Glyburide confers neuroprotection against age-related macular degeneration (AMD).

Glyburide, a sulfonylurea drug used to treat type 2 diabetes, boasts neuroprotective effects by targeting the sulfonylurea receptor 1 (SUR1) and associated ion channels in various cell types, including those in the central nervous system and the retina. Previously, we demonstrated that glyburide therapy improved retinal function and structure in a rat model of diabetic retinopathy. In the present study, we explore the application of glyburide in non-neovascular ("dry") age-related macular degeneration (AMD), another progressive disease characterized by oxidative stress-induced damage and neuroinflammation that trigger cell death in the retina. We show that glyburide administration to a human cone cell line confers protection against oxidative stress, inflammasome activation, and apoptosis. To corroborate our in vitro results, we also conducted a case-control study, controlling for AMD risk factors and other diabetes medications. It showed that glyburide use in patients reduces the odds of new-onset dry AMD. A positive dose-response relationship is observed from this analysis, in which higher cumulative doses of glyburide further reduce the odds of new-onset dry AMD. In the quest for novel therapies for AMD, glyburide emerges as a promising repurposable drug given its known safety profile. The results from this study provide insights into the multifaceted actions of glyburide and its potential as a neuroprotective agent for retinal diseases; however, further preclinical and clinical studies are needed to validate its therapeutic potential in the context of degenerative retinal disorders such as AMD.

Identifying novel candidate compounds for therapeutic strategies in retinopathy of prematurity via computational drug-gene association analysis.

Purpose: Retinopathy of prematurity (ROP) is the leading cause of preventable childhood blindness worldwide. Although interventions such as anti-VEGF and laser have high success rates in treating severe ROP, current treatment and preventative strategies still have their limitations. Thus, we aim to identify drugs and chemicals for ROP with comprehensive safety profiles and tolerability using a computational bioinformatics approach. Methods: We generated a list of genes associated with ROP to date by querying PubMed Gene which draws from animal models, human studies, and genomic studies in the NCBI database. Gene enrichment analysis was performed on the ROP gene list with the ToppGene program which draws from multiple drug-gene interaction databases to predict compounds with significant associations to the ROP gene list. Compounds with significant toxicities or without known clinical indications were filtered out from the final drug list. Results: The NCBI query identified 47 ROP genes with pharmacologic annotations present in ToppGene. Enrichment analysis revealed multiple drugs and chemical compounds related to the ROP gene list. The top ten most significant compounds associated with ROP include ascorbic acid, simvastatin, acetylcysteine, niacin, castor oil, penicillamine, curcumin, losartan, capsaicin, and metformin. Antioxidants, NSAIDs, antihypertensives, and anti-diabetics are the most common top drug classes derived from this analysis, and many of these compounds have potential to be readily repurposed for ROP as new prevention and treatment strategies. Conclusion: This bioinformatics analysis creates an unbiased approach for drug discovery by identifying compounds associated to the known genes and pathways of ROP. While predictions from bioinformatic studies require preclinical/clinical studies to validate their results, this technique could certainly guide future investigations for pathologies like ROP.

Using Advanced Bioinformatics Tools to Identify Novel Therapeutic Candidates for Proliferative Vitreoretinopathy.

Purpose: Proliferative vitreoretinopathy (PVR) is the dreaded cause of failure following retinal detachment repair; however, no cures or preventative therapies exist to date. The purpose of this study was to use bioinformatics tools to identify drugs or compounds that interact with biomarkers and pathways involved in PVR pathogenesis that could be eligible for further testing for the prevention and treatment of PVR. Methods: We queried PubMed to compile a comprehensive list of genes described in PVR to date from human studies, animal models, and genomic studies found in the National Center for Biotechnology Information database. Gene enrichment analysis was performed using ToppGene on PVR-related genes against drug-gene interaction databases to construct a pharmacome and estimate the statistical significance of overrepresented compounds. Compounds with no clinical indications were filtered out from the resulting drug lists. Results: Our query identified 34 unique genes associated with PVR. Out of 77,146 candidate drugs or compounds in the drug databases, our analysis revealed multiple drugs and compounds that have significant interactions with genes involved in PVR, including antiproliferatives, corticosteroids, cardiovascular agents, antioxidants, statins, and micronutrients. Top compounds, including curcumin, statins, and cardiovascular agents such as carvedilol and enalapril, have well-established safety profiles and potentially could be readily repurposed for PVR. Other significant compounds such as prednisone and methotrexate have shown promising results in ongoing clinical trials for PVR. Conclusions: This bioinformatics approach of studying drug-gene interactions can identify drugs that may affect genes and pathways implicated in PVR. Predicted bioinformatics studies require further validation by preclinical or clinical studies; however, this unbiased approach could identify potential candidates among existing drugs and compounds that could be repurposed for PVR and guide future investigations. Translational Relevance: Novel repurposable drug therapies for PVR can be found using advanced bioinformatics models.

