bluuebunny/crossref_metadata_2025_split huggingface dataset:
Translational Traits of a Swine Model of CKD: Inflammation
Authors: Engel Jason Edward , Williams Maxx , Guise Erika , Drummond Heather , Chade Alejandro 
Published: June 2021

The cardiovascular and renal anatomy and physiology of the pig are virtually identical to humans. We recently developed a model of CKD induced by dietary dyslipidemia and bilateral renal artery stenosis in pigs that develops a sustained decrease in renal function (comparable to CKD stage 2) and progressive parenchymal injury. Inflammation plays a role in the increased cardiovascular and all‐cause mortality in CKD and may precede renal fibrosis. Thus, we aim to characterize inflammation in CKD using markers shared by human and pigs to support the translational traits of the model.Ten pigs were divided into either normal or CKD (n=5 each). CKD/sham was induced and pigs observed for 14 weeks. Blood pressure was continuously measured by telemetry. Total RBF and GFR were quantified in vivo using multi‐detector CT. Blood and urine were collected, then pigs were euthanized and ex vivo studies performed to quantify plasma creatinine, blood urea nitrogen (BUN), renal injury markers kidney injury molecule 1 (KIM‐1) and neutrophil gelatinase associated lipocalin (NGAL) (urine, ELISA), renal inflammation (total macrophages, pro‐inflammatory M1‐IDO‐ and anti‐inflammatory M2‐MRC1‐subpopulations) and fibrosis (trichrome)Following fourteen weeks of CKD, pigs showed reduced RBF, GFR, hypertension, elevated plasma creatinine and BUN. These were associated with elevated urinary KIM‐1 and NGAL, inflammation (indicated by significant M1‐IDO+ macrophage infiltration over M2‐MRC1), and fibrosis (Figure).The decline in renal function associated with significant macrophage infiltration and increased markers of renal injury. KIM‐1 and NGAL have been suggested to initially attenuate inflammation and promote a pro‐repair M2 macrophage phenotype. However, they may have been insufficient to prevent the shift towards pro‐inflammatory M1s in our model, suggesting prolonged imbalance between inflammation and repair beyond the acute phase of renal injury. The use of markers shared by pigs and humans underscored the translational potential of this model for CKD research as a feasible platform to study and possibly target inflammation.Support or Funding InformationSupport: AHA‐18490005 and intramural grant UMMC to ARC.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
A Boolean Model of Microvascular Rarefaction to Predict Renal Outcomes in Renovascular Disease
Authors: Guise Erika , Pruett W. Andrew , Chade Alejandro R. 
Published: June 2021

Renal microvascular (MV) rarefaction, a hallmark of renovascular disease (RVD), associates with decreased renal vascular endothelial growth factor (VEGF) and progressive renal damage. We designed a novel bioengineered fusion of an elastin‐like polypeptide (ELP) with VEGF, and demonstrated that ELP‐VEGF therapy decreases MV rarefaction, improves renal function, and reduces renal injury in RVD. Renal angioplasty (PTRA) of a stenotic kidney is a frequently used treatment in RVD that often does not ameliorate renal injury. We thus aimed to create a Boolean model of MV rarefaction to predict the renal outcomes of an RVD kidney after ELP‐VEGF therapy following PTRA.We first created a Boolean model with 20 factors known to be involved in MV rarefaction and progression of renal injury in RVD (assuming each to be either totally present/active or totally absent/inactive) to predict the possible pathophysiological states and outcomes after treatments. The model predicts that MV rarefaction and fibrosis remain active following PTRA, driven by a feed‐forward cycle of inflammation and oxidative stress leading to glomerulosclerosis and fibrosis (Figure). When ELP‐VEGF therapy followed PTRA in the simulation, MV rarefaction, glomerulosclerosis, and fibrosis were inactivated. The model predicted that injurious processes driving progressive renal deterioration are decreased only with ELP‐VEGF therapy following PTRA.We next performed in vivo studies. RVD was induced by renal artery stenosis in 12 pigs fed a high‐cholesterol diet. Six weeks later, single‐kidney blood flow (RBF) and filtration (GFR) were quantified in vivo using multi‐detector CT, then pigs were randomized to either PTRA (RVD+PTRA, n=6) or PTRA followed by single intra‐renal injection of ELP‐VEGF (RVD+PTRA+ELP‐VEGF, n=7). Pigs were observed for 4 additional weeks; in vivo CT studies were repeated, then pigs euthanized and ex vivo renal micro‐CT quantification and fibrosis determined. Administration of ELP‐VEGF following PTRA improved RBF, GFR, MV density, and fibrosis more efficiently than PTRA alone.ConclusionThe Boolean model predicted the in vivo/ex vivo data and confirmed pathological mechanisms and the key role of MV damage in renal injury progression. Our results may support the use of Boolean simulations to predict renal outcomes after treatments. Furthermore, this study unravels a simple but useful tool that may help to design, confirm, or deny pre‐clinical studies and predict therapeutic effects.Support or Funding InformationAHA 18490005 (ARC), Intramural Research Support Program (IRSP) grant from UMMC (ARC), and PO1 HL 51971 (WAP)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Obesity and PM2.5 Exposure Effects Cardiac Function During Exercise in Mice
Authors: Grimmer Jacob , Tanwar Vineeta , Katapadi Aashish , Youtz Dane , Schwieterman Neill , Baer Lisa , Stanford Kristin , Wold Loren 
Published: June 2021

