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Thymoma and Thymic Carcinoma
Published in Dongyou Liu, Tumors and Cancers, 2017
Francesco Facciolo, Mirella Marino, Maria Teresa Ramieri
No environmental or viral risk factor is currently known to play a role in TET development. A genetic basis is recognized for very rare cases occurring in the setting of multiple endocrine neoplasia 1 (MEN1) syndrome. A nine gene-based signature, including three upregulated genes (AKR1B10, JPH1, and NGB), was found to predict the metastatic behavior. Recently, a large microRNA cluster on chromosome 19q13.42, constituting a transcriptional hallmark, was noted in all A and AB tumors. This microRNA cluster, virtually absent in the other THY and normal tissues and overexpressed in A and AB tumors, activates the PI3K/AKT/mTOR pathway. This suggests the potential use of PI3K inhibitors in patients with these tumor subtypes. Moreover, a preliminary mature microRNA signature, detectable in formalin-fixed paraffin embedded (FFPE) tissues, has been identified by microarray and bioinformatics analysis. Distinct groups of miRNAs appear to express differentially expressed among TET and normal thymic tissues and among THY and TC and histotype groups. Correlated putative molecular pathways targeted by these differentially miRNAs include pathways related to cell adhesion/motility and additional pathways related to cancer phenotypes such as Wnt, Notch, TGF-α, ErbB, p53, VEGF, and MAPK signaling pathways. To achieve a comprehensive understanding of the TET genome, the National Cancer Institute (NCI) in the United States promotes the Cancer Genome Atlas-THY (TCGA-THY) in the framework of rare tumor genomic studies, and the results are expected soon.
Aldose reductase inhibitors: 2013-present
Published in Expert Opinion on Therapeutic Patents, 2019
Luca Quattrini, Concettina La Motta
Mylan Stefek and co-workers proposed the 2-(3-mercapto-5H-[1,2,4]triazino[5,6-b]indol-5-yl)acetic acid derivative 69 as the representative compound of a novel class of aldo-keto reductase inhibitors [99,100]. Besides inhibiting both ALR2 obtained from rat lenses (IC50 0.106 ± 0.004 µM) and the human recombinant form of the enzyme (IC50 0.48 ± 0.29 µM), the lead compound proved to inhibit also the parent aldehyde reductase ALR1 (IC50 40.6 ± 2.1), extracted and purified from rat kidneys. In addition, 69 was able to block the catalytic activity of the human recombinant member B10 of the aldo-keto reductase family 1, AKR1B10 (IC50 3.69 ± 0.53). This latter, sharing 70% sequence homology with ALR2, metabolizes lipid substrates like farnesal, geranylgeranial, retinal and carbonyls, playing a key role in promoting carcinogenesis [101]. Tested in an ex-vivo assay, 69 was able to reduce sorbitol accumulation in rat lenses cultured in high glucose medium, in a dose-dependent manner. On the basis of the observed functional profile, the authors claimed the compounds as useful agents to counteract the development of diabetic complications, inflammatory diseases, abnormal proliferation of vascular smooth muscle cells in atherosclerosis and restenosis, lung carcinoma in smokers, and different types of cancer.
The hop-derived compounds xanthohumol, isoxanthohumol and 8-prenylnaringenin are tight-binding inhibitors of human aldo-keto reductases 1B1 and 1B10
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2018
Jan Moritz Seliger, Livia Misuri, Edmund Maser, Jan Hintzpeter
Aldose reductase (AKR1B1) and AKR1B10 are involved in numerous pathologies and have therefore been proposed as suitable targets for drug development. Under hyperglycemic conditions, AKR1B1 promotes osmotic imbalance and modifies physiological ratios of the redox couples of both NAD+ and NADP+, with decreasing antioxidant defense abilities. Finally, it induces a potential increase in protein glycation phenomena due to an increase in AGE levels. This has led to the identification of AKR1B1 as a primary target to prevent the onset of secondary diabetic effects. AKR1B1’s homologue AKR1B10 is overexpressed in multiple cancer types, including malignancies of breast, prostate and lungs, and is deemed suitable as a target in cancer treatment. Recent studies have shown that plant/hops specific XN, IX and 8-PN act as anti-diabetic, anti-carcinogenic and antioxidative agents. Hitherto, it has not been explored how this mode of action relates to the role of AKRs in the pathogenesis of the complications described above.