Using Computational Drug-Gene Analysis to Identify Novel Therapeutic Candidates for Retinal Neuroprotection.

Retinal cell death is responsible for irreversible vision loss in many retinal disorders. No commercially approved treatments are currently available to attenuate retinal cell loss and preserve vision. We seek to identify chemicals/drugs with thoroughly-studied biological functions that possess neuroprotective effects in the retina using a computational bioinformatics approach. We queried the National Center for Biotechnology Information (NCBI) to identify genes associated with retinal neuroprotection. Enrichment analysis was performed using ToppGene to identify compounds related to the identified genes. This analysis constructs a Pharmacome from multiple drug-gene interaction databases to predict compounds with statistically significant associations to genes involved in retinal neuroprotection. Compounds with known deleterious effects (e.g., asbestos, ethanol) or with no clinical indications (e.g., paraquat, ozone) were manually filtered. We identified numerous drug/chemical classes associated to multiple genes implicated in retinal neuroprotection using a systematic computational approach. Anti-diabetics, lipid-lowering medicines, and antioxidants are among the treatments anticipated by this analysis, and many of these drugs could be readily repurposed for retinal neuroprotection. Our technique serves as an unbiased tool that can be utilized in the future to lead focused preclinical and clinical investigations for complex processes such as neuroprotection, as well as a wide range of other ocular pathologies.

Using Advanced Bioinformatics Tools to Identify Novel Therapeutic Candidates for Age-Related Macular Degeneration.

Purpose: Age-related macular degeneration (AMD) is the most common cause of aging-related blindness in the developing world. Although medications can slow progressive wet AMD, currently, no drugs to treat dry-AMD are available. We use a systems or in silico biology analysis to identify chemicals and drugs approved by the Food and Drug Administration for other indications that can be used to treat and prevent AMD. Methods: We queried National Center for Biotechnology Information to identify genes associated with AMD, wet AMD, dry AMD, intermediate AMD, and geographic atrophy to date. We combined genes from various AMD subtypes to reflect distinct stages of disease. Enrichment analysis using the ToppGene platform predicted molecules that can influence AMD genes. Compounds without clinical indications or with deleterious effects were manually filtered. Results: We identified several drug/chemical classes that can affect multiple genes involved in AMD. The drugs predicted from this analysis include antidiabetics, lipid-lowering agents, and antioxidants, which could theoretically be repurposed for AMD. Metformin was identified as the drug with the strongest association with wet AMD genes and is among the top candidates in all dry AMD subtypes. Curcumin, statins, and antioxidants are also among the top drugs correlating with AMD-risk genes. Conclusions: We use a systematic computational process to discover potential therapeutic targets for AMD. Our systematic and unbiased approach can be used to guide targeted preclinical/clinical studies for AMD and other ocular diseases. Translational Relevance: Advanced bioinformatics models identify novel chemicals and approved drug candidates that can be efficacious for different subtypes of AMD.

Improving mitochondria and ER stability helps eliminate upper motor neuron degeneration that occurs due to mSOD1 toxicity and TDP-43 pathology.

