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Oxidative damage is one of the major contributors to retinal degenerative diseases such as age-related macular degeneration (AMD), while RPE mediated antioxidant defense plays an important role in preventing retinopathies. However, the regulatory mechanisms of antioxidant signaling in RPE cells are poorly understood. Here we show that transcription factor MITF regulates the antioxidant response in RPE cells, protecting the neural retina from oxidative damage. In the oxidative stress-induced retinal degeneration mouse model, retinal degeneration in Mitf+/- mice is significantly aggravated compared to WT mice. In contrast, overexpression of Mitf in Dct-Mitf transgenic mice and AAV mediated overexpression in RPE cells protect the neural retina against oxidative damage. Mechanistically, MITF both directly regulates the transcription of NRF2, a master regulator of antioxidant signaling, and promotes its nuclear translocation. Furthermore, specific overexpression of NRF2 in Mitf+/- RPE cells activates antioxidant signaling and partially protects the retina from oxidative damage. Taken together, our findings demonstrate the regulation of NRF2 by MITF in RPE cells and provide new insights into potential therapeutic approaches for prevention of oxidative damage diseases., Graphical abstract Image 1, Highlights • MITF haploinsufficiency exacerbates oxidative stress-induced retinal degeneration. • Specific overexpression of MITF in RPE cells protects retinas from oxidative damage in vivo. • MITF directly regulates the transcription and nuclear translocation of NRF2. • Partial rescue of retinal oxidative damage in Mitf ±mice by gene transfer mediated RPE cell specific expression of NRF2.

Purpose MicroRNA-34a (miR-34a) has been implicated in many biological processes. It is downregulated in uveal melanoma, and introduction of miR-34a inhibits the proliferation and migration of uveal melanoma cells. Leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4) is a novel target of miR-34a identified first in retinal pigment epithelial cells. In this study, we sought to evaluate the interaction of miR-34a and LGR4 in uveal melanoma and its downstream mechanisms. Methods The expression of LGR4, epithelial-mesenchymal transition (EMT)-associated factors, and matrix metalloproteinase 2 (MMP2) in uveal melanoma cells was assessed by immunoblotting and immunofluorescence analysis. MicroRNA-34a mimic molecules, LGR4 small interfering RNA (siRNA), or MMP2-specific siRNA were transiently transfected into uveal melanoma cells. In vitro scratch and Transwell assays were used to evaluate the migratory and invasive potential of the resultant uveal melanoma cells. Results LGR4 is upregulated in uveal melanoma cells. Introduction of miR-34a significantly decreased the expression level of LGR4. Transfection with miR-34a or knockdown of LGR4 attenuated the aggressiveness of uveal melanoma cells. In addition, there was a decrease in the expression of mesenchymal markers N-cadherin, vimentin, and Snail following miR-34a introduction or knockdown of LGR4. Finally, MMP2 was found to be a downstream effector for miR-34a and LGR4 that regulates the migration and invasion of uveal melanoma cells. Conclusions MicroRNA-34a negatively controls LGR4, thereby inhibiting the migration and invasion of uveal melanoma cells. Ultimately, both miR-34a and LGR4 impact the aggressiveness of uveal melanoma with alterations in the markers of the EMT. MMP2 is a downstream effector that influences the metastasis seen with uveal melanoma cells.

Aim Previous evidence has found that some single nucleotide polymorphisms (SNPs) in cardiomyopathy-associated 5 gene (CMYA5) were associated with schizophrenia in the Caucasian and Chinese Han populations. In this study, we aimed to investigate the relationship between CMYA5 gene polymorphisms and schizophrenia in Chinese Uygur population and perform a meta-analysis to synthetically analyse the association of CMYA5 gene polymorphisms with schizophrenia in Asian populations. Method We retrospectively analysed 985 schizophrenia cases and 1123 healthy controls in Chinese Uygur population. Four SNPs (rs259127, rs3828611, rs4704591 and rs6883197) of CMYA5 were genotyped using TaqMan SNP genotyping assay. Meta-analysis was conducted across Asian studies by Review Manager 5.2. Results Results showed no significant difference in either allelic or genotypic frequency in four SNPs of the CMYA5 gene between cases and controls (P > 0.05). However, the age of onset and the PANSS positive-factor subscale score were significantly lower in schizophrenia patients with the A/A genotype of rs6883197 than those with A/G and G/G genotypes (P

