Modifications of small RNAs and their associated proteins.

Small regulatory RNAs and their associated proteins are subject to diverse modifications that can impinge on their abundance and function. Some of the modifications are under the influence of cellular signaling, thus contributing to the dynamic regulation of RNA silencing.

TUT4 in concert with Lin28 suppresses microRNA biogenesis through pre-microRNA uridylation.

As key regulators in cellular functions, microRNAs (miRNAs) themselves need to be tightly controlled. Lin28, a pluripotency factor, was reported to downregulate let-7 miRNA by inducing uridylation of let-7 precursor (pre-let-7). But the enzyme responsible for the uridylation remained unknown. Here we identify a noncanonical poly (A) polymerase, TUTase4 (TUT4), as the uridylyl transferase for pre-let-7. Lin28 recruits TUT4 to pre-let-7 by recognizing a tetra-nucleotide sequence motif (GGAG) in the terminal loop. TUT4 in turn adds an oligouridine tail to the pre-let-7, which blocks Dicer processing. Other miRNAs with the same sequence motif (miR-107, -143, and -200c) are regulated through the same mechanism. Knockdown of TUT4 and Lin28 reduces the level of stem cell markers, suggesting that they are required for stem cell maintenance. This study uncovers the role of TUT4 and Lin28 as specific suppressors of miRNA biogenesis, which has implications for stem cell research and cancer biology.

Posttranscriptional crossregulation between Drosha and DGCR8.

The Drosha-DGCR8 complex, also known as Microprocessor, is essential for microRNA (miRNA) maturation. Drosha functions as the catalytic subunit, while DGCR8 (also known as Pasha) recognizes the RNA substrate. Although the action mechanism of this complex has been intensively studied, it remains unclear how Drosha and DGCR8 are regulated and if these proteins have any additional role(s) apart from miRNA processing. Here, we report that Drosha and DGCR8 regulate each other posttranscriptionally. The Drosha-DGCR8 complex cleaves the hairpin structures embedded in the DGCR8 mRNA and thereby destabilizes the mRNA. We further find that DGCR8 stabilizes the Drosha protein via protein-protein interaction. This crossregulation between Drosha and DGCR8 may contribute to the homeostatic control of miRNA biogenesis. Furthermore, microarray analyses suggest that a number of mRNAs may be downregulated in a Microprocessor-dependent, miRNA-independent manner. Our study reveals a previously unsuspected function of Microprocessor in mRNA stability control.

Identification of IGF-1 Effects on White Adipose Tissue and Hippocampus in Alzheimer's Disease Mice via Transcriptomic and Cellular Analysis.

Alzheimer's disease (AD) stands as the most prevalent neurodegenerative disorder, characterized by a multitude of pathological manifestations, prominently marked by the aggregation of amyloid beta. Recent investigations have revealed a compelling association between excessive adiposity and glial activation, further correlating with cognitive impairments. Additionally, alterations in levels of insulin-like growth factor 1 (IGF-1) have been reported in individuals with metabolic conditions accompanied by memory dysfunction. Hence, our research endeavors to comprehensively explore the impact of IGF-1 on the hippocampus and adipose tissue in the context of Alzheimer's disease. To address this, we have conducted an in-depth analysis utilizing APP/PS2 transgenic mice, recognized as a well-established mouse model for Alzheimer's disease. Upon administering IGF-1 injections to the APP/PS2 mice, we observed notable alterations in their behavioral patterns, prompting us to undertake a comprehensive transcriptomic analysis of both the hippocampal and adipose tissues. Our data unveiled significant modifications in the functional profiles of these tissues. Specifically, in the hippocampus, we identified changes associated with synaptic activity and neuroinflammation. Concurrently, the adipose tissue displayed shifts in processes related to fat browning and cell death signaling. In addition to these findings, our analysis enabled the identification of a collection of long non-coding RNAs and circular RNAs that exhibited significant changes in expression subsequent to the administration of IGF-1 injections. Furthermore, we endeavored to predict the potential roles of these identified RNA molecules within the context of our study. In summary, our study offers valuable transcriptome data for hippocampal and adipose tissues within an Alzheimer's disease model and posits a significant role for IGF-1 within both the hippocampus and adipose tissue.

Circular RNA Tmcc1 improves astrocytic glutamate metabolism and spatial memory via NF-κB and CREB signaling in a bile duct ligation mouse model: transcriptional and cellular analyses.

