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Role of beta-catenin in glaucomatous optic neuropathy
No full textThe Wnt/beta-catenin signaling pathway comprises a family of proteins that plays a critical role in developing adult tissue such as the optic nerve head by mediating cell proliferation, survival, behavior, and fates. This pathway is tightly controlled, and faulty regulation of this pathway has been shown to cause ocular malformations and ultimately a glaucomatous phenotype. Despite the significance of this pathway in glaucoma, the specific mediators involved in its pathophysiology remain poorly understood. This systemic review aims to analyze beta-catenin's role in the optic nerve head (ONH) cells and in the development of glaucoma. This review includes assessments of primary studies, meta-analyses, and narrative reviews. Additionally, to further understand the role of beta-catenin in OHN cells, immunohistochemistry will be performed to determine its expression in ONH cells. The results of this experiment will be updated in the final literature. In summary, our review shows that glaucomatous injury to the ONH downregulates Wnt signaling and the expression of beta-catenin. This leads to fibrosis of the ONH and an eventual elevation in intraocular pressure. This review also discusses the practical implications of these findings and how they can be used to develop potential therapeutics for glaucoma
Association of Tobacco Use and Suicidal Ideation among Adults with Metal Health Issues
No full textPurpose: People with mental health disorders are at higher risk of tobacco use. Studies have demonstrated higher prevalence of tobacco use among people with mental health disorders. We aimed to examine the association between tobacco use and suicidal ideation (SI) among adults with major depressive episode (MDE) and serious psychological distress (SPD) using data from the 2021 National Survey on Drug Use and Health (NSDUH).
Methods: Weighted multiple logistic regression modeling and descriptive analyses were conducted on a representative sample of 47,291 from the US general population. Respondents were classified as having past-year SI if they answered yes to SI or suicide planning in the past year. Past-year SPD was defined as a score of 13 or higher on the K6 scale of nonspecific psychological distress. MDE was defined based on the diagnostic criteria from DSM-5. Self-reported data on the use of tobacco products was used. Models were adjusted for sex, age category, and race/ethnicity.
Results: Tobacco use was significantly associated with SI among adults with past-year MDE and SPD after accounting for covariates. Among adults with past-year MDE, individuals using/having used tobacco products were more likely to have SI (aOR 1.474; 95% CL 1.107, 1.962). Among adults with past-year SPD, adults using/having used tobacco products were more likely to have SI (aOR= 1.268; 95% CL 1.031, 1.558) compared to adults with no tobacco use history.
Conclusion: Findings suggest the need to screen tobacco use as a risk factor in suicidal risk factors among adults with mental health disorders
Studies Directed Toward the Synthesis of Novel Bitopic Ligands of the Muscarinic Acetylcholine Receptor Subtype 4
No full textResearch Appreciation Day Winner - HSC College of Pharmacy, 2024 Pharmaceutical Science Research Award - 1st PlacePurpose: Alzheimer’s disease (AD) is characterized by amyloid deposits that build up in the brain and cause neurodegeneration. It is estimated that 6.7 million Americans currently have AD and at age 45, the lifetime probability of developing AD are 1 in 5 for women and 1 in 10 for men. Cognitive and behavioral impairments in AD are associated with dysregulation of cholinergic signaling that occurs due to neuronal damage and a decreased availability of the acetylcholine neurotransmitter. Muscarinic acetylcholine receptors are a family of G protein-coupled receptors (GPCRs) with five subtypes (M₁₋₅). Clinical trials with the M₁/M₄-preferring orthosteric agonist xanomeline previously demonstrated promise in treating cognitive and behavioral impairments in AD patients; however, further advancement of the experimental drug was prevented due to adverse effects associated with activation of M₂ and/or M₃ receptors. Achieving subtype selectivity with orthosteric agonists remains challenging due to high homology at the binding site. On the other hand, positive allosteric modulators (PAMs) have demonstrated more promising selectivity profiles. We hypothesize that bitopic ligands that engage both the orthosteric and allosteric binding sites of M₄ will selectively and directly activate the receptor, offering a pharmacological profile advantageous for the treatment of the cognitive and behavioral symptoms associated with AD. We will utilize published crystal structures and molecular docking studies to design bitopic ligands of M₄ that consist of xanomeline covalently linked to known M₄ PAMs. The objective of the current study is to design and execute viable syntheses of select putative M₄ bitopic ligands to enable their pharmacological evaluation.