ObjectiveStudies have demonstrated that particulate matter with diameter <2.5μm (PM2.5) exposure is linked to cardiovascular disease (CVD). Risk factors, such as obesity, correlate with higher occurrences of CVD. We aimed to study PM2.5 effects on cardiac function of obese mice and whether exercise could alter function.MethodsObese mice (Ob/Ob) (leptin deficient, FVB background) were exposed to either filtered air (FA) or PM2.5 (within the annual average range of 15 μg/m3 according to National Ambient Air Quality Standards (NAAQS)) for 6 h/day, 7 days/week for 9 months. The mice were divided into four groups: (1) FA sedentary, (2) FA treadmill exercise, (3) PM2.5 sedentary, and (4) PM2.5 treadmill exercise. After 8 weeks of exercise, echocardiography was used to examine global cardiac function. Following sacrifice, cardiomyocytes were isolated for studying cardiomyocyte function. Separate groups of sedentary mice were sacrificed for studying baseline myocardial mRNA expression.ResultsEchocardiography showed increased left ventricular end systolic (LVESd) and diastolic (LVEDd) diameters and decreased posterior wall thickness during systole (PWTs) and diastole (PWTd) in ob/obPM2.5 sedentary mice compared to ob/ob FA sedentary mice. Morphological alterations were associated with lower systolic function as indicated by reduced percent fractional shortening (%FS) in ob/ob PM2.5 sedentary mice compared to ob/obFA sedentary mice. These functional results are suggestive of contractile dysfunction leading to left ventricular volume overload. Cardiomyocytes isolated from sedentary ob/obPM2.5 mice showed no change in peak shortening (%PS) but marked reduction in positive and negative contractile velocity (±dL/dT) and increased calcium transient amplitude (Δ340/380) suggesting cellular contractile dysfunction. Comparison of mice after 8 weeks of exercise training demonstrated significant decrease in %FS, increase in LVESd and no change in LVEDd in ob/obPM2.5 exercised mice compared to ob/obFA exercised mice, suggesting systolic dysfunction. On comparing ob/obPM2.5 exercise and ob/obFA exercise with their respective sedentary counterparts decrease in %FS, PWTs and PWTd and increase in LVESd was observed. qPCR data showed increased inflammatory markers ICAM‐1, VCAM and CRP in ob/obPM2.5 sedentary mice compared to ob/obFA mice. These results indicated exercise did not improve cardiac function following exposure to PM2.5.ConclusionsPM2.5 exposure in combination with obesity induced cardiac dysfunction as seen through echocardiography. Exercise training, however, did not improve cardiac function in obese PM2.5 mice.Support or Funding InformationThis work is supported by funding from National Institutes of Health (RO1ES019923) to LEW.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Resistive exercise with or without super‐imposed whole‐body vibration acutely induces bone resorption
Authors: Lau Patrick , Beijer Åsa , Rosenberger André , Zange Jochen , Rittweger Jörn 
Published: June 2021

