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Supplemental Figure 1 (S1) for Manuscript titled "Rodents Exposed to Placental Ischemia in Utero Display Sex Differences in Brain miRNA Expression, Mitochondrial Function, and Blood Pressure in Adulthood"
Full text linkFigure Legend: Supplemental Figure 1: Litter size for normal pregnant and placental ischemia dam
Genetically-engineered Salmonella typhimurium expressing FGF21 promotes neurological recovery in ischemic stroke via FGFR1/AMPK/mTOR pathway
Full text linkBACKGROUND: Ischemic stroke (IS) remains a leading cause of mortality and disability, with limited therapeutic options due to poor drug delivery to ischemic lesions. To address this challenge, an engineered Salmonella based therapeutic method for targeted drug delivery and long-term treatment is herein designed to mitigate ischemic damage. METHODS: We engineered an attenuated luminescent Salmonella typhimurium (S.t -DeltapG) strain with an L-arabinose-inducible pBAD system to secrete bioactive FGF21. C57BL/6 mice were used to to measure neuron apoptosis and the activity of immune cells following IS induction plus S.t-DeltapG injection. Bioluminescence imaging was applied for bacterial colonization. ELISA and glucose uptake assays were performed to detect FGF21 secretion and the bioactivity. Neurological tests, TTC staining, and TUNEL labeling were used to assess the therapeutic effects of barterially secreted FGF21. Immunofluorescence assay of FGF21/FGFR1 dominant pathway was explored to investigate neuroprotective mechanism, while IBA-1 staining, CD3/CD68 immunostaining, cytokine profiling, and hepatorenal histopathology were detected to evaluate biosecurity. RESULTS: S.t-DeltapG(FGF21) selectively colonized peri-infarct regions and secreted functional FGF21, reducing neurologic deficits (48%) and infarct volume (46%) versus controls (p < 0.01). Mechanistically, immunofluorescence demonstrated that bacterially secreted FGF21 activated neuronal FGFR1/AMPK/mTOR pathway to enhance autophagy, whereas autophagy inhibition abolished its neuroprotection. Further, bacterial exclusion from neuron was validated via MAP2/NeuN plus Salmonella co-staining in primary neuron cells and brain tissue. Critically, CD3/CD68 immunostaining, serum cytokine profiling, and hepatorenal histopathology confirmed the long-term biosafety of this approach. CONCLUSION: Our study presents a novel, Salmonella - based platform for targeted and sustained FGF21 delivery, offering a promising therapeutic strategy for ischemic stroke with robust efficacy and minimal systemic toxicity.This research was funded by grants from the National Natural Science Foundation of China (U24A20697, 82271345 and 82171469), Zhejiang provincial natural Science Foundation (LQ22H090010), and the Wenzhou Municipal Science and Technology Bureau Project (Y20240105)
Enhancing Oral Absorption of an Ester Prodrug by Coating Drug Crystals with Binary Lipid Systems and Evaluating the Influence of Compositions
Full text linkBackground/Objectives: Prodrug strategies are a vital aspect of drug development, with ester prodrugs particularly notable for modifying parent drug properties through ester functional groups to enhance oral absorption. However, ester prodrugs are prone to hydrolysis by water and enzymes, making stability in the gastrointestinal (GI) tract prior to absorption a key challenge. Few formulation strategies effectively address this degradation issue. We recently introduced binary lipid systems (BLS), comprising a lipid and a water-soluble surfactant only that form stable microemulsions. This study aimed to explore the application of BLS for enhancing the oral absorption of ester prodrugs by coating drug crystals with BLS in solid granules and study the impact of the compositions of BLS on oral absorption. Methods: Olmesartan medoxomil (OLM), a methyl ester prodrug of olmesartan (OL), was selected as a model drug. Various lipids were combined with TPGS to form BLS and used to prepare OLM solid granules containing OLM crystals. Results: Among the tested formulations, OLM MCM-TPGS granules significantly enhanced drug release and protected OLM from enzyme-mediated degradation in two-step dissolution studies with esterase. Pharmacokinetic and tissue distribution studies in rats confirmed that OLM MCM-TPGS granules improved oral absorption by 145% and increased tissue uptake compared to OLM powder. Conclusions: This approach overcomes solubility limitations when using lipids and surfactants as excipients, enabling high drug loading in solid dosage forms and expanding the utility of lipids and surfactants for water-insoluble drugs. This novel formulation strategy holds great potential for enhancing oral absorption of ester prodrugs, representing a significant advancement in formulation technologies and offering more effective and versatile drug delivery solutions.This work was supported by the National Institutes of General Medical Sciences [1R35GM138225] to Dong, X
