bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lipoprotein lipase activation is a novel vascular anti-contractile mechanism that is lost in aging
Authors: Wilson Emily , Costa Tiago , Fontes Milene , Waigi Emily , Townsend Paul , McQuail Joseph , Wenceslau Camilla , McCarthy Cameron 
Published: May 2023

Increasing incidence of cardiovascular events with age can be attributed to the natural deterioration in organ function, and manifests through a range of vascular phenotypes that include, endothelial dysfunction, hypercontractility, stiffening and remodeling, inflammation, and oxidative stress. Given the aging global population, the identification and translation of novel mechanisms and therapeutics will be essential to increase longevity and prevent premature death and disability. Physiologically, perivascular adipose tissue (PVAT) is known to impact vasculature by exerting an anti-contractile effect mediated by the biosynthesis and liberation of a myriad of anti-contractile molecules (e.g., adipokines). However, this anti-contractile function declines with age and in related diseases. Therefore, our study aimed to restore the anti-contractile effect of PVAT in arteries from aged animals. Specifically, we predicted that increasing lipoprotein lipase (LPL) activity would reinstate the anti-contractile effect of PVAT on aged arteries. To assess this hypothesis, mesenteric resistance arteries (MRA), with (+) and without (-) PVAT, were isolated from male Fisher 344 rats aged 3 (3M) or 16 months (16M) and mounted on a wire myograph. Phenylephrine (PE) concentration-response curves were measured in the presence or absence of LPL activator, NO-1886 (Ibrolipim, 10uM). As expected, PVAT exerted significant anti-contractile effect in MRA, regardless of age [PE 100uM (%), 3M (-PVAT): 112.4±13.3 vs. 3M (+PVAT): 27.6±28.5 {Figure 1.a.} and 16M (-PVAT): 115.4±23.1 vs. 16M (+PVAT): 35.0±34.1 {Figure 1.b.}]. Contrary to our hypothesis, NO-1886 had no effect on the anti-contractile effect of PVAT in 3M or 16M rats [PE 100uM (%), 3M (+PVAT +vehicle): 30.0±34.3 vs. 3M (+PVAT +NO-1886): 47.9±29.8 {Figure 1.c.} and 16M (+PVAT +vehicle): 48.6±42.3 vs. 16M (+PVAT +NO-1886): 60.0±36.9 {Figure 1.d.}]. Surprisingly, we observed an effect of NO-1886 in MRA in the absence of PVAT. Specifically, NO-1886 significantly decreased phenylephrine-induced contraction in 3M rats, but not 16M rats [PE 100uM (%), 3M (-PVAT +vehicle): 112.4±13.3 vs. 3M (-PVAT +NO-1886): 37.8±22.2 {Figure 1.e.} and 16M (-PVAT +vehicle): 115.4±23.1 vs. 16M (-PVAT +NO-1886): 103.1±23.1 {Figure 1.f.}]. Overall, this suggests that LPL has an important physiological role in controlling vascular contraction and this novel anti-contractile mechanism of LPL diminishes with biological age. Funding: NHLBI (R00HL151889), NIGMS (1P20GM103641 - Pilot Project), NIA (K01AG061263), UofSC SOM (Startup funds) 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.