Methods: Autodock tools were used to prepare the model of M₄ using the published crystal structure (PDB code 5DSG), and potential ligands were docked with Autodock Vina. Compounds were synthesized using solution phase chemistry and microwave-assisted organic synthesis (MAOS) when possible. Automated normal and/or reverse phase chromatography were used to purify intermediates and final products as needed. All compounds were characterized to confirm structure and purity utilizing Bruker Fourier 300HD for ¹H and ¹³C nuclear magnetic resonance (NMR) and Agilent 6230 time-of-flight (TOF) LC/MS for high resolution mass spectrometry (HRMS).
Results: Molecular docking studies revealed multiple putative M₄ bitopic ligands predicted to have a high affinity for the receptor. Included among these compounds are analogs with xanomeline linked to known M₄ PAMs VU6003130 and VU0152100. Synthetic approaches to select analogs have been designed and their execution initiated.
Conclusions: Progress toward the synthesis of novel M₄ bitopic ligands has been made. Next steps for the project include completion of the synthesis of select ligands and their evaluation in functional assays to determine potency at M₄ and selectivity versus other family members
Unassigned Albuterol: A Rapid Review of School-Based Stock Inhaler Programs and Asthma Outcomes
No full textBackground: Asthma affects over 6 million children in the US and poorly managed asthma is a leading cause of school absenteeism. An estimated60% of children with current asthma have at least one attack each year. Guidelines recommend that quick-relief medication (albuterol)always be available to those with asthma, but it is estimated only20% of children with reported asthma have their own medication at school. As a result, it’s estimated over 3 million US children with current asthma attend school each day without timely access to quick-relief medication. To address this problem, schools may “stock” albuterol and administer this medication for episodes of respiratory distress using standing delegation orders. Timely administration of albuterol may potentially prevent asthma episodes from escalating and may be lifesaving. While stock albuterol is not new, implementation has been slow and peer-reviewed literature has been limited until recently. The purpose of this study is to assess the current evidence base regarding stock albuterol by conducting a rapid systematic literature review focused on three research questions: (Q1) What is currently known about the impacts of unassigned albuterol on asthma outcomes? (Q2) What outcome categories have been reported in the existing literature? (Q3) What barriers to implementation have been identified?
Methods: We conducted a rapid review using PRISMA guidelines and Covidence software. PubMed, SCOPUS, and CINAHL databases were included. Inclusion and exclusion criteria were established, and a data extraction tool developed. The search was expanded to include grey literature with a focus on conference proceedings using Google Scholar.
Results: Our initial search yielded 262 articles. After removing 164 duplicates and screening titles and abstracts,31articles were included in the final review.
(Q1) Eleven articles reported on short term outcomes, including disposition of students after stock albuterol was used, EMS calls, and asthma associated absences. No articles evaluated the impact of stock albuterol policies on asthma control or measures of intermediate to long term asthma outcomes.
(Q2) Current research has also included the following topics: barriers to implementation, legislation, nursing satisfaction, the role of unlicensed assistive personnel, and the relationship of stock albuterol to social determinants of health and disparities. Among these, implementation barriers were most frequent, being included in 21 of the 31 articles. Four articles addressed disparities.
(Q3) Among the 21 articles addressing implementation barriers, the most frequently reported were perceived liability risk, funding, obtaining prescriptions, and delays between policy change and program implementation.
