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Recombinant vaccines: Gag-based VLPs
Published in Amine Kamen, Laura Cervera, Bioprocessing of Viral Vaccines, 2023
Laura Cervera, Irene González-Domínguez, Jesús Lavado-García, Francesc Gòdia
Several compounds were described to enhance Gag-based VLPs. [105]. Two main groups of transfection enhancers were tested. One group was selected on the basis that they can either facilitate the entry of PEI/DNA transfection complexes into the cell or cell nucleus. Another group was selected according to their capacity to increase the levels of gene expression. Among the eight reagents tested (trichostatin A, valproic acid, sodium butyrate, DMSO, lithium acetate, caffeine, hydroxiurea, and nocodazole), an optimal combination of compounds exhibiting the greatest effect on gene expression was identified. The addition of 20 mM lithium acetate, 3.36 mM of valproic acid, and 5.04 mM of caffeine increased production levels by fourfold, while maintaining cell culture viability at 94%.
Metal Oxide Nanocomposites: Cytotoxicity and Targeted Drug Delivery Applications
Published in Kaushik Pal, Hybrid Nanocomposites, 2019
Jaison Jeevanandam, Yen S. Chan, Sharadwata Pan, Michael K. Danquah
Besides cancer and diabetes management, several hydrogel-based nanocomposites have been fabricated and recommended to be valuable to treat neurodegenerative diseases [210, 211]. Iron oxide–based hydrogel nanocomposites are prospective in magnetically targeting and reaching the nerve cells, followed by drug delivery, which will reduce the amount of drug used and control the toxicity exhibited by those drugs toward normal cells. Thus, nanocomposites will strengthen their position as a potent, drug delivery entity in the future for timely prognosis of neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and Lafora. Lafora is a rare, autosomal recessive, neurodegenerative genetic syndrome that is illustrated by the occurrence of inclusion bodies within the cellular cytoplasm in the lung, liver, muscle, and/or skin [212, 213]. Unfortunately, with the manifestation of this disease, the majority of affected patients pass away before attaining the age of 25 [214]. It has been found out that the antisense oligonucleotides and molecules that inhibit glycogen synthase happen to be the key factor for recovery from this ailment [215–217]. Thus, nanocomposites may be employed for the targeted delivery of the glycogen synthase–inhibiting molecule, which will act as a potential nanomedicine for the treatment of Lafora in the future, as shown in Fig. 3.6A. Similarly, a rare and early maturing syndrome, progeria, is manifested by a point mutation in the LMNA gene, which encodes for a protein called prelamin A [218, 219]. This syndrome is often discovered in children and leads to aging-related problems at a very early age [220]. Recently, the drug lonafarnib [221] and a novel combination of mevinolin to induce defarnesylation of progerin protein and chromatin-modifying agents, such as 5-azadeoxycytidine, anacardic acid, and trichostatin, were used for progeria treatment [222]. In future, nanocomposites may be employed for specific and regulated drug transport, as shown in Fig. 3.6B. It is also possible to use nanocomposites for LMNA gene delivery, which may possibly alleviate the severity of the disorder.
Regulation of cytochrome P450 expression by microRNAs and long noncoding RNAs: Epigenetic mechanisms in environmental toxicology and carcinogenesis
Published in Journal of Environmental Science and Health, Part C, 2019
Dongying Li, William H. Tolleson, Dianke Yu, Si Chen, Lei Guo, Wenming Xiao, Weida Tong, Baitang Ning
CYP expression is also affected by many epigenetic factors, including DNA methylation, histone modification, and ncRNA regulation.30,31 DNA methylation at the CpG sites in the promoter region leads to transcriptional repression and has widespread effects on the expression of CYPs in different organs, such as the lung and liver.31–33 Exposure to DNA methylating agents may lead to hypermethylation of CYPs genes by DNA methyltransferases and inhibition of CYP expression.34,35 The amino-terminal tails of histone proteins are accessible for post-translational modifications, including acetylation, methylation, phosphorylation, ubiquitination, and sumoylation.36 Histone modifications can influence gene expression by altering chromatin architecture and recruiting remodeling enzymes and trans-regulatory factors. For example, CYP2E1 upregulation induced by trichostatin A (TSA) is associated with histone H3 acetylation and the recruitment of acetylated histone H3, HNF-1, and HNF-3β to the CYP2E1 promoter.37 DNA methylation and histone modification may work in concert in regulating gene expression activities and are contributing mechanisms to carcinogenesis.38–40
Targeting gap junctional intercellular communication by hepatocarcinogenic compounds
Published in Journal of Toxicology and Environmental Health, Part B, 2020
Kaat Leroy, Alanah Pieters, Andrés Tabernilla, Axelle Cooreman, Raf Van Campenhout, Bruno Cogliati, Mathieu Vinken
In addition to regulation at the cell plasma membrane, GJIC is also modulated at the expression level (Solan and Lampe 2018). The first type of expression control is epigenetic mechanisms, such as histone acetylation, DNA methylation and microRNA interactions. Histone acetylation is carried out by histone acetyltransferases. These enzymes stimulate transcriptional activation through chromatin decondensation, while gene suppression is achieved by actions of histone deacetylases that condensate chromatin. Various inhibitors of histone deacetylases were linked to enhanced connexin production and gap junction functionality (Vinken 2016). In this respect, trichostatin A reestablishes GJIC in rat liver epithelial cells (Jung et al. 2006) and downregulates Cx43 production in human liver cancer, while leaving Cx26 and Cx32 unaffected (Yamashita et al. 2004). This has been associated with suppression of tumor aggressiveness due to reduction of tumor invasiveness and proliferation mediated by Cx43 (Menezes et al. 2019). Another epigenetic mechanism is facilitated by DNA methyltransferase enzymes. These enzymes typically hypermethylate gene promotors leading to inhibition of gene transcription. In liver cancer, the decrease of Cx26 expression was associated with enhanced levels of DNA methyltransferase mRNA (Shimizu et al. 2007) and methylated CpG dinucleotides located within the Cx26 gene promotor (Piechocki, Burk, and Ruch 1999). Similarly, Cx32 and Cx43 gene promotor sites are methylated in liver epithelial cells lacking Cx32 expression and a rat hepatoma cell line missing Cx43, respectively (Piechocki, Burk, and Ruch 1999). MicroRNA-related mechanisms constitute another level of epigenetic control. MicroRNAs are small complementary sequences that bind mRNA target molecules, thereby inhibiting translation or cleavage of mRNA (Vinken 2016; Wang et al. 2020, 2019a). Cx43 may be regulated by microRNA-206 amongst many others, thereby influencing metastasis (Lin et al. 2016) and differentiation (Anderson, Catoe, and Werner 2006). Connexin gene transcription is also modulated by conventional cis/trans mechanisms. Both general and tissue-specific transcription factors are involved in this process. In liver, Cx32 gene expression is mediated, at least in part, by the ubiquitous transcription factor specificity protein 1 as well as by the liver-enriched transcription factor hepatocyte nuclear factor 1α (Koffler et al. 2002; Plante, Charbonneau, and Cyr 2006).