Association of glutathione S-transferase polymorphisms (GSTM1 and GSTT1) with primary open-angle glaucoma: An evidence-based meta-analysis

Studies investigating the associations between glutathione S-transferase (GST) genetic polymorphisms and primary open-angle glaucoma (POAG) have reported controversial results. Therefore, a meta-analysis was performed to clarify the effects of GSTM1 and GSTT1 polymorphisms on POAG risk. Published literatures from PubMed, EMBASE, ISI Web of Science and CBM databases were retrieved. All studies evaluating the association between GSTM1/GSTT1 polymorphisms and POAG were included. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using fixed- or random-effects model. Eleven studies on GSTM1 (1339 cases and 1412 controls) and seven studies on GSTT1 (958 cases, 1003 controls) were included. Overall analysis showed that the association between GSTM1 and GSTT1 null genotype and POAG risk is not statistically significant. Subgroup analyses showed that the null genotype of GSTM1 increased the risk of POAG in Asians. In GSTM1–GSTT1 interaction analysis, individuals with dual null genotype were associated with a significantly increased risk of POAG when compared with the dual present genotype. In conclusion, the present meta-analysis suggested that GSTM1 null genotypes are associated with increased POAG risk in Asian populations but not in Caucasian and mixed populations. Dual null genotype of GSTM1/GSTT1 is associated with increased risk of POAG. Given the limited sample size, the finding on GST polymorphisms needs further investigation.     

Are glutathione S-transferase polymorphisms (GSTM1, GSTT1) associated with primary open angle glaucoma? A meta-analysis

Background

Glutathione S-transferase (GST) variants have been considered as risk factors for the pathogenesis of primary open angle glaucoma (POAG). However, the results have been inconsistent. In this study, we performed a meta-analysis to assess the association between GSTM1 and GSTT1 null genotypes and the risk for POAG.

Methods

Published literature from PubMed and EMBASE databases was retrieved. All studies evaluating the association between GSTM1/GSTT1 variants and POAG were included. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using fixed- or random-effects model.

Results

14 studies (1711 POAG cases and 1537 controls) were included in the meta-analysis of GSTM1 genotypes and 10 studies (1306 POAG cases and 1114 controls) were included in the meta-analysis of GSTT1 genotypes. The overall result showed that the association between GSTM1 and GSTT1 null genotypes and risk for POAG was not statistically significant (GSTM1: OR = 1.19, 95% CI = 0.82–1.73, p = 0.361; GSTT1: OR = 1.26, 95% CI = 0.77–2.06, p = 0.365). The results by ethnicity showed that the association between the GSTM1 null genotype and risk for POAG is statistically significant in East Asians (OR = 1.41, 95% CI = 1.04–1.90, p = 0.026), but not in Caucasians (OR = 1.13, 95% CI = 0.69–1.84, p = 0.638) and Latin-American (OR = 1.09, 95% CI = 0.62–1.92, p = 0.767). In addition, there was no significant association of GSTT1 null genotype with risk for POAG in either ethnic population.

Conclusions

The present meta-analysis suggested that there might be a significant association of GSTM1 null genotype with POAG risk in East Asians.     

Axonal protection by Nmnat3 overexpression with involvement of autophagy in optic nerve degeneration