Peroxisome proliferator-activated Receptor Alpha agonist Fenofibrate Suppresses Corneal Fibrosis
No full textPurpose: The transparency of the cornea is critical to its function. Corneal haze brought on by fibrosis due to insult can lead to partial or complete vision loss. Currently, corneal transplantation is the gold standard for treating severe corneal fibrosis, which comes with the risk of rejection and the challenges of donor tissue shortages. Peroxisome proliferator-activated receptor alpha (PPAR-α), a transcription factor belonging to the nuclear hormone receptor family, has been linked to inhibiting hepatic and renal fibrosis. Our group has also shown the role of PPARα in the human diabetic cornea. Herein, using primary healthy human corneal fibroblasts (HCFs), we investigated the role of PPAR-α activation in corneal fibrosis, in vitro. Methods: HCFs were isolated, plated on polycarbonate membranes, and stimulated with a stable 0.5 mM Vitamin C (VitC) derivative (3D in vitro model). The groups tested were: (1) Control (no treatment-VitC only); (2) 0.1ng/ml Transforming Growth factor β1 (TGF-β1); (3) 10 µM Fenofibrate; (4) 20 µM Fenofibrate (5) Rescue groups: (TGF-β1administered for 2 weeks followed by the different concentrations of fenofibrate for another for 2 weeks); (6) Prevent groups (the different concentrations of fenofibrate administered for 2 weeks followed by TGF-β1 for another for 2 weeks). All 3D constructs were examined for protein expression of fibrotic markers using western blots. Results: Our data indicated that TGF-β1 treatment resulted in significant increases in α-SMA, Col III, cFN, and TSP-1 protein expressions. However, these increases were notably reduced by 20 µM fenofibrate in both the rescue and prevention groups. Furthermore, the fenofibrate (10µM significantly suppressed the elevated levels of α-SMA, Col III, and TSP-1 in both rescue and prevention groups. This effect was observed in all instances of 10 µM fenofibrate treatment except for Col III in the rescue group and cFN in both groups. Conclusions: Our data demonstrated that fenofibrate downregulate corneal fibrosis, in vitro; suggesting that PPAR-α may serve as a potential therapeutic target for corneal fibrosis. However, further studies are needed to thoroughly delineate PPAR-α signaling mechanisms underlying corneal fibrosis
Association between rurality and meeting cervical cancer prevention screening guidelines by age and race-ethnicity
No full textBackground: Despite screen and treatment strategy advancement, cervical cancer remains a significant public health concern. Seventy-two percent of women with a cervix aged 21–65 years adhered to the United States Preventative Services Task Force recommendations for cervical cancer screening (CCS) in 2021. Recommendations state that those aged 21 to 29 years old should receive a pap test every three year, those aged 30 to 65 years old should receive a pap test alone every three years, or a pap test with a high-risk human papillomavirus test every five years. Research indicates residing in a rural area (rurality) and associated sociodemographic factors influence the incidence of cervical cancer; however, few studies have assessed their effect on CCS. Therefore, this study aimed to examine associations between CCS adherence and rurality, explore related demographic characteristics, and evaluate potential effect modification of race-ethnicity and age. Methods: Cross-sectional data from the 2017-2019 National Survey of Family Growth were used to evaluate CCS adherence among women aged 21-49 years (n=4579). Descriptive statistics were generated including count and survey-weighted percentages for each variable of interest. A survey-weighted multivariable logistic regressions estimated odds of adherence by residence type (suburban and rural versus urban), adjusting for race-ethnicity, educational attainment, insurance, and age (21-29 vs. 30-49 years). Models were further stratified by age and race-ethnicity to assess potential effect modification. Results: Overall, 78.9% of participants adhered to CCS guidelines with differences by residence type (urban: 77.7%; suburban: 76.0%; rural: 71.5%). After adjusting for age, race/ethnicity, educational level, and insurance status, rural residents had 0.74 (95% CI: 0.55-1.01) lower odds of adherence compared to urban residents. Those with single-service plans or no insurance had lower odds of adherence (OR = 0.73, CI [0.57-0.94]), compared to those with private insurance, as did non-Hispanic Black women (OR = 1.45 (95% CI=0.99-2.12)) relative to non-Hispanic White women and women aged 30-49 (OR = 0.75, 95% CI [0.0.61-0.93]) relative to those aged 21-29. Race/ethnicity and age did not modify associations between CCS adherence and rurality. Conclusion: Results suggest rurality is potentially a barrier to CCS uptake. Future research should explore factors unique to rurality, such as access to care and cultural beliefs, as potential modifiers to CCS uptake. The effects of rural residents’ lower screening rates on later stage disease identification and disease severity should also be explored. Understanding the effect of rurality on the utilization of preventative services is crucial in developing tailored interventions, programs, and policies
