bluuebunny/crossref_metadata_2025_split huggingface dataset:
Aortic baroreceptor afferent activity during systemic inflammation
Authors: Brognara Fernanda , Castania Jaci , Dias Daniel , Salgado Helio , Paton Julian , Carnio Evelin 
Published: May 2023

Objective: Neuroimmune interactions have been extensively explored to find new therapeutic targets for inflammatory diseases. We postulated that baroreceptors (essential for arterial pressure control) might be susceptible to systemic inflammation. Thus, the present study investigated the effect of early-stage systemic inflammation on aortic baroreceptor afferent activity. Hypothesis: Aortic depressor nerve activity is increased during systemic inflammation. Methods: Anesthetized (urethane; 1 g/kg; i.p.) male Sprague-Dawley rats (7-8 weeks old) were used, and lipopolysaccharide (LPS; 1.5 mg/kg; i.v.) injected to induce systemic inflammation. The femoral artery and vein were cannulated for pulsatile arterial pressure recording and LPS administration, respectively. Following 30 min since injections of either saline (control; n = 10) or LPS (n = 16), pulsatile arterial pressure and aortic depressor nerve activity were recorded. Nerve activity recordings were rectified and integrated on a time basis. Body temperature was measured via rectal thermometer. The results are presented as mean ± standard error of the mean. Results: Compared to saline-treated rats, there was an increase in aortic depressor nerve activity (LPS: 1.04 ± 0.02 vs saline: 0.98 ± 0.01 a.u.; p = 0.007); this was accompanied by increases in diastolic arterial pressure (LPS: 83 ± 2 vs saline: 73 ± 4 mmHg; p = 0.031), mean arterial pressure (LPS: 102 ± 3 vs saline: 91 ± 4 mmHg; p = 0.035) but not systolic pressure (LPS: 140 ± 6 vs saline: 122 ± 6 mmHg; p = 0.057; strong trend) or heart rate (LPS: 425 ± 11 bpm vs saline: 393 ± 14; p = 0.085). Importantly, in the LPS-injected rats, a reduction in body temperature was noted compared to saline-treated rats (LPS: 36.7 ± 0.1 vs saline: 37.2 ± 0.2°C; p = 0.005), an indicative of systemic inflammation. Conclusions: Since the diastolic and mean arterial pressures increased after LPS administration, it remains unclear whether the elevated aortic depressor nerve activity reflects this increased pressure or results from the inflammatory mediated sensitization. However, our preliminary data support the notion that aortic baroreceptor afferents participate in the neuroimmune communication response in the early stages of inflammation. Funding sources: FAPESP (protocols #2021/03764-8 and #2021/05554-0). 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.
Improving White Blood Cell Morphology Education Through Standardized Questions
Authors: Memmott Audrey , Tanner Dylan , Cordner Ryan 
Published: May 2023

Medical laboratory scientists routinely evaluate blood smears in the clinical laboratory. A high level of skill in white blood cell morphology is required to do the task quickly and accurately. Educational approaches to teaching white blood cell morphology consist of showing examples of cells to students and allowing them to practice using trial and error to hone their skills. Student progress with this traditional approach is often quite slow. In order to expedite the learning process, we created a series of questions that can guide morphological identification; these questions focus on the shape and description of the nucleus, cytoplasm, granules and cell overall. We hypothesized that white blood cells can be accurately and uniformly identified using the criteria we’ve outlined. We confirmed the accuracy of this approach to white blood cell identification using a random forest classifier algorithm on a data set of 3600 cells that we had previously categorized. Our approach has the potential to standardize white blood cell morphology training in undergraduate medical laboratory scientist programs, and could help improve the consistency of manual differential results between hospital laboratories. This work is funded by a Teaching Development Grant from the Brigham Young University College of Life Sciences 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.
Activation of renal vascular smooth muscle TRPV4 channels by 5-hydroxytryptamine impairs kidney function in neonatal pigs
Authors: Michael Olugbenga , Afolabi Jeremiah , Falayi Olufunke , Kanthakumar Praghalathan , Mankuzhy Pratheesh , Soni Hitesh , Adebiyi Adebowale 
Published: May 2023