Axonal degeneration often leads to the death of neuronal cell bodies. Previous studies demonstrated the crucial role of nicotinamide mononucleotide adenylyltransferase (Nmnat) 1, 2, and 3 in axonal protection. In this study, Nmnat3 immunoreactivity was observed inside axons in the optic nerve. Overexpression of Nmnat3 exerts axonal protection against tumor necrosis factor-induced and intraocular pressure (IOP) elevation-induced optic nerve degeneration. Immunoblot analysis showed that both p62 and microtubule-associated protein light chain 3 (LC3)-II were upregulated in the optic nerve after IOP elevation. Nmnat3 transfection decreased p62 and increased LC3-II in the optic nerve both with and without experimental glaucoma. Electron microscopy showed the existence of autophagic vacuoles in optic nerve axons in the glaucoma, glaucoma+Nmnat3 transfection, and glaucoma+rapamycin groups, although preserved myelin and microtubule structures were noted in the glaucoma+Nmnat3 transfection and glaucoma+rapamycin groups. The axonal-protective effect of Nmnat3 was inhibited by 3-methyladenine, whereas rapamycin exerted axonal protection after IOP elevation. We found that p62 was present in the mitochondria and confirmed substantial colocalization of mitochondrial Nmnat3 and p62 in starved retinal ganglion cell (RGC)-5 cells. Nmnat3 transfection decreased p62 and increased autophagic flux in RGC-5 cells. These results suggest that the axonal-protective effect of Nmnat3 may be involved in autophagy machinery, and that modulation of Nmnat3 and autophagy may lead to potential strategies against degenerative optic nerve disease.     

曲伏前列素滴眼液治疗开角型青光眼的疗效及对血流动力学的影响

目的:探讨曲伏前列素滴眼液治疗开角型青光眼的疗效及对血流动力学的影响。方法:选择2013年3月~2015年12月在我院接受治疗的164例开角型青光眼患者为研究对象,按照随机数字表法分为对照组和试验组,每组82例,对照组给予马来酸噻吗洛尔滴眼,试验组给予曲伏前列素滴眼,12周后观察两组患者的降眼压效果和视力改变情况,彩色多普勒超声检测眼动脉(OA)、睫状后短动脉(SPCA)及视网膜中央动脉(CRA)的收缩期血流峰值速度(PSV)、舒张末期血流速度(EDV)和阻力指数(RI),并观察其不良反应。结果:两组患者治疗前和治疗后2周的眼压和视力比较,差异无统计学意义(P0.05)。治疗后,两组患者的眼压与治疗前比较均降低,视力与治疗前比较均提升,且试验组眼压降低及视力提升更显著,差异有统计学意义(P0.05);治疗6周和12周后,试验组患者的眼压低于对照组,视力高于对照组,差异有统计学意义(P0.05)。治疗12周后试验组患者OA、SPCA及CRA的EDV、PSV均高于对照组,而RI均低于对照组,差异有统计学意义(P0.05)。两组患者的不良反应主要为轻度异物感、轻度结膜充血、虹膜色素加深等,两组患者的不良反应发生率比较,差异无统计学意义(P0.05)。结论:曲伏前列素滴眼液治疗开角型青光眼可降低眼压,提高视力,改善眼部血流动力学指标,且安全性较好,值得临床推广应用。     

Possible role of differentially expressing novel protein markers (ligatin and fibulin‐7) in human aqueous humor and trabecular meshwork tissue in glaucoma progression

The pathological mechanism underlying glaucoma has always been a complex aspect of this permanently blinding disease but proteomic studies have been helpful in elucidating it to a great extent in several studies. This study was designed to evaluate the expression and to get an idea about the function of two novel markers (ligatin and fibulin‐7) identified in human aqueous humor (hAH) in relation to glaucomatous progression. A significant increase in the protein content of glaucomatous hAH compared to that of non‐glaucomatous controls (NG‐Ctrls) was observed. Ligatin, fibulin‐7, and its proteolysis were revealed in hAH of primary open angle glaucoma (POAG), primary angle closure glaucoma (PACG) and NG‐Ctrls. Quantification confirmed no significant difference in expression of ligatin, whereas fibulin‐7 was significantly (P < 0.05) low in hAH of PACG in comparison to NG‐Ctrls and POAG. Importantly the immunohistochemical assay for both indicated their possible involvement in the maintenance of the appropriate structure of TM in vivo. Since oxidative stress is a major contributor to glaucomatous pathogenesis, in vitro analysis of nuclear and cytoplasmic fractions indicated intracellular changes in localization and expression of ligatin upon oxidative insult of human trabecular meshwork (TM) cells. While no such changes were found for fibulin‐7 expression. This was also corroborated with the immunocytochemical assay. Though a study with a small sample size, this is the first report which confirms the presence of ligatin and fibulin‐7 in hAH, quantified their differential expression, and indicated the possibility of their involvement in the maintenance of the TM structure.     

