bluuebunny/crossref_metadata_2025 huggingface dataset:
17-B estradiol ameliorates oxidative stress, inflammation and apoptosis in the heart and aorta of ovariectomized Sprague Dawley rat model of collagen induced rheumatoid arthritis (CIA)
Authors: Shahzad Huma
Published: May 2023

Menopause and rheumatoid arthritis (RA) are both known to cause elevation of blood Pressure in women, and it is known that RA is more prevalent in women around menopausal age. However, the mechanism of elevated blood pressure in postmenopausal RA women is not known. Thus, the aim of this study was to identify the underlying mechanisms of increased blood pressure in postmenopausal RA women by using ovariectomised RA rat models. Ratswere randomly divided into six groups: sham, ovariectomised (Ovx), RA induced ovariectomised (Ovx+RA), and RA induced ovariectomised plus 17 β-oestradiol, baricitinib orlosartan. Blood pressure was measured through carotid artery cannulation. Haematoxylin andEosin (H&E) and Picro Sirius Red staining was performed on the aorta and heart tissues toevaluate histological alterations and collagen deposition. Immunohistochemistry, immunofluorescence and qPCR methods were used to evaluate the oxidative, inflammatory, growth and fibrosis, and apoptosis markers in the aorta and heart tissues. Mean arterial pressure(MAP) was significantly raised in the Ovx rats compared to sham rats and slightly raised without significant difference in the Ovx+RA rats compared to Ovx rats. MAP in the RA induced ovariectomised rats were significantly reduced with 17 β-oestradiol and losartantreatment. H&E and Picro Sirius staining revealed enhanced collagen deposition in the aortaand heart tissues and increased fibrosis in the heart tissue of the Ovx+RA rats. The collagen deposition and fibrosis were reduced with 17 β-oestradiol treatment. Immunohistochemistry, immunofluorescence and qPCR studies revealed that Ovx+RA rats had elevated expression of oxidative markers such as endothelial nitric oxide synthase (eNOS), inducible nitric oxidesynthase (iNOS), NADPH oxidase 2 (Nox2) and NADPH oxidase 4 (Nox4), inflammatory markers such as toll-like receptor 4 (TLR4) and nuclear factor kappa-light-chain-enhancer ofactivated B cells (NF-ĸB), growth and fibrosis marker such as vascular endothelial growth factor (VEGF), and apoptosis marker such as caspase-3 in the aorta and heart tissues. The expressions of these markers were reduced with 17 β-oestradiol treatment. In conclusion, hypertension in postmenopausal RA women occurs due to enhanced oxidative stress, inflammation, fibrosis, and apoptosis; oestrogen treatment reduces the blood pressure inpostmenopausal RA women by inhibiting these mechanisms.

The research work is supported by Fundamental research grant scheme 2020, Ministry of Higher education, Malaysia.

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.
Developing a multiscale mathematical model of protein uptake along the mouse proximal tubule
Authors: Shipman Katherine , Baty Catherine , Edwards Aurelie , Weisz Ora
Published: May 2023

The proximal tubule (PT) efficiently reclaims albumin and other proteins that escape the glomerular filtration barrier to maintain a protein free urine. The recovery of filtered proteins occurs via receptor-mediated endocytosis facilitated by the multiligand receptors megalin and cubilin. PT health is impacted by excess albumin uptake that occurs when the glomerular barrier is breached and by nephrotoxic drugs that enter cells in a megalin/cubilin dependent manner. Understanding where and how endocytic uptake occurs along the PT axis is key to predicting disease outcomes and to devising strategies to protect PT cells from nephrotoxic insults. Transcriptomic and proteomic studies in male rodents have demonstrated a difference in the expression of megalin and cubilin across the S1, S2, and S3 sub-segments that comprise the PT. Based on these differences in expression, we previously developed an axial model of protein uptake in mice which predicts that most uptake under normal conditions occurs in the S1 segment, with later PT segments providing excess uptake capacity under nephrotic conditions. Separately, we created a kinetic model that predicts rates of megalin trafficking rates in S1 segment cells. This model demonstrated that both the actual level and the fraction of total receptor present at the apical surface are critical determinants of endocytic capacity. To integrate our cell-based kinetic model of megalin traffic into the axial model, we used imaging-based approaches to quantify the expression and distribution of megalin and cubilin in SGLT2-positive S1 and SGLT2-negative S2 segments in fixed cortical kidney sections from wild-type C57BL/6 age-matched male and female mice. The fraction of megalin and cubilin at the apical surface was determined by colocalization with the brush border marker, villin, in regions where AP2, a marker for endocytic vesicles, was excluded. These data will be incorporated into our current axial model to develop a multiscale model of protein uptake along the length of the PT. The expanded model will improve our understanding of how endocytic capacity along the PT in vivo is regulated under normal and disease conditions and allow us to determine whether there are sex-based differences in the recovery of filtered proteins.

