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Quercetin and Related Analogs as Therapeutics to Promote Tissue Repair
Get PDFQuercetin is a polyphenol of the flavonoid class of secondary metabolites that is widely distributed in the plant kingdom. Quercetin has been found to exhibit potent bioactivity in the areas of wound healing, neuroprotection, and anti-aging research. Naturally found in highly glycosylated forms, aglycone quercetin has low solubility in aqueous environments, which has heavily limited its clinical applications. To improve the stability and bioavailability of quercetin, efforts have been made to chemically modify quercetin and related flavonoids so as to improve aqueous solubility while retaining bioactivity. In this review, we provide an updated overview of the biological properties of quercetin and proposed mechanisms of actions in the context of wound healing and aging. We also provide a description of recent developments in synthetic approaches to improve the solubility and stability of quercetin and related analogs for therapeutic applications. Further research in these areas is expected to enable translational applications to improve ocular wound healing and tissue repair.This study was funded by the National Institutes of Health/National Eye Institute grant R01EY028888 (DK)
Application of Structural Retinal Biomarkers to Detect Cognitive Impairment in a Primary Care Setting
No full textIntroduction
Alzheimer’s Disease (AD) is the most prevalent form of dementia and a leading cause of death in the elderly. The detection of AD remains poor in primary care despite the advancement of neurodiagnostic procedures. There are no rapid and cost-effective tools available to primary care providers to conduct cognitive examinations to diagnose AD. The goal of this study is to determine the predictive ability of structural retinal biomarkers to identify cognitive impairment in a primary care setting.
Methods
Participants were recruited from Alzheimer’s Disease in Primary Care (ADPC) study. As part of the ADPC Retinal Biomarker Study (ADPC RBS), visual acuity, an ocular history questionnaire, eye pressure, optical coherence tomography (OCT) imaging and fundus imaging was performed. Exclusion criteria included high intraocular pressure defines as greater than or equal to 30 mmHg in either eye, history of adverse effects with pupillary relation, known hypersensitivity to tropicamide or any ingredient in the formulation, active ocular infection or inflammation, history of angle closure glaucoma, or having undergone ocular surgery within the last 6 months. Cognitive diagnoses were assigned algorithmically and verified at consensus review by an expert in the field of dementia.
Results
Data were examined on a total of 91 participants (59 cognitively unimpaired, 32 cognitively impaired (26 mild cognitive impairment (MCI), 6 AD)). The top biomarkers for predicting cognitive impairment included the inferior quadrant of the outer retinal layers, all four quadrants of the peripapillary retinal nerve fiber layer (pRNFL), and the inferior quadrant of the macular retinal nerve fiber layer. While all four quadrants of the pRNFL are highly important biomarkers for identifying those with cognitive impairment, the inferior and superior quadrants displayed higher relative importance compared to the temporal and nasal quadrants.
Conclusion
This study was the first to examine the utility of retinal biomarkers in diagnosis cognitive impairment in a primary care setting with models reflecting how it could be employed as a screening tool in practice. The current data provides strong support for continued investigation into structural retinal biomarkers, particularly the retinal nerve fiber layer, as screening tools for AD. In prior studies, preferential thinning of the inner retinal layers is found in AD compared to healthy controls. This study can help distinguish those with cognitive impairment from those cognitively unimpaired. The availability of such a biomarker could increase access to disease modifying treatments once available
Lessons Learned from Age-Friendly, Team-Based Training
Get PDFAccording to the Institute of Medicine, immediate steps must be taken across the United States to educate and train the healthcare workforce to work collaboratively to address the needs of the growing older adult population. The Geriatric Practice Leadership Institute (GPLI) was designed to support professional teams working in acute and post-acute care in transforming their organization into a designated Age-Friendly Health System. The program was built around the Institute for Healthcare Improvement's Age-Friendly Health Systems 4Ms framework. This framework focuses on What Matters, Medication, Mentation, and Mobility (the 4Ms) in supporting care for older adults. The GPLI program is an online, seven-month team-based program with four to seven participants from one organization per team. Additionally, each team selected, developed, and completed a quality improvement project based on Age-Friendly Health Systems 4Ms. The curriculum also includes organizational culture, leadership, and interprofessional team-building modules. Using a post-completion survey, the experiences of 41 participants in the GPLI program were assessed. All respondents found the information in the program 'very' or 'extremely' valuable, and their executive sponsor 'very' or 'extremely' valuable in supporting their team's involvement and project. The GPLI program has trained over 200 healthcare professionals and teams that have successfully implemented projects across their organizations.This work was supported by the Health Resources and Services Administration (HRSA) of the U.S. Department of Health and Human Services (HHS) under grant number U1QHP28735. The contents are those of the authors and do not necessarily represent the official views of, nor an endorsement, by HRSA, HHS, or the U.S. Government
Molecular Docking Studies for Designing and Identification of Novel Bitopic Ligands for Sigma-1 Receptor
No full textPurpose: Our goal is to identify more specific ligands for the Sigma-1 Receptor (S1R) by designing and docking various bitopic ligands then ranking them based on their interactions. The S1R is an intracellular, multifunctional receptor that is a target in many pathologies. S1R is found throughout the body, within the membranes of the nucleus, ER, and mitochondria, and the CNS is the primary site of activity. Bitopic ligands are those that combine the high affinity by binding to orthosteric sites and high selectivity by binding to allosteric sites on the same receptor. They are used to gain insights on molecular functioning of the receptor.
