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Developing a nanoparticle platform for selective delivery of the anti-cancer drug MIH 2.4Bl to breast cancer cells
No full textBased on data from the World Health Organization, breast cancer is the most common cancer among women, accounting for about 15% of all cancer-related deaths. Thus, new treatment options are urgently needed to decrease this mortality rate. In recent years, mesoionic compounds have shown promising potential as anti-cancer agents due to their unique structure and reaction properties. We reported that a 1,3-thiazolium-5-thiolate mesoionic compound (MIH 2.4Bl) inhibited the growth of most of the breast cancer cell lines tested compared with normal human mammary epithelial cells. Treatment of MCF-7 breast cancer cells with MIH 2.4Bl resulted in alterations in cell cycle distribution with an increased proportion of cells in the G2/M phase compared with untreated cells. MCF-7 cells treated with MIH 2.4Bl also showed morphological changes consistent with apoptotic cell death. In addition, treating MCF-7 cells with MIH 2.4Bl resulted in a significant reduction in all mitochondrial respiratory parameters compared with the control cells, indicative of an overall decrease in mitochondrial membrane potential. These findings suggest that MIH 2.4Bl is a promising candidate for treating breast cancer. However, cancer therapy's primary challenge is the selective destruction of malignant cells while sparing normal cells to preserve tissue integrity. The development and use of drug delivery systems is a recognized approach to improving the efficacy of chemotherapy agents. However, drug delivery systems have been unexplored in mesoionic compounds. The reconstituted high-density lipoprotein (rHDL) nanoparticles have several advantages, including enhanced safety, efficacy, and biocompatibility. The payload, which is contained in the core of the HDL particle, is taken up by SR-B1 receptors, making this method particularly useful for targeted cancer chemotherapy. The upregulation of the SR-B1 receptor by tumor cells and tissues might be helpful in cancer treatment by specifically delivering drug-loaded nanoparticles to the tumors. In this preliminary work, we present an improved delivery strategy of a newly developed formulation of MIH 2.4Bl compound with rHDL nanoparticles as the delivery agent. Initial synthesis, optimization, physicochemical characterization, drug loading, and drug release assessment of the nanoparticles were performed. These studies support the potential therapeutic use of MIH 2.4Bl in treating breast cancer. To advance potential translational studies for monitoring in vitro drug delivery and colocalization of the drug in the cells, we have begun studies of the fluorescence properties of MIH 2.4Bl, using steady-state and time-resolved fluorescence techniques. The fluorescence characteristics of free MIH 2.4Bl was evaluated using UV/VIS and fluorescence spectroscopy. The steady-state and time-resolved measurements were designed to understand the optical properties of MIH 2.4Bl in solution for monitoring in vitro drug delivery and cellular colocalization. All samples, dissolved in various solvents, exhibited maximum absorbance between 440 and 480 nm; excitation at 440 nm elicited the highest emission at approximately 580 nm in methanol. These results may allow future detection and localization of MIH 2.4Bl in vitro and in vivo. Follow-up studies utilizing fluorescence confocal microscopy are anticipated to reveal drug accumulation's site(s) in situ and how cytotoxicity is induced in cancer cells
Effect of 2018 American College of Cardiology/American Heart Association Guideline Change on Statin Prescription for People Living with HIV
No full textThe American College of Cardiology (ACC)/American Heart Association (AHA) guidelines were updated in 2018 to explicitly recommend statin use for primary cardiovascular disease prevention among people living with HIV (PLWH), but little is known about the effect of this guideline change. We aimed to assess the effect of the 2018 ACC/AHA guideline change on statin prescription among PLWH. We used data from an institutional HIV registry to identify PLWH aged 40-75 years, engaged in HIV care between June 2016 and May 2021, had a LDL cholesterol between 70 and 189 mg/dl, 10-year atherosclerotic cardiovascular disease (ASCVD) risk score >/=7.5%, no prior statin prescription, and no history of diabetes or ASCVD. Our outcome of interest was a new statin prescription within 12 months of eligibility. We estimated standardized risk difference (RD) with 95% confidence limits (CL) by comparing prescription probabilities before and after guideline change. Our study population comprised 251 PLWH (171 before, 80 after the guideline change), of whom 57% were aged <55 years, 82% were male, and 45% were non-Hispanic black. The standardized 12-month statin prescription risk was 43% (95% CL: 31%, 60%) after the guideline change and 19% (95% CL: 13%, 26%) before the guideline change (RD = 25%, 95% CL: 9.1%, 40%). Our results suggest that the 2018 ACC/AHA guideline change increased statin prescription among PLWH, but a sizable proportion of eligible PLWH were not prescribed statin. Future studies are needed to identify strategies to enhance implementation of statin prescription guidelines among PLWH
