bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modulation of opioid overdose susceptibility due to context-dependent tolerance
Authors: Ayyalaraju Anika , Szujewski Caroline , Sullere Shivang , Garcia Alfredo 
Published: May 2023

The US is in the midst of an opioid epidemic, which is primarily being driven by repeat opioid use (ROU). The primary cause of opioid overdose is opioid-induced respiratory depression (OIRD). It has been shown that the risk of overdosing, and subsequently death, can change depending on the environment in which the user takes the drug. This phenomenon is called context-dependent tolerance. However, how OIRD changes depending on the location of drug delivery is not known. The objective of this pilot study is to investigate context-dependent respiratory tolerance to OIRD and overdose. We repeatedly paired an injection of fentanyl (0.7 mg/kg/day i.p.) with a distinctive environmental context (fentanyl-paired (FP) environment) and saline with another distinctive context (saline-paired (SP) environment) in adult mice for five days while monitoring breathing via unrestrained whole-body plethysmography. The ROU protocol was followed by two test days where fentanyl was administered in both environments and breathing was measured. We found that minute ventilation was greater during OIRD in the FP environment as compared to the SP environment (n=4). In the second set of mice (n=6?), we tested overdose susceptibility following ROU by administering a high dose of fentanyl (5mg/kg) in both contexts. In contrast to the FP environment where no mice overdosed (n=0/6), n=4/6 mice overdosed in the SP environment. These data suggest a greater susceptibility to OIRD and overdose when in an environment not previously paired with fentanyl administration. This context-dependent effect on OIRD may be a significant psychophysiological factor driving opioid-related deaths in the ongoing opioid epidemic. NIH: R01NS107421; R01HL163965; R01DA057767. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Protective role of short chain fatty acids against Angiotensin II-induced mitochondrial dysfunction in brain endothelial cells: Potential role of Heme Oxygenase 2
Authors: Ait-Aissa Karima , Munkhsaikhan Undral , Abidi Ammaar H. , Kassan Adam , Kassan Modar 
Published: May 2023

Objectives: Short chain fatty acids (SCFAs), the main metabolites released from the gut microbiota, are reduced during hypertension. SCFAs play a beneficial role on the cardiovascular system. However, the effect of SCFAs on cerebrovascular endothelial cells is yet to be uncovered. In this study, we used brain endothelial cells to investigate the in vitro effect of SCFAs on heme oxygenase 2 (HO-2) and mitochondrial function following Angiotensin-II treatment. Methods: Brain human microvascular endothelial cells were treated with Angiotensin II (Ang-II, 500nM for 24hours) in the presence and absence of SCFAs cocktail (1mM; acetate, propionate, and butyrate) and/or HO-2 inhibitor (SnPP 5 μM). At the end of the treatment, HO-2, endothelial markers (p-eNOS, NO production), inflammatory markers (TNFα, NFkB-p50 and -p65), calcium homeostasis, mitochondrial membrane potential, mitochondrial ROS and hydrogen peroxide (H2O2), and mitochondrial respiration were determined in all groups of treated cells. Results: Our data showed that SCFAs rescued HO-2 after Angiotensin II treatment. Additionally, SCFAs rescued Angiotensin II-induced eNOS reduction, mitochondrial membrane potential impairment and mitochondrial respiration damage. On the other hand, SCFAs reduced Angiotensin II-induced inflammation, calcium dysregulation, mitochondrial ROS, and H2O2. All these beneficial effects of SCFAs on endothelial cells and mitochondrial function occurred through HO-2. Conclusions: SCFAs treatment restored endothelial cells and mitochondrial function following Angiotensin II-induced oxidative stress. SCFAs exert these beneficial effects by acting on HO-2. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
A trigger-substrate model of student engagement with learning
Authors: Witchel Harry 
Published: May 2023

