rad21 Is Involved in Corneal Stroma Development by Regulating Neural Crest Migration.

Previously, we identified RAD21R450C from a peripheral sclerocornea pedigree. Injection of this rad21 variant mRNA into Xenopus laevis embryos disrupted the organization of corneal stroma fibrils. To understand the mechanisms of RAD21-mediated corneal stroma defects, gene expression and chromosome conformation analysis were performed using cells from family members affected by peripheral sclerocornea. Both gene expression and chromosome conformation of cell adhesion genes were affected in cells carrying the heterozygous rad21 variant. Since cell migration is essential in early embryonic development and sclerocornea is a congenital disease, we studied neural crest migration during cornea development in X. laevis embryos. In X. laevis embryos injected with rad21 mutant mRNA, neural crest migration was disrupted, and the number of neural crest-derived periocular mesenchymes decreased significantly in the corneal stroma region. Our data indicate that the RAD21R450C variant contributes to peripheral sclerocornea by modifying chromosome conformation and gene expression, therefore disturbing neural crest cell migration, which suggests RAD21 plays a key role in corneal stroma development.

Growth hormone-releasing hormone receptor mediates cytokine production in ciliary and iris epithelial cells during LPS-induced ocular inflammation.

The receptor for growth hormone-releasing hormone (GHRH-R) has been shown to upregulate specifically in the ciliary and iris epithelial cells and infiltrating cells in the aqueous humor in a rat model of acute anterior uveitis. Treatment with GHRHR-R antagonist alleviates significantly these inflammatory responses. Herein we investigated whether the ciliary and iris epithelial cells can respond directly to lipopolysaccharide (LPS) without the influences of circulating leukocytes to produce inflammatory mediators through a GHRH-R mediated mechanism. In explant cultures of rat ciliary body and iris, LPS caused a substantial increase of GHRH-R in 24 h. Immunohistochemistry showed a localization of TLR4, the receptor for LPS, and an elevated expression of IL-6 and IL-1ß in ciliary and iris epithelial cells after LPS treatment. LPS also elevated the level of IL-1ß, IL-6, and iNOS and increased secretion of IL-1ß and IL-6 from the explants. The GHRH-R antagonist, MIA-602, suppressed the elevated expression of IL-1ß and IL-6, and reduced the release of IL-6. Such effects were not seen for the GHRHR agonist, MR-409. When co-cultured with leukocytes, expression of GHRH-R in the ocular explants was further enhanced during LPS treatment. Our results demonstrate a direct action of LPS on ciliary and iris epithelial cells to produce pro-inflammatory factors through a GHRH-R mediated mechanism, and suggest a role of these epithelial cells, in addition to the resident antigen presenting cells, in immune surveillance of the eye. Infiltrating leukocytes may enhance these inflammatory responses by regulating GHRH-R in ciliary and iris epithelial cells, in addition to their functions of synthesizing proinflammatory cytokines.

Eye-tracking training improves visuospatial working memory of children with attention-deficit/hyperactivity disorder and autism spectrum disorder.

Given the close connection between eye movement and frontal lobe functions and some evidence supporting the effect of eye-tracking training on enhancing cognitive performance mediated by the frontal lobe, this study aimed to explore if after-school eye-tracking training can improve the visuospatial working memory (VSWM) and cognitive flexibility performance in children with attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). This study is a non-randomized cluster trial. Forty children from eight primary schools were selected, half receiving eye-tracking training for 20 sessions over 9 months, while the other half served as a waitlist control. They were matched on demographic characteristics and baseline cognitive performance. Their VSWM and cognitive flexibility were assessed at the beginning and end of the study. Results showed that children who received eye-tracking training, but not those on a waitlist, exhibited significant improvements in the total score and working memory span of the VSWM tests, and the correct responses in cognitive flexibility tests. Specifically, VSWM performance at higher span levels (5 or above) yielded a greater improvement. The findings suggest that eye-tracking training can be a feasible and effective after-school program for improving working memory and cognitive flexibility performance in children with ADHD and ASD. This study was prospectively registered at ClinicalTrials.gov (https://clinicaltrials.gov/, trial number: NCT05428657).

