beta-D-glucopyranoside (2). CONCLUSION: Compound 2 separated from E. pungens leaves was a new compound.