Morphological variability in the inner ear of mice with osteogenesis imperfecta
No full textOsteogenesis imperfecta (OI) is known to cause hearing loss in ~60% of the affected human population. While OI-related pathologies have been studied in the middle ear, the development of cochlear pathologies is less well understood. In this study, we examine OI-related pathologies of the cochlea in a mouse model of OI to (1) document variation between OI and unaffected mice, and (2) assess the intrusion of the otic capsule onto the cochlea by analyzing differences in duct volumes. Juvenile and adult OIM C57BL/6mice were compared to unaffected wildtype (WT) mice using three-dimensional models of the cochlea generated from high resolution micro-CT scans. Two-tailed Mann-Whitney U tests were then used to investigate duct volume differences both within and between the OI and WT samples. Areas of higher ossification were observed at the cochlear base in the OI sample. OI mice also had significant intraindividual differences in duct volume between right and left ears (4%-15%), an effect not observed in WT mice. WT and OI duct volumes showed a large degree of overlap, although the OIM volumes were more variable. Our findings indicate that OIM mice are likely to exhibit more asymmetry and variation in cochlear volume despite minor differences in sample cochlear volumes, possibly due to bony capsule intrusion. This suggests a potential mechanism of hearing loss, and a high potential for cochlear and otic capsule alteration in OIM mice.The authors wish to thank Drew Brown for his assistancewith collecting microCT scans, and Courtney Miller for herfeedback on project design. This research was supported bythe Ralph W. and Grace M. Showalter Research Trust, anIndiana University Collaborative Research Grant, and anUNTHSC Department of Physiology & Anatomy SeedGrant
Osteogenesis Imperfecta: Implications of Using Micro-CT for Visualizing Developmental Variation in the Middle and Inner Ear of OIM Mice
No full textOsteogenesis Imperfecta: Implications of Using Micro-CT for Visualizing Developmental Variation in the Middle and Inner Ear of OIM Mice
Dallin R. Judd1, Brenton R. Stucki1, Courtney A. Miller2, Emma Handler3, Rachel A. Menegaz2, Lauren A. Gonzales2
1 Texas College of Osteopathic Medicine, University of North Texas Health Science Center, TX
2 Department of Physiology and Anatomy, University of North Texas Health Science Center, TX
3 Department of Anatomy and Cell Biology, University of Iowa, IA
Osteogenesis imperfecta (OI), also known as brittle bone disease, is a genetic bone disorder caused by mutations in the genes COL1A1 and COL1A2, which are responsible for encoding type I collagen. Much is known regarding the effects of the disease on cranial and postcranial elements. However, little is known regarding the pathogenesis and physical manifestations of OI in the ear despite the high rates of hearing loss in patients with OI (~60% of the population is affected). Because ossification or demineralization of structures in the ear may affect the efficacy of certain treatments like cochlear implants, this information deficit limits the treatment options available for OI patients. Thus, the purpose of our research is to visualize and document anatomic variation in the ears of mice bred to have the Type III OI genetic variant in order to better understand the cause of OI-related hearing loss.
3D models of the middle and inner ears were created from micro-CT scans that also employed two new contrast-enhanced methods to visualize the cochlea and middle ear (malleus, incus, and stapes). All CT scanning were done on the UNTHSC campus using the new Small Animal Imaging Facility (SAIF) as part of a previous study. The scan resolution was approximately 20μm. The studied WT and OIM mouse samples include three time points intended to capture a developmental sequence: 0-day-old (WT=20, OIM=29), 7-day-old (WT=23, OIM=23), and 14-day-old mice (WT=22, OIM=18). The visualization software Avizo was then used to digitally segment the bone of the inner ear and middle ear. Gross anatomic differences are currently being documented for each region.