Stabilization of Cx43 mRNA by RNA-binding protein HuR enhances intestinal epithelial barrier function
Authors: Rao Jaladanki , Wang Shelley , Mallard Caroline , Cairns Cassandra , Xiao Lan , Chung Hee , Yu Ting-Xi , Wang Jian-Ying 
Published: May 2023

BACKGROUND & AIMS: Connexin 43 (Cx43) acts as a gap junction protein and is involved in many aspects of different cellular processes including intercellular communication. The levels of cellular Cx43 change markedly in response to various pathobiological stresses, but the exact mechanism underlying Cx43 expression in the intestinal epithelium remains largely unknown. The RNA-binding protein HuR regulates the stability and translation of target mRNAs and is identified as a biological regulator of the intestinal epithelium homeostasis. In this study, we tested if HuR regulates Cx43 expression at the posttranscription level and further examined the influence of HuR/Cx43 interaction on the intestinal epithelial barrier function. METHODS: Studies were conducted in differentiated IEC-Cdx2L1 and Caco-2 cells. HuR binding to the Cx43 mRNA was determined by mRNP/IP assays, and the stability of Cx43 mRNA was examined by its half-life with qPCR analysis. Functions of HuR and its regulator Chk2 kinase were examined by their gene silencing or overexpression. Epithelial barrier function was assayed by transepithelial electrical resistance (TEER) and membrane-impermeable trace FITC-dextran. RESULTS: HuR directly bound to the Cx43 mRNA through its 3’-untranslated region (UTR) rather than 5’-UTR and coding region. HuR silencing decreased Cx43 levels by destabilizing Cx43 mRNA and caused the epithelial barrier dysfunction, as evidenced by a decrease in TEER and an increase in paracellular flux of FITC-dextran. In contrast, Cx43 overexpression rescued the epithelial barrier function in HuR-silenced cells. HuR mediated-Cx43 expression was regulated by ChK2 dependent HuR phosphorylation since decreasing the levels of phosphorylated HuR by silencing ChK2 lowered Cx43 levels and disrupted the barrier function. Reduction in phosphorylated HuR levels by polyamine depletion also inhibited HuR binding to the Cx43 mRNA and decreased Cx43 protein by destabilizing the Cx43 mRNA, which was associated with the epithelial barrier dysfunction. Ectopic overexpression of ChK2 in polyamine-deficient cells not only rescued Cx43 expression but also restored the barrier function. CONCLUSIONS: These results indicate that the Cx43 mRNA is a novel target of HuR and that HuR-induced expression of Cx43 via stabilization of its mRNA plays a critical role in the maintenance of intestinal epithelial barrier function. US Department of Veterans Affairs and NIH 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.
Fibroadipogenic progenitor-derived Gdf10 regulates neuromuscular junction and fat content in tongue muscles
Authors: Choo Hyojung , Kim Seung-Hyun , Du Delia 
Published: May 2023

Obstructive sleep apnea (OSA) is the most prevalent sleep disorder globally 4.5% in men and 2.5% in women. OSA increases the risk of more severe diseases such as heart attack, high blood pressure, type 2 diabetes, obesity, mild cognitive impairment, and depression. The known craniofacial anatomical changes leading to OSA are relaxed muscles and/or enlarged soft tissues by fat infiltration in the soft palate, pharynx, and particularly tongue, which blocks the upper airway during sleep. Although obesity is one of the main causes to induce OSA, the underlying mechanism of those changes has not been researched. The objective of our study is to understand the mechanism leading to those craniofacial changes that generate foundations to develop potential therapeutics for OSA. We hypothesize that high-fat diet-induced obesity regulates the fibroadipogenic progenitors, which are critical for neuromuscular interaction and is mainly responsible for increased fat content in skeletal muscles. To test this hypothesis, we used a mouse model fed with a high-fat diet to induce obesity or a normal diet (control group) for 6 months. Then we isolated tongue muscles for histology analysis, such as muscle size, neuromuscular junction integrity, and adipocyte content.We found that a high-fat diet leaded adipocyte hypertrophy and reduced intact neuromuscular junction in tongue muscles. To investigate the role of fibroadipogenic progenitors for tongue phenotypes by a high-fat diet, we isolated fibroadipogenic progenitor cells to measure transcript levels of Gdf10, also known as Bmp3b, since fibroadipogenic progenitor-derived Gdf10 has been known to stabilize Schwann cells for neuromuscular integrity in muscles. The role of Gdf10 has been suggested to protect from obesity by limiting adipocyte hypertrophy. Using single-cell RNA sequencing analysis, Gdf10 is specifically expressed in fibroadipogenic progenitors but not adipocyte or Schwann cells. We found that Gdf10 transcript levels are significantly reduced by a high-fat diet in tongue fibroadipose progenitors. Taken together, the reduced Gdf10 of fibroadipogenic progenitors by a high-fat diet reduces neuromuscular integrity but induces fat infiltration in tongue muscles in a paracrine manner. Therefore, targeting to increase Gdf10 expression is a potential therapeutic to reduce OSA by maintaining healthy tongue muscle. NIH R01AR071397 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.
