bluuebunny/crossref_metadata_2025_split huggingface dataset:
Netrin-1 increases epithelial cell proliferation and promotes renal cyst formation by activating Rac2 in collecting duct cells
Authors: Mohamed Riyaz , Sullivan Jennifer C 
Published: May 2024

Despite recent advances in our understanding of the pathogenesis of polycystic kidney disease (PKD), the underlying molecular mechanisms involved in cystogenesis are not fully understood. Common features of PKD are excessive epithelial cell proliferation and fluid-filled cyst formation in the kidney, leading to loss of kidney function. We recently demonstrated that netrin-1 is upregulated in primary human PKD cystic cells and in the kidneys of rodent models of PKD. Moreover, overexpression of netrin-1 in tubular epithelium increases cell proliferation (p<0.01) and induces renal cyst development (p<0.0001), while decreasing netrin-1 reduces cyst growth (p<0.01) and improves kidney function (p<0.05). However, the underlying mechanism by which netrin-1 induces cystic cell proliferation is unknown. We hypothesize that netrin-1 increases cystic epithelial cell proliferation by activating Ras-Related C3 Botulinum Toxin Substrate 2 (Rac2) in collecting duct (CD). 4-week-old male tubular overexpressed netrin-1 transgenic mice (NTN-1 Tg6) and 8-week old Pkd1RC/RC mice were randomized to receive vehicle or the specific Rac2 inhibitor EHT 1864 (20 mg/kg/48hr i. p; n=4-5/group) for 4 weeks. Blood and kidneys were collected for biochemical, histological, and Western blot analysis. Renal co-localization of Rac2 with CD specific marker Auaphorin-2 in kidney of human and mouse PKD was assessed by immunofluorescence staining and protein expression was measured by Western blot analysis. Renal Rac2 activity was measured using Rac2 activation kit. Cystic index were measured using H&E staining. Cell proliferation was measured using MTT assay and renal function was measured using BUN assay kit. Rac2 is upregulated in the CD of both human PKD and Pkd1RC/RC mice (p<0.01) compared to controls. Moreover, overexpression of netrin-1 activates Rac2 in the cystic kidney (p<0.001) and in human cystic cells (p<0.05). Overexpression of Rac2 increases cell proliferation and phosphorylation of ERK in CD cells (p<0.01). Inhibition of Rac2 reduces netrin-1-induced CD cell proliferation (p<0.01) and cyst growth (p<0.01) in both netrin-1 transgenic (NTN-1 Tg6) and Pkd1RC/RC mice. Our results demonstrate that overexpression of netrin-1 increases cystic epithelial cell proliferation via activating Rac2 in CD cells and contributes to cyst growth. Future studies will be carried out to dissect the downstream signaling mechanism of netrin-1/Rac2 mediated cell proliferation cyst formation in PKD. This work is supported by Intramural grant award (IGPP00043) from Augusta University to R. Mohamed; National Institute of Health (1P01HL134604-01) to J.C. Sullivan. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
β-Hydroxybutyrate Recapitulates the Beneficial Effects of Time-Restricted Feeding and Periodic Fasting in Multiple Rodent Models of Polycystic Kidney Disease
Authors: Torres Jacob A , Holznecht Nickolas , Asplund David , Kroes Bradley , Amarlkhagva Tselmeg , Haeffner Matthias , Sharpe Elizabeth 
Published: May 2024