BACKGROUND: Hepatic encephalopathy-induced hyperammonemia alters astrocytic glutamate metabolism in the brain, which is involved in cognitive decline. To identify specific therapeutic strategies for the treatment of hepatic encephalopathy, various molecular signaling studies, such as non-coding RNA functional study, have been conducted. However, despite several reports of circular RNAs (circRNAs) in the brain, few studies of circRNAs in hepatic encephalopathy-induced neuropathophysiological diseases have been conducted. METHODS: In this study, we performed RNA sequencing to identify whether the candidate circRNA cirTmcc1 is specifically expressed in the brain cortex in a bile duct ligation (BDL) mouse model of hepatic encephalopathy. RESULTS: Based on transcriptional and cellular analysis, we investigated the circTmcc1-dysregulation-induced changes in the expression of several genes that are associated with intracellular metabolism and astrocyte function. We found that the circTmcc1 binds with the NF-κB p65-CREB transcriptional complex and regulates the expression of the astrocyte transporter EAAT2. Furthermore, circTmcc1 contributed to the secretion of proinflammatory mediators and glutamate metabolism in astrocytes and subsequently modulated an improvement in spatial memory by mediating neuronal synaptic plasticity. CONCLUSIONS: Thus, circTmcc1 may be a promising circRNA candidate for targeted interventions to prevent and treat the neuropathophysiological complications that occur due to hepatic encephalopathy.

Human cytomegalovirus microRNA miR-US4-1 inhibits CD8(+) T cell responses by targeting the aminopeptidase ERAP1.

Major histocompatibility complex (MHC) class I molecules present peptides on the cell surface to CD8(+) T cells, which is critical for the killing of virus-infected or transformed cells. Precursors of MHC class I-presented peptides are trimmed to mature epitopes by the aminopeptidase ERAP1. The US2-US11 genomic region of human cytomegalovirus (HCMV) is dispensable for viral replication and encodes three microRNAs (miRNAs). We show here that HCMV miR-US4-1 specifically downregulated ERAP1 expression during viral infection. Accordingly, the trimming of HCMV-derived peptides was inhibited, which led to less susceptibility of infected cells to HCMV-specific cytotoxic T lymphocytes (CTLs). Our findings identify a previously unknown viral miRNA-based CTL-evasion mechanism that targets a key step in the MHC class I antigen-processing pathway.

Association between Sight-Threatening Eye Diseases and Death by Suicide in South Korea: A Nationwide Population-based Cohort Study.

PURPOSE: Although associations between visual impairment (VI) and suicide are posited, specific risks across the sight-threatening eye disease (STED) spectrum remain to be assessed. We determined whether individuals with STED die more often by suicide than do other people and assessed the temporal associations. DESIGN: A nationwide, population-based cohort study. PARTICIPANTS: All persons aged 40 years or older in South Korea from 2010 to 2020. METHODS: Persons diagnosed with STEDs (i.e., glaucoma, exudative age-related macular degeneration [AMD], or diabetic retinopathy [DR]) were identified in the Korean National Health Insurance (NHI) service database. Both NHI health checkup records and the National Disability Registration were used for coexisting severe VI. Death by suicide was defined as diagnostic codes as recorded in the Korea National Statistical Office. Incidence rate ratios (IRRs) were estimated by quasi-Poisson regressions and adjusted for sociodemographics, comorbidity, psychiatric diagnoses, and VI. The temporal relationship between time since first STED diagnosis and suicide risk was determined by identifying patients with STED newly diagnosed during the period from 2010 to 2011. MAIN OUTCOME MEASURES: The IRR of death by suicide in people with STED relative to those without. RESULTS: Of the 2.8 million people (45% male) observed for 24 300 969 person-years, 13 205 died by suicide. Among them, 34% (n = 4514) had a STED diagnosis, for a suicide rate of 69 per 100 000 person-years (95% confidence interval [CI], 67-72), relative to 51 per 100 000 person-years (95% CI, 50-52) for non-STED individuals. People with STED had an adjusted IRR of 1.33 (95% CI, 1.26-1.41) relative to those without. The largest excess adjusted IRR of suicide mortality was that for DR (1.40, 95% CI, 1.29-1.52). For exudative AMD, the adjusted IRR was 1.20 (95% CI, 1.04-1.39), whereas for glaucoma, the corresponding value was 1.09 (95% CI, 1.02-1.17). With coexisting severe VI, the IRR for any STED was 1.49 (95% CI, 1.29-1.73). The highest suicide hazard ratio was between 3 and 6 months postdiagnosis (5.33; 95% CI, 4.59-6.20). CONCLUSIONS: In South Korea between 2010 and 2020, a higher suicide rate was evident among those with diagnosed STED than for persons not so diagnosed. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Placebo Effect and Its Determinants in Ocular Hypotensive Therapy: Meta-analysis and Multiple Meta-regression Analysis.

