bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cardio-centric hemodynamic management with and without adjuvant ethyl nitrite improves mean arterial pressure in rodents with chronic high-thoracic traumatic spinal cord injury
Authors: Duffy Jennifer , Hoiland Ryan , Wearing Oliver , Erskine Erin , Kwon Brian , West Christopher 
Published: May 2023

Objective: Traumatic spinal cord injury (SCI) causes an initial injury followed by a protracted phase of spinal cord tissue hypoxia. This tissue hypoxia contributes to secondary injury, leading to worse motor and cardio-autonomic outcomes in the chronic setting. No neuroprotective agents to mitigate secondary injury have been identified as efficacious in clinical trials. However, we have demonstrated that taking a cardio-centric approach to hemodynamic management following SCI by augmenting cardiac output and mean arterial pressure (MAP) with the b1-adrenoceptor agonist dobutamine (DOB), and further coupling DOB infusion with the inhalation of ethyl nitrite (ENO), an S-nitrosylating agent, is associated with improved spinal cord oxygenation in the acute phase post-SCI. Aim: To determine the influence of a cardio-centric approach to hemodynamic management with adjuvant ENO inhalation following SCI on long term outcomes. We hypothesized that treatment with DOB and ENO in the acute phase following SCI would mitigate secondary injury and improve cardiovascular outcomes in the chronic setting. Methods. A total of 34 male Wistar rats underwent a T3 contusion injury (300 kdyn) and were assigned into 4 treatment groups: control (n=6), ENO (n=6), DOB (n=12), and combined DOB and ENO (n=10). At 11-weeks post-SCI, a locomotor assessment was conducted using the Basso, Beattie and Bresnahan (BBB) locomotor rating scale. At 12-weeks post-SCI, rodents were anesthetized with intravenous urethane (2.44±0.50 g/kg) and instrumented with a solid-state pressure transducer in the carotid artery to measure MAP. Results. We observed a higher MAP in both DOB (113.6 ± 11.4 mmHg; p = 0.030) and ENO+DOB (116.7 ± 14.6 mmHg; p=0.013) treated groups when compared with controls (94.65 ± 11.62 mmHg). The MAP of ENO treated animals (91.6 ± 7.3 mmHg; P= 0.97) was not different from controls. No differences in BBB scores were found between DOB (15.17 ± 4.49), ENO+DOB (13.95 ± 3.86), ENO (12.5 ± 2.5) and control (11.8 ± 2.7)(P=0.29). Collectively, these data suggest that DOB treatment, alone or in combination with ENO, improves systemic hemodynamics in the chronic high-thoracic SCI setting US Department of Defense, ICORD Seed Grant, Craig H. Neilsen Foundation 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.
Glucocorticoid excess and insulin resistance in aged spontaneously hypertensive rats/stroke-prone
Authors: Lansdell Theresa , Hernaiz-Ojeda Angel , Lewis Ally , Dorrance Anne 
Published: May 2023

Vascular diseases cause chronic cerebral hypoperfusion and neuronal injury and are the second most common cause of dementia. A significant cause of chronic cerebral hypoperfusion is hypertension. Insulin resistance is an important risk factor for hypertension. Aside from age, insulin resistance is also the most important risk factor for the development of dementia. While Insulin resistance is considered an important risk factor for the development of hypertension and dementia, little consideration has been given to the idea that hypertension could initiate insulin resistance and fuel a destructive cycle that hastens dementia. We hypothesized that hypertension initiates insulin resistance through sustained activation of the hypothalamic-pituitary-adrenal axis. To test this hypothesis, we measured corticosterone and the expression of steroid biosynthetic genes in six-month-old spontaneously hypertensive rat/stroke-prone (SHRSP) and normotensive Sprague Dawley (SD) rats. To measure glycemic control, rats were subjected to glucose tolerance and insulin tolerance tests. SHRSP were hypertensive and cognitively impaired. SHRSPs had increased corticosterone compared to SD (Male SD vs. SHRSP: 167±29 pg/g vs.1091±166 pg/g, P<0.0001; Female SD vs. SHRSP: 134±19 pg/g vs. 376±47 pg/g, P=0.0017). Adrenal CYP11B1 mRNA expression was increased in SHRSP (Males 14.44±1.44, P=0.0009; Females 710±59, P=0.0016). STARD1 mRNA expression provided a marker of HPA negative feedback. Male SHRSPs had decreased STARD1 mRNA expression (0.56±0.09, P = 