Conclusions: The review reveals consistent, positive short-term outcomes following the use of stock albuterol and benefits including reduced EMS and potential decreases in absences. General barriers to implementation have been well-defined. The review also suggests several areas where the existing evidence base is thin or lacking. This includes impacts of policy implementation on asthma control and intermediate to long term outcomes, disparities, and inclusion of context specific barriers and facilitators of implementation
Novel Small Molecules with Anti-Inflammatory and Anti-Angiogenic Activity in a Mouse Model of Oxygen-Induced Retinopathy
Get PDFRetinopathy of prematurity (ROP) has a dual-phase disease pathology; in phase 1, hyperoxia-induced vaso-obliteration occurs in the retinal vasculature due to increased oxidative stress (OS) and inflammation, followed by phase 2, where hypoxia increases the overproduction of growth factors, inducing retinal neovascularization. Toll-like receptor 2 and -4 (TLR2 and TLR4) overactivation, hyper-inflammation, macrophages, and neutrophil infiltration contribute to the developing ROP. AVR-121 and AVR-123 are novel classes of small-molecule dual inhibitors of TLR2/4 tested in a human leukemia monocytic cell line (THP-1) and cord-blood-derived mononuclear cells (CBMCs). Both compounds inhibited TLR2/4 signaling-related inflammatory cytokines in THP-1 cells and inhibited VEGF-induced neovascularization in human retinal endothelial cells (HRECs), which are hallmarks of ROP. In an oxygen-induced retinopathy (OIR) murine model, the intraperitoneal injection of AVR-123 in the hyperoxia phase (P7-P12) or a nanosuspension eyedrop of AVR-123 in the hypoxic phase (P12-P17) significantly reduced vaso-obliteration, angiogenesis, and inflammatory cytokine profiles while not inhibiting the necessary growth factor VEGF in the juvenile mouse eyes. The results are consistent with our hypothesis that targeting the dual TLR2/4 pathway will reduce inflammation, angiogenesis, and vaso-obliteration in vitro and in vivo and reduce cytotoxic immune cells. AVR-123 has the potential to be developed as a therapy for ROP.This research received no external funding
Patient Perspectives Unveiled: An Analysis of Common Questions and Concerns to Empower Informed Healthcare Dialogues with Elderly Patients Taking Multiple Medications
No full textPurpose: Health literacy is often a barrier to patient understanding and effective communication with healthcare providers. Patients are often unaware of what questions to ask during their visits and leave their provider offices without fully understanding their conditions or medication regimens. Past studies have shown that facilitating patient dialogue through structured questions during the encounter results in fewer patient callbacks and improved comprehension. The goal of this study was to identify the most common questions and concerns that patients 50 years and older who are on five or more medications would like to discuss with their physicians about their medications. Such data could help physicians anticipate and educate patients with information most valuable to them during office visits. Methods: We designed a 20-question survey to better understand what patients desired from their primary care visit including questions to ask, concerns to tell, and positive behaviors to report to their provider. We focused on the ask and tell sections which involved presenting questions or concerns that were pertinent to the patient's conditions or medications. Participants included patients at family medicine clinics from a county hospital system (240) and a private practice (211) in Fort Worth who were 50 years of age or older and taking five or more medications. Surveys were administered at a clinical visit by the medical assistant before the physician/patient encounter. Descriptive statistics are provided. Results: Out of 451 surveys completed, the questions that patients were most interested in talking with their physician included: 1) What should I eat, and what should I not eat for my condition? (20.4%) 2) Can I take fewer medicines than I am taking? (15.3%) 3)How do I learn more about my condition? (14.6%) The least common questions were 1) Why do I need several medications for my condition? (8.2%) 2) Other questions: (8.6%) 3) How can I stop my blood sugar, heart rate, or blood pressure from getting too low? (9.1%) The most common concerns about their medications were: 1) I stopped or skipped these medicines, due to: cost, side effects, or other reasons (11.1%) 2) I have new medicines from other doctors (offices, hospitals or emergency rooms) (8%) 3) I have concerns with my medicines (examples: cost, hard to read, not helping much) (5.7%) Conclusions: It is evident that patients are interested in learning about their conditions and making appropriate lifestyle changes. The most commonly raised concerns were related to medication access, polypharmacy, and efficacy. These data show some of the potential topics patients want to discuss with their providers. The most common topics from this study can be implemented into a question prompt lists (QPL [https://onlinelibrary.wiley.com/doi/abs/10.1111/ecc.12489?casa_token=kGVvFBSWANEAAAAA:NOhQ46f92KtdNp9XgslcAiwEoB6MI0N4K1vOA2P7FyFQ_BBgv0BycKPBy4sLKk_e9Cki971trjdfoL1k]) specific to medications and chronic disease management. Providers could give lists to patients to review while waiting for care. Having these topics beforehand would help the patients be prepared when presented with “what questions do you have?”; thus, revealing the patient's perspective and helping to increase their health literacy.Agency for Healthcare Research and Qualit
Discovery and Structure-Based Optimization of Benzimidazole-Derived Activators of Slack Potassium Channels
No full textPurpose:
Fragile X syndrome (FXS) is a genetic disorder caused by the absence of Fragile X Mental Retardation Protein (FMRP) in neurons resulting in intellectual disability, behavioral, and learning challenges. FMRP is an RNA-binding protein that also interacts with numerous cytoplasmic and nuclear proteins. Preclinical studies have shown that FMRP binds the C-terminus of the sodium-activated potassium channel Slack, to modulate electrical activity in the brain. This finding was validated by biochemical and electrophysiological studies which confirmed that sodium-activated potassium currents in neurons are decreased in Fmr1-knockout versus Slack WT mice.
Thus, evidence suggests that the deficiency of FMRP in FXS may affect the physiological role of Slack in regulating neuronal excitability, contributing to cognitive dysfunction associated with FXS. We therefore hypothesize that Slack dysfunction can be restored with small molecules in the treatment of intellectual disability associated with neurodevelopmental disorders.
