bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long-term intermittent fasting induces sex-dependent changes in small intestine from SAMP8 aged mice
Authors: Vroegop Spencer , Smith Nicholas , Sudler Sydney , Potter Ross , Shim Minsub , Broderick Tom , Aziz Ann-Marie 
Published: May 2024

Background: Intermittent fasting (IF) is a popular and effective method to decrease body weight. Yet, the effects of IF on aged intestine is unknown. SAMP8 (Senescence Accelerated Mouse-Prone 8) mice are used as a model for studying aging. This study aimed to examine the potential for IF to ameliorate age-associated disturbances in murine jejunum. Methods: Two-month-old male and female SAMP8 mice were randomly assigned to either an IF protocol or an ad-libitum diet (AL) for the 8-month study (n=7-10 group). Fasted mice followed a 24-hour alternate day fasting protocol. At the end of the study mice were euthanized and jejunum stored at −80°C until use for western blot or other assay, and a segment was fixed for histology. Results: IF resulted in significantly less weight gain in both males (22% less, n=7-10, p<0.05) and females (33% less, n=7-8, p<0.05) and response to glucose load (glucose tolerance testing) was comparable in both sexes: area under curve for AL > IF. Interestingly, IF significantly reduced fasting serum glucose levels in males (30% less, n=6, p<0.05), but IF had no effect on fasting serum glucose in females. In jejunum, we assessed: protein expression, health, and morphology. In females, IF led to a 57% decrease in GLUT2 expression (n=5-6, p<0.05) versus AL. GLUT2 moves glucose/galactose and fructose out of the enterocyte into the blood, suggesting restructuring of monosaccharide transport due to IF. IF had no effect on jejunum GLUT5 or SGLT1 expression. Cleaved Caspase-3 expression was decreased by IF in both sexes versus AL. This reduction was greater in females, suggesting a sex-dependent protective role of IF against apoptosis. Moreover, IF induced a significant increase 1.4-fold (n=5=6, p<0.05) in jejunum superoxide dismutase (SOD) activity in both sexes. Jejunum morphology was significantly changed in females only: IF induced both a decrease in villi length (by 21%, n=4/group, p<0.05) and a decrease in wall thickness (by 7%, n=4/group, p<0.05). Conclusions: In both sexes, IF decreased body weight, yet in females resting glucose levels were unchanged by IF. In females, IF reduced monosaccharide absorption out of intestines, yet improved overall intestinal health, increasing antioxidant levels with SOD. These findings collectively highlight the complex effects of IF on cellular processes and demonstrate significant sex-dependent aged intestinal responses. Unraveling the underlying molecular mechanisms driving these sex-dependent IF-induced effects is currently under evaluation. Midwestern-Arizona Alzheimer’s Consortium Grant, Midwestern University Intramural Grant. This is the full abstract presented at the American Physiology Summit 2024 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.
CD8 Cell PHD2 Deficiency Amplifies Pressure Overload-Induced Cardiac Inflammation through Metabolic Reprogramming of CD8 Cells
Authors: Pan Lihong , Bhattarai Umesh , He Xiaochen , Niu Ziru , Zeng Heng , Chen Jianxiong , Chen Yingjie 
Published: May 2024

Prolyl hydroxylase domain (PHD) proteins function as oxygen sensors and regulate various cellular metabolism. PHD2 is well-known for its role in oxygen sensing and has been implicated in cardiac hypertrophy and fibrosis through HIF-2α. However, the specific impact and the mechanism of CD8 cell PHD2 deficiency on cardiac inflammation and heart failure (HF) development remains unclear. Here, we explored the role of CD8 cell-specific PHD2 deficiency (CD8-PHD2 KO) in HF development by using transverse aortic constriction (TAC) mouse model. Our findings reveal that CD8 PHD2 knockout exacerbated TAC-induced left ventricular (LV) hypertrophy, as evidenced by increased LV weight relative to bodyweight or tibial length. CD8-PHD2 KO also leads to a significant increase in lung and right ventricular weight relative to bodyweight or tibial length following TAC. Furthermore, CD8-PHD2 KO worsens TAC-induced reductions in LV ejection fraction, LV fractional shortening, and LV dilatation. Additionally, CD8-PHD2 KO exacerbates TAC-induced LV cardiomyocyte hypertrophy, fibrosis, and immune cell infiltration. Moreover, our study demonstrated that CD8-PHD2 KO amplified the infiltration and activation of antigen-presenting cells, CD4 T cells, and CD8 T cells in the heart and lungs after TAC. At the molecular level, we characterized the PHD2-deficient CD8 cells showed typical features of anaerobic glycolysis, which were paralleled by augmented hypoxia-inducible factor 1α (HIF-1α) protein levels. Collectively, these results highlight the critical role of PHD2 in CD8 cells in regulating cardiac inflammation and HF development in response to systolic overload. National Institutes of Health Project Number 5R01HL161085-02. This is the full abstract presented at the American Physiology Summit 2024 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.
Urocortin 2 Gene Transfer in Mice Improves Diastolic Function in Heart Failure with Preserved Ejection Fraction
Authors: Lai N. Chin , Gao Mei Hua , Lai Yin Jie , Suarez Jorge , Hammond H. Kirk 
Published: May 2024