0.0217). However, female SHRSPs had increased STARD1 mRNA expression (12.5± 2.25, P=0.0028). Female, but not male, SHRSPs had increased fasting blood glucose, decreased fasting insulin, and reduced rates of glucose clearance (SD vs. SHRSP: 73±6 vs. 92±4 mg/dL glucose, P=0.0045; 33±2.0 vs. 12±5 pmol/L insulin, P=0.0111; AUC 185±37 vs. 279±27 mg/dL/h, P=0.0368). When fasting rats were challenged with insulin, both male and female SHRSPs had decreased clearance of glucose compared to SDs (Male SD vs. SHRSP AUC 87 ± 2 vs. 58 ± 4 mg/dL/h, P< 0.0001, Female SD vs. SHRSP AUC 82 ± 2 vs. 68 ± 3 mg/dL/h, P=0.0007). These results indicate that hypertension is associated with impaired HPA function and insulin resistance, with female SHRSP succumbing faster to hyperglycemia than males. Alzheimer's Association Research Fellowship 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.
Intestinal epithelial ZO-2 is critical for downregulation of injury-induced proliferation after mucosal repair is complete
Authors: Abtahi Shabnam , Chanez-Paredes Sandra , Rincon-Cruz Lorena , Nandivada Prathima , Hunziker Walter , Turner Jerrold 
Published: May 2023

Zonula occludens-2 (ZO-2), encoded by TJP2, is a multi-domain scaffolding protein that recruits claudin proteins to tight junctions. In MDCK cells, Tjp2 knockdown inhibits Hippo signaling pathway and activates Yap/Taz. In humans, TJP2 mutations within the region that mediates claudin binding are associated with cholestasis that is exacerbated by defects in bile acid conjugation. Similarly, liver-specific Tjp2 knockout mice are phenotypically normal but hypersensitive to bile-acid induced cholestatic disease. We sought to determine whether ZO-2 has similar protective functions in intestinal epithelia. Like humans with TJP2 mutations, intestinal epithelial-specific Tjp2-knockout in mice did not induce spontaneous gut disease. There was, however, increased epithelial proliferation, mucosal hyperplasia, and Yap/Taz activation. Nuclear activated Yap was increased 1.9±0.1-fold in Tjp2 knockout enterocytes relative to wild type. In hepatocytes, bile acid stress elicited liver disease. We therefore asked if intestinal epithelial Tjp2 knockout increased mucosal injury induced by systemic T cell activation, TLR3 activation (poly I:C injection), or irradiation. In contrast to hepatocytes lacking ZO-2, intestinal epithelial ZO-2 deletion accelerated proliferation and repair. However, unlike wildtype mice, intestinal epithelial proliferation remained increased in Tjp2 knockout mice after repair was complete and mitotic activity had returned to baseline in wildtype mice. This phenotype is intrinsic to epithelial cells, as Tjp2 knockout enteroids excessive proliferation and formed complex cysts with exuberant budding. These data indicate that ZO-2 is a critical regulator of proliferative homeostasis within the intestinal epithelium and suggest that ZO-2 loss may contribute to dysregulated growth of intestinal neoplasms. Supported by: National Institutes of Health grants R01DK61931 and R01DK068271 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 low-dose pemetrexed-cisplatin combination regimen induces significant nephrotoxicity in mice compared with pemetrexed or cisplatin alone
Authors: Iwhiwhu Samson , Kumar Ravi , Afolabi Jeremiah , Adebiyi Adebowale 
Published: May 2023

Pemetrexed is a cytostatic agent used to treat solid tumors and autoimmune diseases. Pemetrexed exerts its antineoplastic activity by multitargeted disruption of folate-dependent processes that mediate cell replication. Pemetrexed is now combined with cisplatin to treat non-small cell lung cancer and malignant mesothelioma. Cisplatin nephrotoxicity is well-established. Recent evidence in humans suggests that pemetrexed monotherapy can cause kidney injury. However, the mechanisms of pemetrexed-induced kidney injury remain unclear. Whether pemetrexed-cisplatin combination chemotherapy exacerbates nephrotoxicity is also unknown. In this study, we investigated acute kidney injury (AKI) in mice administered a low-dose regimen of pemetrexed or cisplatin alone and compared it with a pemetrexed-cisplatin combination. C57BL/6J (8-10 weeks old) male mice were randomly divided into four groups and administered (intraperitoneally) the experimental drugs solubilized in Captisol (sulfobutylether-b-cyclodextrin). Group 1 received Captisol (excipient control), Group 2 pemetrexed (10 