The results of administering escalating, i.v. doses of targeted nanoparticles containing a siRNA targeting the M2 subunit of ribonucleotide reductase to non-human primates are reported. The nanoparticles consist of a synthetic delivery system that uses a linear, cyclodextrin-containing polycation, transferrin (Tf) protein targeting ligand, and siRNA. When administered to cynomolgus monkeys at doses of 3 and 9 mg siRNA/kg, the nanoparticles are well tolerated. At 27 mg siRNA/kg, elevated levels of blood urea nitrogen and creatinine are observed that are indicative of kidney toxicity. Mild elevations in alanine amino transferase and aspartate transaminase at this dose level indicate that the liver is also affected to some extent. Analysis of complement factors does not reveal any changes that are clearly attributable to dosing with the nanoparticle formulation. Detection of increased IL-6 levels in all animals at 27 mg siRNA/kg and increased IFN-␥ in one animal indicate that this high dose level produces a mild immune response. Overall, no clinical signs of toxicity clearly attributable to treatment are observed. The multiple administrations spanning a period of 17-18 days enable assessment of antibody formation against the human Tf component of the formulation. Low titers of anti-Tf antibodies are detected, but this response is not associated with any manifestations of a hypersensitivity reaction upon readministration of the targeted nanoparticle. Taken together, the data presented show that multiple, systemic doses of targeted nanoparticles containing nonchemically modified siRNA can safely be administered to non-human primates.systemic administration ͉ RNA interference
Long non-coding RNA (lncRNA) FYVE, RhoGEF and PH domain containing 5 antisense RNA 1 (FGD5-AS1) has been reported as an oncogene in colorectal cancer, promoting its tumorgenesis. The present paper focused on searching the potential function of FGD5-AS1 in non-small cell lung carcinoma (NSCLC). There are connections between the expression of lncRNA FGD5-AS1 and human NSCLC tumor growth and progression. Also, the relationships between FGD5-AS1, hsa-miR-107 and mRNA fibroblast growth factor receptor like 1 (FGFRL1) are going to test their interaction in NSCLC cell lines, which may cause a series of biological behaviors of NSCLC cells. qRT-PCR analysis was conducted to test the expression of RNAs in different situation. CCK-8 experiment and clone formation assay were performed to assess proliferation of NSCLC cells. Also, connection between FGD5-AS1 and hsa-miR-107 were investigated by luciferase reporter assay and RNA pull-down assay. Rescue experiments were performed to verify the modulating relationship between FGD5-AS1, hsa-miR-107 and FGFRL1. High-level expression of FGD5-AS1 was found in NSCLC. FGD5-AS1 may promote the proliferation of NSCLC cells. Also, the combination between hsa-miR-107, FGD5-AS1 and NSCLC have been proved, which means they can play an interaction function in NSCLC cells. Thence, we concluded that lncRNA FGD5-AS1 promotes non-small cell lung cancer cell proliferation through sponging hsa-miR-107 to up-regulate FGFRL1.
Background The lncRNA Colorectal Neoplasia Differentially Expressed (CRNDE) gene has been reported as a potential oncogene in NSCLC. Nevertheless, the molecular mechanism of CRNDE in NSCLC progression remains largely unknown. Material/Methods qRT-PCR assay was performed to detect the expression levels of CRNDE, miR-641, and cyclin-dependent kinase 6 (CDK6) in NSCLC. Western blot assay was employed to assess CDK6 protein level in treated NSCLC cells. si-CRNDE#1, si-CRNDE#2, miR-641 mimics, miR-641 inhibitors, or Vector-CDK6 were transfected into NSCLC cells to change the expression levels of CRNDE, miR-641, or CDK6. Dual-luciferase reporter assay was performed to validate the direct interrelated miRNA of CRNDE and the potential target of miR-641. MTT and flow cytometry assays were performed to assess the capacities of cell proliferation and apoptosis, respectively. Results CRNDE level was upregulated in NSCLC, and its knockdown suppressed NSCLC cells proliferation and enhanced apoptosis, whereas miR-641 antagonized the regulatory effect of CRNDE knockdown by directly binding to CRNDE. Moreover, CDK6 was a target of miR-641 and miR-641 exerted anti-proliferation and pro-apoptosis effects through CDK6. Conclusions CRNDE promoted proliferation and inhibited apoptosis of NSCLC cells at least in part by regulating the miR-641/CDK6 axis, suggesting that CRNDE is a potential therapeutic target for NSCLC treatment.
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