BackgroundExercise is one of the well‐known constituents to improve bone mass and to retain bone strength. Only few studies have reached the effects of resistive exercise on sclerostin levels, a protein that is thought to play a key role in orchestrating bone's mechanical adaptation. Sclerostin is produced and released by osteocytes and acts as an inhibitor of bone formation through inhibition of the Wnt/β‐catenin‐signaling pathway. The objective of this study was to evaluate acute and long‐term effects of exercise on bone biochemical marker expression. More specifically, we aimed to understand differences in the responses to resistance exercise with or without whole‐body vibration.MethodsA six week training intervention was performed including 26 healthy males (26 years, SD=4) in in a randomized parallel design. Performing either resistive exercise (RE, n=13) or resistive vibration exercise (RVE, n=13) training, with weekly increasing vibration frequencies 20–40 Hz. Serum samples were collected both at the initial and final exercise session. Changes in carboxy‐terminal cross‐linked telopeptide of type I collagen (sCTX‐I), as a marker of bone resorption, and of procollagen type I amino terminal propeptide (P1NP) as a specific marker of bone formation as well as serum sclerostin concentrations were measured via ELISA (sCTX‐I and sclerostin) or RIA (P1NP) measurements.ResultsSerum markers of sCTX‐I decreased by 15% within the first minutes following either training intervention, both regarding the initial and final training session. Subsequently, levels of sCTX‐I returned back to pre‐bout baseline after RE (time effect: P<0.001), and they depicted an overshoot by 18% after 75 min. Serum levels of P1NP depicted an acute increase by 15% to exercise (P<0.001). P1NP levels were non‐substantially increased in RE at the end of the 6 week intervention (P<0.001), but decreased by 10% in RVE, as compared to baseline (P< 0.001). Pre‐bout levels of sclerostin were marginally lowered at the end of the 6 week training phase. After the exercise bouts, sclerostin levels increased within the first minutes both RE and RVE (time effect: P<0.001). Notably, sclerostin responses to the initial exercise bouts differed significantly between RE and RVE P=0.029.ConclusionThe present findings suggest that in young healthy adults both conditions RE and RVE elicited an acute exercise‐induced bone resorption without any acute change in bone formation. Results are compatible with the idea that this response was mediated by sclerostin.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
CaMKKβ regulates store‐operated calcium entry (SOCE) through controlling the expression of STIM1 in endothelial cells
Authors: Regmi Sushil C. , Soni Dheeraj , Wang DongMei , Tiruppathi Chinnaswamy 
Published: June 2021

Here, we provide evidence for the first time that CaMKKβ regulates store‐operated Ca2+ entry (SOCE) through controlling the transcription of stromal interaction molecule 1 (STIM1), a crucial activator of SOCE in endothelial cells (ECs). Surprisingly, we observed drastically reduced expression of both mRNA and protein for STIM1 in lung tissue and lung ECs of CaMKKβ knockout (CaMKKβ−/−) mice compared with wild type. Interestingly, expression of STIM2, TRPC1, TRPC4, Orai1, Orai2, and Orai3 was unaltered in CaMKKβ−/− mice. Knockdown of CaMKKβ in human lung microvascular endothelial cells (HLMVECs) also suppressed STIM1 expression. Importantly, we observed complete loss of SOCE in LECs of CaMKKβ−/− mice compared to the wild type mice. Since CaMKKβ may regulate gene expression through epigenetic mechanism, we analyzed STIM1 gene sequence and observed the presence of methylation‐prone CpG sites in 5′‐regulatory of both human and mouse STIM1 genes. DNA methylation analysis revealed hypermethylation of ST1M1 promoter in CaMKKβ−/− mice compared to WT mice. Interestingly, i.p injection of 5‐azacytidine, a methyl transferase inhibitor restored STIM1 expression in lungs of CaMKKβ−/− mice. In addition, liposome‐mediated in vivo delivery of WT‐CaMKKβ but not by K193A‐CaMKKβ plasmid restored STIM1 expression in lung ECs of CaMKKβ−/− mice. These findings demonstrate the prerequisite role of CaMKKβ in regulating STIM1 transcription through epigenetic mechanism in endothelial cells.Support or Funding InformationNational Institute of Health Grants R01 HL‐128359 and R01 GM‐117028This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
INCREASED PLASMA IL‐1 CONCENTRATIONS IN POLYCYSTIC OVARYINDUCED RATS
Authors: Sanches Reginaldo Batistela Pietro , Alves Eduardo Donato , Benevenuto Luiz Guilherme Décore , Montrezor Luís Henrique 
Published: June 2021