mg/kg), Group 3 cisplatin (1 mg/kg), and Group 4 pemetrexed (10 mg/kg) plus cisplatin (1 mg/kg). The mice were treated every other day for two weeks, three times per week. Transdermal glomerular filtration (GFR) measurement was performed on the third day after the last treatment, followed by a necropsy. Whereas body weight changes and kidney-to-body weight ratio were comparable in the control vs. pemetrexed or cisplatin alone group, these indices were significantly increased in the pemetrexed-cisplatin combination group. There was a relative decrease in the GFR of mice treated with pemetrexed or cisplatin alone and in the pemetrexed-cisplatin combination. However, only mice treated with cisplatin and pemetrexed-cisplatin combination showed a significant reduction in GFR. There were trends of increases in the plasma or urinary levels of AKI biomarkers, including blood, urea nitrogen (BUN), creatinine, neutrophil gelatinase-associated lipocalin (NGAL), and cystatin C in control vs. pemetrexed or cisplatin alone. Renal lipid peroxidation and DNA damage were comparable in control vs. pemetrexed or cisplatin alone. However, the mice administered with a combination of pemetrexed and cisplatin showed amplified lipid peroxidation, proteinuria, and AKI. These findings indicate that combining pemetrexed and cisplatin promotes considerable kidney damage at individual doses that do not cause significant nephrotoxicity. Hence, patients treated with pemetrexed-cisplatin combination chemotherapy should be monitored closely for AKI. Disclosure of Funding: NIH: R01 HL151735-01. 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.
Sleeping while diving: seals at sea drift in and out of sleep at depth
Authors: Kendall-Bar Jessica , Williams Terrie , Costa Daniel 
Published: May 2023

In mammals, sleep is critical and ubiquitous. However, in marine mammals that spend months or entire lifetimes at sea, sleep can limit access to air and foraging opportunities and leave animals vulnerable to predation. Large, deep-diving northern elephant seals (Mirounga angustirostris) travel thousands of kilometers and spend up to 7 months at sea in search of food. We posited that combined demands to feed and avoid predators would strongly restrict aquatic sleep in seals. We built a portable, non-invasive system to simultaneously monitor electroencephalogram (EEG), electrocardiogram (ECG), three-dimensional motion, and swimming behavior. EEG activity of 13 young (< 3-years-old) female northern elephant seals (N = 5 in the lab, N = 8 in the wild [N = 3 at sea]) revealed that total sleep time was indeed strongly restricted at sea compared to on land (> 6-fold difference; 10.8 ± 3.0 h/day on land, 1.7 ± 0.7 h/day at sea). Seals at sea slept during short naps (< 20 min) while resting on the ocean floor (64-249 m deep) or drifting through the water column (82-377 m deep). REM sleep in mammals co-occurs with sleep paralysis. Our data support the presence of sleep paralysis through a persistent supine inversion (belly-up posture) whenever the seal was in REM (100% of REM sleep in the open ocean). Unexpectedly, elephant seals at sea exhibited a large proportion of REM sleep (29.1 ± 4.3% of at-sea total sleep time), compared to aquatic sleep in captive Caspian seals, harp seals, walruses, and fur seals (11%, 6%, 5%, and 1% respectively). This suggests that sleep at depth allows seals to drift safely in and out of sleep paralysis. However, time for sleep is limited by near-constant foraging to support high energetic demands due to their large body size. The extreme flexibility in sleep duration exhibited by northern elephant seals is unprecedented among mammals – approaching that which is observed in migrating birds. These insights into sleep for a large, highly mobile marine mammal can contribute to our understanding of sleep’s function and pathology across mammals, including humans. Funding: NSF Graduate Resesarch Fellowship, Laurel Clark Sea to Space Physiology Research Grant, ARCS Fellowship, Sooy Graduate Fellowship, National Geographic Early Career Grant, Special Research Grant – UC Santa Cruz, Joint Industry Project (JIP2207-23) [DPC], Office of Naval Research (Grants # N00014-08-1-1195 [DPC], N00014-18-1-2822 [DPC], N00014-00-1-0880 [DPC], N00014-03-1-0651 [DPC], N00014-08-1-1195 [DPC], N00014-20-1-2762 [TMW], N00014-19-1-2178 [TMW]) 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.