Inhibition of Ferroptosis in the Subacute Phase of Ischemic Stroke Worsens Aversive Learning In Diabetic Rats: A Randomized Double-Blind Preclinical Trial
Authors: Edgerton-Fulton Mia , Phoenix Ashley , Abdelsaid Kareem , Abdul Yasir , Jamil Sarah , Li Weiguo , Ergul Adviye 
Published: May 2023

Diabetes increases the risk of hemorrhagic transformation as well as post-stroke cognitive impairment (PCSI). We have shown that iron chelation in the subacute phase improves stroke cognitive outcomes in experimental models of diabetes. We hypothesized that inhibition of ferroptosis, iron-induced cell death, in the post-stroke period will prevent PSCI in diabetic animals. Methods: Male rats, housed in reverse light cycle, underwent sham or 60-min middle cerebral artery occlusion surgery 8 weeks after diabetes onset. After MRI, rats that met the preset inclusion criteria (adhesive removal time > 35 sec. and either a modified Bederson score <= 6 or weight loss > 10% on Day 3) were randomized to ferroptosis inhibitor UAMC-3 (2mg/kg) or vehicle treatment for 2 weeks (n=8-12). Sensorimotor and cognitive outcomes were monitored for 8 weeks in the dark (active) cycle. Results: As confirmed by MRI, inclusion criteria predicted successful stroke surgery in 95% of the animals. There were significant acute neurological deficits. Long-term weight gain and survival were better in this cohort as compared to our historical data collected in regular light cycle experiments. Blood glucose levels were comparable. In contrast to our previous data, there were no significant differences in indices measured by novel object recognition (NOR), Y-maze, and sucrose preference tests after stroke but there was a trend for a greater number of animals showing a cognitive decline in treated cohorts. Step-through latency in the passive avoidance test (PAT) was lower in the treated stroke group. Open field (OF) suggested anxiety-like behavior in RX group. Conclusions: Preset inclusion criteria were effective in controlling for stroke severity. Ferroptosis inhibition impaired aversive learning and appeared to worsen cognitive outcomes in some of the animals. Better post-stroke weight gain/maintenance and greater engagement of animals in behavioral tests conducted in the “dark” cycle may explain the lack of a progressive memory decline after stroke. While further studies are required to better understand whether ferroptosis and housing lighting impacts stroke recovery in diabetes, based on current findings, inhibition of ferroptosis with UAMC-3 is not desirable. 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.
Xanthine oxidase mediates stress-induced Alzheimer's Disease progression in triple transgenic mice
Authors: Prabhu Saina , Burrage Emily , Luthman Jenna , Oudomvilay Crystal , Luna Natalia , Childers Ryan , Hanshew Alec , Englund Phillip , Tierno Vincent , Hoover Jacob , Simpkins James , Kelley Eric , Chantler Paul 
Published: May 2023

Alzheimer’s disease (AD) is a progressive disorder associated with oxidative stress and neuroinflammation promoting the deposition of β-amyloid (Aβ) plaques and neurofibrillary tau tangles. Xanthine oxidoreductase (XOR) is a molybdoenzyme responsible for the metabolism of hypoxanthine and xanthine to uric acid. Under inflammatory conditions, high plasma uric acid levels upregulate XOR leading to increased free radical production and promoting cerebrovascular dysfunction. Chronic stress induces cerebrovascular dysfunction and cognitive decline in C57BL/6 mice mediated by XOR, suggesting a link between chronic stress and dementia. However, there is no published data that link XOR and stress to AD pathology and progression. Thus, we tested the hypothesis that chronic stress accelerates AD pathology via the XOR pathway.At 4 months of age, male and female WT (B6129) and triple transgenic (3xTg) AD mice underwent the Unpredictable Chronic Mild Stress (UCMS) model paradigm for 8 weeks. Mice were euthanized at two different time points at 6 and 9 months of age for both control and UCMS groups, and the tissues were harvested. Brain tissue lysates were homogenized, and the total tau and XOR protein was quantified using Western blot and normalized to β-actin. Aβ (1-40) levels in mouse brain homogenates using Aβ ELISA kit. Immunohistochemical staining was performed to study the colocalization of XO and CD-31 in WT and 3xTg coronal sections and analyzed using Fiji ImageJ.UCMS accelerated Aβ(1-40) expression levels (p<0.05) at both 6 and 9 months of age in the 3xTg mice. Tau levels were significantly increased at 6 months of age (p<0.05), but showed no significant differences in protein expression at 9 months of age. XOR levels were significantly upregulated (p<0.05) in the UCMS group at 6 months of age. At 9 months of age, no significant differences were seen in XOR expression across groups indicating that mice taken off from the UCMS protocol had normal levels of XOR due to reduced oxidative stress buildup in the brain. At 6 months of age, a significant decrease in microvessel density (p<0.05) was seen in 3xTg-UCMS mice vs 3xTg controls, with no significant differences seen at 9 months of age, indicating the role of chronic stress on the decline in cerebrovascular functions. Thus, the study establishes the premise that chronic stress mediated by XOR accelerates AD pathology in our early-onset AD model. NIH, NINDS BINP R01 NS117754, Psychosocial Stress-Induced Vascular Contributions to Cognitive Impairment and Alzheimer's Disease: The Role of Xanthine Oxidase 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.