Polycystic kidney disease is a monogenic disease caused predominantly by mutations in the PKD1 or PKD2 genes. These mutations result in the formation of large fluid-filled cysts derived from kidney epithelial cells that slowly replace functional healthy tissue. Affected kidneys rely heavily on glycolysis to meet energy demands, and is accompanied by a reduction in fatty acid oxidation and mitochondrial function. We previously reported that interventions inducing a state of ketosis, including caloric restriction, time-restricted feeding (TRF), ketogenic diet, extended fasting, and ketone supplementation, ameliorate or reverse polycystic kidney disease progression in multiple animal models. To elaborate on the capability of ketosis to alter disease progression, we compared, head-to-head, the effects of a daily 16:8 TRF regimen to periodic 48-hour fasting (PF) in both juvenile and adult Cy/+ rats. We found that alternative fasting interventions prevent juvenile disease progression and partially reverse established kidney disease in adults. Further, to test our hypothesis that an increase in β-hydroxybutyrate (BHB) may mediate these beneficial effects, we administered BHB to adult Cy/+ rats and stereospecific isomers to two orthologous mouse models of PKD ( P kd1RC/RC, Pkd1-Ksp:Cre). BHB recapitulates the effects of fasting in these models independent of stereoisomer, reducing mTORC1 signaling, increasing GSK-3β phosphorylation, expression and translocation of Nuclear factor erythroid 2-related factor 2 (Nrf2) in cystic epithelia, and subsequent downstream targets of Nrf2. These findings extend and expand our previous report on the beneficial effects of ketosis on cystic disease progression and suggest that ketogenic metabolic interventions and BHB supplementation are capable of metabolic reprogramming in polycystic kidney disease. This work was supported by grants from the NIH (Grants R01DK109563, R01DK124895) and the US Department of Defense (Grant W81XWH2010827) to T.W., and gifts from the Amy P. Goldman Foundation and the Jarrett Family Fund to University of California, Santa Barbara, to support the work of T.W. The MRL Shared Experimental Facilities are supported by the MRSEC Program of the NSF under Award No. DMR 1720256; a member of the NSF-funded Materials Research Facilities Network (www.mrfn.org). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Decoding the role of genetically-distinct sensory nerves in controlling cardiopulmonary reflexes
Authors: Darcey Teresa , Taylor-Clark Thomas , Hooper Shane , Kim Seol-Hee 
Published: May 2024

Activation of airway sensory nerves causes respiratory and autonomic reflexes. The majority of the airway sensory afferents are only sensitive to noxious stimuli, such as inflammation, irritants, and pollutants. Activation of these nociceptive afferents evokes protective mechanisms such as apnea, cough, and bradycardia. These reflexes may contribute to disease morbidity when excessively activated. Airway nociceptors, largely projecting from the vagal ganglia (nodose and jugular ganglion), are heterogeneous with respect to gene expression and neuroanatomy, and our objective is to characterize the reflexes evoked by activation of specific afferent subsets using chemogenetics. To selectively activate vagal afferent subpopulations in vivo, mice were exposed to nebulized selective stimuli such as capsaicin (transient receptor potential (TRP) vanilloid 1 (V1) agonist), allyl isothiocyanate (AITC, TRP ankyrin 1 (A1) agonist), and clozapine-N-oxide (CNO, selective agonist for the designer receptor exclusively activated by designer drug (DREADD) stimulatory receptor hM3Dq). hM3Dq expression by ROSA26-loxP-STOP-loxP mice was selectively expressed in sensory subpopulations by breeding with Cre recombinase-expressing mice: TRPV1 (all nociceptors), Tac1-Cre (peptidergic/jugular-originating nerves), and P2X2-Cre (nodose-originating nerves). An intersectional approach using TRPV1-flp mice and the above Cre mice combined with bilateral vagal injections of an AAV delivering dual recombinase-dependent DREADD constructs was used to express hM3Dq in afferent populations defined by two genes (e.g. TRPV1+ and P2X2+). ECGS were recorded via radiotelemetry, and respiration was measured via whole-body plethysmography. CNO administration in TRPV1-hM3Dq mice, P2X2-hM3Dq mice, and Tac1-hM3Dq mice evoked bradypnea and bradycardia. When CNO was administered in the dual recombinase-dependent ConFon (Cre-On/Flp-On) Tac1-Cre/TRPV1-Flp mouse (selectively activating the vagal jugular nociceptors), a significant bradypnea was evoked; however, when CNO was administered in the dual recombinase-dependent ConFon P2X2-Cre/TRPV1-Flp mouse (selectively activating the nodose nociceptors), no bradypnea was observed. Our preliminary data suggest that functionally-distinct nociceptive subpopulations differentially regulate the cardiopulmonary reflexes. NIH R01: 152219, NIH T32: HL160529. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
A preliminary assessment of physical function in aged male mice with constitutive activation of the aryl hydrocarbon receptors in skeletal muscle
Authors: Wimberly Keon , Lackey Jacob , Tice Abigail , Hepple Russell , Ryan Terence 
Published: May 2024