BACKGROUND: There is much controversy and disagreement about engagement with learning, in its definition, its causes and its effects. The recent APS book on “Technologies in Biomedical and Life Sciences Education” outlines these controversies. AIM: To develop upon previously proposed engagement models by using trigger and substrate interactions between contributory factors in order to explain how causative factors may have minimal or no effects on learning when required coincident factors are absent. METHOD: Trigger-substrate steps include a longer-lasting, undergirding substrate factor as well as a short-lived trigger factor, which together act as the cause for the outcome. RESULTS: The model that we propose has engagement, effort and use of resources resulting from the triggers of teaching and providing resources, with a substrate of internalized motivation and a sense of belonging. Continuing forward, engagement, effort and use of resources is a trigger for learning and other benefits, and these results require a substrate of strategies and preparedness in the student. Learning can lead to both positive and negative feedback effects via assessment, feedback (from instructors and the institution), and emotions, which can act via metacognition, incentives and social reinforcement, and achievement, identification (of the student with the learning and outcomes), and the educational climate. CONCLUSIONS: Trigger-substrate causality may help to clarify the inconsistencies seen in education results between traditional theories based on teaching and more recent theories that have focused on the learner. The research has been funded by Brighton and Sussex Medical School This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Bitter melon extract affects cell-extracellular matrix interaction in human metastatic breast cancer cells
Authors: Bhetwal Bhupal , Bittar Elias , Throop Chase , Remedi Marissa , Kopecek Kalie 
Published: May 2023

Introduction: Bitter melon extract (BME) is known to exhibit cytotoxic effects on breast cancer cells (MCF-7). However, the molecular mechanisms by which BME exerts cytotoxic effects are not established. Integrins (which are transmembrane cell surface proteins) are universally expressed in all cell types and play critical roles in anchoring cells to the extracellular matrix and hence their survival. Integrin proteins when activated in turn activates a cascade of intracellular signaling steps (such as activation of focal adhesion kinase, FAK) which facilitates cell attachment, migration, survival, division etc. Aims: We aimed to investigate if BME exerts cytotoxic effects on MCF-7 cells via inhibiting attachment of cells to the extracellular matrix. We hypothesized that BME decreases expression of integrins and hence activation of FAK leading to cell cytoxicity. Methods: Fresh bitter melons were purchased from an Asian grocery store and the extract (BME) was extracted, centrifuged, and filter sterilized. The MCF-7 cells were cultured in DMEM medium with 1% BME (v/v). After culturing cells for 48 hours, pictures of cultures were taken to confirm cytotoxic effects on cells. In our earlier experiments, BME induced decrease in cell viability was also confirmed using Trypan blue exclusion and MTT assays. The cells were harvested and changes in the protein expression of β1-integrin and phospho-FAK (activated FAK) were determined using anti-β1-integrin and anti-phospho-FAK antibodies in the western blotting. Results & Discussion: BME exerted cytotoxic effects on MCF-cells (N=4). BME also reduced expression level of β1-integrin protein by more than 50% (N=3 with duplicate gels). Also, BME reduced expression of phospho-Tyr 397-FAK to below 20% (N=3), and total FAK to below 40% (N=3). The loading control protein GAPDH was not affected by the BME treatment (N=3). The data together supports our hypothesis. In the future, we will be running more sets of experiments to confirm our findings. FRD-MUCOM. All authors contributed equally to this work. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
SKQ1 Improves Trimethylamine-N-Oxide-Induced Endothelial Dysfunction by Attenuating Oxidative Stress and Restoring Junctional Proteins
Authors: Koka Saisudha , Powers Zachary , Boini Krishna 
Published: May 2023