Effects of food insecurity on nutrition, stress, and resilience
Authors: Bubis Sabrina , Chowdhury Ushima , Nagorny Katerina , Welch Megan , Rosenberg Lexis , Begdache Lina 
Published: May 2023

Food Insecurity is a pressing issue that impacts many Americans, specifically the college student population. Along with the various burdens that come with university life, lacking adequate access to nutritious dense foods poses a serous threat to the resilience and stress levels of students. However, there is a lack on research addressing the relationship between food insecurity, stress and resilience among college students. To assess how food insecurity and low income impact stress, resilience, and diet, an anonymous online survey targeting 18 and older was distributed via social media and emails. This survey included demographic questions and several validated scales such as Food Insecurity Experience Scale, Brief Resilience Scale, Academic Motivation Scale, Kessler Psychological Distress Scale, Stress Mindset Measure, and Perceived Stress Scale. A total of 1005 participants completed the survey. The data were analyzed using Pearson’s Correlation Coefficient in SPSS version 25.0. The results indicate that there is a positive correlation between food insecurity and consumption of pre-packaged food. A negative correlation exists between food insecurity and consumption of fruits, dark green leafy vegetables, whole grain products, and frequent breakfast consumption. This suggests that those who are food insecure are more likely to be deficient in essential nutrients that accompany a well-balanced diet. Additionally, there is a positive correlation between stress and food insecurity as well as a negative correlation between food insecurity and resilience. This indicates that students who are food insecure are more likely to feel stressed and less confident in their ability to handle their personal problems. On the other hand, consuming dark leafy vegetables has a negative correlation with hopelessness, and consuming fruits has a negative correlation with feelings of stress and nervousness. This points to a strong relationship between food insecurity, stress, resilience, and diet. In conclusion, the lack of nutritious foods consumed stemming from food insecurity negatively impacts college students by increasing their stress levels and lowering their resilience. Binghamton 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.
Glucagon-like peptide 1 (GLP1) neurons provide highly collateralized axonal input to multiple brain regions
Authors: Rinaman Linda , Zheng Huiyuan 
Published: May 2023

GLP1-immunopositive axons are present within a large number of subcortical brain regions in rats and mice. GLP1 neurons are activated/recruited by stress-related stimuli, and central GLP1 receptor signaling contributes to a variety of behavioral and physiological stress responses. GLP1-positive axons originate from a small cluster of glutamatergic GLP1 neurons, whose cell bodies occupy the hindbrain caudal nucleus of the solitary tract (cNTS) and intermediate reticular nucleus (IRt). The present study sought to determine whether GLP1 axonal inputs to distinct brain regions arise from distinct subsets of these hindbrain neurons. We recently developed and characterized a new knock-in Sprague Dawley rat model (Gcg-Cre) in which GLP1 neurons within the cNTS and IRt express iCre (DOI: 10.1016/j.molmet.2022.101631 ). Using this rat model, specific hypothalamic and limbic forebrain nuclei that receive GLP1 input were stereotaxically microinjected with Cre-dependent retrograde AAVs (i.e., AAVrg-EF1a-DIO-hChR2:mCherry and AAVrg-EF1a-DIO-hChR2:EYFP). These AAVs fully label the cell bodies, dendrites, and axon collaterals of Cre-expressing neurons that project to each injection site. AAVrg injections into the paraventricular nucleus of the hypothalamus (PVN) labeled GLP1-positive neurons within the cNTS and IRt. Interestingly, labeled axon collaterals of PVN-projecting GLP1 neurons were present within not only the PVN, but in every brain region previously described as containing GLP1-positive axons. Similar results were obtained after AAVrg was injected into the bed nucleus of the stria terminalis. While labeling generated from other AAVrg injection sites remains to be examined, results thus far suggest that individual GLP1 neurons have widely branching axons that target multiple CNS regions. The data suggest that GLP1 neurons broadcast signals simultaneously to multiple subcortical targets, consistent with GLP1 receptor-mediated modulation of overall behavioral state, rather than elicitation of specific behaviors or physiological processes. NIH grant MH059911 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.