Our research has identified the hit compound VU0519388 (VU388), as a moderately potent Slack activator. Using medicinal chemistry strategies, we seek to generate analogs with enhanced Slack activity, which may serve as valuable tools to characterize the pathophysiological role of Slack in FXS.
Method: Our approach involved identifying multiple regions of VU388that could be readily diversified and designing short efficient synthetic routes used to produce small libraries of analogs. Structure and purity of all analogs were confirmed using spectra obtained from a Bruker Fourier 300HD NMR spectrometer and an Agilent 6230 time-of-flight LC/MS. Cellular activity was then evaluated using a Tl+ flux assay in HEK-293 cells that stably express wild-type (WT) Slack channels.
Results: Each region of the VU388 scaffold proved tolerant of modification to some degree. Substitution with a variety of electron withdrawing and donating groups at various positions on the western benzimidazole ring and eastern aryl ring produced analogs with superior potency relative to VU388. Monosubstitution on the eastern aryl ring was well tolerated compared to disubstitution.
Conclusion: Our systematic optimization plan has identified clear structure-activity relationships and multiple Slack activator analogs with improved activity relative to VU388. Multiple regions of the scaffolds are amenable to SAR development, which greatly enhances the probability of reaching our goal of highly optimized probes. Additional modifications that combine optimal features may provide additional SAR and analogs with optimal potency for use as a molecular probe.We gratefully acknowledge the National Institute of Mental Health (R21MH125257) for their support of our research directed toward the discovery of new small molecule activators of Slack potassium channels
Hypoxia and oxidative stress reduce placental efficiency and impair the balance between autophagy and cell death mechanisms in trophoblasts
No full textIntroduction: Hypoxia and oxidative stress can activate autophagy, a lysosomal degradation pathway that maintains cellular homeostasis. Impairments in autophagy mechanisms have been observed in placentas from obstetric complications associated with placental hypoxia and oxidative stress, such as preeclampsia and intrauterine growth restriction. Purpose: The objective of this study was to investigate the effects of hypoxia and oxidative stress on placental autophagy. We hypothesized that exposure to oxidative stress and hypoxia would alter the balance between cytotoxic and cytoprotective mechanisms in human trophoblast cells and rat placentas and would adversely affect placental efficiency. Methods: We used an in vitro model incorporating human trophoblast cells (BeWo cells) exposed to an oxidative stressor, antimycin A (10, 100, 320 μM) or vehicle for 4 hours. Trophoblast cell death and autophagy mechanisms were assessed via flow cytometry and western blotting. Additionally, we used a rodent model of gestational sleep apnea, a pregnancy complication associated with placental hypoxia. Long Evans timed-pregnant dams were exposed to chronic intermittent hypoxia (CIH; n=6-8) or normoxia (NX; n=8-9) during their sleep cycle from gestational day (GD) 15 to 20 (late pregnancy, term=21-23 days). Results: In trophoblast cells (n=5-9 independent experiments), antimycin A increased necrosis and LC3 A/B II/I ratio (autophagy marker) at 100 μM compared to vehicle (p<0.015). Necrosis remained elevated at 320 μM, while BAX (pro-apoptotic marker) and p62 (autophagosomal flux marker) were reduced compared to vehicle (p<0.0001). LC3 A/B II/I ratio returned to vehicle levels at 320 μM (p>0.05 vs. vehicle). Placental weights from CIH exposed dams were greater (NX: 0.51±0.02 g vs. CIH: 0.60±0.03 g, p=0.015) and fetal to placental weight ratios (marker of placental efficiency) were reduced compared to control pregnancies (NX: 5.25±0.13 vs. CIH: 4.43±0.14, p=0.0006) on GD20. Gestational CIH did not affect (p>0.05) fetal weights (NX: 2.76±0.06 g vs. CIH: 2.61±0.06 g), crown to rump length (NX: 3.32±0.03 cm vs. CIH :3.18±0.12 cm), abdominal girth (NX: 3.22±0.06 cm vs. CIH: 3.32±0.12 cm), or litter size (NX: 11.9±0.90 vs. CIH: 10.5±0.82). Conclusion: Oxidative stress alters the balance between cytotoxic and cytoprotective mechanisms in trophoblast cells, promoting cell necrosis. Although assessment of autophagy machinery and cell death in placentas from hypoxic pregnancies is ongoing, our results indicate that maternal CIH during pregnancy adversely affects placental efficiency.NIH R01 HL146562, AHA 22PRE-900431, T32 AG020494, AHA 22POST-903250
Neuroprotection by Novel Sigma 1 ligands