High glucose-stimulated secretion of Semaphorin-3G by proximal tubule cells inhibits angiogenesis in peritubular endothelial cells
Authors: Caceres Paulo 
Published: May 2023

Hyperglycemia in the diabetic kidney causes tubular and microvascular abnormalities that eventually lead to kidney damage. Given the close association between the proximal tubule and peritubular capillaries, a thorough understanding of their interaction could help identify mechanisms of diabetic kidney disease. Microvascular abnormalities are known to occur in diabetic patients and animal models. Despite known growth factors produced by the proximal tubule that could potentially target neighboring endothelial cells, it is not well understood whether the proximal tubule regulates angiogenesis. Here we propose that the proximal tubule secretes Semaphorin-3G (Sema3G), an anti-angiogenic protein. We hypothesize, that high glucose stimulates Sema3G secretion by proximal tubule cells and inhibits angiogenesis in peritubular endothelial cells.To study the role of secreted Sema3G, we collected the conditioned media from cultured polarized proximal tubule cells (RPTEC cell line) where we silenced Sema3G via lentivirus-delivered shRNAs. To study angiogenesis, we developed primary cultures of mouse kidney peritubular endothelial cells and analyzed angiogenesis via tubulogenesis assays in matrigel.We observed that the basolateral conditioned medium from RPTEC cells stimulated angiogenesis of peritubular endothelial cells in matrigel over 8 hours (p<0.01). However, RPTEC cells pre-grown on high glucose (25 mM) lost this ability. The apical media did not have any effect. To identify a potential proximal tubule anti-angiogenic factor, we measured release of Sema3G from polarized RPTEC cells. We found that RPTEC cells secreted Sema3G basolaterally and high glucose stimulated this by 5.5-fold. (p<0.01). Next, we tested the anti-angiogenic potential of Sema3G in peritubular endothelial cells. While adding recombinant Sema3G (200ng/ml) produced a modest inhibition (28%, p<0.05) of baseline peritubular endothelial cell angiogenesis, instead it completely blocked the stimulatory effect of a dose-response treatment (50–100ng/ml) with the potent angiogenic factor VEGF (p<0.01). Finally, to test the role of endogenous proximal tubule Sema3G, we silenced Sema3G via lentivirus-delivered shRNA in RPTEC cells. We then collected the conditioned medium from cells on normal or high glucose and performed angiogenesis assays. We found that silencing Sema3G in RPTEC cells on high glucose restored the ability of the conditioned medium to stimulate peritubular endothelial angiogenesis.We conclude that RPTEC proximal tubule cells secrete Sema3G, which is stimulated by high glucose, and this anti-angiogenic factor inhibits angiogenesis in mouse peritubular endothelial cells. Henry Ford Hospital, American Heart Association 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.