Sex-specific effects of mild to moderate renal dysfunction on vascular endothelial function and large elastic artery stiffness
Authors: Coppock McKinley , Darvish Sanna , Murray Kevin , Craighead Daniel , Seals Douglas , Chonchol Michel , Rossman Matthew 
Published: May 2023

BACKGROUND: Cardiovascular disease (CVD) risk is elevated in patients with advanced chronic kidney disease (CKD). Vascular dysfunction, including vascular endothelial dysfunction and large elastic artery stiffening, is a key contributor to increased CVD risk in advanced CKD. Individuals with mild to moderately reduced renal function may also be at increased risk for CVD, but endothelial function and arterial stiffness are not well characterized in this group. Further, women with CKD have lower risk for CVD than men. Whether women are protected from renal dysfunction-related decreases in vascular function is unknown. PURPOSE: We sought to determine: i) whether individuals with mild to moderate renal dysfunction (MRD) have lower endothelial function and greater arterial (aortic) stiffness compared to healthy controls (HC) and ii) if the presence of vascular dysfunction in individuals with MRD is influenced by sex. METHODS & RESULTS: Fifty-nine adults were split into two groups based on renal function. Thirty-two adults (mean±SEM: 66±2 years; 16 women) were identified with MRD, characterized as an estimated glomerular filtration rate (eGFR) of 45-89 (CKD-EPI; 75.0±2.0 mL/min/1.73m2) and/or the presence of microalbuminuria (albumin: creatinine ratio between 30-300 mg/g). Twenty-seven adults (63±2 years; 13 women) were identified as HC with an eGFR >90 (CKD-EPI; 98.7±0.9 mL/min/1.73m2). Subject characteristics known to influence vascular function (e.g., blood pressure, cholesterol, blood glucose, etc.) were not different between groups (all p>0.05). Endothelial function, assessed by brachial artery flow mediated dilation, was not different between groups (MRD: 4.4±0.5%, HC: 4.6±0.5%, p=0.75). Aortic stiffness, assessed via carotid-femoral pulse wave velocity, also was not different (MRD: 950.7±50.6 cm/s, HC: 864.3±33.1 cm/s, p=0.18). When analyzed by sex, men with MRD had lower endothelial function (MRD: 2.8±0.4%, HC: 4.4±0.6%, p=0.04) and tended to have stiffer arteries (MRD: 879.0±42.7 cm/s, HC: 787.7±35.5 cm/s, p=0.11) compared to HC men. In women with MRD, there were no differences in endothelial function (MRD: 5.9±0.8%, HC: 4.8±0.8%, p=0.36) or aortic stiffness (MRD: 1022.3±89.9 cm/s, HC: 953.6±49.4 cm/s, p=0.55) versus HC women. CONCLUSIONS: Men with MRD exhibit vascular dysfunction, while women appear to be protected from MRD-related vascular dysfunction. The lower risk of CVD in women versus men with CKD may, in part, be due to resistance against renal dysfunction-related vascular dysfunction. NIH K01DK115524 to MJR; 5T32DK007135-46 to KOM; K01HL153326 to DHC 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.