National Institutes of Health T32 DK007052, F31 DK121394, R01 DK125049, R01 DK118726 and ASN Foundation for Kidney Research Pre-Doctoral Fellowship Award

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.
Differential effects of the clock protein BMAL1, diet, and sex on purinergic receptor expression in the distal nephron
Authors: Johnston Jermaine , Costello Hannah , Wingo Charles , Gumz Michelle , Crislip Gene
Published: May 2023

The circadian clock protein BMAL1 is a core component of the intrinsic molecular clock mechanism that governs circadian rhythms. We use a kidney-specific Bmal1 knockout mouse model (KS-BMAL1KO) with loss of BMAL1 expression in the distal segments of the kidney. When placed on a potassium-deficient, high salt diet (0K+HS), male KS-BMAL1KO mice do not show an elevation in blood pressure compared to their littermate controls (CNTL), suggesting a protective effect due to loss of BMAL1 in the distal nephron. A low K+ diet predisposes to salt-sensitive hypertension by a high salt diet, in part due to increased sodium retention. Our lab has previously shown that inappropriately high ENaC activity in mice on a high salt diet is due in part to impaired purinergic signaling. The purinergic signaling pathway regulates water and electrolytes in the kidney via purinergic receptors (P2) and our gene expression data show their oscillation in a circadian manner in the kidney. We hypothesized that BMAL1 in distal segments contributes to the regulation of P2 receptor expression. Kidneys from male and female KS-BMAL1KO and CNTL mice were harvested at zeitgeber time (ZT) 0 or ZT12 from mice on a normal or a 0K+HS diet for 10 days. RNA was isolated from the renal medulla and prepared for RNA sequencing (5-9 pooled samples for males, 4-8 for females). Expression levels of P2X and P2Y receptor transcripts were examined. Loss of BMAL1 in distal segments modified P2 receptor expression, as KS-BMAL1KO mice exhibited lower P2Y14 gene expression than CNTL after 0K+HS in both males (78 ± 0, n=7 vs. 49.5 ± 0.7 CPM, n=7, P<.05) and females (85.5 ± 3.5 n=4 vs. 46 ± 8.5 CPM, n=4, P<.05). 0K+HS diet increased P2X7 in CNTL mice compared to normal diet in both males (88.5 ± 9.2, n=5 vs. 189.50 ± 33.2 CPM 114.1, n=7, P<.05) and females (79.5 ± 3.5, n=5 vs. 130.50 ± 3.5 CPM, n=4, P<.05) with no difference in genotype (P=NS). Sex differences were also apparent, as P2Y2 also increased following 0K+HS, but only in male CNTL (327.5 ± 27.6, n=5 vs. 499 ± 24 CPM, n=7, P<.05) and KS-BMAL1KO mice (264 ± 41, n=6 vs. 510 ± 11.3 CPM n=7, P<.05), without a genotype difference. These results support our hypothesis that BMAL1 in distal segments of the nephron contributes to the regulation of selective P2 receptors in the renal medulla, potentially modulating P2 receptor expression through interactions with circadian clock-, dietary- and sex-dependent factors.

Our work is supported by the NIH, NIDDK, ASN, and AHA.

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.
Association between depressive symptomatology and central arterial stiffness in healthy young adults
Authors: Sirotnik Brianna , O'Leary Deborah , Iannarelli Nathaniel , Dempster Kylie , Wade Terrance
Published: May 2023

Depression symptomology is linked with incident cardiovascular disease (CVD). Increased central arterial stiffness represents a potential mechanism connecting depression and increased cardiovascular risk. Therefore, the objective of this study was to examine the association between depressive symptomology and central arterial stiffness in healthy young adults without cardiovascular disease. The study tested the hypothesis that higher depressive symptomology is associated with greater central arterial stiffness. Using existing data from the Niagara Longitudinal Heart Study (NLHS), a sample of 293 young adults (22.5±1.71 years; 55% female) was included. Depressive symptomology (Centre for Epidemiological Studies Depression Scale; CESD), central arterial stiffness (carotid-femoral pulse wave velocity; cfPWV), beat-by-beat mean arterial pressure (MAP; finger photoplethysmography), and heart rate (HR; electrocardiogram) were measured. Multiple linear regression analyses were used to examine the association between depressive symptomology and cfPWV, adjusting for age, sex, body mass index, physical activity, smoking status, MAP, and HR. Depressive symptomology was categorized as low (CESD score < 16), moderate (CESD score ≥16 and < 26), and high (CESD score ≥ 26), where low symptomology was used as the reference group. After adjusting for covariates, high depressive symptomology was predictive of a faster cfPWV (β = 0.134, p = 0.026), whereas moderate depressive symptomology was not (β = 0.053, p = 0.365). These findings suggest that high depressive symptomatology is associated with a faster cfPWV, signifying elevated central arterial stiffness. Therefore, central arterial stiffness may act as a mechanism connecting depression to CVD. Future research should aim to decipher the causal direction between depression and cfPWV.

This work was supported by the Canadian Institute of Health Research (CIHR) and Brock University.

