Targeting Oxidative Stress for Treatment of Glaucoma and Optic Neuritis

Glaucoma is a neurodegenerative disease of the eye and it is one of the leading causes of blindness. Glaucoma is characterized by progressive degeneration of retinal ganglion cells (RGCs) and their axons, namely, the optic nerve, usually associated with elevated intraocular pressure (IOP). Current glaucoma therapies target reduction of IOP, but since RGC death is the cause of irreversible vision loss, neuroprotection may be an effective strategy for glaucoma treatment. One of the risk factors for glaucoma is increased oxidative stress, and drugs with antioxidative properties including valproic acid and spermidine, as well as inhibition of apoptosis signal-regulating kinase 1, an enzyme that is involved in oxidative stress, have been reported to prevent glaucomatous retinal degeneration in mouse models of glaucoma. Optic neuritis is a demyelinating inflammation of the optic nerve that presents with visual impairment and it is commonly associated with multiple sclerosis, a chronic demyelinating disease of the central nervous system. Although steroids are commonly used for treatment of optic neuritis, reduction of oxidative stress by approaches such as gene therapy is effective in ameliorating optic nerve demyelination in preclinical studies. In this review, we discuss oxidative stress as a therapeutic target for glaucoma and optic neuritis

Characterization of Mn-Doped PIN-PMN-PT Single Crystal Grown by Continuous-Feeding Bridgman Method

Mn-doped Pb(In1/2Nb1/2)O3-Pb(Mg1/3Nb2/3)O3-PbTiO3 (Mn:PIN-PMN-PT) single crystals are attractive piezoelectric materials owing to their high mechanical quality factor. However, the single crystal boules grown by the conventional Bridgman method show compositional variation along the growth direction. In particular, the Mn content exhibits large variation due to its severe segregation. To improve the compositional uniformity, we applied the continuous-feeding Bridgman method to the growth of a Mn:PIN-PMN-PT single crystal boule. Then, the composition and property distributions of the boule along the growth direction were evaluated. The results showed that excellent composition and property uniformity were carried out over 80mm in boule length. The ranges of the electromechanical coupling coefficient (k33) and the piezoelectric coefficient (d33) were 0.931–0.934 and 1352–1517 pC/N, respectively. The ranges of the mechanical quality factor (Qm31) and the depolarization field (Ed) were 417–535 and 785–859 V/mm, respectively. The Qm31 and the Ed values were higher than those of the non-doped PIN-PMN-PT single crystals. The continuous-feeding Bridgman method is therefore an effective technique for improving the uniformity of the Mn content. As a result, the Mn:PIN-PMN-PT single crystal grown by the continuous-feeding Bridgman method possesses excellent property uniformity with characteristics suitable for high power piezoelectric applications

Identification and Functional Characterization of a Novel Androgen Receptor Coregulator, EAP1

The androgen receptor (AR) plays an essential role in the development of prostate cancer, and androgen-deprivation therapy is used as a first-line treatment for prostate cancer. However, under androgen-deprivation therapy, castration-resistant prostate cancer inevitably arises, suggesting that the interacting transcriptional coregulators of AR are promising targets for developing novel therapeutics. In this study, we used novel proteomic techniques to evaluate the AR interactome, including biochemically labile binding proteins, which might go undetected by conventional purification methods. Using rapid immunoprecipitation mass spectrometry of endogenous proteins, we identified enhanced at puberty 1 (EAP1) as a novel AR coregulator, whereas its interaction with AR could not be detected under standard biochemical conditions. EAP1 enhanced the transcriptional activity of AR via the E3 ubiquitin ligase activity, and its ubiquitination substrate proteins included AR and HDAC1. Furthermore, in prostate cancer specimens, EAP1 expression was significantly correlated with AR expression as well as a poor prognosis of prostate cancer. Together, these results suggest that EAP1 is a novel AR coregulator that promotes AR activity and potentially plays a role in prostate cancer progression

Endogenous Purification of NR4A2 (Nurr1) Identified Poly(ADP-Ribose) Polymerase 1 as a Prime Coregulator in Human Adrenocortical H295R Cells

Aldosterone is synthesized in zona glomerulosa of adrenal cortex in response to angiotensin II. This stimulation transcriptionally induces expression of a series of steroidogenic genes such as HSD3B and CYP11B2 via NR4A (nuclear receptor subfamily 4 group A) nuclear receptors and ATF (activating transcription factor) family transcription factors. Nurr1 belongs to the NR4A family and is regarded as an orphan nuclear receptor. The physiological significance of Nurr1 in aldosterone production in adrenal cortex has been well studied. However, coregulators supporting the Nurr1 function still remain elusive. In this study, we performed RIME (rapid immunoprecipitation mass spectrometry of endogenous proteins), a recently developed endogenous coregulator purification method, in human adrenocortical H295R cells and identified PARP1 as one of the top Nurr1-interacting proteins. Nurr1-PARP1 interaction was verified by co-immunoprecipitation. In addition, both siRNA knockdown of PARP1 and treatment of AG14361, a specific PARP1 inhibitor suppressed the angiotensin II-mediated target gene induction in H295R cells. Furthermore, PARP1 inhibitor also suppressed the aldosterone secretion in response to the angiotensin II. Together, these results suggest PARP1 is a prime coregulator for Nurr1