Control of microvascular reactivity by 5-hydroxytryptamine (5-HT; serotonin) is complex and may depend on vascular bed type and 5-HT receptors. 5-HT receptors consist of seven families (5-HT1-5-HT7), with 5-HT2 predominantly mediating renal vasoconstriction. Regulation of cyclooxygenase (COX) and smooth muscle cell (SMC) intracellular Ca2+ concentration ([Ca2+]i) levels have been implicated in 5-HT-induced vascular reactivity. Although 5-HT receptor expression and circulating 5-HT levels are known to be dependent on postnatal age, control of neonatal renal microvascular function by 5-HT is unclear. The objective of this study is to use the translational swine model to examine the effects of 5-HT on newborn renal microcirculation. We demonstrate that 5-HT activates human transient receptor potential cation channel subfamily V member 4 (TRPV4) channels that were transiently expressed in Chinese hamster ovary cells. 5-HT2A is the predominant 5-HT2 receptor subtype in freshly isolated neonatal pig renal microvascular SMC. HC-067047 (HC), a selective TRPV4 blocker, attenuated cation currents induced by 5-HT in neonatal pig renal vascular SMC. HC also inhibited the 5-HT-induced increase in renal microvascular [Ca2+]i and constriction. Intrarenal artery infusion of 5-HT had minimal effects on systemic hemodynamics but reduced renal blood flow (RBF) and increased renal vascular resistance (RVR) in the pigs. Transcutaneous determination of glomerular filtration rate (GFR) indicated that kidney infusion of 5-HT reduced GFR. HC diminished 5-HT-induced alteration of RBF, RVR, and GFR. Moreover, plasma and urinary COX-1 and COX-2 levels in 5-HT-treated pigs were unchanged. These data suggest that activation of renal microvascular SMC TRPV4 channels by 5-HT impairs kidney function in neonatal pigs independently of COX production. NIH R01DK120595 and R01DK127625 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.
Identification of MEST as a critical player in mechanotransduction of endothelial cells in response to shear stress in atherosclerosis
Authors: Zeng Ye , Fu Bingmei 
Published: May 2023

OBJECTIVE: Atherosclerosis (AS) is a chronic disease characterized by the inflammation and the deposition of cholesterol in arterial intima, which is the common pathological basis of various cardiovascular and cerebrovascular diseases. Fluid shear stress (FSS) is an important regulatory factor of cellular cholesterol metabolism during the occurrence and progression of AS. However, the mechanism by which FSS regulated the deposition of cholesterol in AS remains unclear. METHODS: By using a novel cell model of foaming established by piled vascular endothelial cells, the transcriptome sequencing and the bioinformatics data mining were carried out to screen the key differential genes involved in the foaming of vascular endothelial cells and the FSS mechanotransduction, and then the qRT-PCR validation of them was performed. Also, the levels of the identified molecules in ApoE-/- atherosclerotic mice were detected. Finally, the role of MEST in vascular endothelial cells was explored by BODIPY staining upon MEST knockdown. RESULTS: We identified MEST that regulated by FSS is downregulated in foaming endothelial cells, and is also reduced in the atherosclerotic lesions. MEST might be closely associated with lipid metabolism, vascular endothelial glycocalyx, G protein-coupled receptor signaling, and cell-to-cell communication. Knockdown of MEST induced lipid accumulation in vascular endothelial cells. CONCLUSION: MEST is an antiatherogenic molecule, which might control the endothelial injury and atherogenic initiation. This project was supported by the National Natural Science Foundation of China (12272246). 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.
Cytosolic full-length PTEN-induced putative kinase 1 enhances mitophagic potential and mtDNA integrity in angiotensin II-induced hypertensive mice
Authors: Park Joon-Young , Hong Soon-Gook , Shin Junchul , Saredy Jason , Choi Soo-Young , Wang Hong 
Published: May 2023