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.
Cardiorespiratory Capacity and Body Composition are Improved with Concomitant Moderate Intensity or High-intensity Interval Training During Doxorubicin Treatment
Authors: Nguyen Branden , Baumfalk Dryden , Dowllah Imtiaz , Boeno Franccesco , Smuder Ashley
Published: May 2023

Doxorubicin (DOX) is a highly effective chemotherapeutic agent used to treat a variety of solid tumor malignancies including breast cancer. However, following DOX treatment breast cancer patients often suffer from reduced cardiorespiratory capacity and weight gain with increased body fat. These adverse changes following DOX treatment increase the risk of developing cardiovascular disease, thus, increasing patient mortality. In this regard, exercise has been shown to be effective in improving cardiorespiratory capacity and body composition. Therefore, using a clinically translational rodent model of DOX treatment we determined whether participation in moderate intensity aerobic training or high intensity interval training (HIIT) during treatment is sufficient to prevent these adverse effects. The DOX dosing protocol was administered in adult female Sprague-Dawley rats following a standard clinical treatment regimen (i.e., intravenous infusion of DOX once every 3 weeks for 4 total cycles, cumulative dose of ~160 mg/m2). Rats prescribed exercise training followed current exercise guidelines for cancer patients. Moderate exercise consisted of treadmill running at ~70% VO2max 1 hour/day 3x/week. HIIT consisted of 4x4 minute bouts of running at ~90% VO2max 3x/week. Dependent measures were assessed prior to the initiation of DOX treatment and one-week following the last cycle. Similar to patients, DOX reduced cardiorespiratory capacity and increased fat mass in sedentary rats. However, moderate intensity exercise and HIIT improved exercise tolerance, reduced fat mass and increased lean mass in DOX treated rats. These findings mimic the clinical effects of DOX on cardiorespiratory capacity and body composition in breast cancer patients and demonstrate that exercise training during treatment can reduce these negative effects of DOX chemotherapy.

Funding NIH R01 HL144858

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.
Effect of hypokalemia and right atrial stretch on atrial arrhythmogenesis with aging
Authors: Cayton Jessica , Nourian Zahra , Lambert Michelle , Domeier Timothy
Published: May 2023

Atrial Fibrillation (AF) is the most common sustained arrhythmia, and more than 2.7 million people are living with AF in the United States. The elderly are at greatest risk for AF with prevalence estimated at ~10% in individuals over the age of 80. The aged myocardium is subjected to chronic stretch, and atrial muscle stretch is an established risk factor for atrial arrhythmogenesis. Low potassium levels associate with arrhythmias and increase cardiovascular mortality by up to 10-fold. The goal of this investigation was to test factors leading to changes in rhythm and rate in an aging C57BL/6 mouse model. To test these factors, we used isolated hearts with combined cannulation of the aorta and superior vena cava in a modified right-sided working heart perfusion technique. Hearts of Aged (25-29 month) male (n=12) and female (n=14) C57BL/6 mice were subjected to normal Krebs-Henseleit buffer control conditions (control, 6 mM K+) followed by 30 minutes of right-atrial stretch (12 cmH20 right atrial preload), hypokalemia (2 mM K+), or combined stretch and hypokalemia. Heart rate and incidence of atrial arrhythmias were monitored using right-atrial placement of an intracardiac electrocardiogram. Under control conditions average heart rate across all groups was 248±13 BPM with no incidence of atrial tachycardia, fibrillation, or flutter. There were modest (P>0.05) differences in rate and rhythm with stretch (n=8), but hypokalemia decreased (P=0.001) heart rate by 20% and 4/8 hearts exhibited spontaneous atrial tachycardia/fibrillation/flutter. Hearts with combined hypokalemia and stretch exhibited normal heart rate (97% of control) and 5/10 hearts exhibited spontaneous atrial tachycardia/fibrillation/flutter. Observed atrial arrhythmias were present in hearts of both Aged male mice and Aged female mice. In conclusion, the aged mouse atria exhibit arrhythmias in response to hypokalemia and increases in right-atrial preload under hypokalemic conditions. The aged C57BL/6 mouse model is therefore useful for pre-clinical studies of atrial arrhythmogenesis.

JC was funded by 2T32 OD011126 and the project was funded by NIH R01 HL136292 and University of Missouri School of Medicine TRIUMPH award (Domeier)

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.
Combined acute intermittent hypoxia and task specific training with hypercapnia improve breathing capacity after chronic cervical spinal cord injury
Authors: Gonzalez-Rothi Elisa , Gonzalez-Rothi Elisa , Berschel Mackenzie , Molyneaux Alex , Mitchell Gordon
Published: May 2023