Progressive retinal ganglion cell loss in primary open-angle glaucoma is associated with temperature circadian rhythm phase delay and compromised sleep

Advanced primary open-angle glaucoma (POAG) is characterized by progressive retinal ganglion cell complex (RGCC) damage that may cause subsequent disruption of the circadian rhythms. Therefore, we evaluated circadian body temperature (BT) rhythm and sleep characteristics of 115 individuals (38 men and 77 women) diagnosed with POAG. GLV (global loss volume; %), a measure of RGCC damage, was estimated by high-definition optical coherence tomography, and RGC functional ability was assessed by pattern electroretinogram amplitude (PERGA). Depending on dynamics of POAG progression criteria, two groups were formed that were distinctively different in GLV: Stable POAG group (S-POAG; GLV = 5.95 ± 1.84, n = 65) and Progressive POAG group (P-POAG; GLV = 24.27 ± 5.09, n = 50). S-POAG and P-POAG groups were not different in mean age (67.61 ± 7.56 versus 69.98 ± 8.15) or body mass index (24.66 ± 3.03 versus 24.77 ± 2.90). All subjects performed 21 around-the-clock BT self-measurements during a 72-h period and kept activity/sleep diaries. Results showed pronounced disruption of circadian physiology in POAG and its progression with increasing severity of the disease. The daily mean of BT was unusually low, compared to age-matched controls. Moreover, our results revealed distinctive features of BT circadian rhythm alterations in POAG development and POAG progression. S-POAG is associated with lowered BT circadian rhythm robustness and inter-daily phase stability compared to controls. In the P-POAG group, the mean phase of the circadian BT rhythm was delayed by about 5 h and phases were highly scattered among individual patients, which led to reduced group mean amplitude. Circadian amplitudes of individuals were not different between the groups. Altogether, these results suggest that the body clock still works in POAG patients, but its entrainment to the 24-h environment is compromised. Probably because of the internal desynchronization, bedtime is delayed, and sleep duration is accordingly shortened by about 55 min in P-POAG compared to S-POAG patients. In the entire POAG cohort (both groups), later sleep phase and shorter mean sleep duration correlate with the delayed BT phase (r = 0.215; p = 0.021 and r = 0.322; p = 0.0004, respectively). An RGCC GLV of 15% apparently constitutes a threshold above which a delay of the circadian BT rhythm and a shortening of sleep duration occur.     

Neurobiology of glaucomatous optic neuropathy: diverse cellular events in neurodegeneration and neuroprotection

Although glaucomatous optic nerve degeneration is a leading cause of worldwide blindness, neither the precise cellular mechanisms underlying neurodegeneration in glaucoma, nor effective strategies for neuroprotection are yet clear. This review focuses on diverse cellular events associated with glaucomatous neurodegeneration whose balance is critical for determination of ultimate cell fate. An improved understanding of the site of primary injury to optic nerve, the mediator pathways of apoptotic cell death and intrinsic protection mechanisms in retinal ganglion cells, the role of glial activation on the survival and death of retinal ganglion cell bodies and their axons, and the protective and destructive consequences of immune system involvement can facilitate development of effective neuroprotective strategies in glaucoma.     

Synthesis of new sulfonamide inhibitors of carbonic anhydrase

Four different derivatives of aromatic sulfonamides have been synthesized: 1,2-bis[(4-sulfonamidobenzamide)ethoxy]ethane (SBAM), 1,2-bis[(4-sulfonamidobenzoate)ethoxy]ethane, 1,2-bis[(2,4-dichloro-5-sulfonamidobenzamide)ethoxy]ethane, and 1,2-bis[(2,4-dichloro-5-sulfonamidobenzoate)ethoxy]ethane. SBAM is a most potent inhibitor on ciliary epithelium carbonic anhydrase and is approximately 13 times more active against carbonic anhydrase isoform II than against isoform I.