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Aquaporin 3 (AQP3) and phospholipase D2 (PLD2) are abnormally expressed and/or localized in squamous cell carcinoma (SCC). AQP3 transports glycerol to PLD2 for the synthesis of lipid second messenger, which can mediate the effect of the AQP3/PLD2 signaling module in the regulation of keratinocyte proliferation and differentiation. However, the role of the AQP3/PLD2 signaling module in the pathogenesis of SCC remains to be fully elucidated. In the present study, the expression levels of AQP3 and PLD2 in tissue samples were examined using immunohistochemistry, it was found that the expression levels of AQP3 and PLD2 in tissue samples of actinic keratosis (AK), Bowen's disease (BD) and SCC were significantly increased. AQP3 small interfering RNA (siRNA) and PLD2 siRNA were constructed and used for transfection into the human A431 SCC cell line, and their anticancer effect on SCC was examined. The mRNA expression and protein expression levels of AQP3 and PLD2 were significantly downregulated following siRNA transfection. AQP3 siRNA and PLD2 siRNA inhibited the proliferation and promoted the apoptosis of A431 cells. Taken together, the findings of the present study suggested that increased levels of AQP3 and PLD2 were correlated with tumor progression and development in SCC. AQP3 siRNA and PLD2 siRNA significantly downregulated the mRNA and protein levels of AQP3 and PLD2 in the A431 cells; inhibiting proliferation and promoting apoptosis in vitro. The concomitant effects of AQP3/PLD2 signaling by inhibiting the expression of siRNA may be important for the treatment of SCC in the future.
Andes virus (ANDV) is the most common causative agent of hantavirus pulmonary syndrome (HPS) in the Americas, and is the only hantavirus associated with human-to-human transmission. Case fatality rates of ANDV-induced HPS are approximately 40%. There are currently no effective vaccines or antivirals against ANDV. Since HPS severity correlates with viral load, we tested small interfering RNA (siRNA) directed against ANDV genes as a potential antiviral strategy. We designed pools of 4 siRNAs targeting each of the ANDV genome segments (S, M, and L), and tested their efficacy in reducing viral replication in vitro. The siRNA pool targeting the S segment reduced viral transcription and replication in Vero-E6 cells more efficiently than those targeting the M and L segments. In contrast, siRNAs targeting the S, M, or L segment were similar in their ability to reduce viral replication in human lung microvascular endothelial cells. Importantly, these siRNAs inhibit ANDV replication even if given after infection. Taken together, our findings indicate that siRNAs targeting the ANDV genome efficiently inhibit ANDV replication, and show promise as a strategy for developing therapeutics against ANDV infection.
Colorectal cancer (CRC) is associated with numerous genetic disorders and cellular abnormalities, and liver metastasis is a common health concern in patients with CRC. Exploring newer and more efficient therapies to block liver metastasis is pivotal for prolonging patient survival. Therefore, small interfering RNAs (siRNAs) are expected to be remarkable tools capable of regulating gene expression by participating in a process called RNA interference (RNAi). RNAi is a biological process among eukaryotes wherein specific messenger RNA (mRNA) molecules are destroyed and gene expression is inhibited. This technology is a promising therapeutic agent in the treatment of CRC liver metastasis (CRLM). Nevertheless, crucial problems in siRNA therapeutics, including inherent poor serum stability and nonspecific uptake into biological systems, must be recognized. For this reason, delivery systems are being developed in an attempt to solve these problems. Here, we discuss the utility of siRNA therapy for the treatment of CRCLM by targeting the major metastasis-related signaling pathways. siRNA therapy has the potential to be one of the most effective methods for CRLM treatment in the future.