Enhancing oral absorption of ester prodrugs by applying a binary lipid coating to drug crystals and evaluating the influence of coating composition
No full textPurpose: Olmesartan medoxomil (OLM), a widely used antihypertensive drug, suffers from low bioavailability of approximately 26% due to poor water solubility and high susceptibility to carboxylesterase-mediated hydrolysis in the gastrointestinal (GI) tract. Recently, our lab discovered a novel lipid-based system, named binary lipid systems (BLS), composed of one lipid and one water-soluble surfactant that form stable microemulsions. This study aimed to explore the application of BLS in enhancing the oral absorption of ester prodrugs by coating drug crystals with BLS in solid granules. Methods: BLS were developed using various lipids (Capmul MCM C8, Miglyol 812, Capmul PG8) and D-α-tocopheryl polyethylene glycol succinate (TPGS) in different combinations. OLM crystals were mixed with BLS and loaded on Aeroperl 300 to prepare OLM solid granules. Two-step dissolution studies mimicking human and rat GI conditions, both with and without carboxylesterase (CE), were performed to evaluate drug release and assess the protective effects of BLS against hydrolysis. Pharmacokinetic studies in rats determined the oral bioavailability of OLM, while tissue distribution studies evaluated OLM uptake in organs such as the liver, kidney, heart, and spleen. The physical state of OLM within the different formulations was characterized using powder X-ray diffraction (XRD). Results: XRD confirmed that OLM was present in its crystalline form within the formulations. The drug loading was 10%. In dissolution studies, OLM MCM-TPGS granules demonstrated significantly improved drug release and protection against CE-mediated degradation. Pharmacokinetic studies confirmed that OLM MCM-TPGS granules increased oral bioavailability by 145% compared to OLM powder. The tissue distribution studies revealed enhanced uptake of OLM in the liver and heart, with no significant changes observed in the mesenteric lymph nodes. A significantly higher Cₘₐₓ and AUC were also seen for the OLM MCM-TPGS granules compared to other formulations, indicating a higher systemic exposure and enhanced absorption compared to other OLM granules and OLM powder. Conclusions: This approach eliminates solubility as a limiting factor when selecting lipids and surfactants, enabling high drug loading in solid dosage forms and expanding the utility of lipids and surfactants for water-insoluble drugs. This novel formulation strategy holds great potential for enhancing oral absorption of ester prodrugs, representing a significant advancement in formulation technologies and providing more effective and versatile drug delivery solutions
Chemotherapeutic Approaches to Radiation-Induced Angiosarcoma
No full textPurpose: Malignancy is a well-established risk associated with radiation therapy. Angiosarcomas are rare, aggressive mesenchymal neoplasms, often presenting on the skin. Radiation is a well-recognized risk factor for angiosarcoma, with over 200 cases having been reported in the literature. The median survival for angiosarcomas secondary to irradiation has been reported as 12 months, making the prognosis dismal. The first-line treatment for angiosarcoma is surgical resection; however, due to the aggressive nature of the neoplasm, about 50% of individuals with localized disease develop local recrudescence and distant metastasis. Chemotherapy is the treatment of choice in cases of metastatic angiosarcoma. Due to the heterogeneity of the histopathological characteristics of angiosarcomas, it has been difficult to standardize an optimal chemotherapeutic regimen. This study aims to explore the efficacy of various chemotherapeutic agents in improving overall survival in patients with post-radiation angiosarcoma. Methods: An electronic search was completed on Pubmed, SCOPUS, and Google Scholar. Articles that fit into the theme of “chemotherapeutic agents improving survival in patients with post-radiation angiosarcoma” were then identified and extracted. 