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Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
This approach involves delivering a DNA construct, usually in a viral vector, to cells so that the siRNA can be expressed internally rather than delivered externally. The obvious issues relating to this approach include the selective delivery of vectors to the target cells without causing potential genetic damage to healthy cells, and the transcription and formation of double-stranded RNA of the appropriate length, although production of a hairpin RNA can solve the requirement for double-stranded RNA.
Neuropathogenesis of viral infections
Published in Avindra Nath, Joseph R. Berger, Clinical Neurovirology, 2020
Avindra Nath, Joseph R. Berger
Interferons (IFN) are a group of proteins that derive their name from their ability to interfere with viral replication in an indirect fashion. There are three major families of interferons: IFN-α, IFN-β, and IFN-γ. IFN-α and IFN-β have potent antiviral properties within cells exposed to them, whereas IFN-γ enhances the immune system’s ability to clear infected cells mainly after the induction of the adaptive immune response. Therefore, expression of IFN-α and IFN-β early in the course of infection is crucial to preventing the further spread of the virus. IFN-α and IFN-β may become expressed by the presence of a variety of intracellular inducers, including the presence of foreign nucleic acids. In fact, the presence of double-stranded RNA is a potent inducer of their expression. IFN-γ is also important in controlling viral infection even in the absence of other cell mediated immune responses. For example, in measles virus infection, it can clear the virus from infected neurons without causing neuronal cell loss [29]. However, IFN-γ may also inhibit the proliferation of neural progenitor cells and thus affect brain repair and development [30].
Evolution
Published in Paul Pumpens, Single-Stranded RNA Phages, 2020
Much later, the evolution of tertiary structure of a long list of the viral RNA-dependent polymerases including the Qβ replicase was studied by Černý et al. (2014). The authors stated that the sequence similarity of the enzymes was too low for the phylogenetic studies, although general protein structures were remarkably conserved. The major strength of this work consisted of the unification of the sequence and structural data into a single quantitative phylogenetic analysis, using the powerful Bayesian approach. The resulting phylogram of the enzymes demonstrated that the RNA-dependent DNA polymerases of viruses within the Retroviridae family clustered in a clearly separated group, while the RNA-dependent RNA polymerases of double-stranded and single-stranded RNA viruses were mixed together. This evidence supported the hypothesis that the enzymes replicating the single-stranded RNA viruses evolved multiple times from the enzymes replicating the double-stranded RNA viruses, and vice versa. The authors recommended their phylogram as a scheme for the general RNA virus evolution. This phylogenetic tree of the evolution of the RNA-dependent polymerases and possibly of the RNA viruses is shown in Figure 18.6.
Recent advances in anti-multidrug resistance for nano-drug delivery system
Published in Drug Delivery, 2022
Changduo Wang, Fashun Li, Tianao Zhang, Min Yu, Yong Sun
The sequence-specific gene silencing offers a relatively safe method for P-gp downregulation without side effects compared with small-molecule agents of P-gp inhibitors. Obviously, it is an efficacious strategy for MDR to targeting P-gp coded by the MDR1 gene (Tariq et al., 2020). Ribonucleic acid (RNA) interference (RNAi) takes an advantage of small interfering RNA (siRNA) molecules to silence specific genes and regular gene expression, which has presented an immense potential in anticancer research as well as overcoming MDR. Double-stranded RNA (dsRNA) firstly cleaves by the enzyme DICER into smaller special length and structure segments, known as siRNA, which will be embedded into the RNA-induced silencing complex (RISC), and then unwinds the double-stranded siRNA into single-stranded segments. With the SiRNA guide, the RISC complex could cleave and degrade targeted mRNA under the Ago2 protein enzymolysis to achieve the targeted gene silencing (Horak, 2020).
Efficacy of siRNA-loaded nanoparticles in the treatment of K-RAS mutant lung cancer in vitro
Published in Journal of Microencapsulation, 2022
Ayse Gencer, Ipek Baysal, Emirhan Nemutlu, Samiye Yabanoglu-Ciftci, Betul Arica
The mechanism of the cancer formation is directly or indirectly related to genetic mutations and activation of oncogenes (Heng et al.2010). Gene therapy involves strategies such as repairing, suppressing, or silencing genes that cause cancer formation. The advantage of gene therapy over other treatment approaches is that it is highly specific and suitable for developing individual treatment strategies (Cross and Burmester 2006, Amer 2014). RNA interference is one of the most important genes therapy techniques. It effects through a pathway where double-stranded RNA is attached to the target mRNA of the gene to be silenced and degrades thus, preventing the synthesis of the protein associated with cancer after transcription. For this purpose, small interfering RNA (siRNA) molecules of 20–25 nucleotides length, are obtained by breaking down double stranded RNA (dsRNA) into small RNA fragments by the Dicer enzyme (an RNase III endonuclease which is involved in the biogenesis of small RNAs) are used (Song and Rossi 2017). After the transfection of siRNA into cells via different transfection methods, it forms a complex with RNA-Induced Silencing Complex (RISC) containing endonuclease, exonuclease, and helicase enzymes in its structure. This complex binds to target mRNA by recognise it through the siRNA. As a result, the mRNA is degraded and inactivated by RISC (Devi 2006, Rao et al.2013, Mansoori et al.2014).
Back to basics: review on vitamin D and respiratory viral infections including COVID-19
Published in Journal of Community Hospital Internal Medicine Perspectives, 2020
Mamtha Balla, Ganesh Prasad Merugu, Venu Madhav Konala, Vikram Sangani, Hema Kondakindi, Mytri Pokal, Vijay Gayam, Sreedhar Adapa, Srikanth Naramala, Srikrishna V Malayala
Vitamin D shows its effect on both adaptive and innate immune responses. Various in vitro studies showed that 1, 25 (OH) D affected the development of Th1 mediated immunity by inhibiting it, which is essential for cellular response induction. Cytokines that are dependent on the activity of nuclear factor κB (NF-κB) in multiple cells, including macrophages, by blocking the activation of NF-κB p65 through upregulation of the NF-kB inhibitory protein 1κBα are also directly modulated by 1,25 (OH)2 D[16]. Toll-like receptors (TLRs) are transmembrane proteins that recognize molecular motifs of viral and bacterial origin and initiate innate immune responses. TLR3, which is mainly involved in defense against viruses, recognizes viral double-stranded RNA. The treatment with Vitamin D has shown to reduce double-stranded RNA-TLR3–induced expression of IL-8 in respiratory epithelial cells[12]. Both 25 (OH) D and 1, 25 (OH)2 D were shown to modulate T-cell adaptive immunity. The mechanism is by decreasing the pro-inflammatory type 1 cytokines such as IL-6, IL-8, IL-12, IFN-γ, as well as IL-17 and tumor necrosis factor-α) and also by increasing regulatory T cells and anti-inflammatory type 2 cytokines such as IL-4, IL-5, and IL-10 [17–19]. In the summer months, reduction in the pro-inflammatory levels of IL-1, IL-6, TNF-α, IFN-γ, and IL-10 are observed on TLR stimulation of human peripheral blood mononuclear cells when compared to the winter where the respiratory viral infections are at its peak[20].