BACKGROUND: Aging involves a gradual deterioration of physical and physiological functions, ultimately leading to mortality. Unfortunately, there are no treatments available that successfully mitigate the age-associated decline in physical function. Recent studies have revealed a strong association between elevated levels of L-kynurenine (L-Kyn) and frailty, muscle weakness, and neuromuscular junction degeneration in humans and mice, however a causal relationship has not been tested. L-Kyn is a product of tryptophan catabolism that has been linked to motor neuron death, skeletal muscle atrophy, and mitochondrial dysfunction, all hallmarks of aging muscle. Interestingly, L-Kyn is an endogenous ligand of the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor widely known for its role in xenobiotic metabolism. Though both pro- and anti-aging effects of the AHR have been reported in the literature, there are several chronic diseases that involve chronic AHR activation and produce strikingly similar phenotypes to exacerbated aging/frailty. OBJECTIVE: The objective of this study was to determine of constitutive activation of the AHR has a causal role in the decline of physical function with aging. METHODS: Aged (16-mo.) C57BL6 male mice (N=48) were obtained from the NIA breeding colony and were randomized to interventions employing muscle-specific adeno-associated virus with the following three treatment groups: 1) a constitutively active AHR mutant was constructed by deleting the ligand binding domain (amino acids 277-418); 2) a transcriptionally deficient AHR mutant (arginine to aspartate mutation at amino acid 39); and an empty vector control. Treadmill endurance, forelimb grip strength, and maximal walking speed were measured at 24-mos. of age. Results: Treadmill endurance capacity in mice with constitutively AHR activation was 5.3% lower than mice treated with the empty vector ( P=0.25) and 12.1% lower than mice treated with the transcriptionally deficient AHR mutant ( P=0.09). Grip strength and walking speed were not significantly different between groups ( P>0.57 and 0.22 respectively) at this 24-mo. age. CONCLUSIONS: These preliminary results in aging male C57BL6 mice may indicate possible role of AHR activation in the decline of physical function. Continued enrollment to increase the sample size and obtaining measures at later ages when physical function declines more severely, as well as examining female mice will provide a more thorough analysis. Funding Supported by grants from the National Institutes of Health R01-AG076490 (Ryan & Hepple) and T32 AG062728 (Wimberly). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Effect of Sodium Fluoride on Oxidative Stress and Antioxidant System in Male Wistar Rats
Authors: Ayegboyin Olusola A. , Ige Abayomi O. , Adewoye Elsie O. 
Published: May 2024

This research aimed to examine the effect of sodium fluoride (NaF) on oxidative stress and antioxidant systems in the serum, aorta, and cardiac tissues of male Wistar rats. The increased attention to sodium fluoride and its detrimental effects on human health in recent years has led to concerns. Excessive ingestion and accumulation of sodium fluoride from water, toothpaste, and pesticides could initiate oxidative stress in the blood, aorta, and heart. This heightened oxidative stress and disturbance in the antioxidant system pose a significant risk and may predispose the body to severe vascular and cardiovascular-related diseases, which are leading causes of global mortality. In this study, ten male Wistar rats weighing 150-180g were grouped into two (n=5). Group I Control received distilled water, and Group 2 received 10mg/kg NaF orally for 21 days. Markers of oxidative stress malondialdehyde (MDA) and reduced glutathione (GSH), antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and total antioxidant capacity (TAC) were measured in the serum, aorta, and heart. Data were analyzed using descriptive statistics of student t-test at α0.05. The data were presented as mean ± SEM. The oral administration of sodium fluoride resulted in an elevation of MDA levels in the serum, aorta, and heart of the rats exposed to NaF. Additionally, the oral administration of sodium fluoride led to a reduction in superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) levels in the serum, aorta, and heart of rats exposed to NaF. Furthermore, the oral administration of sodium fluoride resulted in a decrease in the total antioxidant capacity (TAC) in the serum, aorta, and heart of rats exposed to sodium fluoride. This study demonstrated that sodium fluoride exposure diminishes the antioxidant capacity in the serum, aorta, and heart, indicating that sodium fluoride exposure induces oxidative stress, potentially affecting the functions of the aorta and heart. Therefore, the continuous exposure to fluoride in populations residing in regions with endemic fluorosis worldwide should be a topic of considerable concern. This research work was self-funded. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Effects of age and sex on cardiac function in mice
Authors: Medarev Steven , Evola Vito , Castano Antonio , Gordon Steven , Ogando Anthony , Balenko Jasen , Maggitas Charles 
Published: May 2024