7 articles were identified and included in the literature review. Results: As expected, the results across the articles vary. The primary treatment of choice is surgery for those who can tolerate surgery and as long as the tumor has not metastasized. However, since a large number of angiosarcomas have already metastasized, chemotherapy is the next treatment option. Many of the articles selected highlight the difficulty in choosing a treatment regimen for post-radiation angiosarcomas due to the heterogeneity of the histopathological characteristics of angiosarcomas. The first line treatment across the literature suggests combination chemotherapy with a regimen including taxanes, doxorubicin, and ifosfamide is the most efficacious. A majority of the articles suggest Taxol therapy as a front-runner if monotherapy were to be used, as it seems to consistently show the longest survival rate. However, doxorubicin is another commonly used chemotherapy that also shows success in treating post-radiation angiosarcomas. Conclusions: Post-radiation angiosarcoma causes difficulty with regards to treatment due to its unique histopathological characteristics. Based on the literature, combination chemotherapy appears to be the most effective, particularly regimens containing taxanes, doxorubicin, and ifosfamide. If monotherapy were to be used, Taxol therapy has shown very promising results. Future research should compare chemotherapeutic regimens used to treat post-radiation angiosarcoma with and without Taxol therapy to further isolate its efficacy
The Association Between Asthma and Anxiety: An Evidence Base for Comprehensive Integrated School Health
No full textPurpose: Asthma and anxiety are two highly prevalent and often co-morbid conditions in the pediatric population, with growing evidence supporting a bidirectional relationship. The complex interplay between these comorbid conditions is mediated by behavioral, physiological, and psychosocial mechanisms. Using a comprehensive biopsychosocial model, we can learn about the outcomes of these concomitant health morbidities. The goal of our rapid review is to evaluate the current interventions for school-aged children who experience concomitant asthma and anxiety. Our hope is that this project can highlight the importance of an integrated approach. Methods: A systematic review was completed to screen for pertinent studies that evaluate the association between chronic asthma, behavioral health factors, and the structural determinants of health. The project also investigates what interventions have been initiated to respond to children with concomitant asthma and anxiety or depression, and their effectiveness. Results: 380 sources were screened using inclusion and exclusion criteria, and the systematic review was narrowed to 31 texts. A template was created for use to extract data from each article of text, and a chart was created to compare all of the relevant research. 27 articles were then extracted, which each demonstrated a strong association between asthma and mental health conditions such as anxiety or depression in children. This connection appears to be influenced by demographic factors (e.g., gender) and warrants attention for better healthcare outcomes. Interventions were studied in 13 of the 27 articles. Systematic reviews or database analysis studies typically did not include information on interventions being evaluated. Interventions included mental health services, therapy sessions such as art and music therapy, and educational and behavioral support all conducted in controlled environments. Conclusions: Of the 27 studies that progressed to full data extraction, there was a strong association between concomitant pediatric asthma and its association with mental health conditions such as anxiety and depression. In the 13 studies that examined interventions in order to reduce the impact of mental health conditions on pediatric health outcomes, studies generally found proof of positive outcomes that improved mental health and reduced symptoms of anxiety or depression. Furthermore, these studies showed that certain interventions enhanced the measured quality of life in children. These results reinforce the importance of the biopsychosocial model and the importance of the recognition of the concomitant relationship between pediatric asthma and anxiety and depression. Furthermore, this analysis demonstrates the need for more tailored studies on interventions that can be performed in order to reduce symptoms and improve the overall quality of life in children living with asthma
Comparison of Fidaxomicin vs. Vancomycin use in Clostridioides difficile Infection at a Community Hospital