Therapeutic acute intermittent hypoxia (tAIH) is simple, safe, and effective means of inducing respiratory motor plasticity and improving breathing in rodent models of acute cervical spinal cord injury (SCI). Unfortunately, tAIH effects on breathing function are less effective with chronic injury. On the other hand, tAIH restores non-respiratory (limb) motor function with chronic SCI, but only when combined with task specific training (TST). The efficacy of combined tAIH and respiratory TST on breathing ability in rodent models (or humans) with chronic SCI has not been investigated. Here, we explore the potential for tAIH and respiratory TST to increase breathing ability; we further differentiate automatic vs. volitional TST, since the ability to sustain independent breathing is dependent on automatic (and not volitional) breathing function, which relies on distinct neural pathways. Hypercapnia is a powerful respiratory stimulant, increasing breathing via (automatic) chemoreceptor feedback, independent of voluntary control. Thus, we explore the impact of 7 days of tAIH (10, 5-min episodes of 10.5% O2) combined with automatic, hypercapnia-induced TST (30 min, 9% inspired CO2) on breathing in unanesthetized rats with chronic (7-8 weeks) C2 spinal hemisection. In preliminary analyses, breathing capacity (i.e., ventilatory response to maximal chemoreflex activation) increased following treatment with daily AIH combined with hypercapnia (i.e., respiratory TST) in rats with chronic C2 hemisection (~17% increase). Similar improvements in breathing function were not observed with tAIH or respiratory TST alone. These are the first studies to investigate the therapeutic efficacy of combined tAIH and respiratory TST targeting automatic breathing. These initial results indicate that, similar to non-respiratory motor systems, pairing tAIH with TST improves breathing function in rodents with chronic cervical SCI.

Craig H. Neilsen Foundation (SCIRP891379), NIH HL147554, and the McKnight Brain Institute

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 brief online single session intervention increases undergraduate confidence speaking out in an active learning physiology course
Authors: Cooper Katelyn , Cohen Katherine , Ghosh Arka , Busch Carly
Published: May 2023

Increasingly, college physiology courses are transitioning from traditional lecture to active learning because students learn more and fail less when they engage in their learning through activities and discussions in class. Fear of negative evaluation (FNE), defined as a student’s sense of dread associated with being unfavorably evaluated while participating in a social situation, discourages undergraduates from participating in small group discussions, whole class discussions, and conversing one-on-one with instructors. FNE disproportionately impacts women, persons excluded because of their ethnicity or race (PEERs), LGBTQ+ individuals, and those coming from low socioeconomic backgrounds. To equip undergraduates with skills to cope with fear of negative evaluation and bolster their confidence, clinical psychologists and biology education researchers developed Project Engage, a digital, self-guided single-session intervention for college students. It teaches students strategies for coping with and reducing fear of negative evaluation by providing biologically-informed psychoeducation, utilizing interactive elements for engagement, and generating a personalized action plan. In a study of 300 upper-level physiology students, participants randomized to complete Project Engage reported greater increases in overall confidence in engaging in small group discussions (p < 0.01), whole class discussions (p < 0.001) and one-on-one interactions with instructors (p<0.05), from baseline to immediate post-intervention, compared to participants in an active control condition. This work provides a foundation for a freely-available, easily accessible intervention to bolster student confidence contributing in class, with the hope of creating more equitable active learning physiology courses.

NSF grant #2141681

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.
Steady-state intracellular pH and recovery from NH3/NH4+-induced intracellular acid loads in primary cultures of rat hippocampal neurons and astrocytes
Authors: Ruffin Vernon , Boron Walter
Published: May 2023

Intracellular pH (pHi) homeostasis is of vital importance because pHi fluctuations alter the net charge on intracellular weak acids and bases (e.g., amino-acid residues of proteins, metabolic intermediates, solutes like inorganic phosphate), and can result in cellular dysfunction. The rate of pHi change (dpHi/dt) is determined by the balance between acid loading (e.g., metabolic production of H+, influx of H+, efflux of HCO3 − via transmembrane proteins of the SLC4 family) and acid extrusion (e.g., efflux of H+ via Na-H exchangers in the SLC9 family, influx of HCO3 − by members of the SLC4 family). A powerful approach for studying pHi regulation is to impose an acute intracellular acid load using the NH4 +/NH3 prepulse technique, and then assess dpHi/dt during the subsequent pHi recovery. Using two such prepulses and recoveries (twin pulses), one can compare 2 experimental conditions. The goal of the present study is to develop a data-analysis approach that facilitates a meaningful presentation of all twin-pulse experiments in a data set. Using primary cultures (~2 weeks) of embryonic (E18–E20) rat hippocampal neurons and astrocytes on coverslips, we loaded cells with the ratiometric pH-sensitive fluorescent dye BCECF, subjected the cells to twin NH4 +/NH3 pulses, and calibrated BCECF at the end of each experiment with nigericin at pH=7.0. A standard 12-point nigericin calibration curve allowed us to compute pHi vs. time. Because we studied cells in 21% O2 but the nominal absence of CO2/HCO3 −, the pHi recoveries mainly reflect Na-H exchange. We fitted the pHi-recovery time course with a double exponential (DExp) to reduce bias. Nevertheless, in both neurons and astrocytes plots of dpHi/dt vs. pHi appeared rather linear, indicating that the pHi recoveries were “quasi” single exponential (SExp). To exploit the near-linearity, for each pHi recovery, we fitted the plot of dpHi/dt vs pHi with a line, the slope of which is the quasi-single exponential rate constant (kqSExp), and the x-intercept of which is the asymptotic pHi of the recovery. We summarize the twin pHi recoveries from individual cells as miniature plots (“thumbnails”) in which we display, for each recovery, both the dpHi/dt values (from the DExp fit of pHi vs. time) vs. pHi and the line of best fit for these dpHi/dt values vs. pHi. A single figure can replicate such twin-pulse experiments from many dozens of cells, so that a reader, at a glance, can surmise the essentials of each pHi recovery. The present work provides background data for additional work in which we studied pHi recoveries at a reduced [O2], with or without CO2/HCO3 −.

