Deacon, R. M. J., Hurley, M. J., Rebolledo, C. M., Snape, M., Altimiras, F. J., Farias, L., et al. (2017). Nrf2: a novel therapeutic target in fragile X syndrome is modulated by NNZ2566. Genes Brain Behav., 16(7), 1–10.
Abstract: Fragile X-associated disorders are a family of genetic conditions resulting from the partial or complete loss of fragile X mental retardation protein (FMRP). Among these disorders, fragile X syndrome (FXS) is the most common cause of inherited intellectual disability and autism. Progress in basic neuroscience has led to identification of molecular targets for treatment in FXS; however, there is a gap in translation to targeted therapies in humans. This study introduces a novel therapeutic target for FXS, nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a transcription factor known to induce expression of over 100 cytoprotective genes. We also show that NNZ2566, a drug that has successfully completed a phase 2 clinical trial in FXS, is effective in modulating this target in FXS, partially reversing the FXS phenotype; NNZ2566 has a therapeutic role as Nrf2 activator. Effectively, treatment with NNZ2566 normalizes the translocation of Nrf2 to the nucleus, inducing expression of numerous oxidative stress-related genes including NQO1 (NAD(P) H dehydrogenase quinone 1), GST-alpha 1 (glutathione S-transferase alpha-1) and EH (epoxide hydrolase) and has a knockdown effect on E-cadherin. In summary, the Nrf2/ARE (antioxidant response element) pathway appears to be a novel promising therapeutic target for FXS and NNZ2566 appears to be acting as an activator of the Nrf2/ARE pathway and suggests a potential benefit across multiple symptoms that could be associated with the pathobiological processes underlying FXS.
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Diaz-Rullo, J., Rodriguez-Valdecantos, G., Torres-Rojas, F., Cid, L., Vargas, I. T., Gonzalez, B., et al. (2021). Mining for Perchlorate Resistance Genes in Microorganisms From Sediments of a Hypersaline Pond in Atacama Desert, Chile. Front. Microbiol., 12, 723874.
Abstract: Perchlorate is an oxidative pollutant toxic to most of terrestrial life by promoting denaturation of macromolecules, oxidative stress, and DNA damage. However, several microorganisms, especially hyperhalophiles, are able to tolerate high levels of this compound. Furthermore, relatively high quantities of perchlorate salts were detected on the Martian surface, and due to its strong hygroscopicity and its ability to substantially decrease the freezing point of water, perchlorate is thought to increase the availability of liquid brine water in hyper-arid and cold environments, such as the Martian regolith. Therefore, perchlorate has been proposed as a compound worth studying to better understanding the habitability of the Martian surface. In the present work, to study the molecular mechanisms of perchlorate resistance, a functional metagenomic approach was used, and for that, a small-insert library was constructed with DNA isolated from microorganisms exposed to perchlorate in sediments of a hypersaline pond in the Atacama Desert, Chile (Salar de Maricunga), one of the regions with the highest levels of perchlorate on Earth. The metagenomic library was hosted in Escherichia coli DH10B strain and exposed to sodium perchlorate. This technique allowed the identification of nine perchlorate-resistant clones and their environmental DNA fragments were sequenced. A total of seventeen ORFs were predicted, individually cloned, and nine of them increased perchlorate resistance when expressed in E. coli DH10B cells. These genes encoded hypothetical conserved proteins of unknown functions and proteins similar to other not previously reported to be involved in perchlorate resistance that were related to different cellular processes such as RNA processing, tRNA modification, DNA protection and repair, metabolism, and protein degradation. Furthermore, these genes also conferred resistance to UV-radiation, 4-nitroquinoline-N-oxide (4-NQO) and/or hydrogen peroxide (H2O2), other stress conditions that induce oxidative stress, and damage in proteins and nucleic acids. Therefore, the novel genes identified will help us to better understand the molecular strategies of microorganisms to survive in the presence of perchlorate and may be used in Mars exploration for creating perchlorate-resistance strains interesting for developing Bioregenerative Life Support Systems (BLSS) based on in situ resource utilization (ISRU).
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Vera-Maldonado, P., Aquea, F., Reyes-Díaz, M., Cárcamo-Fincheira, P., Soto-Cerda, B., Nunes-Nesi, A., et al. (2024). Role of boron and its interaction with other elements in plants. Front. Plant Sci., 15, 1332459.
Abstract: Boron (B) is an essential microelement for plants, and its deficiency can lead to impaired development and function. Around 50% of arable land in the world is acidic, and low pH in the soil solution decreases availability of several essential mineral elements, including B, magnesium (Mg), calcium (Ca), and potassium (K). Plants take up soil B in the form of boric acid (H3BO3) in acidic soil or tetrahydroxy borate [B(OH)4]- at neutral or alkaline pH. Boron can participate directly or indirectly in plant metabolism, including in the synthesis of the cell wall and plasma membrane, in carbohydrate and protein metabolism, and in the formation of ribonucleic acid (RNA). In addition, B interacts with other nutrients such as Ca, nitrogen (N), phosphorus (P), K, and zinc (Zn). In this review, we discuss the mechanisms of B uptake, absorption, and accumulation and its interactions with other elements, and how it contributes to the adaptation of plants to different environmental conditions. We also discuss potential B-mediated networks at the physiological and molecular levels involved in plant growth and development.
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Viveros, M. F. A., Inostroza-Blancheteau, C., Timmermann, T., Gonzalez, M., & Arce-Johnson, P. (2013). Overexpression of GlyI and GlyII genes in transgenic tomato (Solanum lycopersicum Mill.) plants confers salt tolerance by decreasing oxidative stress. Mol. Biol. Rep., 40(4), 3281–3290.
Abstract: The glyoxalase system plays an important role in various physiological processes in plants, including salt stress tolerance. We report the effects of overexpressing glyoxalase I and glyoxalase II genes in transgenic tomato (Solanum lycopersicum Mill.) cv. Ailsa Craig. Stable expression of both transgenes was detected in the transformed tomato plants under salt stress. The transgenic lines overexpressing GlyI and GlyII under a high NaCl concentration (800 mM) showed reduced lipid peroxidation and the production of H2O2 in leaf tissues. A greater decrease in the chlorophyll a+b content in wild-type (WT) compared with transgenic lines was also observed. These results suggest that the over expression of two genes, GlyI and GlyII, may enhance salt stress tolerance by decreasing oxidative stress in transformed tomato plants. This work will help our understanding of the putative role of the glyoxalase system in the tolerance to abiotic stress in tomato plants.
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