No full textPurpose: Clostridioides difficile infection (CDI) is a highly contagious bacterial infection causing severe diarrhea that is associated with substantial morbidity and mortality. As the number of recurrences of CDI increases, mortality rate also increases. The purpose of this research is to evaluate the medication choice of fidaxomicin vs. vancomycin in the treatment of initial or recurrent episodes of either non-severe or severe CDI in terms of clinical cure, recurrence rate and safety outcomes in a real-world setting. Methods: This retrospective chart review was conducted at Medical City Arlington, reviewing data between January 1, 2014, and March 1, 2024. Eligible patients were 18 years or older, diagnosed with initial or recurrent episodes of non-severe or severe CDI, and treated with either fidaxomicin or vancomycin. Patients received either fidaxomicin 200 mg orally twice daily or vancomycin 125 mg orally four times daily for 10 days. Results: The primary outcome is the clinical cure, which is defined as the resolution of symptoms and no further treatment was needed for CDI after the first course of antibiotics. The secondary outcomes are the recurrence rate within 2-8 weeks after treatment has been completed, re-admittance to Medical City Arlington and all-cause mortality. The safety outcomes include reported adverse events (e.g., nausea, vomiting, abdominal pain, hypokalemia). The fidaxomicin-treated group (24 patients) had a clinical cure rate of 66.7%, compared to 92% in the vancomycin-treated group (25 patients) (P = 0.037). Recurrence rate and readmittance for recurrence occurred in 4.2% of the fidaxomicin group, vs. 8% in the vancomycin group (P = 1.0). One patient in the fidaxomicin-treated group experienced all-cause mortality (4.2%), compared to no patients in the vancomycin-treated group (P = 0.049). Both fidaxomicin-treated and vancomycin-treated groups have comparable safety outcomes, with one patient in each group experiencing hypokalemia. Conclusion: Within our internal analysis, there was a significant difference in clinical cure between fidaxomicin and vancomycin groups, but no significant difference in recurrence rate, although the recurrence rate was higher in the vancomycin group
The Effect of Lower Extremity Joint Pain Location on Postural Sway
No full textPurpose: Falls are the leading cause of deaths from injury among adults aged ≥65 years. Postural sway (used as an independent predictor of fall risk) is a measurement of balance and refers to the movement of a person’s center of mass while maintaining an upright position. Numerous studies have concluded that lower extremity (LE) joint pain decreases postural stability. However, few studies have determined whether pain in a particular LE joint (hip, knee, foot/ankle) significantly increases sway more than the others. Investigating this relationship has implications for the early identification of high fall-risk individuals, thereby facilitating proactive interventions. Methods: In this chart review study, data was collected from patients at the University of Texas Health Science Center health clinics. Patients were excluded from this study if they were under 18 years of age or unable to stand unassisted for more than 5 minutes. Participants stood on the Bertec Force Plate for 30 seconds, first with eyes open (EO) and then with eyes closed (EC). The sway data collected for each encounter were then merged with the patient’s medical record in a de-identified data warehouse. Postural sway measurements for all patients containing ICD-10 codes associated with LE joint pain were pulled and divided into three subpopulations: hip pain (182 patients), knee pain (113 patients), foot/ankle pain (19 patients). Three single tail T-tests were conducted to compare sway variables (range of the center of pressure (COP) in the medial-lateral (ML) and the anterior posterior (AP) axis, total length of the COP path (Totex), and average sway angle (ASA)) among each of the subpopulations. Statistical significance was denoted at p < 0.02 using a Bonferroni correction. Results: For the EO condition, Range COP ML was significantly elevated in the knee pain subpopulation compared to the hip and foot/ankle pain subpopulations (p = 0.019 and 0.0007, respectively). Similarly, Totex was elevated in the knee pain subpopulation versus the hip and foot/ankle pain subpopulations (p = 0.006 and 0.007, respectively). For the EC condition, Range COP ML was also elevated in the knee pain subpopulation compared to the hip and foot/ankle pain subpopulations (p = 0.006 and 0.003, respectively). Similarly, Totex was elevated in the knee pain subpopulation versus the hip and foot/ankle pain subpopulations (p = 0.0003 and 0.002, respectively). Further, knee pain patients had elevated Range COP AP and ASA compared to hip pain patients (p = 0.001 and 0.004, respectively). Conclusions: The knee pain subpopulation had significantly elevated variables of sway compared to the other LE joints, suggesting that knee pain is more debilitating to postural stability and thus relatively increases fall-risk. A proposed mechanism for this is that the knee, lacking the hip's extensive ligamentous and labral reinforcement, exhibits less anatomical stability. This lack of anatomical constraint may predispose patients with knee pain to relatively greater postural instability. Clinicians should recognize this relationship when evaluating patients with knee pain and consider implementing proactive fall-prevention interventions