Patients with heart failure and preserved ejection fraction (HFpEF) comprise about 50% of patients with heart failure in the US (>3 million people). There are currently no treatments for HFpEF that prolong life, and few that reduce HF hospitalization rates. The Schlager BPH (Blood Pressure-High) mouse is a genetic model of hypertension, a major contributing factor in left ventricular (LV) diastolic dysfunction and HFpEF. This study test the hypothesis that intravenous (i.v.) delivery of a long-term expression vector encoding murine urocortin 2 (AAV8.m Ucn2) can improve LV diastolic function in mice with impaired LV diastolic function. Twelve male and 12 female BPH mice (21.3±0.5 g; 3.1±0.1 months-old) with an ejection fraction (EF) of 60±2% (echocardiography) were studied. Prior to Ucn2 gene transfer their unsedated systolic/diastolic blood pressures (tail cuff) were (183/146±2/7 mmHg, n=24), conforming the presence of severe hypertension. The BPH mice were separated into two groups (6M & 6F in each group). One group (BPH + Ucn2) received AAV8.m Ucn2 (2x1013 gc/kg, i.v) and the other group (BPH) received saline, i.v. Seven weeks after randomization, LV EF showed a group difference (BPH: 54±2%, n=12; BPH+Ucn2: 74±2%, n=12; p<.0001) that was same as with systolic/diastolic blood pressure (BPH: 183/154±4/4 mmHg, n=12; BPH +Ucn2: 142/117±4/4 mmHg; p<0.0001). In addition, physiological studies conducted in vivo showed accelerated cardiac relaxation in the Ucn2-treated mice (see Tau in Table), indicating superior LV relaxation after Ucn2 gene transfer. Conclusion: Ucn2 gene transfer improves LV diastolic and systolic function in mice with HFpEF, indicating that such a strategy may be applicable in clinical settings. [Formula: see text] Merit grant from the Department of Veterans Affairs (I01 BX003774). This is the full abstract presented at the American Physiology Summit 2024 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.
Doxorubicin treatment reduces expression of cardiac iron transporters
Authors: Lapierre-Nguyen Stephanie , Morales Marianna , Doerr Vivian , Dowllah Imtiaz , Jacintho Moritz Cesar , Smuder Ashley 
Published: May 2024

Doxorubicin (DOX) is an effective anticancer therapy. Unfortunately, the toxicity of DOX is not limited to cancerous cells, with the heart particularly prone to DOX-induced damage. While the mechanisms of DOX cardiotoxicity remain unclear, accumulation of iron within the heart may exacerbate the detrimental effects of DOX. Thus, understanding the effects of DOX on iron transport and storage protein expression would provide further insight on the mechanisms of disrupted iron handling and may lead to potential therapeutic targets for cardioprotection. Our goal was to investigate changes in gene expression of iron transporters in a preclinical model of DOX-induced cardiotoxicity. Female Sprague Dawley rats (2-3 month-old) were randomly divided to receive DOX or saline consistent with standard clinical treatment (i.e., intravenous infusion once every 3 weeks for 4 total cycles and a cumulative dose of ~160 mg/m2). One week following the fourth cycle measures of cardiac function, assessed by echocardiography, and cardiorespiratory capacity, determined by a graded exercise tolerance test, were completed. Cardiac tissue was also collected and cardiac mitochondria were isolated for measurement of reactive oxygen species production. At endpoint, DOX treatment resulted in a lower heart weight to tibia length ratio, reduced cardiorespiratory capacity, impaired ventricular fractional shortening and greater cardiac mitochondrial hydrogen peroxide emission. We found significant reductions in expression of transmembrane/cytoplasmic iron transporters (transferrin receptor 1 and divalent metal transporter 1) and the inner mitochondrial membrane transporter mitoferrin-2 with DOX treatment compared to saline. Expression of genes encoding for ferroportin-1, mitoferrin-1, ABCB8 and ferrochelatase were also downregulated in the DOX-treated group compared to saline, but these did not reach statistical significance. These findings are the first to describe changes in gene expression of proteins involved in iron homeostasis in a clinically relevant model of DOX-induced cardiotoxicity. Further studies are needed to investigate interventional approaches that improve cardiac iron handling to determine if they provide cardioprotection during DOX treatment. This research was funded by the National Institute of Health (NIH), R01 HL144858. This is the full abstract presented at the American Physiology Summit 2024 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.
Eplerenone Reduces Blood Pressure and Improves Vascular Function in a Mouse Model of Leptin-induced Preeclampsia
Authors: Mellott Elisabeth , Moronge Desmond , Cooper Gibson , Ogbi Safia , Faulkner Jessica 
Published: May 2024