TOPIC: The placebo effect and its potential determinants in ocular hypotensive therapy. CLINICAL RELEVANCE: The placebo effect has been studied and documented within a wide clinical context. It remains unclear whether placebo is effective in glaucoma treatment or, if so, which factors are determinative of effect size (ES). METHODS: Randomized controlled trials (RCTs) of topical ocular hypotensive therapy for patients with open-angle glaucoma or ocular hypertension, conducted through June 2, 2022, were included. First, a perceived placebo effect was measured as the overall intraocular pressure (IOP) change from the baseline. It was evaluated in terms of the ES (mean difference between the baseline and the end point) and then was compared with the ES, as obtained from the untreated control participant to obtain a true placebo effect. The primary outcome was ES based on 4 weeks of treatment. Meta-analysis-based statistical pooling was performed where appropriate, and 95% confidence intervals (CIs) were used for comparison. Potential placebo effect determinants were scrutinized using a multiple meta-regression model (PROSPERO identifier, CRD42022348098). RESULTS: A total of 40 RCTs (7829 eyes) with 33 placebo groups (2055 eyes) along with 7 untreated groups (1184 eyes) were included. Among placebo-controlled trials, placebo was determined to be effective in lowering IOP (ES, -1.30 mmHg; 95% CI, -1.75 to -0.84 mmHg). Using NMA, the ES for placebo was -2.27 mmHg (95% CI, -3.52 to -1.01 mmHg) greater than ES for untreated control participants.. According to the multiple meta-regression model, the active treatment ES was a significant factor to predict the amount of placebo effect. Placebo additionally lowered IOP by -0.45 mmHg per -1 mmHg of active treatment effect. Add-on study design and larger sample size also were associated with greater amount of placebo effect. No publication bias was evident in either a funnel plot or the Begg and Mazumdar adjusted rank correlation test results (P = 0.24). DISCUSSION: This meta-analysis indicated that placebo is effective in lowering IOP and is superior to the effect observed for the untreated control participants. However, caution is required in interpreting the results because of the small number of untreated controlled trials and potential bias from the lack of direct comparison between the placebo and untreated arms. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Unveiling the Therapeutic Potential and Healthcare Applications of Marine Therapy: A Systematic Review with Meta-Analysis and Meta-Regression.

This study was conducted to estimate the effectiveness of marine-derived resources for treating specific diseases, as well as identify the most effective methods for applying such resources in therapeutic applications. Bibliographic databases (PubMed, Embase, and Cochrane) were searched from their inception until May 2023 using Medical Subject Headings terms and text keywords related to seawater, mineral water, or ocean therapy. Fifteen eligible studies were included, involving 1325 participants aged 42.7-63.0 years. In the subgroup analysis based on treatment type, the mean difference was -1.581 (95% CI: -1.889, -1.274) for seawater with sun exposure and -1.210 (95% CI: -1.417, -1.002) for seawater with sun exposure, mud pack application, and sulfur pool therapy. The pooled standardized mean difference was calculated for different outcomes; the results were -1.110 (95% CI: -3.028, 0.806) for osteoarthritis severity, -0.795 (95% CI: -0.982, -0.607) for arthritis pain, -1.623 (95% CI: -2.036, -1.209) for fibromyalgia pain, and -1.498 (95% CI: -1.888, -1.108) for quality of life. Marine therapy is, therefore, promising for treating chronic skin issues, easing musculoskeletal discomfort, and enhancing the quality of life among patients with musculoskeletal pain.

Trends in the Prevalence of Blindness and Correlation With Health Status in Korean Adults: A 10-Year Nationwide Population-Based Study.