Coronavirus disease 2019 (COVID-19) rapidly transformed into a global pandemic, for which a demand for developing antivirals capable of targeting the SARS-CoV-2 RNA genome and blocking the activity of its genes has emerged. In this work, we presented a database of SARS-CoV-2 targets for small interference RNA (siRNA) based approaches, aiming to speed the design process by providing a broad set of possible targets and siRNA sequences. The siRNAs sequences are characterized and evaluated by more than 170 features, including thermodynamic information, base context, target genes and alignment information of sequences against the human genome, and diverse SARS-CoV-2 strains, to assess possible bindings to off-target sequences. This dataset is available as a set of four tables, available in a spreadsheet and CSV (Comma-Separated Values) formats, each one corresponding to sequences of 18, 19, 20, and 21 nucleotides length, aiming to meet the diversity of technology and expertise among laboratories around the world. A metadata table (Supplementary Table S1), which describes each feature, is also provided in the aforementioned formats. We hope that this database helps to speed up the development of new target antivirals for SARS-CoV-2, contributing to a possible strategy for a faster and effective response to the COVID-19 pandemic.
Airway hyperresponsiveness is the hallmark of allergic asthma and caused by multiple factors. Nerve growth factor (NGF), a neurotrophin, is originally known for regulation of neural circuit development and function. Recent studies indicated that NGF contributes to airway hyperresponsiveness and pathogenesis of asthma. The objective of this study is to develop a small interfering RNA against NGF to attenuate airway hyperresponsiveness and further elucidate the underlying mechanism. In a murine model of allergic asthma, the ovalbumin-sensitized mice were intratracheally delivered small interfering RNA against NGF or administered an inhibitor targeting NGF receptor, tropomyosin-related kinase A, as a positive treatment control. In this study, knockdown NGF derived from pulmonary epithelium significantly reduced airway resistance in vivo. The levels of NGF, proinflammatory cytokines and infiltrated eosinophils in airway were decreased in small interfering RNA against NGF group but not in tropomyosin-related kinase A inhibitor and mock siRNA group. Furthermore, induction of neuropeptide (substance P) and airway innervation were mediated by NGF/tropomyosin-related kinase A pathway. These findings suggested that NGF targeting treatment holds the potential therapy for antigen-induced airway hyperresponsiveness via attenuation of airway innervation and inflammation in asthma.
A survivin small interfering RNA sequence specific for a human and mouse homogenous sequence was constructed. Survivin small interfering RNA could significantly inhibit glioma cell proliferation and induce apoptosis when it was transfected into either a human glioma cell line U251 or rat glioma C6 cells in vitro. In addition, treatment of rat orthotopic glioma models with survivin small interfering demonstrated the inhibition of glioma growth in vivo. Our experimental findings suggest that the use of RNA interference techniques to target the survivin sequence may be useful in the treatment of glioma.
Cellular delivery of small interfering RNAs to target cells of a tissue has the potential to travel by two intercellular pathways. For intimately apposed cells gap junctions allow transport exclusive of the extracellular space. For cells not in intimate contact, exocytotic release of vesicular contents and subsequent retrieval via endocytosis of exosomes and other vesicular contents represent an alternative intercellular delivery system that utilizes the extracellular space. Previous studies have shown siRNA/miRNA transfer from a delivery cell to a target cell via gap junction channels. We hypothesized that siRNA can be delivered via gap junctions and downregulate the expression of a reporter gene, the cyclic nucleotide-gated cation channel gene (mHCN2), in the recipient cells of cell pairs. Whole-cell patch clamp was used to measure the mHCN2-induced current and junctional conductance. The target cells were HEK293 cells that endogenously express Cx43 or HeLaCx43 cells, both transfected with mHCN2. The source cells were HEK293 or HeLaCx43 cells transfected with fluorescent-labeled siRNA targeting mHCN2. We found that siRNA targeting mHCN2 resulted in significant downregulation of mHCN2 currents both in single cells and the recipient cell of a cell pair. In addition we also documented downregulation in target cells that were not in contact with source cells suggesting an extracellular-mediated delivery. To test further for extracellular delivery HEK293/HCN2 or HeLaCx43/HCN2 cells were cultured in medium collected from HEK293 or HeLaCx43 cells transfected with fluorescent-labeled siRNA or fluorescent-labeled morpholino designed to target HCN2. After 24 h single HEK293/HCN2 or HeLaCx43cells showed accumulation of siRNA. The mHCN2 currents were also down regulated in cells with siRNA uptake. Application of 200 nmol/L Bafilomycin A1, which has been shown to affect endosome acidification and endocytotic activity, resulted in a smaller accumulation of fluorescent-labeled siRNA in single target cells. In distinction to siRNA, morpholinos targeting HCN2 exhibited greatly reduced extracellularly mediated transfer while in cell pairs, target cells exhibited reduced HCN2 currents consistent with effective gap junction-mediated delivery.