In recent years, the role of microbiota and microbial metabolites in the progress of aging and age-related diseases has been attracting increased attention. In this context, trimethylamine N-oxide (TMAO) is a pro-atherogenic and pro-inflammatory metabolite derived from the gut microbial metabolism of trimethylamine and is found to be elevated in patients with age-related cardiovascular disorders. We identified that TMAO treatment in mice has enhanced mitochondrial ROS production, endoplasmic reticulum stress and caused significant endothelial dysfunction. The present study investigated whether mitochondria-targeted antioxidant SKQ1 protected against TMAO-induced endothelial dysfunction. Endothelial cells were treated with or without TMAO (30μM) in the cell culture media. TMAO treated cells showed significant increase in both total ROS as well as mito-ROS production compared to untreated control group (n=8/group; p<0.05). In addition, western blot analysis demonstrated that TMAO treatment significantly decreased tight junction proteins such as occludin, ZO-1 and VE-Cadherin which were restored upon SKQ1 treatment (150nM, 12h). TMAO (30μM) treatment for 24 h induced significant mitochondrial dysfunction as evidenced by decreased mitochondrial membrane potential, increased mitochondrial ROS levels, and enhanced endothelial cell permeability compared to the control group (n=8/group; p<0.05). Treatment with a SKQ1 (150nM, 12h) significantly inhibited TMAO-induced ROS production and protected against increased endothelial cell permeability and mitochondrial ROS production (n=8/group; p<0.05). In conclusion, mitochondria-targeted antioxidant SKQ1 protects against TMAO induced endothelial dysfunction by attenuating ROS production and disruption of tight junction proteins. This work is supported by NIH R01 HL148711 award to Saisudha Koka This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
17 Beta-estradiol impedes aortic root dilation and rupture in male Marfan mice
Authors: Saddic Louis , Escopete Sean , Zilberberg Lior , Kalsow Shannon , Egbhali Mansoureh , Parker Sarah 
Published: May 2023

Background: Marfan syndrome causes a hereditary form of TAA with dilation of the aortic root. Male patients with Marfan syndrome are more likely than women to have aortic dilation and dissection and mouse models of Marfan syndrome demonstrate larger aortic roots in males compared to females even after adjustment for body size. In this study we examine the effects of estrogen17 β-estradiol on aortic dilation and rupture in a Marfan mouse model. Methods: Marfan male mice were administered estrogen17 β-estradiol pellets with 60 day release and the growth in aortic root size was measured every 2 weeks for 8 weeks. Aortic root tissue from vehicle and 17 b-estradiol mice were subjected to proteomic analysis and bioinformatics was used to ascertain enriched pathways. Marfan mice with and without 17 b-estradiol were also treated with continuous angiotensin II infusion and survival was determined for 30 days. Results: Male Marfan mice with estrogen17 β-estradiol had a significant reduction in the ratio of aortic diameter 8 weeks after pellet implantation to baseline aortic diameter compared to the same ratio in Marfan mice with sham surgery. Proteomic analysis demonstrated complement C3 and C4 protein upregulation in Marfan mice compared to wild type and Marfan mice treated with 17 b-estradiol. Aortic smooth muscle cells express complement components in vivo and in vitro and expression of these factors are regulated by cytokines and estrogen17 β-estradiol in vitro. Additionally, 17 b-estradiol and female sex protect against aortic rupture when Marfan mice are treated with continuous infusion of angiotensin II and this protection correlates with lower protein levels of C3. Conclusions: Our findings support a protective role of 17 b-estradiol in preventing the dilation and rupture of aortic roots in Marfan male mice and suggest that these therapeutic actions may develop through anti-inflammatory properties. FAER Foundation for Anesthesia Education and Research This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Impaired endothelial function via fatty acids and the potential role of oxidative stress
Authors: Kovarik Jack , Holwerda Seth 
Published: May 2023