Previous work has shown higher levels of ossification and marked bony encroachment of the otic capsule onto the cochlea in the adult OIM mouse model, potentially damaging the soft tissue of the membranous labyrinth. This research uses micro-CT imaging designed to capture a developmental sequence, giving us the potential to elucidate how and when the bony intrusions are impacting surrounding structures. Insight into this anatomical damage may help further clarify OI-related pathology, including the distinction between hearing loss associated with the middle ear (conductive hearing loss) vs. hearing loss associated with the inner ear (sensorineural hearing loss). Furthermore, a preliminary analysis of the developmental sequence should provide insight into when these anatomical changes are first occurring. Upon completion, this research will demonstrate the efficacy of using these new imaging approaches for studying minute structures of the ear and may markedly advance our understanding of the pathogenesis of OI-related hearing loss
Withaferin A: A Pleiotropic Anticancer Agent from the Indian Medicinal Plant Withania somnifera (L.) Dunal
Get PDFCancer represents the second most deadly disease and one of the most important public health concerns worldwide. Surgery, chemotherapy, radiation therapy, and immune therapy are the major types of treatment strategies that have been implemented in cancer treatment. Unfortunately, these treatment options suffer from major limitations, such as drug-resistance and adverse effects, which may eventually result in disease recurrence. Many phytochemicals have been investigated for their antitumor efficacy in preclinical models and clinical studies to discover newer therapeutic agents with fewer adverse effects. Withaferin A, a natural bioactive molecule isolated from the Indian medicinal plant Withania somnifera (L.) Dunal, has been reported to impart anticancer activities against various cancer cell lines and preclinical cancer models by modulating the expression and activity of different oncogenic proteins. In this article, we have comprehensively discussed the biosynthesis of withaferin A as well as its antineoplastic activities and mode-of-action in in vitro and in vivo settings. We have also reviewed the effect of withaferin A on the expression of miRNAs, its combinational effect with other cytotoxic agents, withaferin A-based formulations, safety and toxicity profiles, and its clinical potential.This work was supported by the National Research Foundation of Korea (NRF) and the grant was funded by the Korean government (MSIP) (NRF-2021R1I1A2060024)
Moderation effects of serotype on dengue severity across pregnancy status in Mexico
Get PDFBACKGROUND: Pregnancy increases a woman's risk of severe dengue. To the best of our knowledge, the moderation effect of the dengue serotype among pregnant women has not been studied in Mexico. This study explores how pregnancy interacted with the dengue serotype from 2012 to 2020 in Mexico. METHOD: Information from 2469 notifying health units in Mexican municipalities was used for this cross-sectional analysis. Multiple logistic regression with interaction effects was chosen as the final model and sensitivity analysis was done to assess potential exposure misclassification of pregnancy status. RESULTS: Pregnant women were found to have higher odds of severe dengue [1.50 (95% CI 1.41, 1.59)]. The odds of dengue severity varied for pregnant women with DENV-1 [1.45, (95% CI 1.21, 1.74)], DENV-2 [1.33, (95% CI 1.18, 1.53)] and DENV-4 [3.78, (95% CI 1.14, 12.59)]. While the odds of severe dengue were generally higher for pregnant women compared with non-pregnant women with DENV-1 and DENV-2, the odds of disease severity were much higher for those infected with the DENV-4 serotype. CONCLUSION: The effect of pregnancy on severe dengue is moderated by the dengue serotype. Future studies on genetic diversification may potentially elucidate this serotype-specific effect among pregnant women in Mexico.There was no funding for this study. U.H. was supported by Rutgers Global Health Institute
Demographic and Psychosocial Correlates of COVID-19 Vaccination Status among a Statewide Sample in Texas
Get PDFThe COVID-19 pandemic has been a global public health concern since early 2020 and has required local and state-level responses in the United States. There were several Food and Drug Administration (FDA) approved vaccines available for the prevention of COVID-19 as of August 2022, yet not all states have achieved high vaccination coverage. Texas is a particularly unique state with a history of opposing vaccination mandates, as well as a large and ethnically/racially diverse population. This study explored the demographic and psychosocial correlates of COVID-19 vaccinations among a statewide sample in Texas. A quota sample of 1089 individuals was surveyed online from June-July 2022. The primary outcome in this study was COVID-19 vaccination status (fully vaccinated, partially vaccinated, or unvaccinated) and included independent variables related to demographics, COVID-19 infection/vaccine attitudes and beliefs, and challenges related to the COVID-19 pandemic. Hispanic/Latinx individuals were more likely than non-Hispanic White individuals to be partially vaccinated as opposed to unvaccinated. Higher education levels and confidence that the FDA would ensure a safe COVID-19 vaccine were strongly associated with a higher likelihood of being fully vaccinated. In addition, some challenges brought on by the pandemic and concerns about becoming infected or infecting others were associated with a higher likelihood of being partially or fully vaccinated. These findings emphasize the need to further investigate the interaction between individual and contextual factors in improving COVID-19 vaccination rates, especially among vulnerable and disadvantaged populations.This study was funded by the National Institutes of Health (NIH) Agreement 1OT2HL156812-02 as part of the NIH Community Engagement Alliance (CEAL). The funding agency had no role in the design of the study or in the writing of the manuscript
Case Study on the Effect of Osteopathic Manipulation on Gallbladder Ejection Fraction
No full textResearch Appreciation Day Award Winner - Texas College of Osteopathic Medicine, 2023 OMM-I.M. Korr, Ph.D. Memorial Research AwardBackground:
There is minimal research regarding the effects of osteopathic manipulative treatment (OMT) upon biliary emptying. Despite the limited research, OMT has been used to treat gallbladder dysfunctions in clinical practice.