Methods: A set of 3 linkers were tested with a known allosteric binding compound and the one with highest affinity was selected to continue in the design process. Nine bitopic ligands were designed using known allosteric compounds, the selected linker, and a high affinity orthosteric compound. Ligands were minimized with Avogadro then PDBQT files for minimized ligands and S1R open-state confirmation were prepared with AutoDock Tools. All newly designed ligands were docked on S1R using Vina to determine their binding affinities. Interactions were visualized using Pymol and quantified using Protein Ligand Interaction Profiler.
Results: After testing 3 linkers from the literature, we identified 1 that gave highest affinity with our allosteric compound and selected to use it in the design of new bitopic ligands. Our results shows that all ligands docked in a bend conformation in the S1R. Specifically, bitopic ligands having benzazepine derivatives showed greater affinity to S1R. The number of hydrophobic bonds, hydrogen bonds, pi bonds, and salt bridges were identified for each interaction between the ligand and S1R.
Conclusions: The 1-2 compounds with the highest affinity and favorable interactions are candidates to be used for future drug design models
The Effect of Trusted News Sources on the Confidence in the Safety of COVID-19 Vaccination
No full textPurpose: COVID-19 vaccination prevents severe disease manifestations; yet uptake has been suboptimal. Confidence in the safety and efficacy of the vaccine influences COVID-19 vaccination decisions. Exposure to information from a trusted news source can impact perceptions and may contribute to vaccine decisions. This study assessed the association between trusted news sources and confidence in the safety of COVID-19 vaccination among Texas adults.
Methods: Participants were recruited through an online panel using quota sampling based on the racial and ethnic distribution of Texas in July 2022 (n=1089). The primary predictor variable was self-reported trusted news sources for COVID-19 related news (16 options), in which respondents were asked to endorse any news source they trusted, with options ranging from print media to cable news to local news. The outcome was confidence in the safety of the COVID-19 vaccine (not at all confident to very confident). Multinomial regression analyses were conducted to model confidence in COVID-19 vaccination and trusted news sources while controlling for education, age, gender, and self-reported race.
Results: Through an initial descriptive analysis, Fox News, local cable TV programs, and news broadcasting from one’s home abroad were associated with lower confidence levels. After grouping those three sources as "top news sources” and assessing their effect on confidence through a multinomial model, it was found that individuals who trusted those top sources were significantly less likely to endorse "somewhat confident” (OR=0.59, 95%CI 0.4-0.89) or "very confident” (OR=0.41, 95%CI 0.27- 0.62) compared to being "not at all confident” in the safety of the COVID-19 vaccine.