It is well established that maximal cardiac output declines with advancing age. Age-related decline in cardiac output could result from changes in either systolic or diastolic function that are also apparent at rest. We investigated the effects of age on systolic and diastolic function in male and female mice. Mice were studied at 4-7months and 17-20 months. Echocardiography was performed with FujiFilm Visual Sonics VevoF2 to obtain ejection fraction, fractional shortening, and E/A ratio. In male mice, fractional shortening decreased by 25% (young: 31.26±1.24, old: 23.31±1.82, P=0.002 young v. old) and ejection fraction decreased by 19.77% (young: 58.23±1.63, old: 46.71±3.05, P=0.002 young v. old) with age. In female mice, fractional shortening and ejection were stable with age. E/A decreased with age in both male (young: 1.53±0.09, old: 1.18±0.07, P=0.02 young v. old) and female (young: 1.64±0.08, old: 1.28±0.07, P=0.002 young v. old) mice. These data indicate that systolic function declines with age in male, but not female mice. In contrast, diastolic function declines with age in both male and female mice. Further analysis is needed to determine how these changes in resting cardiac function correlate with changes in exercise capacity in male and female mice. NIH R01HL166591. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Impact of Long-Term Ibuprofen Usage on Cardiac Signaling Pathways
Authors: Zheng Emily , Gomes Aldrin , Rivera Gabriela , Sule Rasheed 
Published: May 2024

Ibuprofen, a common over-the-counter drug, is taken worldwide to alleviate pain and reduce inflammation. While the recommended dosage is generally regarded as safe for consumption, complications arise when the drug is taken chronically, even in the prescribed quantities. Previous research suggests that ibuprofen alters the productivity of various signal transduction pathways throughout the body and stimulates the production of reactive oxygen species (ROS) in liver tissue. Our research aimed to determine if proteins involved in proteolysis and energy producing pathways were altered in cardiac tissue as a result of ibuprofen usage. The study involved eight nine-week-old female mice divided into two treatment groups: control and ibuprofen. Female control mice received pure water while female ibuprofen mice received 100 mg/kg of ibuprofen in water daily for one week before euthanization. The ibuprofen used corresponds to less than 500 mg ibuprofen/day in humans. Heart samples removed from euthanized mice were homogenized, labeled with Tandem Mass Tags (TMT), and then analyzed by liquid chromatography-tandem Mass Spectrometry (MS). Spectral analysis yielded 120 proteins that were altered in a statistically significant manner (p ≤ 0.0028 according to the Benjamini-Hochberg procedure). Pathway analysis conducted on statistically significantly altered proteins suggests moderate ibuprofen consumption results in changes in aerobic respiration, oxidative stress, the proteasome proteolytic system, the nucleotide metabolic process, and muscle cell development pathways. We conclude that ibuprofen consumption at recommended dosages significantly alters many pathways in cardiac tissue, which may be associated with the clinically observed increased risk of cardiovascular disease for those taking ibuprofen. This research is funded by the NIEHS/Superfund Research Program (P42 ES004699). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Differential serum inflammatory cytokine elaboration in Nepali brick factory workers
Authors: A Chang , Curtis KL , Fleming AA , Fleming BT , Black AD , Johnston JD , Beard JD 
Published: May 2024