Effectiveness of lifestyle medicine on cognitive functions in mild cognitive impairments and dementia: A systematic review on randomized controlled trials.

Mild cognitive impairment (MCI) and dementia are associated with lifestyle risk factors, making lifestyle medicine a potentially viable intervention for people with MCI and dementia. The present study aims to examine the effectiveness of lifestyle medicine on cognitive functions among people with MCI and dementia, by performing a systematic review and meta-analysis on randomized controlled trials (RCT). A systematic literature search was conducted to extract RCTs adopting lifestyle interventions of diet, exercise, and stress management or emotional well-being. Results showed that 65 studies were eligible. Exercise was the most promising lifestyle intervention that improved various cognitive functions among people with MCI and dementia, and was more effective in MCI than in dementia. Interventions on stress management or emotional well-being did not show a significant effect on people with MCI, and the evidence for people with dementia was insufficient to conclude. Similarly, due to the lack of RCTs on a healthy dietary pattern, the effectiveness of diet interventions was not examined. In conclusion, the exercise component of lifestyle medicine can be an effective and clinically significant intervention for protecting people with MCI and dementia against cognitive declines, especially when served as an early intervention at the stage of MCI.

Enhancement effect of nanoscale zero-valent iron addition on microbial degradation of BDE-209 in contaminated mangrove sediment.

Chemical and biological methods have been employed to remedy polybrominated diphenyl ether contamination, but the removal of decabromodiphenyl ether (BDE-209) by either method still has limitations. The present study aims to evaluate the combined effect of nanoscale zero-valent iron (nZVI) (from 0.1 to 10%) reduction and microbial debromination on BDE-209 removal in mangrove sediments under an anaerobic condition. During the 12-months incubation, nZVI significantly enhanced BDE-209 removal, with 17.03% to 41.99% reduction in sterilized sediments. The reduction was even higher in non-sterilized sediments with living indigenous microorganisms, achieving 15.80%, 33.50%, 55.83% and 66.95% removal of BDE-209 at 0 (control without nZVI), 0.1%, 1% and 10% nZVI, respectively. In control sterilized sediments, no debromination was found, and debromination occurred according to spiked levels of nZVI, with BDE-153 being the dominant congener. The concentrations of debrominated congeners in non-sterilized sediments also increased with nZVI levels, but were significantly higher than the respective sterilized sediment. The relative proportions of different debrominated congeners in non-sterilized sediments depended on nZVI levels, with BDE-99 being the dominant congener in low nZVI amended sediments but shifted to BDE-153 under high nZVI. Higher concentrations of ferrous iron (Fe2+) were detected in both sterilized and non-sterilized sediments spiked with more nZVI, and their concentrations significantly correlated with BDE-209 removal. Growth of total bacteria in sediments with 1% and 10% nZVI was inhibited within first two months, but their numbers resumed to that in the control at the end of 12 months. The present study demonstrates the synergy between chemical and microbiological methods, and a combination of nZVI and indigenous microorganisms could be an efficient and feasible mean to remedy BDE-209 in contaminated sediments.

Effect of light on the transformation of BDE-47 by living and autoclaved cultures of Microcystis flos-aquae and Chlorella vulgaris.

Polybrominated diphenyl ethers (PBDEs) are ubiquitous and toxic contaminants found in high concentrations in watercourses, and are not well removed by conventional wastewater treatment facilities. This study aimed to evaluate the removal and transformation of BDE-47, one of the environmentally predominant PBDE congener, by a green alga (Chlorella vulgaris) and a cyanobacterium (Microcystis flos-aquae) under different light conditions. Living and autoclaved cultures were exposed to BDE-47 at a concentration of 10 µg L-1 for 7 days. Both species removed >90% of BDE-47 very shortly after spiking. Light intensity affected the transformation of BDE-47 in living cultures of both species, since 5 to 11 times more debromination products were measured at a light intensity of 100 µmol photons m-2 s-1 than at 20 µmol photons m-2 s-1. Living cultures of M. flos-aquae transformed BDE-47 at a rate of 0.22 day-1 while no transformation was observed in the respective autoclaved cultures. On the contrary, both living and autoclaved cultures of C. vulgaris had similar BDE-47 transformation rates of 0.05-0.06 day-1. Debromination of BDE-47 was a predominant transformation pathway in cultures of C. vulgaris, with two times higher BDE-28 concentrations measured than in M. flos-aquae, while hydroxylation was more dominant with the cyanobacterium. Most BDE-47 and its debromination product BDE-28 were found on the cell surface of both species. These results reveal that different transformation mechanisms were involved in C. vulgaris and M. flos-aquae cultures and confirm the importance of species selection for the removal of PBDEs from contaminated environments.