BACKGROUND: Upper motor neurons (UMNs) are a key component of motor neuron circuitry. Their degeneration is a hallmark for diseases, such as hereditary spastic paraplegia (HSP), primary lateral sclerosis (PLS), and amyotrophic lateral sclerosis (ALS). Currently there are no preclinical assays investigating cellular responses of UMNs to compound treatment, even for diseases of the UMNs. The basis of UMN vulnerability is not fully understood, and no compound has yet been identified to improve the health of diseased UMNs: two major roadblocks for building effective treatment strategies. METHODS: Novel UMN reporter models, in which UMNs that are diseased because of misfolded superoxide dismutase protein (mSOD1) toxicity and TDP-43 pathology are labeled with eGFP expression, allow direct assessment of UMN response to compound treatment. Electron microscopy reveals very precise aspects of endoplasmic reticulum (ER) and mitochondrial damage. Administration of NU-9, a compound initially identified based on its ability to reduce mSOD1 toxicity, has profound impact on improving the health and stability of UMNs, as identified by detailed cellular and ultrastructural analyses. RESULTS: Problems with mitochondria and ER are conserved in diseased UMNs among different species. NU-9 has drug-like pharmacokinetic properties. It lacks toxicity and crosses the blood brain barrier. NU-9 improves the structural integrity of mitochondria and ER, reduces levels of mSOD1, stabilizes degenerating UMN apical dendrites, improves motor behavior measured by the hanging wire test, and eliminates ongoing degeneration of UMNs that become diseased both because of mSOD1 toxicity and TDP-43 pathology, two distinct and important overarching causes of motor neuron degeneration. CONCLUSIONS: Mechanism-focused and cell-based drug discovery approaches not only addressed key cellular defects responsible for UMN loss, but also identified NU-9, the first compound to improve the health of diseased UMNs, neurons that degenerate in ALS, HSP, PLS, and ALS/FTLD patients.

Toward a Sustainable Health System: A Call to Action.

"Toward a Sustainable Health System: A Call to Action" speaks of the challenge that the climate crisis poses for health systems. The scale of the accelerating crisis will require that health systems adapt in response and also become visible champions for change, mitigating the environmental harms of their operation and mobilizing their social networks and leadership potential to build community resilience and transformative capacity. The authors pay principal attention to the issues of environmental sustainability and also review the linked challenges of social and economic sustainability, given the imperatives of environmental and social justice and the need for a revitalized economic vision to support livable futures. The authors' aim is to accelerate ambition in Canada, where coordinated effort and national leadership have been lacking. They close with recommendations to achieve a net-zero health system in Canada by or before 2050.

Leveraging Our Strengths to Achieve Sustainable Healthcare.

We are fortunate to have the reflections and wisdom of experts from multiple disciplines in this issue's discussion of healthcare sustainability. In the lead paper of this issue of Healthcare Papers, we issued a call to action drawing on the capacity of the Canadian health sector to address climate change (Miller and Xie 2020). Our colleagues agree on the need to deliver sustainable care and raise important questions about how such an aim can be achieved. In this response, we consider and revisit three themes: feasibility of a sustainable healthcare system, theories of change that support our recommendations and capacities that enable change.

Mortality among patients with frequent emergency department use for alcohol-related reasons in Ontario: a population-based cohort study.

BACKGROUND: Little is known about the risk of death among people who visit emergency departments frequently for alcohol-related reasons, including whether mortality risk increases with increasing frequency of visits. Our primary objective was to describe the sociodemographic and clinical characteristics of this high-risk population and examine their 1-year overall mortality, premature mortality and cause of death as a function of emergency department visit frequency in Ontario, Canada. METHODS: We conducted a population-based retrospective cohort study using linked health administrative data (Jan. 1, 2010, to Dec. 31, 2016) in Ontario for people aged 16-105 years who made at least 2 emergency department visits for mental or behavioural disorders due to alcohol within 1 year. We subdivided the cohort based on visit frequency (2, 3 or 4, or ≥ 5). The primary outcome was 1-year mortality, adjusted for age, sex, income, rural residence and presence of comorbidities. We examined premature mortality using years of potential life lost (YPLL). RESULTS: Of the 25 813 people included in the cohort, 17 020 (65.9%) had 2 emergency department visits within 1 year, 5704 (22.1%) had 3 or 4 visits, and 3089 (12.0%) had 5 or more visits. Males, people aged 45-64 years, and those living in urban centres and lower-income neighbourhoods were more likely to have 3 or 4 visits, or 5 or more visits. The all-cause 1-year mortality rate was 5.4% overall, ranging from 4.7% among patients with 2 visits to 8.8% among those with 5 or more visits. Death due to external causes (e.g., suicide, accidents) was most common. The adjusted mortality rate was 38% higher for patients with 5 or more visits than for those with 2 visits (adjusted hazard ratio 1.38, 95% confidence interval 1.19-1.59). Among 25 298 people aged 16-74 years, this represented 30 607 YPLL. INTERPRETATION: We observed a high mortality rate among relatively young, mostly urban, lower-income people with frequent emergency department visits for alcohol-related reasons. These visits are opportunities for intervention in a high-risk population to reduce a substantial mortality burden.