PTEN-induced putative kinase 1 (PINK1) is an essential molecule in mitophagy process in mammalian cells. The primary purpose of this study was to determine the expression and subcellular localization of PINK1 under physiological fluidic conditions in endothelial cells (ECs) and elucidate the implication these phenomena in the endothelial homeostasis and disease prevention. Unidirectional laminar shear stress (LSS) significantly elevated both mRNA and protein expression levels of the full-length PINK1 (FL-PINK1) in ECs. Extensive mitochondrial fractionation assays and confocal microscopic analyses demonstrated significantly reduced FL-PINK1 accumulation in the mitochondrial compartment yet increased in the cytosolic pool of FL-PINK1 after exposed to prolonged high LSS (15 dyne/cm2 for 48h). We also observed that mitophagy flux was significantly decreased without changes in mitochondrial membrane structures and membrane potential under the LSS condition. Moreover, increased cytosolic PINK1 increased mitophagic sensitivity to the cumulative fragmented mitochondria in the ECs. When treated with angiotensin II (AngII), LSS-preconditioning significantly decreased mtDNA lesions and displayed rapid Parkin recruitment followed by mitophagy induction in response to a mitochondrial uncoupler, carbonyl cyanide m-chlorophenyl hydrazone, -mediated oxidative stress condition. In addition, voluntary running exercise-preconditioning showed elevated PINK1 expression and enhanced mitophagy induction and reduced mtDNA lesions in the AngII-induced hypertensive mice. Taken together, LSS specifically increases a cytosolic pool of FL-PINK1, which elevates mitophagic sensitivity to dysfunctional mitochondria in endothelial cells. Our data suggest that enhanced unidirectional laminar shear stress promotes mitochondrial quality control and cell protection mechanisms via a PINK1-dependent pathway. This work was supported by funding from the National Institute of Heart, Lung, and Blood Institute at the National Institutes of Health (R01 HL126952 to J.Y.P.); and The American Heart Association/Beatrice F. Nicoletti research grant (19POST34450157 to J.C.S). 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.
Overexpression of ABCB6 does not protect against doxorubicin cardiotoxicity
Authors: Jacintho Moritz Cesar Eduardo , Montalvo Ryan N. , Doerr Vivian , Nguyen Branden L. , Smuder Ashley J. 
Published: May 2023

Doxorubicin (DOX) is a highly effective chemotherapeutic agent used in the treatment of a broad spectrum of human cancers. However, the clinical use of DOX is limited due to dose-dependent cardiotoxicity, which adversely affects quality of life and survival. Therefore, new strategies to mitigate the cardiotoxic effects of DOX are needed to improve the clinical usefulness of DOX and long-term health outcomes. The mitochondria-localized ATP-binding cassette (ABC) proteins (i.e. ABCB6, ABCB7, ABCB8 and ABCB10) are a family of transporters with the potential to mediate xenobiotic efflux and/or may play a role in maintaining mitochondrial redox balance and iron homeostasis. Previous data showed that exercise training mediated an increase in the expression of each mitochondria-localized ABC transporter in the heart. To determine the specific role of increased ABCB6 expression in the heart prior to DOX treatment female Sprague Dawley rats were randomly divided into the following groups: 1) Saline-Saline; Saline-ABCB6; 3) DOX-Saline; and 4) DOX-ABCB6. Four weeks before DOX (20 mg/kg; i.p.) or saline administration the animals received rAAV-ABCB6. Dependent measures were evaluated 48 hours after DOX/saline treatment. Cardiorespiratory fitness assessed via a graded exercise tolerance test performed just prior to endpoint demonstrated a significant effect of DOX on time to fatigue, with no beneficial adaptation of ABCB6 overexpression. Moreover, weight change from treatment to endpoint and the heart weight/tibia length ratio were also decreased after treatment in both DOX groups with no effect of ABCB6. Additionally, cardiac fractional shortening (FS) and posterior wall shortening velocity (PWSV) were reduced in both DOX groups. Similarly, myocardial performance index (MPI) increased in the DOX-Saline and DOX-ABCB6 groups. These data demonstrate that overexpression of the ABCB6 transporter in the heart is not capable to mitigate the deleterious effects of DOX treatment on the heart. Further studies are needed to investigate the potential therapeutic effects of mitochondria-localized ABC transporters as a clinical approach to prevent cardiotoxicity effects triggered by DOX. This research was funded by the National Institute of Health (NIH), R01HL144858. 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.
The Effect of Exercise on Doxorubicin-Induced Nephrotoxicity in Male and Female Rats
Authors: Patel Jay , Montalvo Ryan , Boeno Franccesco , Doerr Vivian , Smuder Ashley 
Published: May 2023