R01 NS018400, R01 HL160857, R01 DK128315

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.
Dietary vitamin D supplementation partially rescues heart rate in Ts65Dn mice, a model of Down syndrome
Authors: DeRuisseau Keith , Derfel Silas , MacDonald Jessica , DeRuisseau Lara
Published: May 2023

Down syndrome is the most common developmental and intellectual disability that leads to co-morbidities including lower heart rate and blood pressure. We previously showed that Ts65Dn mice also display reduced heart rate and blood pressure compared to wild-type (WT) colony controls. Lower serum Vitamin D (VitD) levels have been reported among individuals with Ds. In other populations, VitD is a regulator of nitric oxide synthase and a known modulator of cardiovascular outcomes. VitD effects on cardiovascular physiology in Ds is unknown. In this preliminary study, we hypothesized that Ts65Dn mice supplemented with VitD would display improved heart rate compared to Ts65Dn mice on a control diet. Two-month old male Ts65Dn mice were placed onto a control diet (1IU VitD/g; n=4) or VitD supplemented diet (50IU/g; n=5) for two weeks and subsequently tested for resting heart rate. Mice were fitted with a MouseOx neck collar to monitor heart rate while freely moving within the cage. After habituation to the collar, heart rate was recorded for 30 minutes in the light cycle. Heart rate in Ts65Dn on the control diet was 510±67 bpm vs. 636±78 on the VitD diet (p=.038; t-test). As expected, WT (n=5; control diet) displayed a higher heart rate of 729±62 bpm. These preliminary data reveal a partial rescue of resting heart rate in Ts65Dn following VitD supplementation. Future studies can evaluate serum VitD levels, nitric oxide synthase, and cardiovascular metrics including blood pressure, heart rate, and pulse wave velocity in Ts65Dn and WT mice supplemented with dietary VitD.

This work was supported by NIH R21HD099573

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.
Assessment of the Response of Young and Aged Sarcospan-Deficient Mice to Nutrient Excess
Authors: Olateju Bolade , Rahimi Kahmini Aida , Valera Isela , Reis Gisienne , Samarah Luaye , Mumbi Florence , Mohammadipour Nazanin , Parvatiyar Michelle
Published: May 2023

This study follows up on human genome-wide association studies that have identified variants in the SSPN locus. This locus encodes the protein sarcospan that segregates with several anthropometric traits. One of these traits includes an increase in waist circumference. In this study, we compared the response of young and old SSPN-deficient (SSPN-/-) and WT control mice to high fat diet (HFD) (60% fat). The HFD was initiated in 2 month and 1 year old male and female for 4 months and 5 months respectively. This study showed that SSPN-deficiency provided partial protection from weight gain in young male mice when compared to age-matched WT mice and a significantly smaller increase in body weight (BW) compared to controls. Also, young female SSPN-/- mice gained 50% less BW than WT age matched mice compared to controls and visceral WAT fat pad weights were significantly lower. To examine whether these differences are lost in aging (e.g. due to hormonal decline), we subjected 12-month old WT and SSPN-/- mice to 5 months of HFD and assessed anthropometric traits, blood lipids, glucose tolerance, body composition, and alterations of cytokine/adipokine/chemokine levels in blood serum and adipose tissue. There were signs of inflammation/fibrosis in young WT male WAT. This was largely absent in SSPN-/- mice. Interestingly, a specific subset of upregulated inflammatory mediators was found in WT WAT including leptin. However, another distinct subset of adipokines/chemokines were upregulated including adiponectin in SSPN-/- WAT. Therefore, we are investigating whether SSPN affects obesity-associated inflammatory signaling in adipocytes that influences adipose tissue expansion and ectopic triglyceride accumulation in the liver.

FDOH JEK 21K12

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.
Peptide-Based Fibrin-Targeting Fluorescent Probes for Murine Stasis Venous Thrombus Resolution
Authors: Ha Khanh , Vijay Aatira , Hagearty-Mattern Catherine , Jaffer Farouc , McCarthy Jason
Published: May 2023

