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Epigenetic Alterations in Alzheimer’s Disease and Its Therapeutic and Dietary Interventions
Published in Atanu Bhattacharjee, Akula Ramakrishna, Magisetty Obulesu, Phytomedicine and Alzheimer’s Disease, 2020
P. M. Aswathy, C. M. Shafeeque, Moinak Banerjee
DNA methylation profiles of hippocampal tissues from control and AD patients have identified the presence of promoter hypermethylation of the gene Dual‐Specificity Phosphatase 22 (DUSP22), that inhibits protein kinase A (PKA) activity and, thereby determines tau phosphorylation status and cyclic AMP-responsive element-binding protein (CREB) signaling in AD (Sanchez-Mut et al. 2014). The methylation status of DUSP22 correlated positively with the Braak stages of the patient (Sanchez-Mut et al. 2014). Decreased expression of another phosphatase, DUSP6, that regulates tau production, through hypermethylation, was recently shown in AD brains (Watson et al. 2016). The Bridging Integrator1 (BIN1), which mediates AD risk by modulating tau pathology (Chapuis et al. 2013), was shown to be aberrantly hypermethylated in AD, resulting in Aβ load (De Jager et al. 2014; Yu et al. 2015).
Micronutrients in the Prevention and Improvement of the Standard Therapy for Alzheimer’s Disease
Published in Kedar N. Prasad, Micronutrients in Health and Disease, 2019
Elevated expression of miR-125b and reduced levels of its two target proteins phosphatases DUSP6 (dual specificity phosphatase 6) and PPP1CA (protein phosphatase1 catalytic subunit alpha) was found in the autopsied brain tissue of patients with AD.58 In the primary neurons in culture, overexpression of miR-125b caused hyperphosphorylation of tau protein. These results suggest that miR-125b increases the phosphorylation of tau protein by decreasing the phosphatases activities.
The inherited basis of hypergonadotropic hypogonadism
Published in Philip E. Harris, Pierre-Marc G. Bouloux, Endocrinology in Clinical Practice, 2014
The hypothesis that mutations in genes encoding a broader range of modulators of the FGFR1 pathway might contribute to the genetics of CIHH as causal or modifier has been tested in a large group of IHH individuals and has revealed that mutations in members of the so-called FGF8 synexpression group, namely FGF17, IL17RD, DUSP6, SPRY4, and FLRT3, harbor potential loss-of-function mutations in CIHH patients.80 On the basis of their protein–protein interaction patterns with proteins known to be altered in CIHH, FGF17 and IL17RD were predicted to be potentially important genes in IHH. Most of the FGF17 and IL17RD mutations altered protein function in vitro. IL17RD mutations were found only in KS individuals and were strongly linked to hearing loss (six of eight individuals). Mutations in genes encoding components of the FGF pathway were found to be associated with complex modes of CIHH inheritance acting primarily as contributors to an oligogenic genetic architecture underlying CIHH.
Dual Specific Phosphatase 14 Deletion Rescues Retinal Ganglion Cells and Optic Nerve Axons after Experimental Anterior Ischemic Optic Neuropathy
Published in Current Eye Research, 2021
Varun Kumar, Mohammad Ali Shariati, Louise Mesentier-Louro, Angela Jinsook Oh, Kristina Russano, Jeffrey L. Goldberg, Yaping Joyce Liao
We previously demonstrated that AAV2-mediated Dusp14 knockdown protected RGCs one week after rat optic nerve crush injury and promoted limited axonal regeneration.28 Dusp14 knockout also demonstrated significant RGC protection after optic nerve crush.28 Despite the many differences between the AION and optic crush models, inhibition of Dusp14 and activation of ERK1/2 using genetic (this study) or viral28 approaches rescues RGCs after optic nerve insult, suggesting a global role for Dusp14 in RGC death in optic neuropathies. Other Dusp family members such as Dusp6 and Dusp1 share homology with Dusp14, and in other model systems have been similarly linked to survival signaling. For example, embryonic fibroblasts from Dusp6 knockout mice have reduced apoptosis after myocardial infarction injury.44
An overview of binimetinib for the treatment of melanoma
Published in Expert Opinion on Pharmacotherapy, 2020
Biomarker analyses were pre-specified as secondary and exploratory objectives. Van Herpen et al. [21] reported the extent of MAPK pathway inhibition by binimetinib, genetic pathway alterations of interest, and potential predictive markers for binimetinib efficacy. Twenty-five fresh pre- and post-dose tumor sample pairs were collected for biomarker analyses, which included assessment of binimetinib on MEK/MAPK signaling by pharmacodynamic analysis of pERK and DUSP6 expression in pre- vs post-dose tumor biopsies; identification of pERK and DUSP6 expression/efficacy correlations; assessment of baseline tumor molecular status; and exploration of potential predictive biomarkers of efficacy of binimetinib [21]. The postbaseline pERK and DUSP6 expression decreased across all arms; no association between reduced pERK or DUSP6 levels with clinical efficacy was observed. Genetic aberrations were similar to previously reported data on clinical melanoma samples. Genetic pathway alterations occurred predominantly within CDKN2A/B, PTEN, and TRRAP (BRAF-mutation) and CDKN2A/B, TP53, and NOTCH2 (NRAS-mutation). Several patients with BRAF mutations had amplification of genes on chromosome 7q; these patients tended to have shorter progression-free survival than other patients with BRAF-mutant melanoma [21].
LncTUG1 ameliorates renal tubular fibrosis in experimental diabetic nephropathy through the miR-145-5p/dual-specificity phosphatase 6 axis
Published in Renal Failure, 2023
Taoxia Wang, Shubei Cui, Xiaoli Liu, Li Han, Xiaoting Duan, Shuning Feng, Sen Zhang, Guiying Li
Dual-specificity phosphatases (DUSPs) are negative regulators of MAPK signal transduction and can dephosphorylate p38, JNK, and ERK under different conditions [15]. Extracellular signal-regulated kinases 1 and 2 (ERK1/2) are important extracellular signals transductor. DUSP6 can specifically dephosphorylate ERK1/2 on tyrosine and serine/threonine residues, resulting in the inactivation of ERK1/2 in vivo and in vitro. Consistent with a previous report [17], we demonstrated upregulation of DUSP6 could alleviate fibrosis of the kidney. Pfuhlmann et al. [31] indicated that DUSP6 deficiency is associated with impaired systemic glucose tolerance. Our study showed that the expression of DUSP 6 was downregulated in the kidney under the stimulation of glucose toxicity, and this low expression is caused by the upregulation of miR-145-5p. Some research shows that downregulating miR-145-5p can reduce the inflammatory response and diabetic retinopathy progress [32]. Shahrokhi et al. [33] analyzed plasma miR-145-5p expressions in healthy individuals, prediabetic patients, and diabetic patients, and they indicated that miR-145-5p was down-regulated in the prediabetics and T2D patients compared to the controls. While Zamanian Azodi et al. [34] reported expressions of miR-145-5p were upregulated significantly in patients with gestational diabetes mellitus in 2 GSE datasets. Is the difference in expression due to the specificity of organ tissues or the different stages of diabetes? The mechanism of diabetes and its complications is complex and is influenced by the environment and genes, these all need further analysis in follow-up research.