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Nanoparticle-Mediated Small RNA Deliveries for Molecular Therapies
Published in D. Sakthi Kumar, Aswathy Ravindran Girija, Bionanotechnology in Cancer, 2023
Ramasamy Paulmurugan, Uday Kumar Sukumar, Tarik F. Massoud
Small RNA-mediated gene silencing was first discovered in 1993 [88]. Since then, numerous small RNAs, including siRNAs, shRNAs, miRNAs, and piRNAs, have been identified and widely used for different biological applications, including cancer therapy [89]. These RNAs can be listed under two categories: (i) intrinsic and endogenously expressed RNAs, and (ii) synthetic and extrinsic RNAs. In contrast to their different origins, these RNAs follow similar endogenous pathways to achieve target gene silencing. The discovery of siRNA (or RNAi) was serendipitous. Even though siRNA mediated gene silencing was first discovered, siRNA mediated gene silencing and RNAi mediated gene silencing naturally use the endogenous miRNA mediated gene silencing pathway to execute their functions (Figure 13.2). SiRNAs are ~20–25 nucleotide long double-stranded RNA (dsRNA) molecules that, after binding to RNA-induced silencing complex, enable the cleavage and degradation of recognized mRNA. While siRNAs are delivered as synthetic dsRNAs, siRNA can be expressed as a synthetic vector-based expression system called shRNA. Even though the endpoint applications of siRNA and shRNA are similar, the step at which these RNAs target the intrinsic pathway to achieve functional effects is different [90]. The advantage of shRNA compared to siRNA is that, because of its low and continuous expression, shRNA shows long-term functional effects compared to synthetic siRNAs, which are delivered at biologically excess levels that rapidly degrade and lose their long-term functional effects [90].
Molecular Biology and Gene Therapy
Published in R James A England, Eamon Shamil, Rajeev Mathew, Manohar Bance, Pavol Surda, Jemy Jose, Omar Hilmi, Adam J Donne, Scott-Brown's Essential Otorhinolaryngology, 2022
Small interfering RNAs (siRNAs; double stranded) and microRNAs (miRs; single stranded) are biologically significant post-transcriptional regulators of gene expression. siRNAs and miRs are non-coding RNA molecules that base pair with mRNA via the RISC complex, preventing their translation into proteins. In addition, long non-coding RNAs (ncRNAs) have been identified that are thought to regulate various aspects of gene expression and they have been implicated in a number of diseases, including aging and cancer.
Dopamine Receptors, Signaling Pathways, and Drugs
Published in Nira Ben-Jonathan, Dopamine, 2020
Another level of DAR regulation is provided by microRNAs (miRNAs). These noncoding RNAs exert their regulatory translational repression and degradation of mRNA through the RNA-induced silencing complex (RISC). A core component of the RISC complex is the Argonauts (Ago) miRNA binding proteins, particularly Ago2, which generates selective miRNAs from their precursors and mediates miRNA-dependent degradation and translational repression of target mRNAs. Several recent reports have examined the involvement of different miRNAs in DAR regulation. In one study, the 3′UTR of the DRD2 in human dopaminergic neurons was targeted by miR-326 and miR-9. Overexpression of these MiRs resulted in marked reductions of both receptor mRNA and receptor protein synthesis [12]. In another study, inhibition of endogenous miR-142-3p in a mouse CAD catecholaminergic neuronal cell line increased the D1R protein expression levels [13]. As the field of noncoding RNA-mediated translational suppression mechanisms becomes more prominent in the catecholamine research arena, additional knowledge of the overall regulation of DAR expression should be forthcoming.
Fever-range whole body hyperthermia leads to changes in immune-related genes and miRNA machinery in Wistar rats
Published in International Journal of Hyperthermia, 2023
Henryk Mikołaj Kozłowski, Justyna Sobocińska, Tomasz Jędrzejewski, Bartosz Maciejewski, Artur Dzialuk, Sylwia Wrotek
Having observed the effect of FRH on cytokine production, we next investigated the potential role of miRNAs. miRNAs have emerged as key regulators of biological processes including cell development, differentiation and homeostasis [17,54]. Importantly, various miRNA molecules regulate the expression of G-CSF [13], MIF [14], IFN-γ [15] and IL-10 [16]. We, therefore, investigated the influence of heat on the expression of the machinery required for miRNA processing. Mature miRNA duplexes are recruited for the RNA-induced silencing complex (RISC). The miRNA machinery includes e.g. DICER1 (RNase III family member) and transactivation response RNA-Binding Protein (TARBP2 also known as TRBP) [55]. In rats, we observed altered expression of Dicer1 and Tarbp2 in all organs examined. These data are consistent with in vitro studies highlighting the ability of heat to induce the expression of DICER1 [56,57]. Increasing data suggest that other molecules involved in miRNA machinery such as argonaute2 protein (Ago2), may be modulated by heat shock proteins (HSPs) [58,59]. These results reveal that the regulation of miRNA machinery is even more complicated. Therefore, further functional analysis is required. However, to the best of our knowledge, no study has considered heat-induced Tarbp2 expression. Hence, our results provide new insight into the role of miRNA machinery in response to FRH.
Strategies for targeting RNA with small molecule drugs
Published in Expert Opinion on Drug Discovery, 2023
Christopher L. Haga, Donald G. Phinney
MiRNAs are a class of small, single-stranded noncoding RNAs, approximately 22 nucleotides in length, that post-transcriptionally modulate gene expression by complementary binding to the 3’ UTR of a particular target mRNA [49]. MiRNAs originate from transcribed DNA that forms an RNA hairpin loop structure that undergoes several processing steps. First, the pri-miRNA structure is cleaved in the nucleus by Drosha at an internal loop or bulge cleavage site most distal to the hairpin loop to yield the pre-miRNA. The cleaved structure is then exported to the cytoplasm by Exportin. The pre-miRNA is then further processed by Dicer cleavage at the internal loop or bulge proximal to the hairpin loop to yield the mature miRNA. One strand of this miRNA is loaded into the RNA-induced silencing complex, or RISC, which functions in gene silencing through various mechanisms.
Study on co-delivery of pemetrexed disodium and Bcl-2 siRNA by poly-γ-glutamic acid-modified cationic liposomes for the inhibition of NSCLC
Published in Drug Development and Industrial Pharmacy, 2023
Xiaoyu Huang, Ruonan Song, Xiao Wang, Kongfang He, Rumeng Shan, Fei Xie, Guihua Huang
Lung cancer (LC) is the most common malignant tumor in the world with the highest mortality rate, while non-small cell lung cancer (NSCLC) accounts for about 85% of LC [1]. Related research has found smoking, indoor and outdoor air pollution, and relatively harmful occupational exposure are the main reasons for the increase in the incidence of LC [2]. Based on the understanding of disease biology and tumor progression mechanisms, the treatment of NSCLC has made great progress, however, the overall cure rate and survival rate are still very low [3]. Nowadays, the combination of chemotherapy and small interfering RNA (siRNA) for the treatment of advanced NSCLC shows great promise [4]. SiRNA, a double-stranded RNA, plays a key role in knocking out or silencing targeted genes in most cells through the formation of an RNA-induced silencing complex (RISC). It can reduce or eliminate the expression of related proteins, thereby affecting the cell cycle, proliferation, apoptosis, and other cellular pathways to play a role. SiRNA silencing is an excellent tool in cancer research, which can knock out overexpressed genes related to cancer progression and metastasis [5–7].