Sorafenib (SFB) has improved the treatment of hepatocellular carcinoma (HCC) and has fewer severe side effects than other agents used for that purpose. However, due to a lack of tumor-specific targeting, the concentration of the drug in tumor tissue cannot be permanently maintained at a level that inhibits tumor growth. To overcome this problem, we developed a novel SFB-loaded polymer nanoparticle (NP). The NP (a TPGS-b-PCL copolymer that was synthesized from ε-caprolactone and d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) via ring-opening polymerization) contains Pluronic P123 and SFB, and its surface is modified with anti-GPC3 antibody to produce the polymer nanoparticle (NP-SFB-Ab). The Ab-conjugated NPs had higher cellular uptake by HepG2 cells than did non-antibody-conjugated SPD-containing nanoparticles (NP-SFB). The NP-SFB-Ab also displayed better stability characteristics, released higher levels of SFB into cell culture medium, and was more cytotoxic to tumor cells than was non-targeted NP-SFB and free SFB. The NP-SFB-Ab downregulated expression of the anti-apoptosis molecule MCL-1, which led to polymerization of Bax and Bak in mitochondrial cytosol. The NP-SFB-AB also promoted the mitochondrial release of cytochrome C, resulting in cellular apoptosis. Moreover, the NP-SFB-Ab significantly inhibited the growth of HepG2 xenograft tumors in nude mice without producing obvious side effects. These findings suggest that NP-SFB-Ab is a promising new method for achieving targeted therapy of HCC.
Paeoniflorin (PF) is one of the principal components of peony, a plant widely used in traditional Chinese medicine for its anti-inflammatory and immunomodulatory effects. Human β-defensin-2 (hBD-2) is an antimicrobial peptide that acts as the first line of defense against bacterial, viral, and fungal infections. This study aims to determine whether or not PF can regulate the expression of hBD-2 and its possible molecular mechanism in human bronchial epithelial cells (HBECs). Real-time quantitative reverse transcription PCR showed that PF can enhance the mRNA expression level of hBD-2 in a concentration- and time-dependent manner in HBECs. Further studies demonstrated that the mRNA and protein expression levels of hBD-2 were attenuated by the p38 mitogen-activated protein kinase (p38 MAPK) inhibitor SB203580, the extracellular signal-regulated kinase (ERK) inhibitor PD98059, and the nuclear factor kappa B (NF-κB) inhibitor (pyrrolidine dithiocarbamate (PDTC)). The phosphorylation of p38 MAPK, ERK, and c-Jun N-terminal kinase was detected by Western blot analysis, and the NF-κB translocation of 16HBECs after PF treatment was analyzed by immunofluorescence. These results support that PF upregulates hBD-2 expression in HBECs through the p38 MAPK, ERK, and NF-κB signaling pathways. These findings provide a new pharmacological mechanism of PF for the treatment of microbial infections by strengthening epithelial antimicrobial barriers.
Human β-defensin-2(HBD-2) is one of the two major vertebrate antimicrobial peptide families (α and β), which is highly expressed by proinflammatory induction in the lung and exhibit broad-spectrum antimicrobial activity. We observed that IL-22 receptors high expressed on the membrane of A549 cells; HBD-2 mRNA was expressed in a time- and concentration-dependent manners in A549 cells when treated with IL-22; further studies demonstrated that HBD-2 expression was attenuated by AG490, but to JSH-23, inhibitors of p-STAT3 DNA binding and NF-κB/p65 subunit nuclear translocation, respectively. These results support that IL-22-mediated signalling pathway of HBD-2 gene expression involved STAT3 but not NF-κB in human alveolar epithelium. These findings provide a new insight into how IL-22 may play an important link between innate and adaptive immunity, thereby anti-infection locally in the alveolar epithelium.