Purpose: Excess plasma lipids promote oxidative stress and impaired vascular function. Therefore, we tested the hypothesis that a water-soluble antioxidant (ascorbic acid, AA) would attenuate reductions in endothelium-dependent dilation resulting from acutely elevated plasma fatty acids. Methods: A 20% IV fat emulsion (Intralipid) was administered for 2 hours to 8 healthy, middle-aged adults (2 men/6 women) with and without co-infusion of ascorbic acid (separate visits) in a double-blinded, crossover study design. Co-infusion of AA was administered at 0.06g/kg fat free mass in 100 ml saline at 5 mL/min over 20 min (bolus) followed by a drip infusion at 0.02 g/kg fat-free mass in 30 ml saline at 0.33 mL/min over 90 min. Endothelium-dependent dilation was assessed via brachial artery flow-mediated dilation (FMD) and expressed as % increase in diameter from baseline before forearm occlusion. Results: Lipid infusion significantly increase plasma fatty acid concentrations (w/o AA: +36 ± 18 vs. with AA: +41 ± 13 vs. μmol/L, P=0.84). AA infusion significantly increased plasma ascorbic acid concentrations (w/o AA: -1 ± 7 vs. with AA: +26 ± 11 μmol/L, P=0.04). Compared with baseline, FMD was significantly reduced following lipid infusion at (Baseline: 9.3 ± 1.1 vs. 20 min: 4.4 ± 1.3 vs. End: 5.3 ± 2.9 %, P=0.03), and when statistically adjusting for the stimulus (shear rate area under the curve) via analysis of covariance (P=0.02). FMD was also significantly reduced following lipid infusion with co-infusion of AA (Baseline: 8.9 ± 1.0 vs. 20 min: 5.3 ± 1.0 vs. End: 6.4 ± 3.8 %, P=0.02), but not when statistically adjusting for shear rate under the curve (P=0.08). Conclusions: Elevated plasma fatty acids impair endothelium-dependent dilation in healthy adults. However, co-administration of an antioxidant (ascorbic acid) limited the reduction in FMD when correcting for shear rate. Therefore, these preliminary data suggest that fatty acids may reduce endothelium-dependent dilation via an oxidative stress mechanism. Funding and support: R01HL159370-01 (S.W.H.). This work was also supported by a CTSA grant from NCATS awarded to the University of Kansas for Frontiers: University of Kansas Clinical and Translational Science Institute (# UL1TR002366). The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or CTSA. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Development of novel Bexarotene analogs for treating cutaneous T-cell lymphomas
Authors: Warda Ankedo , Staniszewski Lech , Sabir Zhela , Livingston Sarah , Sausedo Michael , Reshi Sabeeha , Ron Eyal , Marshall Pamela , Wagner Carl , Jurutka Peter 
Published: May 2023

Bexarotene, a drug approved for the treatment of cutaneous T-cell lymphoma (CTCL), is classified as a rexinoid due to its ability to act as a retinoid X receptor (RXR) agonist with high specificity. Rexinoids are capable of inducing RXR homodimerization leading to the induction of apoptosis and inhibition of proliferation in human cancers. Numerous studies have shown that bexarotene is effective in reducing viability and proliferation in CTCL cell lines. However, many treated patients present with cutaneous toxicity, hypothyroidism, and hyperlipidemia due to crossover activity with retinoic acid receptor (RAR), thyroid hormone receptor (TR), and liver X receptor (LXR) signaling, respectively. In this study, fourteen novel analogs were evaluated for their potential to bind RXR through modeling and then assayed in an RXR-RXR mammalian-2-hybrid (M2H) system and in RXRE-mediated luciferase reporter assays. In addition, these analogs were tested for their effectiveness to inhibit proliferation in CTCL cells relative to bexarotene. Furthermore, the most effective analogs were analyzed via qPCR to determine efficacy in modulating expression of two critical tumor suppressor genes, ATF3 and EGR3. Our results suggest that these new compounds possess similar or enhanced therapeutic potential as several of our novel rexinoids display more selective RXR activation with equivalent or greater reduction in CTCL cell proliferation, as well as the ability to induce ATF3 and EGR3. This work broadens our understanding of RXR-ligand relationships and permits development of more highly efficacious pharmaceutical drugs. Modifications of RXR agonists can yield agents with enhanced biological selectivity and potency when compared to the parent compound, potentially leading to improved patient outcomes. NCUIRE Undergraduate Research Program (ASU) & National Institutes of Health (NIH) CA140285 (to PWJ, CEW and PAM) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Vav1-HIF1α-Glut1, a novel axis to initiate neurodegenerative disorders
Authors: Hong Jaewoo 
Published: May 2023