GRM8 is a schizophrenia candidate gene that is also thought to be involved in the glutamate pathway, which is very important in the pathogenesis of schizophrenia. In this study, we aim to investigate the association between GRM8 and schizophrenia in the Uygur Chinese population. Rs2237748 and rs2299472, located in the GRM8 gene, were selected for genotyping in a set of Uygur Chinese case-control samples, which included 723 cases and 561 controls, using TaqMan assays and capillary sequencing. The statistical analysis was carried out using the online software program SHEsis, and a meta-analysis was carried out to identify other relevant studies using Review Manager 5. We found that the rs2299472 genotype was significantly associated with schizophrenia (P = 0.015, P = 0.030, after Bonferroni correction). The frequency of the CC genotype was higher in the schizophrenic patients (P = 0.008), and the frequency of the AC genotype was lower (P = 0.008). Furthermore, the meta-analysis incorporating the previous and current studies also showed that rs2299472 is associated with schizophrenia. This study indicates that the GRM8 gene may play an important role in the pathogenesis of schizophrenia.

Previous evidence has found that some single nucleotide polymorphisms (SNPs) in cardiomyopathy-associated 5 gene (CMYA5) were associated with schizophrenia in the Caucasian and Chinese Han populations. In this study, we aimed to investigate the relationship between CMYA5 gene polymorphisms and schizophrenia in Chinese Uygur population and perform a meta-analysis to synthetically analyse the association of CMYA5 gene polymorphisms with schizophrenia in Asian populations.We retrospectively analysed 985 schizophrenia cases and 1123 healthy controls in Chinese Uygur population. Four SNPs (rs259127, rs3828611, rs4704591 and rs6883197) of CMYA5 were genotyped using TaqMan SNP genotyping assay. Meta-analysis was conducted across Asian studies by Review Manager 5.2.Results showed no significant difference in either allelic or genotypic frequency in four SNPs of the CMYA5 gene between cases and controls (P 0.05). However, the age of onset and the PANSS positive-factor subscale score were significantly lower in schizophrenia patients with the A/A genotype of rs6883197 than those with A/G and G/G genotypes (P 0.05). In addition, the meta-analysis showed the significant association of rs3828611 with risk of schizophrenia (P = 0.03, OR = 0.92, 95% CI: 0.91-0.99).Our results support the association between CMYA5 rs6883197 and schizophrenia in Chinese Uygur population. Meta-analysis demonstrated that rs3828611 was significantly associated with schizophrenia in Asian population. Genetic heterogeneity among populations may be the main reason of results conflict between studies. In conclusion, association between CMYA5 gene polymorphisms and schizophrenia was confirmed in Asian population.

The rs10761482 polymorphism of the ANK3 gene has been associated with the occurrence of schizophrenia.Assess the relationship between the ANK3 gene and schizophrenia in individuals of Uyghurian descent.A total of 630 patients with schizophrenia and 535 healthy controls of Uyghur descent were genotyped for the ANK3 gene rs10761482 locus using Taqman probe technology. SHEsis and SPSS17.0 software were used for data analysis.There were no significant differences in the genotype or allele frequencies between the case group and control group. Within the case group there was no relationship between gender or age of onset of schizophrenia and the genotype or allele frequencies. Separate analyses among men and among women also failed to identify significant differences in the allele and genotype frequencies between cases and controls or between patients with adolescent-onset schizophrenia and those with adult-onset schizophrenia.Our findings do not support previous reports about the relationship of the ANK3 gene and schizophrenia. In the Uyghur nationality group recruited for this study there was no significant association between the ANK3 gene rs10761482 polymorphism and schizophrenia. If these results are replicated in further studies, then the focus should change to understanding why this widely acknowledged association does not exist in this particular ethnic group.ANK3基因rs10761482多态性已被发现与精神 分裂症的发生相关联。评估新疆维吾尔族人群ANK3基因和精神分裂 症之间的关联。使用Taqman探针技术对630例新疆维吾尔族 精神分裂症患者和535名新疆维吾尔族健康人群进行病例组和对照组之间的基因型和等位基因频率 无显著差异。在病例组，性别或精神分裂症发病年龄 与基因型或等位基因频率之间没有显著关联。将男性 和女性单独分析，病例组与对照组之间的等位基因和 基因型频率均未发现显著差异，青春期发病与成年后 发病的精神分裂症患者之间的等位基因和基因型频率 也无显著差异。我们的研究结果不支持以往ANK3基因与精神 分裂症有关联的报告。本研究招募的维吾尔族人群中，