RNA-interference (RNAi) agents such as small-interfering RNA (siRNA) and micro-RNA (miRNA) have strong potential as therapeutic agents for the treatment of a broad range of diseases such as malignancies, infections, autoimmune diseases and neurological diseases that are associated with undesirable gene expression. In recent years, several clinical trials of RNAi therapeutics especially siRNAs have been conducted with limited success so far. For systemic administration of these poorly permeable and easily degradable macromolecules, it is obvious that a safe and efficient delivery platform is highly desirable. Because of high biocompatibility, biodegradability and solid track record for clinical use, nanocarriers made of lipids and/or phospholipids have been commonly employed to facilitate RNA delivery. In this article, the key features of the major sub-classes of lipid-based nanocarriers, e.g. liposomes, lipid nanoparticles and lipid nanoemulsions, will be reviewed. Focus of the discussion is on the various challenges researchers face when developing lipid-based RNA nanocarriers, such as the toxicity of cationic lipids and issues related to PEGylated lipids, as well as the strategies employed in tackling these challenges. It is hoped that by understanding more about the pros and cons of these most frequently used RNA delivery systems, the pharmaceutical scientists, biomedical researchers and clinicians will be more successful in overcoming some of the obstacles that currently limit the clinical translation of RNAi therapy. Keywords: Drug delivery, lipid, nanocarrier, RNA interference, small-interfering RNA.
The mechanism of action of fatty acid synthase (FASN) in drug tolerance of breast cancer cells with epithelial-mesenchymal transition (EMT) features was investigated.The breast cancer cell line MCF-7-MEK5 with stably occurring EMT and tumour necrosis factor-α (TNF-α) tolerance was used as the experimental model, whereas MCF-7 acted as the control. Tumour cells were implanted into nude mice for in vivo analysis, and cerulenin was used as a FASN inhibitor. RT-PCR, real-time quantitative PCR and Western blot were employed to detect the expression of FASN, TNFR-1, TNFR-2, Wnt-1, β-catenin and cytC at the RNA and protein levels.Compared with MCF-7, TNFR-1 expression in MCF-7-MEK5 was slightly changed, TNFR-2 was decreased, and FASN, Wnt-1, β-catenin and cytC were increased. The expression of Wnt-1 and β-catenin in MCF-7-MEK5 decreased after cerulenin treatment, whereas cytC expression increased.The important function of FASN in the drug tolerance of breast cancer may be due to the following mechanisms: FASN downregulated TNFR-2 expression through lipid rafts to make the cells less sensitive to TNF-α, and simultaneously activated the Wnt-1/β-catenin signalling pathway. Thus, cytC expression increased, which provided cells with anti-apoptotic capacity and induced drug tolerance.
1,4-naphthoquinone and its derivatives have attracted widespread attention due to their multiple biological activities, such as induction of cancer cell apoptosis; however, most of these compounds have high cytotoxicity. In this study, in order to reduce their toxicity and increase their potential anti-tumor effects, we synthesized a novel 1,4-naphthoquinone derivative named 2-(naphthalene-2-thio)-5,8-dimethoxy-1,4-naphthoquinone (NTDMNQ), and investigated its apoptotic effects and underlying mechanism. Our results showed that NTDMNQ inhibited the viability of HepG2, Hep3B, and Huh7 human hepatocellular carcinoma (HCC) cells. It also increased the accumulation of cells in the G0/G1 phase of the cell cycle by increasing the expression levels of p-p53, p21 and p27, while decreasing the levels of Cyclin D1, Cyclin E, Cyclin-dependent kinase 2 (CDK2), CDK4, and CDK6. Inhibition of reactive oxygen species (ROS) by the ROS scavenger N-acetyl-L-cysteine (NAC) decreased apoptosis in NTDMNQ-treated cells. Western blot analysis showed that NTDMNQ increased the phosphorylation of p38 and c-Jun N-terminal kinase (JNK), and decreased the phosphorylation of extracellular signal-regulated kinase (ERK), AKT, and signal transducer and activator of transcription-3 (STAT3); these effects were blocked by NAC. Both the JNK inhibitor (SP600125) and p38 inhibitor (SB203580) reversed the phosphorylation of STAT3, and the ERK inhibitor (FR180204) and AKT inhibitor (LY294002) reduced the expression of STAT3. Taken together, these findings suggest that NTDMNQ induces apoptosis via ROS-mediated MAPK, AKT and STAT3 signaling pathways in HepG2 cells, and may be a potent anticancer agent.
siRNAs have immense therapeutic potential for the treatment of various gene-related diseases ranging from cancer, viral infections and neuropathy to autoimmune diseases. However, their bench-to-bedside translation in recent years has faced several challenges, with inefficient siRNA delivery being one of the most frequently encountered issues. In order to improve the siRNA delivery especially for systemic treatment, nanocarriers made of polymers, lipids or inorganic materials have become almost essential. The 'negative' aspects of these carriers such as their nanotoxicity and immunogenicity thus can no longer be overlooked. In this article, we will extensively review the nanotoxicity of siRNA carriers. The strategies for mitigating the risks of nanotoxicity and the methodology for evaluating these strategies will also be discussed. By addressing this often overlooked but important issue, it will help clear the way for siRNAs to fulfill their promise as a versatile class of therapeutic agents.