Preeclampsia is a hypertensive pregnancy disease that increases the risks for adverse outcomes of pregnancy for both mother and baby, notably by reducing fetal growth in utero. We have shown that mid-late gestation leptin infusion induces preeclampsia characteristics in pregnant mice in inducing hypertension, endothelial dysfunction, and fetal growth restriction, which is ablated in mice with endothelial mineralocorticoid receptor deletion (ECMR). However, there is a lack of preclinical data and rationale for MR antagonism for use in preeclampsia in the existing literature. Therefore, we hypothesized that leptin increases ECMR expression and that MR antagonism decreases hypertension, endothelial dysfunction, and fetal growth restriction in leptin-induced preeclamptic mice. We infused timed-pregnant Balb/C mice with saline (sham) or leptin (LEP, 0.9 mg/kg/day) via s.c. osmotic minipump and administered vehicle or eplerenone (EPL, 200mg/kg/day) in drinking water from gestation day (GD)11-18 (n=7-12). We measured mean arterial blood pressure (BP) via radiotelemetry, vascular function in 2nd order mesenteric arteries by wire myography, and pup/placental weights on GD18. We isolated endothelial cells from placentas of our mice via magnetic cell sorting. Pairwise comparisons were by student’s t test and myography curves analyzed by 2-W ANOVA w/RM. Leptin increased ECMR mRNA expression (3.1±0.32 WT LEP vs 1.1±0.48 WT sham, fold change, *p<0.05) compared to WT sham mice in placenta indicating a direct role for leptin to upregulate ECMR in pregnancy. EPL ablated leptin-induced increases in BP (98±4 LEP/EPL vs 113±3 lep/veh mmHg, *p<0.05), and when treated with EPL leptin did not induce endothelial dysfunction, as assessed as a lack of decrease in vascular relaxation to acetylcholine (p>0.05 LEP/EPL vs sham/EPL). Interestingly, EPL treatment did not prevent leptin from decreasing placental effciency in pregnant mice (7.42±0.17 LEP/veh vs 6.71±0.15 LEP/EPL, pup/placenta weight ratio, p>0.05). Collectively, these data show that leptin infusion from GD11-18 in pregnant mice increases ECMR activation by increasing expression. Furthermore, MR antagonism by eplerenone ablates the maternal hypertension and endothelial dysfunction in leptin-induced preeclampsia mice, however, fetal growth is not restored by eplerenone. Therefore, eplerenone may be a promising therapeutic for the maternal cardiovascular syndrome of preeclampsia patients, however, MR antagonism therapies may need additional agents to improve fetal outcomes. 1R01HL169576, 4R00HL146948. This is the full abstract presented at the American Physiology Summit 2024 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.
Increase in Plasma S100B Concentration Is Associated With Decrements in Spatial Processing During Acute High-Altitude Exposure
Authors: Figueiredo Peter , Karl James Philip , Landspurg Steven , Femling Jon , Williams Jason , Buller Mark , Staab Janet 
Published: May 2024