Conclusions: Study findings show that some trusted news sources contributed to participants having less confidence or no confidence in the safety of the COVID-19 vaccine. Public health initiatives should consider how to address vaccine confidence among the public given the diversity of information sources people rely on
Peroxisome proliferator-activated receptor-alpha (PPARalpha) regulates wound healing and mitochondrial metabolism in the cornea
Get PDFDiabetes can result in impaired corneal wound healing. Mitochondrial dysfunction plays an important role in diabetic complications. However, the regulation of mitochondria function in the diabetic cornea and its impacts on wound healing remain elusive. The present study aimed to explore the molecular basis for the disturbed mitochondrial metabolism and subsequent wound healing impairment in the diabetic cornea. Seahorse analysis showed that mitochondrial oxidative phosphorylation is a major source of ATP production in human corneal epithelial cells. Live corneal biopsy punches from type 1 and type 2 diabetic mouse models showed impaired mitochondrial functions, correlating with impaired corneal wound healing, compared to nondiabetic controls. To approach the molecular basis for the impaired mitochondrial function, we found that Peroxisome Proliferator-Activated Receptor-alpha (PPARalpha) expression was downregulated in diabetic human corneas. Even without diabetes, global PPARalpha knockout mice and corneal epithelium-specific PPARalpha conditional knockout mice showed disturbed mitochondrial function and delayed wound healing in the cornea, similar to that in diabetic corneas. In contrast, fenofibrate, a PPARalpha agonist, ameliorated mitochondrial dysfunction and enhanced wound healing in the corneas of diabetic mice. Similarly, corneal epithelium-specific PPARalpha transgenic overexpression improved mitochondrial function and enhanced wound healing in the cornea. Furthermore, PPARalpha agonist ameliorated the mitochondrial dysfunction in primary human corneal epithelial cells exposed to diabetic stressors, which was impeded by siRNA knockdown of PPARalpha, suggesting a PPARalpha-dependent mechanism. These findings suggest that downregulation of PPARalpha plays an important role in the impaired mitochondrial function in the corneal epithelium and delayed corneal wound healing in diabetes
Cranial Bone Ossification Trajectories in a Mouse Model of Osteogenesis Imperfecta
No full textResearch Appreciation Day Award Winner - School of Biomedical Sciences, 2023 Department of Physiology & Anatomy-Structural Anatomy & Rehabilitation Sciences Award - 2nd PlacePurpose: Osteogenesis imperfecta (OI) is a genetic disorder that affects the production of type I collagen. Altered collagen production results in delayed or impaired skeletal formation and biomineralization. It also results in the defining characteristics of OI: brittle bones and high rates of fractures. Investigations of skeletal growth in OI have primarily focused on the postcranial skeleton, where interrupted, atypical, and disorganized ossification is seen at long bone growth plates. However, few studies have investigated changes in craniofacial growth in OI and there are currently few early interventions to improve growth trajectories in this region. The current medication prescribed for children with OI to improve skeletal growth, such as bisphosphonates, have major side effects and are not suitable for long-term use. A better understanding of craniofacial development in OI can help with targeting specific developmental stages when new treatments can be administered to provide the best results. The aim of this study is to examine cranial ossification from birth to weaning to determine where and when differences in growth occur in OI. We hypothesize that starting at birth mice with OI will have delayed craniofacial growth due to the poor collagen formation.
Methods: To test our hypothesis, we collected cranial bone volumes from micro-CT scans of the homozygous recessive OI murine model (OIM or B6C3Fe a/a-Col1a2oim/oim) and compared them to their wild type (WT) littermates. The OIM model has a COL1A2 mutation that has been found to express a similar skeletal phenotype to the severe form (type III) of OI in humans. Bone volumes were collected from birth (P0) and weaning (P21) from the nasal, frontal, parietal, interparietal, and occipital bones (n=2/genotype/timepoint).
Results: At birth, OIM and WT bone volumes were similar. By weaning, bone volume was lower in OIM mice compared to WT mice. Our results demonstrate that OIM mice have reduced rates of bone ossification between birth and weaning, and these differences are most profound in the facial and occipital regions. Additionally, OIM skulls are characterized by low bone volume and potential delays in the closure of cranial sutures and fontanelles.