Effectiveness of permanent supportive housing and income assistance interventions for homeless individuals in high-income countries: a systematic review.

BACKGROUND: Permanent supportive housing and income assistance are valuable interventions for homeless individuals. Homelessness can reduce physical and social wellbeing, presenting public health risks for infectious diseases, disability, and death. We did a systematic review, meta-analysis, and narrative synthesis to investigate the effectiveness and cost-effectiveness of permanent supportive housing and income interventions on the health and social wellbeing of individuals who are homeless in high-income countries. METHODS: We searched MEDLINE, Embase, CINAHL, PsycINFO, Epistemonikos, NIHR-HTA, NHS EED, DARE, and the Cochrane Central Register of Controlled Trials from database inception to Feb 10, 2020, for studies on permanent supportive housing and income interventions for homeless populations. We included only randomised controlled trials, quasi-experimental studies, and cost-effectiveness studies from high-income countries that reported at least one outcome of interest (housing stability, mental health, quality of life, substance use, hospital admission, earned income, or employment). We screened studies using a standardised data collection form and pooled data from published studies. We synthesised results using random effects meta-analysis and narrative synthesis. We assessed certainty of the evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach. FINDINGS: Our search identified 15 908 citations, of which 72 articles were included for analysis (15 studies on permanent supportive housing across 41 publications, ten studies on income interventions across 15 publications, and 21 publications on cost or cost-effectiveness). Permanent supportive housing interventions increased long-term (6 year) housing stability for participants with moderate support needs (one study; rate ratio [RR] 1·13 [95% CI 1·01-1·26]) and high support needs (RR 1·42 [1·19-1·69]) when compared with usual care. Permanent supportive housing had no measurable effect on the severity of psychiatric symptoms (ten studies), substance use (nine studies), income (two studies), or employment outcomes (one study) when compared with usual social services. Income interventions, particularly housing subsidies with case management, showed long-term improvements in the number of days stably housed (one study; mean difference at 3 years between intervention and usual services 8·58 days; p<0·004), whereas the effects on mental health and employment outcomes were unclear. INTERPRETATION: Permanent supportive housing and income assistance interventions were effective in reducing homelessness and achieving housing stability. Future research should focus on the long-term effects of housing and income interventions on physical and mental health, substance use, and quality-of-life outcomes. FUNDING: Inner City Health Associates.

Mitoautophagy: A Unique Self-Destructive Path Mitochondria of Upper Motor Neurons With TDP-43 Pathology Take, Very Early in ALS.

Mitochondrial dysfunction is one of the converging paths for many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), and TDP-43 pathology is the most common proteinopathy detected in ALS and ALS/Frontotemporal lobar degeneration (ALS/FTLD). We recently identified mitochondrial problems in corticospinal motor neurons (CSMN) and in Betz cells of patients with TDP-43 pathology. However, the timing and the extent of mitochondrial defects, and their mode of degeneration have not been revealed. Because it is important to reveal when problems first begin to emerge and whether they are shared or unique, we investigated the health and integrity of mitochondria in CSMN of prpTDP-43A315T, PFN1G118V, and hSOD1G93A mice at P15 (post-natal day 15)-a very early age in mice without any sign of cellular degeneration.Utilization of immuno-coupled electron microscopy for a detailed surveillance of mitochondria in CSMN and other non-CSMN cells revealed presence of a novel self-destructive path of mitochondrial degeneration, which we named mitoautophagy. Mitoauthopgy is different from mitophagy, as it does not require autophagosome-mediated degradation. In contrast, in this novel path, mitochondria can clear themselves independently. We find that even at this early age, all diseased CSMN begin to display mitochondrial defects, whereas mitochondria in non-CSMN cells are healthy. Our findings not only reveal mitoautophagy as a novel path of mitochondrial clearance that occurs prior to neuronal vulnerability, but it also highlights that it is present mainly in the upper motor neurons of prpTDP-43A315T and PFN1G118V mice, which mimic many aspects of the disease in patients with TDP-43 pathology.