Colorectal cancer (CRC) is the third most common cancer in the world and its development is associated with oncogenic dysfunction. Therefore, the present study aimed to identify differentially expressed genes (DEGs) in CRC tissues and to determine the role of keratin 80 (KRT80) in CRC cell proliferation. DEGs were initially screened in 32 paired CRC tissues and matched adjacent normal tissues from RNA-Seq datasets in The Cancer Genome Atlas database using the limma package in R software. In total, 2,114 DEGs were identified, of which KRT80 was discovered to be the most upregulated in CRC tissues. Moreover, increased KRT80 expression levels were confirmed in tissues collected from 50 patients with CRC using reverse transcription-quantitative PCR, and its increased expression levels were significantly associated with increased lymph node and distant metastasis and a higher pathological stage. Furthermore, KRT80 knockdown using siRNA decreased the viability and proliferation of CRC cells. Finally, pathway analysis revealed that the proteins co-expressed with KRT80 in CRC were enriched in the cell cycle, DNA replication, immune system, metabolism of protein and RNA, signal transduction and other cellular processes. Among them, the cell cycle and DNA replication pathways contained the highest number of the proteins identified. In conclusion, the findings of the present study suggested that KRT80 may be overexpressed in CRC tissues. Furthermore, KRT80 may be involved in the proliferation of CRC cells, which is likely through its ability to regulate the cell cycle and DNA replication pathways, thus it may serve as a potential therapeutic target for patients with CRC.
Small molecule, peptide, and protein-based drugs have been developed over decades to treat various diseases. The importance of gene therapy as an alternative to traditional drugs has increased after the discovery of gene-based drugs such as Gendicine for cancer and Neovasculgen for peripheral artery disease. Since then, the pharma sector is focusing on developing gene-based drugs for various diseases. After the discovery of the RNA interference (RNAi) mechanism, the development of siRNA-based gene therapy has been accelerated immensely. siRNA-based treatment for hereditary transthyretin-mediated amyloidosis (hATTR) using Onpattro and acute hepatic porphyria (AHP) by Givlaari and three more FDA-approved siRNA drugs has set up a milestone and further improved the confidence for the development of gene therapeutics for a spectrum of diseases. siRNA-based gene drugs have more advantages over other gene therapies and are under study to treat different types of diseases such as viral infections, cardiovascular diseases, cancer, and many more. However, there are a few bottlenecks to realizing the full potential of siRNA-based gene therapy. They include chemical instability, nontargeted biodistribution, undesirable innate immune responses, and off-target effects. This review provides a comprehensive view of siRNA-based gene drugs: challenges associated with siRNA delivery, their potential, and future prospects.
CD86-CD28 interaction has been suggested as the principal costimulatory pathway for the activation and differentiation of naïve T cells in allergic inflammation. However, it remains uncertain whether this pathway also has an essential role in the effector phase. We sought to determine the contribution of CD86 on dendritic cells in the reactivation of allergen-specific Th2 cells.
At the core of the RNA interference (RNAi) pathway in Trypanosoma brucei is a single Argonaute protein, TbAGO1, with an established role in controlling retroposon and repeat transcripts. Recent evidence from higher eukaryotes suggests that a variety of genomic sequences with the potential to produce double-stranded RNA are sources for small interfering RNAs (siRNAs).