BACKGROUND: Contemporary data on vision impairment form an important basis for public health policies. However, most data on the clinical epidemiology of blindness are limited by small sample sizes and focused not on systemic conditions but ophthalmic diseases only. In this study, we examined the ten-year trends of blindness prevalence and its correlation with systemic health status in Korean adults. METHODS: This study investigated 10,000,000 participants randomly extracted from the entire Korean population (aged ≥ 20 years) who underwent a National Health Insurance Service health checkup between 2009 and 2018. Participants with blindness, defined as visual acuity in the better-seeing eye of ≤ 20/200, were identified. The prevalence of blindness was assessed, and the systemic health status was compared between participants with blindness and without blindness. RESULTS: The mean prevalence of blindness was 0.473% (47,115 blindness cases) and tended to decrease over ten years (0.586% in 2009 and 0.348% in 2018; P < 0.001). The following factors were significantly associated with blindness: female sex, underweight (body mass index < 18.5), high serum creatinine (> 1.5 mg/dL), and bilateral hearing loss. In addition, except for those aged 30-39 and 40-49 years, high fasting glucose (≥ 126 mg/dL) and low hemoglobin (male: < 12 g/dL, female: < 10 g/dL) were significantly correlated with prevalent blindness. CONCLUSION: Our ten-year Korean nationwide population-based study suggested a gradual decrease in the prevalence of blindness and its association with specific systemic health status. These conditions might be the cause or consequence of blindness and can be used as a reference for the prevention and/or rehabilitation of blindness to establish public health policies.

Human lncRNA SUGCT-AS1 Regulates the Proinflammatory Response of Macrophage.

Macrophages are the major primary immune cells that mediate the inflammatory response. In this process, long non-coding RNAs (lncRNAs) play an important, yet largely unknown role. Therefore, utilizing several publicly available RNA sequencing datasets, we predicted and selected lncRNAs that are differentially expressed in M1 or M2 macrophages and involved in the inflammatory response. We identified SUGCT-AS1, which is a human macrophage-specific lncRNA whose expression is increased upon M1 macrophage stimulation. Conditioned media of SUGCT-AS1-depleted M1 macrophages induced an inflammatory phenotype of vascular smooth muscle cells, which included increased expression of inflammatory genes (IL1B and IL6), decreased contractile marker proteins (ACTA2 and SM22α), and increased cell migration. Depletion of SUGCT-AS1 promoted the expression and secretion of proinflammatory cytokines, such as TNF, IL1B, and IL6, in M1 macrophages, and transcriptomic analysis showed that SUGCT-AS1 has functions related to inflammatory responses and cytokines. Furthermore, we found that SUGCT-AS1 directly binds to hnRNPU and regulates its nuclear-cytoplasmic translocation. This translocation of hnRNPU altered the proportion of the MALT1 isoforms by regulating the alternative splicing of MALT1, a mediator of NF-κB signaling. Overall, our findings suggest that lncRNAs can be used for future studies on macrophage regulation. Moreover, they establish the SUGCT-AS1/hnRNPU/MALT1 axis, which is a novel inflammatory regulatory mechanism in macrophages.

Roles of non-coding RNAs in intercellular crosstalk in cardiovascular diseases.

Complex diseases including cardiovascular disease are caused by a combination of the alternation of many genes and the influence of environments. Recently, non-coding RNAs (ncRNAs) have been shown to be involved in diverse diseases, and the functions of various ncRNAs have been reported. Many researchers have elucidated the mechanisms of action of these ncRNAs at the cellular level prior to in vivo and clinical studies of the diseases. Due to the characteristics of complex diseases involving intercellular crosstalk, it is important to study communication between multiple cells. However, there is a lack of literature summarizing and discussing studies of ncRNAs involved in intercellular crosstalk in cardiovascular diseases. Therefore, this review summarizes recent discoveries in the functional mechanisms of intercellular crosstalk involving ncRNAs, including microRNAs, long non-coding RNAs, and circular RNAs. In addition, the pathophysiological role of ncRNAs in this communication is extensively discussed in various cardiovascular diseases.

Efficacy and Safety of 8 Atropine Concentrations for Myopia Control in Children: A Network Meta-Analysis.