MCP1-CCR2 and neuroinflammation in the ALS motor cortex with TDP-43 pathology.

BACKGROUND: The involvement of non-neuronal cells and the cells of innate immunity has been attributed to the initiation and progression of ALS. TDP-43 pathology is observed in a broad spectrum of ALS cases and is one of the most commonly shared pathologies. The potential involvement of the neuroimmune axis in the motor cortex of ALS patients with TDP-43 pathology needs to be revealed. This information is vital for building effective treatment strategies. METHODS: We investigated the presence of astrogliosis and microgliosis in the motor cortex of ALS patients with TDP-43 pathology. prpTDP-43A315T-UeGFP mice, corticospinal motor neuron (CSMN) reporter line with TDP-43 pathology, are utilized to reveal the timing and extent of neuroimmune interactions and the involvement of non-neuronal cells to neurodegeneration. Electron microscopy and immunolabeling techniques are used to mark and monitor cells of interest. RESULTS: We detected both activated astrocytes and microglia, especially rod-like microglia, in the motor cortex of patients and TDP-43 mouse model. Besides, CCR2+ TMEM119- infiltrating monocytes were detected as they penetrate the brain parenchyma. Interestingly, Betz cells, which normally do not express MCP1, were marked with high levels of MCP1 expression when diseased. CONCLUSIONS: There is an early contribution of a neuroinflammatory response for upper motor neuron (UMN) degeneration with respect to TDP-43 pathology, and MCP1-CCR2 signaling is important for the recognition of diseased upper motor neurons by infiltrating monocytes. The findings are conserved among species and are observed in both ALS and ALS-FTLD patients.

Exploring miRNA-mRNA regulatory network in cardiac pathology in Na+/H+ exchanger isoform 1 transgenic mice.

Numerous studies have demonstrated that Na+/H+ exchanger isoform 1 (NHE1) is elevated in myocardial diseases and its effect is detrimental. To better understand the involvement of NHE1, we have previously studied cardiac-specific NHE1 transgenic mice and shown that these mice develop cardiac hypertrophy, interstitial fibrosis, and cardiac dysfunction. The purpose of current study was to identify microRNAs and their mRNA targets involved in NHE1-mediated cardiac injury. An unbiased high-throughput sequencing study was performed on both microRNAs and mRNAs. RNA sequencing showed that differentially expressed genes were enriched in hypertrophic cardiomyopathy pathway by Kyoto Encyclopedia of Genes and Genomes annotation in NHE1 transgenic hearts. These genes were classified as contraction defects (e.g., Myl2, Myh6, Mybpc3, and Actb), impaired intracellular Ca2+ homeostasis (e.g., SERCA2a, Ryr2, Rcan1, and CaMKII delta), and signaling molecules for hypertrophic cardiomyopathy (e.g., Itga/b, IGF-1, Tgfb2/3, and Prkaa1/2). microRNA sequencing revealed that 15 microRNAs were differentially expressed (2-fold, P < 0.05). Six of them (miR-1, miR-208a-3p, miR-199a-5p, miR-21-5p, miR-146a-5p, and miR-30c-5p) were reported to be related to cardiac pathological functions. The integrative analysis of microRNA and RNA sequencing data identified several crucial microRNAs including miR-30c-5p, miR-199a-5p, miR-21-5p, and miR-34a-5p as well as 10 of their mRNA targets that may affect the heart via NFAT hypertrophy and cardiac hypertrophy signaling. Furthermore, important microRNAs and mRNA targets were validated by quantitative PCR. Our study comprehensively characterizes the expression patterns of microRNAs and mRNAs, establishes functional microRNA-mRNA pairs, elucidates the potential signaling pathways, and provides novel insights on the mechanisms underlying NHE1-medicated cardiac injury.