Recurrent respiratory tract infection (RRTI) is a common chronic respiratory disease of children.The pathogenesis is complex,etiology and treatment methods are varied.Probiotics are immune modulators with extensive clinical application.This paper reviewed the changes of intestinal microflora in children with recurrent respiratory tract infection and the mechanisms of probiotic treatment including intestinal flora regulation,intestinal mucosal barrier,stimulation of the growth of intestinal mucosa and immune regulation.
Key words:
Probiotics; Recurrent respiratory tract infection; Children
Aim: To develop lipid nano-antiretrovirals (LNAs) for the treatment of HIV-infected macrophages. Materials & methods: LNAs were prepared with docosahexaenoic acid to facilitate brain penetration and surface-decorated with folate considering that infected macrophages often overexpress folate receptors. Results: Folate-decorated LNAs loading rilpivirine (RPV) were efficiently taken up by folate receptor-expressing cell types including activated macrophages. The intracellular Cmax of the RPV-LNAs in activated macrophages was 2.54-fold and the area under the curve was 3.4-fold versus free RPV, translating to comparable or higher (p < 0.01; RPV ≤6.5 ng/ml) activities against HIV infectivity and superior protection (p < 0.05) against HIV cytotoxicity. LNAs were also effective in monocyte-derived macrophages. Conclusion: These findings demonstrate the potential of LNAs for the treatment of infected macrophages, which are key players in HIV reservoirs.
Although promising, it is challenging to develop a simple and universal method for the high‐efficiency delivery of biomacromolecules into diverse cells. Here, a universal delivery platform based on gold nanoparticle layer (GNPL) surfaces is proposed. Upon laser irradiation, GNPL surfaces show such good photothermal properties that absorption of the laser energy causes a rapid increase in surface temperature, leading to enhanced membrane permeability of the cultured cells and the diffusion of macromolecules into the cytosol from the surrounding medium. The high‐efficiency delivery of different macromolecules such as dextran and plasmid DNA into different cell types is achieved, including hard‐to‐transfect mouse embryonic fibroblasts (mEFs) and human umbilical vein endothelial cells (HUVECs), while cell viability is well maintained under optimized irradiation conditions. The platform vastly outperforms the leading commercial reagent, Lipofectamine 2000, especially in transfecting hard‐to‐transfect cell lines (plasmid transfection efficiency: ≈53% vs ≈19% for mEFs and ≈44% vs ≈8% for HUVECs). Importantly, as the gold nanoparticles (GNPs) constituting the GNPL are firmly immobilized together, the potential cytotoxicity caused by endocytosis of GNPs is effectively avoided. This platform is reliable, efficient, and cost‐effective with high‐throughput and broad applicability across different cell types, opening up an innovative avenue for high‐efficiency intracellular delivery.
Objective
To develop a Class Ⅲ twin-block magnetic orthopedic appliance (TMOA-Ⅲ) and to investigate the treatment effects of this appliance on skeletal Class Ⅲ malocclusion of mixed dentition and early permanent dentition.
Methods
The sample consisted of 76 Chinese children (42 males and 34 females, mean age 9.1 years) with Class Ⅲ malocclusion caused by maxillary retrognathism, and the subjects were divided into a treatment group and a control group. The treatment group, 38 subjects (21 males and 17 females), were instructed to wear TMOA-Ⅲ for 5-8 months (mean 7.5 months) and the control group, 38 subjects (21 males and 17 females), did not wear any appliance. Cephalometric radiographs were taken and measurement data were used for analysis.
Results
Compared with the control group, patients of the treatment group showed a favorable increase of maxilla length and anterior movement (PNS-A, P<0.001; SNA, A-NPg, P<0.05), and skeletal Class Ⅲ facial profiles improved (UL-EL, NsPgs-HL, Facial convexity, P<0.001; LL-EL P<0.005).
Conclusions
The results indicate that TMOA-Ⅲ is effective for the treatment of Class Ⅲ malocclusion caused by maxillary retrognathism in mixed dentition and early permanent dentition, which provides another choice for the treatment besides the face mask.
Key words:
Magnetic orthodontic appliance; Skeletal class Ⅲ malocclusion; Maxillary retrusion; Cephalometric measurement; Facial convexity
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