TOPIC: Comparative efficacy and safety of different concentrations of atropine for myopia control. CLINICAL RELEVANCE: Atropine is known to be an effective intervention to delay myopia progression. Nonetheless, no well-supported evidence exists yet to rank the clinical outcomes of various concentrations of atropine. METHODS: We searched PubMed, EMBASE, Cochrane Central Register of Controlled Trials, the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov on April 14, 2021. We selected studies involving atropine treatment of at least 1 year's duration for myopia control in children. We performed a network meta-analysis (NMA) of randomized controlled trials (RCTs) and compared 8 atropine concentrations (1% to 0.01%). We ranked the atropine concentrations for the corresponding outcomes by P score (estimate of probability of being best treatment). Our primary outcomes were mean annual changes in refraction (diopters/year) and axial length (AXL; millimeters/year). We extracted data on the proportion of eyes showing myopia progression and safety outcomes (photopic and mesopic pupil diameter, accommodation amplitude, and distance and near best-corrected visual acuity [BCVA]). RESULTS: Thirty pairwise comparisons from 16 RCTs (3272 participants) were obtained. Our NMA ranked the 1%, 0.5%, and 0.05% atropine concentrations as the 3 most beneficial for myopia control, as assessed for both primary outcomes: 1% atropine (mean differences compared with control: refraction, 0.81 [95% confidence interval (CI), 0.58-1.04]; AXL, -0.35 [-0.46 to -0.25]); 0.5% atropine (mean differences compared with control: refraction, 0.70 [95% CI, 0.40-1.00]; AXL, -0.23 [-0.38 to -0.07]); 0.05% atropine (mean differences compared with control: refraction, 0.62 [95% CI, 0.17-1.07]; AXL, -0.25 [-0.44 to -0.06]). In terms of myopia control as assessed by relative risk (RR) for overall myopia progression, 0.05% was ranked as the most beneficial concentration (RR, 0.39 [95% CI, 0.27-0.57]). The risk for adverse effects tended to rise as the atropine concentration was increased, although this tendency was not evident for distance BCVA. No valid network was formed for near BCVA. DISCUSSION: The ranking probability for efficacy was not proportional to dose (i.e., 0.05% atropine was comparable with that of high-dose atropine [1% and 0.5%]), although those for pupil size and accommodation amplitude were dose related.

Interventions for Glaucoma Medication Adherence Improvement: A Network Meta-analysis of Randomized Controlled Trials.

TOPIC: Comparative effectiveness of interventions to improve glaucoma medication adherence. CLINICAL RELEVANCE: High adherence to ocular hypotensive therapy is essential for prevention of visual impairment in glaucoma patients. Various types of intervention for adherence enhancement have been proposed, although there is still no firm evidence of their relative efficacies. METHODS: We searched PubMed, EMBASE, Scopus, the Cochrane Central Register of Controlled Trials, the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov on November 30, 2021. Randomized controlled trials (RCTs) entailing interventions for improved adherence to ocular hypotensive therapy were identified. A network meta-analysis (NMA) was performed, and the following 11 interventions (single category or combinations of categories) were compared: (1) standard of care ([SOC] control), (2) short message service, (3) telephone call, (4) device reminder, (5) motivational interview, (6) multimedia education, (7) physician education, (8) provision of own medical records, (9) incentives, (10) tailored care, and (11) enhanced SOC. The primary outcome was the postintervention mean adherence score. The standardized mean differences (SMDs) were analyzed, and the effectiveness was ranked by P-score (probability of being best treatment). We appraised trials using the Cochrane risk-of-bias tool for RCTs. Confidence of results was assessed by Confidence in Network Meta-analysis. RESULTS: We obtained data for 19 RCTs (4981 participants). Tailored care, as inclusive of face-to-face needs assessment and a personalized care plan, was superior to SOC in improving adherence (SMD, 1.28; 95% confidence interval [CI], 0.08-2.48; P-score, 0.810). Multifaceted interventions that included tailored care showed further adherence improvement: tailored care + multimedia education (SMD, 1.44; 95% CI, 0.20-2.67; 0.850) and tailored care + multimedia education + device reminder (SMD, 1.61; 95% CI, 0.75-2.47; 0.914). The ranking of the remaining interventions by P-scores was as follows: incentives (0.606), short message service (0.535), enhanced SOC (0.458), multimedia education (0.430), device reminder (0.429), telephone call (0.401), provision of own medical records (0.391), physician education (0.281), SOC (0.230), and motivational interview (0.165). CONCLUSIONS: The NMA indicated that tailored care can improve adherence to glaucoma medication compared with SOC. A multifaceted approach might yield additional improvements.

Obesity-linked circular RNA circTshz2-2 regulates the neuronal cell cycle and spatial memory in the brain.