RNA interference (RNAi) is widespread in eukaryotes and regulates gene expression transcriptionally or post-transcriptionally. In fission yeast, RNAi is tightly coupled to template transcription and chromatin modifications that establish heterochromatin in cis. Exogenous double-stranded RNA (dsRNA) triggers seem to induce heterochromatin formation in trans only when certain silencing proteins are overexpressed. Here, we show that green fluorescent protein (GFP) hairpin dsRNA allows production of high levels of Argonaute-associated small interfering RNAs (siRNAs), which can induce heterochromatin formation at a remote locus. This silencing does not require any manipulation apart from hairpin expression. In cells expressing a ura4(+)-GFP fusion gene, production of GFP siRNAs causes the appearance of ura4 siRNAs from the target gene. Production of these secondary siRNAs depends on RNA-dependent RNA polymerase Rdp1 (RDRP(Rdp1)) function and other RNAi pathway components. This demonstrates that transitivity occurs in fission yeast and implies that RDRP(Rdp1) can synthesize RNA from targeted RNA templates in vivo, generating siRNAs not homologous to the hairpin.
We developed elastic cationic liposomal vectors for transdermal siRNA delivery. These liposomes were prepared with 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) as a cationic lipid and sodium cholate (NaChol) or Tween 80 as an edge activator. When NaChol or Tween 80 was included at 5, 10, and 15% (w/w) into DOTAP liposomal formulations (C5-, C10-, and C15-liposomes and T5-, T10-, and T15-liposomes), C15- and T10-liposomes showed 2.4- and 2.7-fold-higher elasticities than DOTAP liposome, respectively. Although the sizes of all elastic liposomes prepared in this study were about 80-90 nm, the sizes of C5-, C10- and C15-liposome/siRNA complexes (lipoplexes) were about 1,700-1,800 nm, and those of T5-, T10-, and T15-lipoplexes were about 550-780 nm. Their elastic lipoplexes showed strong gene suppression by siRNA without cytotoxicity when transfected into human cervical carcinoma SiHa cells. Following skin application of the fluorescence-labeled lipoplexes in mice, among the elastic lipoplexes, C15- and T5-lipoplexes showed effective penetration of siRNA into skin, compared with DOTAP lipoplex and free siRNA solution. These data suggest that elastic cationic liposomes containing an appropriate amount of NaChol or Tween 80 as an edge activator could deliver siRNA transdermally.
RNA interference is triggered in plants by the exogenous application of double-stranded RNA or small interfering RNA (siRNA) to silence the expression of target genes. This approach can potentially provide insights into metabolic pathways and gene function and afford plant protection against viruses and other plant pathogens. However, the effective delivery of biomolecules such as siRNA into plant cells is difficult because of the unique barrier imposed by the plant cell wall. Here, we demonstrate that 40-nm layered double hydroxide (LDH) nanoparticles are rapidly taken up by intact Nicotiana benthamiana leaf cells and by chloroplasts, following their application via infiltration. We also describe the distribution of infiltrated LDH nanoparticles in leaves and demonstrate their translocation through the apoplast and vasculature system. Furthermore, we show that 40-nm LDH nanoparticles can greatly enhance the internalization of nucleic acids by N. benthamiana leaf cells to facilitate siRNA-mediated downregulation of targeted transgene mRNA by >70% within 1 day of exogenous application. Together, our results show that 40-nm LDH nanoparticle is an effective platform for delivery of siRNA into intact plant leaf cells.