No full textPurpose: Identify neuroprotective compounds that could potentially be used for conditions like Alzheimer’s disease. Sigma 1 receptors are an intracellular chaperone protein involved in endoplasmic reticulum stress response. Ligands of sigma 1 receptor have been shown to be acutely neuroprotective in a number of in vitro and in vivo brain injury models including stroke and traumatic brain injury. We are examining potential for novel sigma 1 compounds to protect the mouse hippocampal cell line HT22 from oxidative stress and endoplasmic reticulum stress. Among the compounds tested are haloperidol, cutamesine, oxeladin which are neuroprotective in stroke, and additional proprietary ligands derived from substituted haloperidol. Methods: Cell death in HT22 cells was determined using Cell Counting Kit 8. Cells were plated in quadruplicate in 96 well plates for 24 hours in DMEM/10%FBS. Cells were then treated with either hydrogen peroxide (H2O2, 0.5 mM) or Tunicamycin (50 ng/mL) for 24 hours with or without sigma 1 ligands (100 nM). Results: Haloperidol, a mixed sigma 1 and dopamine agonist, dose dependently protected cells from both H2O2 and Tunicamycin induced cell death. However, the sedative actions of Haloperidol make it unsuitable for use against neuroprotective diseases in vivo. We tested 3 sigma 1 compounds without dopamine activity to determine whether sigma 1 activity would protect cells against these insults. Preliminary results suggests that all sigma 1 compounds tested show some efficacy against oxidative stress and ER stress dependent cell death. Average percent live cells after treatment with 0.5 mM hydrogen peroxide was 59.55% (n = 3) and average percent live cells after treatment with 0.5 mM hydrogen peroxide and 100 nM Haloperidol was 101.06% (n = 5). Average percent live cells after treatment with 50 ng/mL Tunicamycin and 100 nM Haloperidol was 85.8% (n = 2). Average percent live cells after treatment with 50 ng/mL Tunicamycin and 100 nM Oxeladin was 49.7% (n = 2). Average percent live cells after treatment with 50 ng/mL Tunicamycin and 100 nM Cutamesine was 74.4% (n = 2). Average percent live cells after treatment with 50 ng/mL Tunicamycin and 100 nM of a novel sigma 1 agonist was 85.7% (n = 2). Ongoing studies are examining the intracellular pathways responsible for neuroprotective effects. Conclusion: Novel sigma 1 agonists may be suitable for protecting neurons against neurodegenerative diseases like Alzheimer’s. In terms of examining mechanisms, we are exploring endoplasmic reticulum stress pathways and more traditional apoptotic signaling.NIHR01AG05507
Burnout in CNAs in Nursing Homes Coming out of COVID
No full textBACKGROUND: Certified Nursing Assistants (CNAs) in nursing homes often face high levels of stress and burnout, adversely impacting their health and the quality of care they provide. The need for a comprehensive understanding of their specific challenges is vital for developing targeted interventions.
METHODS: Participants completed the "Collaborative Implementation Strategy to Increase COVID-19 Education and Training" offered by UNTHSC, which consisted of 8 modules that reinforced the skills and knowledge necessary for delivering high-quality and safe care to residents. One module from the training included the Maslach Burnout Inventory, a tool designed to assess three burnout dimensions: emotional exhaustion, depersonalization, and personal accomplishment. Thirty-two CNAs completed the survey, sharing experiences and feedback on various aspects of their work life. De-identified demographic data was collected from each participant before completing the training. Demographic data included age, gender, race, military history, profession, primary work setting (skilled nursing facility, dementia center, assisted living facility, etc.) and self-reported information regarding ethnicity, and presence or absence of disadvantaged background and rural upbringing.
RESULTS: Findings reveal moderate levels of emotional exhaustion but low depersonalization levels, indicating empathy towards patients remains intact despite challenges. CNAs demonstrated high personal accomplishment scores, pointing towards resilience and effective coping mechanisms in the face of high-stress environments.
CONCLUSIONS: The study underlines the importance of targeted interventions that address the unique stressors CNAs face and emphasize supportive environments, reasonable workloads, and personal accomplishment enhancement strategies. The results, despite the study's limitations, provide crucial insights into burnout experiences among CNAs and affirm the necessity of continual research in this field for improving the healthcare industry's long-term care sector.Health Resources and Services Administration (HRSA), US Department of Health and Human Services (HHS), under grant number U1QHP2873