Vasogenic edema consequent to blood-brain barrier (BBB) permeability may contribute to cognitive performance decrements during acute exposure to high altitude. S100B is a putative marker of BBB permeability, but S100B responses to high altitude are poorly characterized and the relation to cognitive performance is unknown. To test the hypothesis that S100B increases upon ascent to high altitude and that increase is associated with changes in cognitive performance, 41 healthy Soldiers (mean±SD; age=26±5yr) were tested at their baseline residence (SL, 331m), transported to Taos, NM (2845m), then immediately hiked (n=21) or were driven (n=20) to a high-altitude (HA, 3600m) facility. Plasma S100B was measured at 06:00 throughout the study; twice at SL and again after the first night at HA (16h exposure). The automated neuropsychological assessment metric (ANAM) was administered four times at SL and once at HA to assess sustained attention, working memory, spatial processing, computation, executive function, and reaction time. ANAM performance was assessed using throughput scores, a metric considering both response speed and accuracy. The last SL morning assessment and the HA morning assessment (19h exposure) were used to generate ΔANAM scores. Correlations between ΔS100B and ΔANAM scores were significant for 1 of 9 modules, simultaneous spatial processing (SPD; r=-0.401; p=0.009). S100B increased (5.3%, p=0.02) from SL to HA while SPD scores decreased (8.2%, p=0.05). Using the reliable change index (RCI) to dichotomize individuals into those demonstrating a decrease in performance that exceeded measurement error and day-to-day variability (responders; RCI <-1.64; n=7) and those who did not (non-responders; RCI >-1.64; n=34) revealed that responders experienced a greater increase (+12.3%, p=0.01) in S100B from SL to HA relative to non-responders (+3.4%, p=0.14) Findings suggest that acute exposure to 3600m may increase BBB permeability, as indicated from plasma S100B concentrations, and the increased BBB permeability may be mechanistically associated with spatial processing decrements. Funding: USAMRDC, PRMRP. Authors’ views not offcial U.S. Army or DoD policy. This is the full abstract presented at the American Physiology Summit 2024 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.
Galantamine Reduces Blood Pressure and Renal Injury in Female Angiotensin II-induced Hypertensive Mice
Authors: Chaudhari Sarika K. , Young-Stubbs Cassandra M. , Dinh Viet Q. , Mathis Keisa W. 
Published: May 2024

Inflammation is a known culprit in the development and progression of hypertension. The autoimmune disease, systemic lupus erythematosus (SLE), is an important model of hypertension in the setting of chronic kidney inflammation. We have shown that administration of an acetylcholinesterase inhibitor, galantamine, attenuates the hypertension, kidney inflammation, and kidney injury in female SLE mice by activating the vagally-mediated cholinergic anti-inflammatory pathway. Although SLE hypertension represents a specific population of patients, we hypothesized that galantamine would have similar anti-inflammatory effects in the angiotensin II (AngII)-induced hypertensive mouse, which more commonly models essential hypertension. Female C57BL/6 mice were implanted with minipumps at 9 weeks of age for subcutaneous delivery of either AngII (1000 ng/kg/min) or saline (controls), and galantamine hydrobromide (4 mg/kg/day) or vehicle, for 21 days. At 12 weeks, carotid catheters were implanted and mean arterial pressure (MAP) was measured in conscious mice for two consecutive days. Mice were then euthanized, and kidneys collected. Markers of kidney inflammation and injury, including interleukin (IL)-6 and kidney injury molecule (KIM)-1, were measured by ELISA and normalized to total kidney protein. MAP (mmHg) was higher in AngII-treated mice compared to controls (174±4 vs. 133±3; n=4-5, p=0.0023). Galantamine lowered MAP in AngII mice (157±8; n=7, p=0.2567) without altering MAP in controls (133±4; n=5, p=0.9999). Renal IL-6 (pg/μg) was not different between AngII and control mice (0.004±0.0001 vs. 0.005±0.0006; p=0.6685). Although galantamine lowered IL-6 in both groups, it was only significant in controls (0.003±0.0002; p=0.0134) and not AngII mice (0.003±0.0003; p=0.4677). Renal cortical KIM-1 (pg/μg) trended higher in AngII mice compared to controls (2.53±0.50 vs 0.63±0.16; p=0.0741). Galantamine lowered KIM-1 in AngII mice (1.18±0.39, p=0.2064), but not controls (1.45 ± 0.59; p=0.6285). In summary, galantamine protected female mice from hypertension and renal injury in a model of AngII hypertension. This suggests that acetylcholinesterase inhibitor therapy may be effective in patients with hypertension. Studies funded by NIH R01HL153703 and K01HL139859 for KWM. This is the full abstract presented at the American Physiology Summit 2024 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.
Evidence of Premature Vascular Dysfunction in Young Adults who Regularly Use E-cigarettes and the Impact of Usage Length
Authors: Simovic Tijana , Matheson Chloe , Heefner Allison , Colon Marisa , Tunon Enrique , Cobb Kolton , Thode Christopher 
Published: May 2024