Case Information:
The purpose of this case study was to examine the effects of OMT on gallbladder ejection fraction (EF) as measured by ultrasound and to determine if there was sufficient evidence of OMT-influenced biliary emptying to base a larger study. OMT was performed by a neuromusculoskeletal medicine board certified osteopathic physician on a medical student, who was acalculous and asymptomatic of any biliary disorder. Interventions included OMT targeting sympathetic and parasympathetic innervation levels, Chapman points, visceral myofascial release, and Sphincter of Oddi release. Results included gallbladder EF as measured by ultrasound. Blinded analysis demonstrated a 8.88% increase in average gallbladder EF following OMT, with a statistically significant difference in mean ejection fraction between OMT (M=46.95, SD=19.83) and no OMT (M=38.07, SD=19.13) conditions (paired t(4)=2.828, p=0.047).
Conclusions:
A limitation in the design of this study is that the comparison EF was measured 15 days after the OMT intervention. In future studies, we would first measure the EF and then perform OMT and measure the EF at least 4 weeks later. The results of this case study provide an enhanced understanding of OMT’s effect on gallbladder EF. Future studies should apply the biliary OMT protocol to a diverse clinical population with and without functional gallbladder disorder to determine if OMT could be used as an alternative treatment
Association of cardiovascular risk factors and blood biomarkers with cognition: The HABS-HD study
No full textINTRODUCTION: To determine if cardiovascular risk factor (CVRF) burden is associated with Alzheimer's disease (AD) biomarkers and whether they synergistically associate with cognition. METHODS: We cross-sectionally studied 1521 non-demented Mexican American (52%) and non-Hispanic White individuals aged >/=50 years. A composite score was calculated by averaging the z-scores of five cognitive tests. Plasma beta-amyloid (Abeta) 42/40, total tau (t-tau), and neurofilament light (NfL) were assayed using Simoa. CVRF burden was assessed using the Framingham Risk Score (FRS). RESULTS: Compared to low FRS (< 10% risk), high FRS (>/= 20% risk) was independently associated with increased t-tau and NfL. High FRS was significantly associated with higher NfL only among Mexican American individuals. Intermediate or high FRS (vs. low FRS) were independently associated with lower cognition, and the association remained significant after adjusting for plasma biomarkers. Hypertension synergistically interacted with t-tau and NfL (p < 0.05). DISCUSSION: CVRFs play critical roles, both through independent and neurodegenerative pathways, on cognition.National Institute on Aging of the National Institutes of Health, Grant/Award Numbers: R01AG054073, R01AG058533, P41EB015922, U19AG078109, R35AG07191
Oxidative Stress and Cancer: Harnessing the Therapeutic Potential of Curcumin and Analogues Against Cancer
No full textReactive oxygen species (ROS) are a class of bioactive molecules that are the by-products of many cellular functions. These molecules are present in normal cells at homeostatic levels but have been studied extensively in cancer due to their dysregulation resulting in pro- and anti-tumorigenic environments. Completely understanding the paradoxical nature of ROS in cancer is imperative to fully realize its modulation as cancer therapy. Studies into ROS have shown far-reaching effects in cancer, including how ROS levels regulate signaling, response to treatment, drug resistance, etc. Many drugs were studied with the hopes of regulating the ROS levels in cancer; however, patient response varied. Plant-derived medications offered new avenues of drug treatment over the last few decades, and the phytochemical Curcumin gained ground as an interesting cancer therapeutic. Curcumin is an active phenolic compound used in traditional medicine around the world. Although it suffers from a poor pharmacokinetic profile, Curcumin exerts anti-tumorigenic, as well as ROS-modulating activities. Analogs and derivatives of Curcumin are under development to improve upon its anti-cancer properties and enhance its bioavailability, currently a major limitation of its usage. This review highlights ROS function in cancer treatment focused on ROS, including Curcumin and its analogs.This work was partially supported by the National Institutes of Health [Award #: 1S21MD01247201; Award #: 2U54MD006882-06 and the Cancer Prevention and Research Institute of Texas (Award #: RP210046