Conclusions: This study suggests that the divergence in cranial ossification rates related to COL1A2 mutations occurs postnatally. Interventions to recover craniofacial bone growth in this experimental model should focus on the critical growth period between birth and weaning. Results from this research have the potential to assist in developing treatments and highlight the importance of early life development of the craniofacial bones in human patients with OI.Ralph W. and Grace M. Showalter Research Trust and Indiana University Collaborative Research Gran
The Role of Mitochondrial Respiration in Müller Glia Survival and Function Under Normal and Glaucomatous Conditions In Vivo
No full textSeveral markers of mitochondrial dysfunction have been observed in the retinas of glaucoma patients and experimental animal models. However, these studies have primarily focused on retinal neuron cells even though glial cells too contain significant amounts of mitochondria. Thus, little is known about how glial cell mitochondrial dysfunction contributes to glaucoma pathology. As the principal macroglial cells of the retina, Müller glia (MG) function is essential to maintaining homeostasis in the retina. However, very little is known about how MG generate energy to support their function in vivo. In this study, we address the role of mitochondrial respiration in MG using an inducible Cox10 knockout transgenic mouse model. Cox10 (protoheme IX farnesyltransferase) encodes a component of cytochrome c oxidase (COX), complex IV, of the electron transport chain. Cox10 deficient cells lack functional COX. Disruption of COX function in MG did not affect MG survival nor retinal structure but impaired visual function and upregulated glycolysis pathway protein expression in the retina. These data suggest that MG-specific mitochondrial respiration is essential for whole retinal energy metabolism and visual processing. Hypoxia-inducible factor 1α (HIF-1α) has been shown to be upregulated in the glaucomatous retina and optic nerve, yet its role in glaucoma pathogenesis remains unexplored. HIF-1α is a transcription factor that promotes glycolysis and metabolic adaptation during hypoxia. By blocking HIF-1α degradation through pharmacologic inhibition, we found that prolonged HIF- 1α stabilization led to retinal glycolysis and oxidative phosphorylation (OXPHOS) protein downregulation and AMP-activated protein kinase (AMPK) activation, indicating low energy status. These changes were accompanied by impaired retinal ganglion cell (RGC) function and glial cell activation. Taken together, these results demonstrate the essential role of MG-specific OXPHOS in the retina, as well as pointing to a role for HIF-1α in neurodegeneration in the retina
Preliminary Results from the DFW Viet-American Health Pilot Study
No full textResearch Appreciation Day Award Winner - School of Public Health, 2023 Community Engaged Research AwardIntroduction
Arthritis is a chronic condition that can cause pain, physical disability, and reduced quality of life (QOL). The prevalence, severity, symptoms, and management of osteoarthritis (OA) are known to differ by race and ethnicity. Studies on racial differences focused mostly on Black or Hispanic populations with little attention on Asian Americans, such as socioeconomically marginalized, medically under-served, and hard-to-reach Vietnamese-Americans (VietAmericans). This pilot study investigated the occurrence, symptoms, knowledge, and management of arthritis among Viet-Americans.
Methods
From 7/1/22-8/31/22 and with help from community leaders of faith-based community organizations, we recruited people of Vietnamese descent of age ≥ 45 years and living in the Dallas-Fort Worth (DFW) metroplex.. We translated and adapted a linguistically and culturally appropriate questionnaire from English to Vietnamese using the Translation, Review, Adjudication, Pretesting, and Documentation(TRAPD) Model. Participants completed the survey which asked about their demographics, height, weight, chronic conditions, the 12-item Knee Injury and Osteoarthritis Outcome Survey (KOOS), the Veterans RAND 12-item Health Survey (VR12), and awareness of knee osteoarthritis (OA). We then calculated the body mass index and summary scores for KOOS pain, function, and QOL.
Results
Of 272 participants who completed the questionnaire (82% enrollment rate), 53% were women and 54% were ≥ 65 years old. The average stay in the US was 30 years (±12.8). The results indicated a low prevalence of overweight (21%) and obesity (6%). Knee OA occurred in 20% of men and 25% of women. Of note, 13% of men and 22% of women said they have rheumatoid arthritis (RA). Only 41% of participants knew that an optimal weight could prevent knee OA. About a third of men and women reported knee pain (KOOS QOL pain score <70). Additionally, 25% of men, 35% of women, and 36% of those ≥65 years reported experiencing pain weekly, daily, or constantly. Furthermore, 40% of men, 53% of women, and 56% of those ≥65 years reported having fair or poor general health. Compared to a year ago, 50% of men and women rated their physical health as slightly or much worse. Although 95% of patients had medical insurance, most of the participants (84%) used alternative pain management such as massages, herbal medicines, and acupressure.
Conclusion
Participants reported a high prevalence of both OA and RA despite a low prevalence of overweight or obesity. Many people were unaware of risk factors related to OA and how weight management is crucial in the prevention of this disease. The results may be limited by the participants’ knowledge of medical conditions such as OA and RA. The next phase of the study will investigate and examine the reliability and validity of the translated instruments, the accuracy of self-reported OA and RA, and factors associated with poor health, including arthritis-related pain.National Institute on Minority Health and Health Disparitie