Endothelial Estrogen Receptor Beta Deletion Augments Endothelial Function in High Fat Diet Fed-Female Mice
Authors: Sharma Neekun , Ramirez-Perez Francisco , Betancourt-Cortes Edgar , Power Gavin , Lazo-Fernandez Yoskaly , Martinez-Lemus Luis Alejandro , Padilla Jaume , Manrique Camila 
Published: May 2023

Arterial stiffening and endothelial dysfunction are key contributors to the development and progression of cardiovascular disease (CVD) in women with obesity. Estrogen actions in the vasculature, mainly mediated via estrogen receptor alpha (ERα), result in enhanced endothelial function, lowered arterial stiffness and decreased blood pressure. However, these vasculoprotective effects seem to be abrogated in obesity. The role that estrogen receptor beta (ERβ) plays in maintaining vascular health in females is not well-characterized and previous studies have pointed toward an inhibitory effect of ERβ signaling on the ERα mediated vascular relaxation. Therefore, the present investigation is aimed at examining the role of endothelial cell (EC) ERβ on endothelial function and arterial stiffness in a model of obesity. EC-ERβKO female mice (ERβ double floxed VE cadherin-Cre+) and their respective littermates (ERβ double floxed Cre-) were fed control chow or a high fat diet (60%) starting at 12 weeks of age for 16 weeks. All reported differences are significant at p<0.05. HFD feeding resulted in significant weight gain in the EC-ERβKO and control groups. Neither, HFD nor EC ERβ deletion impacted blood pressure. As expected, HFD feeding resulted in aortic stiffening in the control cohort. Conversely, ERβ deletion in EC tended (P=0.06) to ameliorate aortic stiffening associated with HFD feeding. After euthanasia and using pressure myography, we also determined ex vivo mesenteric artery vasomotor function and stiffness by measuring flow-mediated dilation (FMD), vascular responses to insulin (INS), sodium nitroprusside (SNP), and the passive mechanical properties of the arterial wall, respectively. Sixteen weeks of HFD resulted in blunted FMD responses only in the control cohort. INS-induced vasodilation was enhanced in the EC-ERβKO group fed HFD. Vasomotor responses to SNP (i.e. endothelial independent) were similar among groups. Contrary to our findings in the aorta, EC ERβ deletion resulted in increased incremental modulus of elasticity (increased stiffness) in mesenteric arteries. Collectively, these findings suggest that deletion of EC ERβ in the setting of obesity enhances endothelial vasodilatory function with a variable impact on arterial stiffening that is dependent on the vascular bed examined. Further studies are needed to delineate the interactions between ERβ and ERα in the endothelium, and their impact in the pathogenesis of CVD in women with obesity and insulin resistance. Funding supported by R01 HL142770 (CM-A). 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 “microbiome-gut-brain axis” in Alzheimer's disease and its role in neurocognitive decline
Authors: Loew Ethan , Sallis Benjamin , Tracy Matthew , Haran John , McCormick Beth 
Published: May 2023

Alzheimer’s disease (AD) is a progressive neurocognitive disease characterized by amyloid beta plaques and neurofibrillary tangles in the brain along with inflammation both in the brain and systemically. This has led to the theory of microbial communities or infections as being causative in the development of neuroinflammation as well as immunosenescence and inflamm-aging seen in AD. Our own research has demonstrated a decreased abundance of anti-inflammatory taxa and an increased abundance of pro-inflammatory taxa in the gut microbiome of AD patients. However, it is unclear how the AD microbiome exerts effects on the central nervous system. To address this gap in knowledge we have performed gut microbiome profiling, analysis of immune cell populations in serum, blood cytokine profiling, and cognitive assessments of AD older adults at 90-day intervals. In our early data collected from this ongoing study we have observed changes in B-cell populations with an increased abundance of class-switched B-cells in older adults with greater levels of cognitive impairment. We have further demonstrated that colonization of mice with the microbiome of AD older adults promotes B-cell class-switching when compared with cognitively impaired older adults without AD. Additionally, we have discovered a loss of phytoestrogen-metabolizing bacteria such as Adlercreutzia equolifaciens among AD older adults with rapidly progressing dementia. Phytoestrogens have been previously identified in protecting the intestinal epithelium from oxidative stress and epithelial permeability. Our preliminary studies have suggested that that the phytoestrogen (s)-equol, produced by A. equolifaciens, confers resistance to epithelial damage in the setting of bacterial lipopolysaccharide. Thus, we hypothesize that Adlercreutzia equolifaciens and similar phytoestrogen-metabolizing bacteria maintain epithelial homeostasis in the setting of inflammation while a gain of pro-inflammatory taxa in AD leads to intestinal barrier disruption, increased antigen presentation, immune cell dysregulation, and ultimately cognitive decline. This continuing work aims to further establish the connection between AD related neurocognitive decline, the microbiome, and immune system. This research was funded by grant numbers R01DK125407, R01AG067483, and 5T32A1007349-31 from the National Institutes of Health 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.