Doxorubicin (DOX) is a first-line chemotherapeutic agent used to treat a wide range of malignancies including breast and lymphatic cancers. However, the clinical use of DOX is limited due to off-target toxicity to healthy organs. DOX-induced nephrotoxicity is established in both cancer patients and experimental models, where it is hypothesized that oxidative damage to renal cells increases glomerular capillary permeability and tubular atrophy. In contrast, endurance exercise preconditioning has the potential to reduce renal edema and inflammation, improving glomerular filtration rate and urine creatinine clearance rate. Therefore, the purpose of this study was to investigate whether exercise preconditioning can protect against DOX-induced nephrotoxicity and elucidate differences between male and female rats. Young-adult male and female Sprague-Dawley rats were randomly separated into 4 groups: i) sedentary saline; ii) sedentary DOX (20 mg/kg IP); iii) exercise-trained saline; and iv) exercise-trained DOX. Exercise trained animals underwent 2 weeks of treadmill preconditioning for (5 days/wk, 60 min/day, 30 m/min @ 0% grade). Animals received saline or DOX 24hrs after the final exercise bout, followed by endpoint 48hrs post-treatment. Evaluation of inflammatory markers within the urine (i.e. IP10, AGP and NGAL) demonstrated elevated levels in DOX-treated males and females, regardless of exercise. Male rats receiving DOX had elevated levels of clusterin which was not found in female rodents suggesting a possible sex-difference. Moreover, urine creatinine levels were significantly increased following DOX treatment and reduced with exercise in males, with no significant differences in females. In summary, animals treated with doxorubicin had higher levels of markers for inflammation and renal disease, with minimal effects of exercise preconditioning to prevent these changes. Additionally, males demonstrated higher levels of renal toxicity suggesting that females may have a greater resistance to DOX-induced nephrotoxicity.R01 HL153140R01 HL144858 R01 HL144858 and R01 HL153140 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.
Targeted disruption of CTCF binding near the Ren gene alters gene expression and plasma renin activity in response to dietary salt
Authors: Vanden Avond Mark , Grzybowksi Michael , Kurth Theresa , Greene Andrew , Liang Mingyu , Cowley Allen , Geurts Aron 
Published: May 2023