Background: Electronic (e-) cigarettes are increasingly popular novel tobacco products on the US market. Traditional tobacco products are well known to cause vascular dysfunction, one of the earliest indicators of cardiovascular disease (CVD) development. Despite the popularity of e-cigarettes, little is known about the effect of regular e-cigarette use on vascular function. The purpose of this study was to investigate the impact of regular e-cigarette use on vascular function and cardiovascular health in young, healthy adults. Methods: Twenty-one regular users of e-cigarettes (ECU, age: 23±3 y.) and twenty-one demographically matched non-users (NU, age: 25±5 y.) completed this study. Vascular health was assessed in the cutaneous microcirculation through different reactivity tests to evaluate overall functionality as well as endothelium-dependent vasodilation (EDD) and endothelium-independent vasodilation (EID). Macrovascular function was assessed using flow-mediated dilation (FMD). Results: Our results suggest that regular users of e-cigarettes present with premature microvascular impairment compared to non-users. Specifically, they exhibit lower hyperemic ( p=0.003), thermal ( p=0.010), and EDD ( p=0.004) responses. No differences in EID between the groups were identified. We also identified that individuals who use e-cigarettes for longer than three years also present with systemic manifestations, as observed by significantly reduced macrovascular ( p=0.002) and microvascular ( p≤0.044) function. Conclusions: Our novel data suggests that young, apparently healthy, regular users of e-cigarettes present with premature vascular dysfunction in the microcirculation compared to non-users. We have also identified systemic vascular dysfunction affecting both the micro and macrovasculature in those young individuals who used e-cigarettes for longer than three years. Taken together, these findings associate regular e-cigarette use with premature vascular dysfunctions and adverse cardiovascular outcomes. Supported in part by a Rapid Response Project NIDA/FDA (PRM). This is the full abstract presented at the American Physiology Summit 2024 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.
Does zinc deficiency promote renal inflammation?
Authors: Barrett Hannah , Rockwood Jananie , Wenegieme Tara-Yesomi , McMichael Kelia , Hasrat Khanzada , Waite Aston , Nshuti Adeline 
Published: May 2024

Background: Renal inflammation is implicated in the pathogenesis of CKD and plays a critical role in kidney damage. CKD-associated tubular damage stimulates the secretion of proinflammatory cytokines (e.g. IL-1β, IL-6, and TNF-α) which expedite CKD progression, further instigating kidney damage and inflammation. Studies have shown that zinc deficiency (ZnD) elevates oxidative stress and affects proinflammatory cytokine abundance. Based on these findings, we hypothesize that ZnD will promote renal inflammation. Experimental Design: To examine if ZnD promotes renal inflammation, wild-type adult mice (C57BL/6J) were placed on a zinc-adequate (ZnA) or zinc-deficient (ZnD) diet for 10 weeks. At week 8, a subset of the ZnD mice were placed back on a ZnA diet (ZnR) for 2 weeks. The kidneys were harvested, embedded in paraffn, and both immunohistochemistry and immunofluorescence were performed to assess morphological changes and proinflammatory cytokine abundance. Results: Compared to ZnA kidneys, morphological changes were observed in ZnD kidneys, such as loss of endothelial cells in the glomerulus and abnormalities in nuclei arrangement in tubular cells. However, these changes were mitigated with the replenishment of zinc. There were no significant changes in TNF-α expression between the ZnA and ZnD kidneys, but there was decreased expression in the ZnR kidney. Conclusions: Based on preliminary findings, we can conclude that ZnD (1) promotes abnormalities in glomerular and tubular morphology and (2) does not have a significant impact on TNF-α expression in the renal cortex. Zinc repletion was shown to mitigate the glomerular and tubular abnormalities instigated by zinc deficiency. Significance: These findings provide evidence for Zn’s influence on renal inflammation, and advocate for zinc supplementation as a plausible therapeutic strategy for CKD. Funding: R21 DK119879, R01 DK-133698. This is the full abstract presented at the American Physiology Summit 2024 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.