Background The characteristics of coal dust (CD) particles affect the inhalation of CD, which causes coal worker’s pneumoconiosis (CWP). CD nanoparticles (CD-NPs, < 500 nm) and micron particles (CD-MPs, < 5 μm) are components of the respirable CD. However, the differences in physicochemical properties and pulmonary toxicity between CD-NPs and CD-MPs remain unclear. Methods CD was analyzed by scanning electron microscopy, Malvern nanoparticle size potentiometer, energy dispersive spectroscopy, infrared spectroscopy, and electron paramagnetic resonance spectroscopy. CCK-8 assay, ELISA, transmission electron microscope, JC-1 staining, reactive oxygen species activity probe, calcium ion fluorescent probe, AO/EB staining, flow cytometry, and western blot were used to determine the differences between CD-NPs and CD-MPs on acute pulmonary toxicity. CCK-8, scratch healing and Transwell assay, hematoxylin–eosin and Masson staining, immunohistochemistry, immunofluorescence, and western blot were applied to examine the effects of CD-NPs and CD-MPs on pneumoconiosis. Results Analysis of the size distribution of CD revealed that the samples had been size segregated. The carbon content of CD-NPs was greater than that of CD-MPs, and the oxygen, aluminum, and silicon contents were less. In in vitro experiments with A549 and BEAS-2B cells, CD-NPs, compared with CD-MPs, had more inflammatory vacuoles, release of pro-inflammatory cytokines (IL-6, IL-1β, TNFα) and profibrotic cytokines (CXCL2, TGFβ1), mitochondrial damage (reactive oxygen species and Ca2+ levels and decreased mitochondrial membrane potential), and cell death (apoptosis, pyroptosis, and necrosis). CD-NPs-induced fibrosis model cells had stronger proliferation, migration, and invasion than did CD-MPs. In in vivo experiments, lung coefficient, alveolar inflammation score, and lung tissue fibrosis score (mean: 1.1%, 1.33, 1.33) of CD-NPs were higher than those of CD-MPs (mean: 1.3%, 2.67, 2.67). CD-NPs accelerated the progression of pulmonary fibrosis by upregulating the expression of pro-fibrotic proteins and promoting epithelial–mesenchymal transition. The regulatory molecules involved were E-cadherin, N-cadherin, COL-1, COL-3, ZO-1, ZEB1, Slug, α-SMA, TGFβ1, and Vimentin. Conclusions Stimulation with CD-NPs resulted in more pronounced acute and chronic lung toxicity than did stimulation with CD-MPs. These effects included acute inflammatory response, mitochondrial damage, pyroptosis, and necrosis, and more pulmonary fibrosis induced by epithelial–mesenchymal transition.
Polymer materials encapsulating drugs have broad prospects for drug delivery. We evaluated the effectiveness of polyethylene glycol-poly (lactic-co-glycolic acid) (PLGA-PEG) encapsulation and release characteristics of PI3K/mTOR inhibitor NVP-BEZ235 (BEZ235). We proposed a strategy for targeting radiosensitization of liver cancer cells. The biocompatibility, cell interaction, and internalization of Glypican-3 (GPC3) antibody-modified, BEZ235-loaded PLGA-PEG nanoparticles (NP-BEZ235-Ab) in hepatoma cells in vitro were studied. Also, the cell killing effect of NP-BEZ235-Ab combined with γ-ray cell was evaluated. We used confocal microscopy to monitor nanoparticle-cell interactions and cellular uptake, conducted focus-formation experiments to analyze the synergistic biological effects of NP-BEZ235-Ab and priming, and studied synergy in liver cancer cells using molecular biological methods such as western blotting. We found that PLGA-PEG has good loading efficiency for BEZ235 and high selectivity to GPC3-positive HepG2 liver cancer cells, thus documenting that NP-BEZ235-Ab acts as a small-molecule drug delivery nanocarrier. At the nominal concentration, the NP-BEZ235-Ab nanoformulation synergistically kills liver cancer cells with significantly higher efficiency than does the free drug. Thus, NP-BEZ235-Ab is a potential radiosensitizer.
Novel 6-substituted-4-cycloalkyloxy-pyridin-2(1H)-ones were synthesized as non-nucleoside reverse transcriptase inhibitors (NNRTIs), and their biological activity was evaluated. Most of the compounds, especially 26 and 22, bearing a 3-isopropyl and 3-iodine group, respectively, exhibited highly potent activity against wild-type HIV-1 strains and those resistant to reverse transcriptase inhibitors (RTIs). The diastereoisomers of 26-trans and 26-cis were synthesized separately and confirmed with HPLC and NOESY spectra. The 26-trans isomers had an activity about 400-fold more potent than that of 26-cis. The pair of 26-trans enantiomers, one of the most potent inhibitors with EC50 of 4 nM and selectivity index (SI) of 75000, was highly effective against a panel of RTIs-resistant strains with single (Y181C and K103N) or double (A17) mutations in reverse transcriptase. The results suggest that these novel pyridinone derivatives have the potential to be further developed as new antiretroviral drugs with improved antiviral efficacy and drug resistance profile.
Liver cancer remains one of the leading causes of cancer deaths worldwide. The therapeutic effect of oxaliplatin on liver cancer is often limited by acquired resistance of the cancer cells. Abnormal activation of the PI3K/AKT pathway plays an important role in the acquired resistance of oxaliplatin. The present study investigated the effects of the PI3K inhibitor LY-294002 and AKT inhibitor MK2206 on the chemosensitivity of oxaliplatin-resistant liver cancer cells and the molecular mechanism involved.
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