Background- The lack of a stasis venous thrombosis model (VT) in female mice has limited investigation of sex differences of anti-VT therapies, such as acetylsalicylic acid (ASA), which appears efficacious in preventing recurrent VT. Here we (i) develop a new extended stasis VT model; and (ii) examine the effects of ASA on stasis VT resolution in both female and male mice using serial intravital microscopy (IVM). Method- To extend stasis thrombus persistence beyond a single ligation (SL) model, the femoral vein was ligated, followed by a second ligation of saphenous vein near popliteal vein (Fig. A). Following FITC-dextran injection (10 mg/kg), FITC light irradiation (475/35nm, 20x) for three minutes across three illumination fields generated stasis VT. Subsequently, Dylight-649-GPIbβ agent was injected (100ug/kg, ex 630nm) to observe platelets. At T30’, fibrin targeting agent-FTP11-CyAm7 (150nmol/kg, ex 750 nm) was injected. ASA pre-treatment was done for 7 days (3mg/kg, n=5-6). Serial epifluorescence IVM images were acquired up to 24 hours (90i, NIS Elements software, Nikon). Thrombus area was quantified (NIH ImageJ). Results- DL thrombus was significantly larger and visualized through 24 hours (Fig B-G) and 48 hours (data not shown) versus SL thrombus (Fig. E). Corresponding sections of thrombus at T60’, T6h and T24h showed formation of a persistent thrombus core consisting platelets and fibrin (Fig. H-J). In the DL model, females developed reproducible stasis VT burden and resolution profiles as in males (Fig. K). ASA pre-treatment resulted in significant reduction in thrombus induction (T0’), and accelerated resolution in both sexes (Fig. L-P). ASA inhibited platelet recruitment to thrombi within T30’, consistent with its known anti-platelet effect via irreversible inhibition of Thromboxane A2. Furthermore, ASA inhibited fibrinogenesis, suggestive of an impaired platelet-fibrin interface. Conclusion- Here we establish a new extended stasis VT model applicable to both female and male mice that develops thrombus for up to 48 hours. Moreover, this model is amenable to study vein wall fibrosis-key aspect of post-thrombotic syndrome. Furthermore, ASA inhibits thrombus formation and accelerates thrombus resolution in a sex-independent manner, supporting its use in prevention of recurrent VT.

AHA 953662; NIH 1R21AR081535-01; NIH R01GM126062

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.
Exercise augments small conductance Ca2+ -activated potassium channel (SK) function in the paraventricular nucleus (PVN) of Sprague Dawley rats to reduce sympathetic outflow
Authors: Miodonski Gregory , Bruning Jessica , Simet Derrick , Ruiter Haley , Johnson Christian , Gu Mingjun , Shan Zhiying , Chen Qinghui
Published: May 2023

Elevated sympathetic outflow is a key feature of cardiovascular disease (CVD) that worsens disease progression. Our lab has shown that SK channels expressed in the PVN play a crucial role in regulating neuronal activity and sympathetic outflow, and that SK channels become dysfunctional in rats fed a high salt diet. Exercise has been shown to be an effective treatment for reducing sympathoexcitation in CVD including hypertension and heart failure, but the underlying mechanisms are not fully understood. We hypothesized that aerobic exercise would upregulate SK channel function in the PVN to reduce sympathetic nerve activity (SNA). To test this, 5–6 week old Sprague Dawley rats were randomly divided into sedentary (SED) and exercise (EXT) two groups and fed a 0.4% NaCl normal salt diet. Following acclimation, EXT groups ran on a motorized treadmill 5 days/week for 8-10 weeks. Conscious blood pressure was measured weekly via tail plethysmography. After 8-10 weeks, animals were anesthetized and underwent in vivo surgery to record the renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) following PVN microinjection of the SK channel blocker, apamin (0.25mM, 60nL/side). The data showed that the RSNA response to PVN apamin was significantly enhanced in EXT rats compared with SED rats (320.8 ± 174.6 % baseline, n=9 vs 184.8 ± 143.1 % baseline, n=9; p = 0.02). The corresponding ABP response to apamin was not significantly different in EXT rats compared with SED rats (20.40 ± 9.98 mmHg, n=9 vs 25.27 ± 9.97 mmHg, n=8; p = 0.1658). Our data indicates exercise enhances PVN SK channel function to reduce sympathetic outflow. This improvement of SK channel function may be one mechanism by which exercise reduces SNA in CVD including hypertension and heart failure.

Support: 1R15HL145655 (Chen); 1R15 HL150703 (Shan); MTU Health Research Institute.

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.
Brief Smell Identification Test-1, An odor impairment Test in Patients of Depression
Authors: BAJPAI MANISH
Published: May 2023

It is often seen that the loss of olfaction is the first symptom in patients of depression. Cognitive functions are frequently altered in depression. Olfaction depends on the integration between olfactory tract and limbic system. Both olfactory bulb and limbic system are highly plastic structures that can change organization network based on environmental input. In patients of depression it is seen that there is significant alteration in olfactory bulb volume from normal healthy subjects. Brief smell identification-12 test, a 12-item version of the University of Pennsylvania Smell Identification Test. The test utilizes microencapsulated “scratch and sniff” odorants (Sensonics International, Haddon Heights, NJ). A BSIT score≤8 was considered abnormal. HYPOTHESIS Olfactory functioning is impaired in patients of depression. OBJECTIVES To study the association of olfactory function in patients of depression with clinical variable, if any. To study the olfactory function in patients of depression and compare it with healthy controls MATERIAL AND METHOD 35 Patients of depression as cases and 32 normal healthy controls attending “ Adult Psychiatry OPD Department, KGMU “ were included in this study (age and sex matched). Depression was classified as per ICD-10. BSIT-12 test for olfaction, MMSE and TMT were done for cognition and attention. RESULT The BSIT-12 test score was found lower in all patients of depression as compared with normal subjects. Statistical analysis t-test and chi-square test found value p <0.001. DISCUSSION AND CONCLUSION BSIT-12 as validated test for olfaction may be useful in diagnosing depression severity and prognosis with treatment.