Background. Epithelial-mesenchymal transition (EMT) of retinal pigment epithelium (RPE) is vital in proliferative vitreoretinopathy (PVR) development. Apoptosis-stimulating proteins of p53 (ASPP2) have recently been reported to participate in EMT. However, the role of ASPP2 in PVR pathogenesis has not been identified. Methods. Immunohistochemistry was used to investigate the expression of ASPP2 in epiretinal membranes of PVR patients. ARPE-19 cells were transfected with ASPP2-siRNA, followed with measurement of cell cytotoxicity, proliferation, and migration ability. EMT markers and related inflammatory and fibrosis cytokines were measured by western blot or flow cytometry. Additionally, PVR rat models were induced by intravitreal injection of ARPE-19 cells transfected with ASPP2-siRNA and evaluated accordingly. Results. Immunofluorescence analysis revealed less intense expression of ASPP2 in PVR membranes. ASPP2 knockdown facilitated the proliferation and migration of RPE cells and enhanced the expression of mesenchymal markers such as alpha smooth muscle actin, fibronectin, and ZEB1. Meanwhile, ASPP2-siRNA increased EMT-related and inflammatory cytokines, including TGF-β, CTGF, VEGF, TNF-α, and interleukins. PVR severities were more pronounced in the rat models with ASPP2-siRNA treatment. Conclusions. ASPP2 knockdown promoted EMT of ARPE-19 cells in vitro and exacerbated the progression of experimental PVR in vivo, possibly via inflammatory and fibrosis cytokines.
Brain capillary endothelial cells (BCECs) play an important role in blood-brain barrier (BBB) functions and pathophysiologic mechanisms in brain ischemia and inflammation. We try to suppress gene expression in BCECs by intravenous application of small interfering RNA (siRNA). After injection of large dose siRNA with hydrodynamic technique to mouse, suppression of endogenous protein and the BBB function of BCECs was investigated. The brain-to-blood transport function of organic anion transporter 3 (OAT3) that expressed in BCECs was evaluated by Brain Efflux Index method in mouse. The siRNA could be delivered to BCECs and efficiently inhibited endogenously expressed protein of BCECs. The suppression effect of siRNA to OAT3 is enough to reduce the brain-to-blood transport of OAT3 substrate, benzylpenicillin at BBB. The in vivo siRNA-silencing method with hydrodynamic technique may be useful for the study of BBB function and gene therapy targeting BCECs.
This study aimed to investigate the impact of S100A4-small interfering RNA (S100A4-siRNA) on apoptosis and enhanced radiosensitivity in non-small-cell lung cancer (A549) cells. We also explored the mechanisms of radiosensitization and identified a new target to enhance radiosensitivity and gene therapy for non-small-cell lung cancer.
In eukaryotes, RNA silencing pathways utilize 20-30-nucleotide small RNAs to regulate gene expression, specify and maintain chromatin structure, and repress viruses and mobile genetic elements. RNA silencing was likely present in the common ancestor of modern eukaryotes, but most research has focused on plant and animal RNA silencing systems. Phytophthora species belong to a phylogenetically distinct group of economically important plant pathogens that cause billions of dollars in yield losses annually as well as ecologically devastating outbreaks. We analyzed the small RNA-generating components of the genomes of P. infestans, P. sojae and P. ramorum using bioinformatics, genetic, phylogenetic and high-throughput sequencing-based methods. Each species produces two distinct populations of small RNAs that are predominantly 21- or 25-nucleotides long. The 25-nucleotide small RNAs were primarily derived from loci encoding transposable elements and we propose that these small RNAs define a pathway of short-interfering RNAs that silence repetitive genetic elements. The 21-nucleotide small RNAs were primarily derived from inverted repeats, including a novel microRNA family that is conserved among the three species, and several gene families, including Crinkler effectors and type III fibronectins. The Phytophthora microRNA is predicted to target a family of amino acid/auxin permeases, and we propose that 21-nucleotide small RNAs function at the post-transcriptional level. The functional significance of microRNA-guided regulation of amino acid/auxin permeases and the association of 21-nucleotide small RNAs with Crinkler effectors remains unclear, but this work provides a framework for testing the role of small RNAs in Phytophthora biology and pathogenesis in future work.
Dengue viruses (DENs) are the wildest transmitted mosquito-borne pathogens throughout tropical and sub-tropical regions worldwide. Infection with DENs can cause severe flu-like illness and potentially fatal hemorrhagic fever. Although RNA interference triggered by long-length dsRNA was considered a potent antiviral pathway in the mosquito, only limited studies of the value of small interfering RNA (siRNA) have been conducted.
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