Previous studies involving workers at brick kilns in the Kathmandu Valley of Nepal have revealed chronic exposure to hazardous levels of fine particulate matter (PM2.5) common in ambient and occupational environments. Such exposures are known to cause and/or exacerbate chronic respiratory diseases including chronic obstructive pulmonary disease (COPD). However, there is a paucity of data regarding the systemic inflammatory status of exposed workers at brick manufacturing facilities. In the current study, we sought to elucidate systemic inflammatory responses by quantifying the molecular cytokine/chemokine profiles in serum from study participants. A sample of participants (N = 48; 54% female; 31.77±9.76 years-old) were distributed among four different job categories. Blood was procured from participants on-site, allowed to clot at room temperature, and centrifuged to obtain total serum. A human cytokine antibody array was used to screen cytokines/chemokines in serum samples. Comparisons were generated between a control group of administration workers vs. fire master workers, administration vs. green brick hand molders, and administration vs. top loaders. We discovered significantly increased concentrations of eotaxin-1, eotaxin-2, GCSF, GM-CSF, IFN-γ, IL-1γα, IL-1β, IL-6, IL-8, TGF-β1, TNF-α, and TIMP-2 in serum samples from fire master workers vs. administration (p < 0.03). Each of these molecules, with the exception of TIMP-2, were also significantly elevated in the serum from green brick hand molders (p < 0.02). In addition, each molecule was significantly elevated in serum from top loaders compared to administration workers (p < 0.03). With few exceptions, the fire master workers expressed significantly more systemic inflammatory molecular abundance when compared to all other job descriptions. These results reveal an association between pulmonary exposure to PM2.5 and systemic inflammatory responses likely mediated by cytokine/chemokine elaboration. Additional characterization of a broader array of inflammatory molecules may provide valuable insight into susceptibility to lung diseases including COPD. This work was supported in part by funding from Undergraduate Mentoring and a Widtsoe Research Grant from Brigham Young University. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
ER stress CHOP Knockout in Beta Cells protects from type 2 diabetes-induced vascular dysfunction
Authors: Alluri Kiran , Srinivas Balaji , Belmadani Souad , Matrougui Khalid 
Published: May 2024

Introduction: Cardiovascular complications are the primary causes of morbidity and mortality in patients with type 2 diabetes (T2D). T2D is a significant risk factor for cardiovascular diseases such as coronary artery disease, stroke, peripheral vascular disease, and heart failure for millions of people in the US. In the present study, we determined the role of the endoplasmic reticulum stress (ER) stress C/EBP homologous protein (CHOP) in beta cells on type 2 diabetes-induced vascular endothelial dysfunction. Methods: male and female CHOPflox/flox and CHOPbeta cells −/− mice were fed a high-fat diet (HFD) for 12 weeks. We measured body weight, running distance, heart/lung/pancreas/kidney weights, glucose tolerance test (GTT), vascular endothelial function, and signaling. Results: Our research indicates that mice with the ER stress CHOPflox/flox genotype, when fed a high-fat diet for 12 weeks, develop obesity and show impaired GTT and running distance. Additionally, they exhibit an increase in the weight of organs such as the heart, lungs, pancreas, and kidneys and experience vascular endothelial dysfunction and a reduction in phosphorylated eNOS levels. However, it's interesting to note that mice that lack the ER stress CHOPbeta cells−/− and were fed the same high-fat diet for 12 weeks displayed a protective effect. Conclusion: The data indicates that beta cell ER stress CHOP plays an essential role in type 2 diabetes. Disrupting the ER stress CHOP, specifically in beta cells, has been shown to protect mice from the vascular endothelial dysfunction caused by type 2 diabetes. Therefore, targeting ER stress CHOP, specifically in beta cells, could be a promising therapeutic approach to safeguard vascular endothelial function. NIH-HL150014 (Matrougui) and NIH-HL151616 (Matrougui). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.