self funded

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.
Nimodipine exerts a protective effect against spreading depolarization and neuroinflammation
Authors: Frank Rita , Pesti István , Menyhárt Ákos , Szarvas Péter , Gulya Károly , Bari Ferenc , Farkas Eszter
Published: May 2023

Hypothesis, objective: Voltage gated Ca2+ channels (VGCCs) are widely expressed in the central nervous system and implicated in neuronal injury and microglial activation. Nimodipine, a potent cerebrovascular dilator and VGCC antagonist is found to be effective against the vasoconstriction caused by spreading depolarization (SD) in preclinical studies of ischemia. However, it is still unclear whether the beneficial effect of nimodipine is achieved by the improvement of perfusion or a direct action on neuronal or glial cells. Our aim was to explore the direct action of nimodipine on the nervous tissue and microglia. Methods: Brain slices prepared from C57BL/6 mice (n=16) were perfused with artificial cerebrospinal fluid (aCSF). After 30 min nimodipine (nimo; 10 μM) incubation, low glucose aCSF (5 mM) and transient anoxia (1 min) were applied to mimic ischemia and to elicit SD. Intrinsic optical signal imaging was used to analyze SD features, TTC staining was applied to assess tissue injury. Primary mixed and pure microglia cultures prepared from the cortex of neonatal SPRD rats were treated with lipopolysaccharide (LPS;20 ng/ml) and nimodipine (5,10,20 μM), alone or in combination for 24 h. Microglial activation was evaluated by Iba1 immunolabeling (degree of arborization expressed by a transformation index (TI)), Western blot analysis and the visualization of phagocytosis with fluorescent microbeads. Results: In brain slices, nimodipine reduced the focal area of SD (2.37±0.94 vs 3.38±0.88%, nimo vs control), the total cortical area affected by SD (17.12±8.63 vs 39.88±22.42%, nimo vs control) and the propagation velocity of SD (0.19±0.79 vs 1.59±2.29mm/min, nimo vs control). Nimodipine decreased tissue injury, viability expressed as the number of TTC-stained particles (4.48±1.45 vs 3.52±1.52 particle/1000 μm2, nimo vs control). Nimodipine reduced microglial activation in LPS-treated cultures reflected by more ramified cell morphology (3.1±0.91 vs 1.89±0.41 TI, LPS+nimo vs LPS), decreased Iba1 intensity in Western blot analysis (108.3±20.1 and 77.2±8.49 vs 213.4±29.7 integrated optical density, LPS+nimo 10 and 20 μM vs LPS) and attenuated phagocytic activity (6±10 vs 22±20 bead/cell LPS+nimo vs LPS). Conclusion: Nimodipine was protective against SD and successfully reduced neuroinflammation by decreasing microglial activation. Neuroprotection was achieved independent of nimodipine’s vascular action. Our data suggest that nimodipine may be applicable against neuroinflammation and ischemia, in which neurodegeneration is believed to be linked to neurotoxic microglial activation.

NKFIH K134377 and K134334, H2020 No. 739593, NAP3.0, TKP2021-EGA-28

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.
Incorporation of heart rate variability into police tactical group small unit tactics selection
Authors: Tomes Colin , Schram Ben , Canetti Elisa , Orr Robin
Published: May 2023

Objective: Police tactical group (PTG) occupational requirements are known to expose officers to high levels of physical, mental, and emotional stressors. As such, selection courses must ensure candidates are not only physically, but mentally and emotionally competent. To assess personnel for suitability likewise requires a holistic approach; wearable technologies may provide organizational decision makers additional information. Heart Rate Variability (HRV), one metric obtainable from wearable technology, has been increasingly utilized as a stress biosignal, but the value of HRV data in the context of specialist police selection remains limited. Hypothesis: Therefore, the hypothesis of this study was: can HRV analysis effectively discriminate between high and low performing candidates attending PTG selection? Methods: This study was a prospective cross-sectional study of three male PTG candidates completing a highly demanding selection course. HR and HRV were measured from 1300 – 1800 on a single day of tactical maneuver training. HRV was analysed as follows: R to R interval (RRI) length, root-mean-square of successive RRI differences (RMSSD), percentage of adjacent RR intervals varying by at least 50ms (pRR50), nonlinear short-term variability (SD1), and nonlinear long-term variability (SD2).Data: Measures of central tendency were generated; the maximum, minimum, mean, and standard deviation were reported for each HRV measure and visualized with a box plot. Results: Data from one participant appeared to skew results; the maximum values for mean RRI (Max: 709ms, Min: 580ms, Mean: 632.67±67.68ms), RMSSD (Max value: 42.3ms, Min value: 18.8ms, Mean: 26.8±13.43ms), pRR50 (Max value: 12.47%, Min value: 1.98%, Mean: 5.76±5.82%), SD1 (Max value: 29.9ms, Min value: 13.3ms, Mean: 18.93±9.50ms), and SD2 (Max value: 61.1ms, Min value: 37.5ms, Mean: 49.87±11.84ms) all occurred in the same participant. That participant also held the lowest maximum HR (138bpm), lowest mean HR (85bpm) and was the highest performer as rated by unit leadership. Conclusions: Given the potential discriminatory capacity of HRV in this context, HRV may be a valuable objective metric to support PTG candidate selection by providing objective measurements of holistic stress response.