Hypertension is the leading risk factor for cardiovascular disease and impacts one in three adults globally. One genetic mechanism that may affect blood pressure regulation and alter hypertension risk in the general population is the disruption of chromatin conformation by common genetic variation. CCCTCF-binding factor (CTCF) has many important functions including regulating the conformation of chromatin by binding to specific DNA sequences and can thereby alter gene expression. The renin locus has multiple CTCF motifs surrounding the renin gene and cellular expression of CTCF is critical for proper renin expression. Despite these important functions, the role that local chromatin conformation plays to regulate normal renin expression including its response to stimuli such as dietary salt intake and in the downstream regulation of blood pressure is unknown. We hypothesize that disruption of local chromatin conformation can alter gene expression, intermediate physiological mechanisms, and blood pressure. A mutant rat model was created using CRISPR-Cas9 in the genetic background of the Dahl salt-sensitive (SS) rat with a disruption to the CTCF binding motif located within an intron of Golt1a near the Ren gene which we have previously demonstrated an interaction with the renin proximal promoter. Here we report the preliminary characterization of this model for renin expression and plasma renin activity (PRA). Chromatin immunoprecipitation-qPCR showed a reduction in CTCF binding at the Golt1a locus in our mutant model compared to wild-type (WT), confirming our mutation resulted in a disruption in CTCF binding in vivo. An expected reduction (p<0.05) in renin expression was found in male and female WT and mutant rats in response to a high salt diet. WT males showed an expected inverse PRA relationship to dietary salt (WT: 0.1% NaCl=17.52, 0.4% NaCl=12.87, 4.0% NaCl=7.13; p<0.05) however, interestingly, mutant males failed to increase PRA in response to very low salt (0.1% NaCl) challenge (0.1% NaCl mutant=13.87; p<0.05 compared to WT 0.1% NaCl). Female mutants showed a similar but non-significant trend. Taken together, these data suggest that the disruption of CTCF binding in a region which interacts with the renin proximal promoter can alter renin expression and the plasma renin activity in response to very low dietary salt in SS rats. NIH 5P01HL149620-03 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.
Mechanisms of Estrogen Induced Skeletal Muscle Fibrosis in Inguinal Herniation
Authors: Potluri Tanvi , Zhao Hong , Stulberg Jonah , Yin Ping , Bulun Serdar , Lieber Richard 
Published: May 2023

Background: Abdominal wall fibrosis weakens these muscles, often resulting in inguinal hernias. Despite its high prevalence and public health burden, the etiology or exploration of non-surgical treatments for muscle fibrosis remains a vastly under-explored area. We developed a mouse model (humanized aromatase mouse – Aromhum ) wherein all male mice develop scrotal hernias at puberty. The lower abdominal muscle (LAM) in these mice produces local estradiol (E2), which acts on stromal fibroblasts to proliferate, leading to muscle fibrosis, atrophy, and hernias. We are using this novel model to uncover mechanisms of muscle fibrosis. Objectives & Hypothesis: The study was to understand the mechanisms of E2-induced muscle fibrosis in scrotal hernias. We hypothesized that manipulating of E2-ERα signaling inhibits or reverses hernia formation by reducing or eliminating LAM fibrosis. Methods: Mice were administered E2-ERα antagonist treatment via Fulvestrant slow-release pellets (0.15mg/kg, 90 days) either prior to or post large hernia development. Hernia sizes were measured weekly, and LAM tissues were harvested for immunohistochemistry analysis.For in vitro experiments, fibroblasts were isolated from herniated LAM tissues and cultured under estrogen-replete (+10nM E2) and deplete (+ 100nM Fulvestrant) conditions. The cells were subsequently processed for ChIP-seq, ATAC-seq, and RNA-seq analysis. Sample size: 10-15 mice/group in 3 technical replicates Results: In vivo: Administration of fulvestrant to mice completely reversed scrotal herniation within 4-5 weeks of treatment (n = 10-15/group, p < 0.0001). In addition, the LAM tissues showed a reversal of fibrosis and a concurrent increase in myofiber cross-sectional area (n = 10-15/group, p < 0.0001) compared to placebo-treated mice. In vitro: Overall, 853 differentially expressed genes were observed between E2 and E2+Fulvestrant treated fibroblasts. Genes associated with the extracellular matrix, WNT signaling, TGFβ, and focal adhesions were enriched in our study. Further, transcription factors like Pbx1, Elk1, and Yy1 were also enriched in ERα cistrome. Integrating the three datasets, we identified 58 core genes that play a crucial role in E2-associated muscle fibrosis. Conclusions: We believe that this is the first skeletal fibrosis model that shows reversibility by inhibiting E2-ERα signaling. We provide mechanistic insight into this process by identifying the genetic, epigenetic, and transcriptomic changes associated with fibrosis in skeletal muscle upon stimulation by E2. These genes and pathways pave the way for potential therapeutic targets for the treatment of hernias and other skeletal muscular disorders. NIH R01 DK121529 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.