Vav1 is a Rho/Rac (Ras-related C3 botulinum toxin substrate) guanine nucleotide exchange factor (GEF) expressed in immune cells and endothelial cells involved in a wide range of cellular functions, including protumorigenesis and inflammation. Vav1 is unstabilized in normoxic conditions and stable in hypoxic conditions. When Vav1 is stable, Vav1 increases the accumulation of the transcription factor HIF (Hypoxia Inducible Factor)-1α, which activates the transcription of target genes on HIF-related element (HRE) to initiate a cellular response to low oxygen. One of the genes induced by HIF-1α is GLUT (Glucose Transporter)-1, the major glucose transporter expressed in vessels that supply glucose, the brain's energy source. Here, we identify a role for Vav1 in providing glucose to the brain to suppress neurodegeneration. We observed that Vav1 deficiency suppresses HIF-1α and GLUT-1 levels in endothelial cells, including blood-brain barrier cells. The decrease of GLUT-1, in turn, reduces glucose uptake to endothelial cells both in vitro and in vivo and reduces glucose transportation to neurons and astrocytes.Furthermore, endothelial cell-specific Vav1 conditional knock-out mice show glucose uptake deficiency as well as impaired brain coordination. Our findings suggest that Vav1 promotes learning and memory by activating HIF-1α and GLUT-1, thereby transporting glucose to the brain. We further demonstrate the importance of glucose transport by endothelial cells in brain functioning and reveal a potential new axis for targeting GLUT-1 deficiency syndromes and other neurodegenerative disorders. This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education (No. 2021R1I1A3043909). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Promotion of hair growth by Lactobacillus and fermented traditional Korean berry in C57BL/6 mice
Authors: Jang Se Jin , Kim Jae Young , Cheon Se Jin , Kim Sae Hun , Lee Jung Yun 
Published: May 2023

Hair loss is the state of losing hair from the scalp or entire body when new hair does not replace the hair that has fallen out. Currently, remedies such as oral finasteride and topical minoxidil are commonly used. However, these drugs may have temporary effects and cause side effects such as depression, irregular heartbeat and weight gain when used long term. Therefore, an alternative hair growth promoting agent is needed. The hair follicle undergoes anagen, catagen, and telogen phase which affect hair growth, and this hair-growth cycle is regulated by growth factors, cytokines, and hormones. Some studies reported that the gut microbiome (GM) regulates the transition between the hair growth cycle by producing hair growth-related factors and nutrients. Also, inflammation by GM affects the cascade of the inflammation in the hair follicle, which may lead to hair growth arrest. Previous studies showed strains of Lactobacillus (LAB) have anti-oxidative and anti-inflammatory effects in an HT-29 human colon epithelial cell model and an HaCaT human keratinocyte cell model. Also, traditional Korean berry has anti-inflammatory effects in an HT-29 model. Thus, LAB and fermented traditional Korean berry by LAB (FB) may promote hair growth by regulating gut microbiome. This study investigated the effect of LAB and FB on hair growth in vivo. Six-week-old male C57BL/6 mice were used for evaluating the hair growth-promoting effects of the LAB and FB. The dorsal hair of mice was depilated, and they were orally treated with LAB at 1010 CFU/kg and FB at 250mg/kg daily for 22 days. As a result, the hair re-growth rate was significantly increased in LAB and FB groups compared with the control group. In the histological analysis of skin, FB increased the number of hair follicle and subcutaneous fat layer thickness. The mRNA expression levels of hair growth-related growth factors such as VEGF and IGF-1 are significantly increased in colon and skin. Moreover, Treatment of LAB and FB changed the composition of the microbiome and short chain fatty acids in mice. Altogether, LAB and FB supplementation may promote hair growth by regulating growth factors and altering gut microbiota compositions. In conclusion, strain of LAB and FB are potential novel approaches for hair growth promotion. This work was supported by Korea Testing Laboratory This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.