Green tea extract attenuates LPS-induced retinal inflammation in rats.

Inflammation is in a wide spectrum of retinal diseases, causing irreversible blindness and visual impairment. We have previously demonstrated that Green Tea Extract (GTE) is a potent anti-inflammatory agent for anterior uveitis. Here we investigated the anti-inflammatory effect of GTE on lipopolysaccharides (LPS)-induced retinal inflammation in rats and explored the underlying mechanism. Adult rats were injected with LPS and GTE was administered intra-gastrically at 2, 8, 26 and 32 hours post-injection. Staining of whole-mount retina showed that the number of activated microglia cells was significantly increased at 48 hours post-injection, which was suppressed after GTE treatment in a dose-dependent manner. Activation of astrocytes and Müller glia in the retina was also suppressed after GTE treatment. Meanwhile, GTE reduced the expression of pro-inflammatory cytokines including IL-1ß, TNF-α and IL-6 in retina and vitreous humor. These anti-inflammatory effects were associated with a reduced phosphorylation of STAT3 and NF-κB in the retina. Furthermore, the surface receptor of EGCG, 67LR, was localized on the neurons and glia in the retina. These findings demonstrate that GTE is an effective agent in suppressing LPS-induced retinal inflammation, probably through its potent anti-oxidative property and a receptor-mediated action on transcription factors that regulate production of pro-inflammatory cytokines.

Preincubation with atrial natriuretic peptide protects NG108-15 cells against the toxic/proapoptotic effects of the nitric oxide donor S-nitroso- N-acetylpenicillamine.

The TUNEL method is used to quantify the proapoptotic effects of an NO donor, S-nitroso- N-acetylpenicillamine (SNAP), in NG108-15 cells. Unlike sodium nitroprusside used in previous studies, SNAP does not release cyanide along with NO, thus NO toxicity was determined without concurrent cyanide toxicity. The present study also determined if pretreatment with ANP could protect against NO-induced apoptosis in NG108-15 cells. Cell death at 24 h following SNAP treatment was associated with apoptotic DNA fragmentation. SNAP at 0.5, 0.75, 1.0, and 2.0 mM caused significant (P<0.05) increases in the percentage of TUNEL-labeled cells from a control of 0.90% to 6.19%, 6.36%, 7.25%, and 15.1%, respectively. Thus, SNAP caused concentration-dependent induction of apoptosis in NG108-15 cells. SNAP-induced apoptosis was confirmed by morphological changes and increased levels of polynucleosome-sized fragments of DNA assessed by capillary electrophoresis. Preincubation for 24 h with ANP at 0.01, 0.1, and 1.0 microM, before the SNAP, significantly (P<0.05) decreased the percentage of labeled cells from 7.25% to 5.10%, 4.36%, and 3.24% in the presence of SNAP (1 mM) and from 15.1% to 7.91%, 6.64%, and 5.60% in the presence of SNAP (2 mM), respectively, representing protection of 24.0%, 34.0%, and 57.0% against SNAP (1 mM) and 26.0%, 37.0%, and 50.9% against SNAP (2 mM). Thus, prior activation of a cGMP-mediated neuroprotective mechanism induced by ANP appears to counterbalance, at least partially, the proapoptotic effects of excess NO. This neuroprotective mechanism involving cGMP may be especially important in protecting against the development of neurodegenerative diseases in which excess NO is thought to contribute to neuronal apoptosis.