Metabolic syndromes, including obesity, cause neuropathophysiological changes in the brain, resulting in cognitive deficits. Only a few studies explored the contribution of non-coding genes in these pathophysiologies. Recently, we identified obesity-linked circular RNAs (circRNA) by analyzing the brain cortices of high-fat-fed obese mice. In this study, we scrutinized a conserved and neuron-specific circRNA, circTshz2-2, which affects neuronal cell cycle and spatial memory in the brain. Transcriptomic and cellular analysis indicated that circTshz2-2 dysregulation altered the expression of cell division-related genes and induced cell cycle arrest at the G2/M phase of the neuron. We found that circTshz2-2 bound to the YY1 transcriptional complex and suppressed Bdnf transcription. Suppression of circTshz2-2 increased BDNF expression and reduced G2/M checkpoint proteins such as Cyclin B2 and CDK1 through BDNF/TrkB signaling pathway, resulting in cell cycle arrest and neurite elongation. Inversely, overexpression of circTshz2-2 decreased BDNF expression, induced cell cycle proteins, and shortened the neurite length, indicating that circTshz2-2 regulates neuronal cell cycle and structure. Finally, we showed that circTshz2-2 affects spatial memory in wild-type and obese mice. Our data have revealed potential regulatory roles of obesity-related circTshz2-2 on the neuronal cell cycle and memory function providing a novel link between metabolic syndromes and cognitive deficits.

Macular sector-wise decision tree model for the prediction of parafoveal scotoma not detected by 24-2 visual field test.

BACKGROUND: Development of a macular sector-wise decision tree model (DTM) for the prediction of parafoveal scotoma. METHODS: This prospective study enrolled 126 patients with early-stage open-angle glaucoma (mean deviation ≥-6 decibels) without the signs of parafoveal scotoma on the 24-2 visual field (VF) test (i.e., any abnormalities at the four innermost points). Based on the central 36 points of the 10-2 pattern deviation plot, patients were classified as being with or without 10-2 parafoveal scotoma. For the discrimination of patients from those without 10-2 parafoveal scotoma, a macular ganglion cell-inner plexiform layer (mGCIPL) sector-wise DTM analysis was performed. RESULTS: Among 126 eyes without 24-2 parafoveal scotoma, 10-2 parafoveal scotoma was detected in 77 (61.1%) eyes. The balanced accuracy of DTM was best in the inferotemporal sector (0.9286; 95% CI, 0.7458-0.9697) and worst in the inferior sector (0.8373; 0.6484-0.9204). DTM revealed that even in the absence of VF abnormalities at the innermost 4 points on the 24-2 test, (1) 10-2 parafoveal scotoma should be strongly suspected when the adjacent 24-2 perifoveal point in the correlated sector is abnormal; (2) if the 24-2 perifoveal point is normal, and if the probability colour codes of the correlated mGCIPL sector are green, the probability of 10-2 parafoveal scotoma is very low. CONCLUSIONS: In clinical practice, the evaluation of the 24-2 perifoveal test points along with the probability colour codes of mGCIPL can be a useful decision-support tool in determining whether 10-2 tests are needed for a given patient.

Transcriptome Profile in the Mouse Brain of Hepatic Encephalopathy and Alzheimer's Disease.

Hepatic encephalopathy (HE) is a chronic metabolic disease accompanied by neuropathological and neuropsychiatric features, including memory deficits, psychomotor dysfunction, depression, and anxiety. Alzheimer's disease (AD), the most common neurodegenerative disease, is characterized by tau hyperphosphorylation, excessive amyloid beta (Aß) accumulation, the formation of fibrillary tangles, hippocampus atrophy, and neuroinflammation. Recent studies have suggested a positive correlation between HE and AD. Some studies reported that an impaired cholesterol pathway, abnormal bile acid secretion, excessive ammonia level, impaired Aß clearance, astrocytic dysfunction, and abnormal γ-aminobutyric acid GABAergic neuronal signaling in HE may also be involved in AD pathology. However, the mechanisms and related genes involved in AD-like pathology in the HE brain are unclear. Thus, we compared the cortical transcriptome profile between an HE mouse model, bile duct ligation (BDL), and an AD mouse model, the 5×FAD. Our study showed that the expression of many genes implicated in HE is associated with neuronal dysfunction in AD mice. We found changes in various protein-coding RNAs, implicated in synapses, neurogenesis, neuron projection, neuron differentiation, and neurite outgrowth, and non-coding RNAs possibly associated with neuropathology. Our data provide an important resource for further studies to elucidate AD-like pathophysiology in HE patients.

