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Genetic Studies of PTSD and Substance Use Disorders
Published in Anka A. Vujanovic, Sudie E. Back, Posttraumatic Stress and Substance Use Disorders, 2019
Christina M. Sheerin, Leslie A. Brick, Nicole R. Nugent, Ana B. Amstadter
Most successful findings have provided support for the role of alcohol-metabolizing enzyme (ADH and ALDH) gene clusters in relation to alcohol dependence. Frank and colleagues (2012) identified a significant marker located between the ADH1B and ADH1C genes in a sample of 3,501, and Park et al. (2013) identified two SNPs within ADH7 and a missense SNP in ALDH2 in a smaller sample of 396. Two SNPs in ALDH2 were found to be associated with alcohol dependence among a sample of 374 males (Quillen et al., 2014). Additionally, Gelernter et al. (2014) conducted a GWAS using a large discovery sample (N = 2,379 European Americans and N = 3,318 African Americans) and replication with independent samples (totaling N = 7,152), identifying several genome-wide significant associations using alcohol dependence symptom count at the ADH locus on chromosome 4, PDLIM5, and a novel SNP on chromosome 2 between MTIF2 and CCDC88A present across different samples.
Ultrasound-sensitive siRNA-loaded nanobubbles fabrication and antagonism in drug resistance for NSCLC
Published in Drug Delivery, 2022
Chunhong Su, XiaoJun Ren, Fang Yang, Bin Li, Hao Wu, Hui Li, Fang Nie
It has been found PDLIM5 gene is overexpressed in NSCLC and was associated with a poor prognosis of NSCLC. Studies have shown that PDLIM5 is a member of the PDZ-LIM protein family, also known as Enigma Homolog (ENH). It is often used as a scaffold protein to be involved in the signal-transducing regulation of membrane-associated proteins, cytoskeletal proteins, various signaling molecules, as well as the progression of various tumors (Edlund et al., 2012; Wang et al., 2016). Recent studies have shown that PDLIM5 regulation of NSCLC drug resistance is related to AMPK/TSC2/mTORC1 signaling pathway. The possible mechanisms are as follows: (1) PDLIM5, as a substrate of adenosine activated protein kinase AMPK, is a major signaling molecule to regulate cell proliferation under the AMPK activation environment. PDLIM5 can directly bind to AMPK, maintain AMPK activation, inhibit AMPK degradation. By knocking out a tumor or intracellular PDLIM5, it can inhibit the proliferation of tumor cells, induce cell cycle stagnation, and promote cell apoptosis (Li et al., 2015; Liu et al., 2017). Activation of AMPK can decrease the metabolic activity of tumor cells under metabolic stress, such as sugar starvation, thereby enhancing the viability of tumor cells. (2) In the case of increased AMPK activity, PDLIM5 is a major signaling molecule to regulate cell migration. The activated AMPK can directly phosphorylate SER177 of PDLIM5 attached to the actin filaments, thus causing changes in the actin skeleton structure. For example, the formation of defective patchy pseudopodia, ventral stress fiber enhancement, and adhesion spots to the edge of cells, thus inhibiting cell migration and invasion (Yan et al., 2015). (3) Activation of AMPK further inhibits its downstream substrate mTOR through the TSC1/2 complex, thus enabling cell survival and proliferation, helping cells adapt to a stressful environment, promoting cell survival, and leading to tumor drug resistance (Kim et al., 2018). Therefore, the specific intervention of PDLIM5 expression may relieve the inhibitory effect of AMPK activation on mTOR under stress state, and then affect cell proliferation, accelerate cell apoptosis, and improve drug sensitivity of tumor cells to EGFR-TKIS. Therefore, the enhanced expression level of PDLIM5 is expected to be a new method for the treatment of drug-resistant NSCLC.