This research was supported by a PhD scholarship awarded to the lead author by Bond University. No other funding or grant from any agency in the public, commercial or not-for-profit sectors was provided or otherwise obtained.

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.
Protectin DX as a therapeutic strategy against frailty in mice
Authors: Perazza Lais , Gower Adam , Brown-Borg Holly , Divieti Pajevic Paola , Thompson LaDora
Published: May 2023

Frailty in aging is driven by the dysregulation of multiple biological pathways. Protectin DX (PDX) is a docosahexaenoic acid (DHA)-derived molecule that alleviates many chronic inflammatory disorders, but its potential effects on frailty remain unknown. Our goal is to identify age-related impairments in metabolic systems and to evaluate the therapeutic potential of PDX on frailty, physical performance, and health parameters. A set of 22-month-old C57BL/6 male and female mice were assigned to vehicle (Old) or PDX daily gavage treatment for 8 weeks, whereas 6-month-old (Adult) mice received only vehicle. Forelimb and hindlimb strength, endurance, voluntary wheel activity and walking speed determined physical performance and were combined with a frailty index score and body weight loss to determine frailty status. Our data shows that old vehicle-treated mice from both sexes had body weight loss paralleling visceromegaly, and old females also had impaired insulin clearance as compared to the Adult group. Aging was associated with physical performance decline together with higher odds of frailty development. There was also age-driven mesangial expansion and glomerular hypertrophy as well as bone mineral density loss. All of the in vivo and in vitro impairments observed with aging co-occurred with upregulation of inflammatory pathways and Myc signaling as well as downregulation of genes related to adipogenesis and oxidative phosphorylation in liver. PDX attenuated the age-driven physical performance (strength, exhaustion, walking speed) decline, promoted robustness, prevented bone losses and partially reversed changes in hepatic expression of Myc targets and metabolic genes. In conclusion, our data provides evidence of the beneficial therapeutic effect of PDX against features of frailty in mice. Further studies are warranted to investigate the mechanisms of action and the potential for human translation.

The authors declare no conflict of interest. Funding: μCT analysis was performed by the Center for Skeletal Research Imaging and Biomechanical Testing Core at Massachusetts General Hospital (NIH P30 AR075042). We acknowledge the Boston University Microarray and Sequencing Resource Core Facility and the Clinical and Translational Science Institute (NIH UL1TR001430) for the RNA sequencing analysis. This work is supported, in part, by the Travis Roy Endowed Professorship (to L.V. Thompson) and the National Institute on Aging (R56 AG-067724 to L.V. Thompson and H. Brown-Borg, K07 AG-072124 to L.V. Thompson).

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.
Evaluating the diagnostic quality of exosomal versus free-circulating microRNAs as biomarkers of canine congestive heart failure
Authors: Belden Halle
Published: May 2023

MicroRNAs (miRNA) show great potential as biomarkers, and eventually therapeutics in the form of mimics and inhibitors, in a diversity of diseases. MiRNA can be found freely-circulating in the bloodstream (FCmiRNA) or secreted from cells in exosomes as exosomal miRNA (exomiRNA). Exosomes are extracellular vesicles that carry cell-specific cargo to targeted cells elsewhere in the body, traveling through body fluids. ExomiRNA shows great potential to be more reliable than FCmiRNA as a biomarker of disease due to the added membrane, which preserves the miRNA cargo, and the theoretical increased likelihood of relevant miRNA to be present in exosomes. Multiple miRNAs have already been associated with the development of canine congestive heart failure (CHF) in dogs.In this study, we compared the expression of four miRNAs: miRNA 133, miRNA 1, miRNA29, and miRNA302 between healthy dogs and dogs with CHF, and compared the expression levels of these miRNAs as FCmiRNAs and exomiRNAs.Data from my previous study suggests that exomiRNA is better preserved in FCmiRNA from canine plasma samples. We predict that the results from this study will confirm association of the selected miRNAs and CHF status, meaning elevated levels of miRNA133 and miRNA1 correlate with presence of CHF, while decreased levels of miRNA29 and miRNA302 correlate with presence of CHF. We predict that exomiRNA expressions will be consistently higher than FCmiRNA expression among all four miRNAs, which suggests the exosomes protect the structural integrity of the miRNAs, and exomiRNA could be more reliable than FCmiRNA as a biomarker in diagnostic and prognostic clinical scenarios.

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.