Transcriptome Profile of Thyroid Glands in Bile Duct Ligation Mouse Model.

Thyroid hormone (TH) contributes to multiple cellular mechanisms in the liver, muscle cells, adipose tissue, and brain, etc. In particular, the liver is an important organ in TH metabolism for the conversion of thyronine (T4) into triiodothyronine (T3) by the deiodinase enzyme. TH levels were significantly decreased and thyroid-stimulating hormone (TSH) levels were significantly increased in patients with liver failure compared with normal subjects. Among liver failure diseases, hepatic encephalopathy (HE) deserves more attention because liver damage and neuropathologies occur simultaneously. Although there is numerous evidence of TH dysregulation in the HE model, specific mechanisms and genetic features of the thyroid glands in the HE model are not fully understood. Here, we investigated the significantly different genes in the thyroid glands of a bile duct ligation (BDL) mouse model as the HE model, compared to the thyroid glands of the control mouse using RNA sequencing. We also confirmed the alteration in mRNA levels of thyroid gland function-related genes in the BDL mouse model. Furthermore, we evaluated the increased level of free T4 and TSH in the BDL mouse blood. Thus, we emphasize the potential roles of TH in liver metabolism and suggest that thyroid dysfunction-related genes in the HE model should be highlighted for finding the appropriate solution for an impaired thyroid system in HE.

Novel Small Molecule Inhibitors Targeting the IL-6/STAT3 Pathway or IL-1ß.

Development of small molecules that inhibit inflammatory cytokines is a desirable strategy for the treatment of inflammatory diseases such as rheumatoid arthritis (RA). Following up a previous study, we synthesized 10 novel compounds with a 2,5-diaminobenzoxazole moiety and evaluated their biological activities. Among them, compound 3e showed potent inhibitory activity on Interleukin 6 (IL-6)/Signal Transducer and Activator of Transcription 3 (STAT3) signaling inhibition (71.5%), and 3a showed excellent inhibitory activity on Interleukin 1 (IL-1ß) (92.1%). To test in vivo anti-inflammatory activity, compounds 3a and 3e were administered by intraperitoneal (IP) injection after subcutaneous (SC) injection of zymosan A into the right footpad of mice. Inflammation on the footpad was reduced after administration of compounds 3a and 3e. Especially, compound 3a showed a significant ameliorative effect on zymosan-induced inflammation. From the in vivo and in vitro test results, we confirmed that our synthesized compounds are effective on the RA animal model through inhibition of the IL-6/STAT3 signaling pathway. Since drugs developed with small molecule inhibitors have several advantages over biological drugs, further study on these compounds is needed for the development of potent SMI drugs on RA.

Visual outcomes and associated factors of primary congenital glaucoma in children.

PURPOSE: We evaluated the long-term visual outcomes in children with primary congenital glaucoma and determined the factors associated with the final visual outcomes. METHODS: Medical records of children with primary congenital glaucoma between 2005 and 2016, seen at Seoul National University Children's Hospital in South Korea, were reviewed. The minimum follow-up period after surgery for primary congenital glaucoma was 3 years. Visual acuity (VA) was categorized into good (≧20/70) and poor (< 20/70). Factors including age, VA, refractive errors, intraocular pressure (IOP), laterality, and cup-to-disc (C/D) ratio were compared between the groups. RESULTS: A total of 71 eyes of 44 patients were included. The patients' age at the time of surgery was 14.7 ± 12.2 months. The mean IOP was 28.3 ± 7.0 mmHg. During 6.7 ± 2.7 years of mean follow-up after surgery, 39 eyes (54.9%) needed occlusion treatment. After occlusion, patients with lower IOP values, lesser additional surgeries, reversal of optic disc cupping, and better initially measured VA achieved a better visual outcome. At the final assessment, the mean age was 7.8 ± 2.6 years, and the mean VA gain was 15.0 ± 19.4 letters. There were 44 eyes (62.0%) with VA ≧20/70. CONCLUSIONS: In children with primary congenital glaucoma, IOP control and the optic disc configuration over time are important factors associated with visual outcome. Regular follow-up and correction of refractive errors-along with occlusion for those with difference in VA between the two eyes-might be helpful for achieving better visual outcomes.