Polycystic ovary syndrome (PCOS) is a clinical disorder that affects up to 15% of women of reproductive age, and is the most common endocrine disorder among pre‐menopausal women. PCOS is characterized by impairment of ovulation, reduced fertility, and imbalance of reproductive hormones. In addition, women with PCOS often exhibit obesity, metabolic syndrome, hyperinsulinemia, insulin resistance, and dyslipidemia. Adipose tissue secretes hormones that contribute to processes that regulate metabolism, inflammatory responses, immunity, and reproduction. In obesity, body fat deposits are hypertrophied, stimulated by androgens that influence the expression of enzymes and proteins involved in lipid and carbohydrate metabolism, oxidative stress, and differentiation of pre‐adipocytes into mature adipocytes. A consequence of hypertrophy and adipose hyperplasia is the expression of pro‐inflammatory cytokines. The goal of this study was to analyze the plasma variations of interleukin‐1 (IL‐1) in rats induced to polycystic ovary (PCO). Ten female adult Wistar rats weighing 200–340 g were divided into control (n = 5) and PCO (n = 5) groups. PCO was induced in the rats by single injection of estradiol valerate (EV) (2 mg/kg/bw, i.m.). The two groups of rats were then evaluated after 30 days. The results were reported as means ± SEM. Statistically significant differences among the means for the treatment groups were identified using p<0.05. This study was approved by the local Animal Care and Use Committee (CEUA–UNIARA, protocol n° 031/16). The results showed that the body mass of the control group (344 ± 13.56 g) was higher than that of the PCO group (306.4 ± 32.35 g). The ovary mass of the control group (0.072 ± 0.004 g) was higher than for the PCO group (0.048 ± 0.005 g), and the gonadal somatic index of the control group (0.0257 ± 0.006) was also higher than for the PCO group (0.0166 ± 0.008). Finally, the plasma IL‐1 concentration of the PCO group (55.68 ± 13.15 pg/mL) was higher than for the control group (21.62 ± 5.78 pg/mL). The results were indicative of metabolic and inflammatory changes in the rats 30 days after the PCO induction.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Oral NaHCO3 activates the splenic anti‐inflammatory pathway; evidence vagal efferent signals are transmitted to the spleen via a neuronal like function of mesothelial cells.
Authors: O'Connor Paul M. , Marshall Brendan , Baban Babak , Ocasio Hiram , Wilson Katie , Sun Jingping , Ray Sarah 
Published: June 2021

We tested the hypothesis that ‘Oral NaHCO3 intake stimulates splenic anti‐inflammatory pathways. Following oral NaHCO3 loading, macrophage polarization was shifted from predominantly M1 (inflammatory) to M2 (regulatory) phenotypes in the spleen and kidneys of rats, and in the blood of human subjects. Surprisingly, we found that gentle manipulation to visualize the spleen at midline during surgical laparotomy (sham splenectomy) was sufficient to abolish the response and resulted in hypertrophy/hyperplasia of the capsular mesothelial cells. Thin collagenous connections lined by mesothelial cells were found to connect to the capsular mesothelium. Mesothelial cells in these connections stained positive for the pan‐neuronal marker PGP9.5 and acetylcholine esterase and contained many ultrastructural elements which visually resembled neuronal structures, including synaptic ribbons (the presence of which was confirmed by immunohistochemistry). Both disruption of these fragile connections or transection of the vagal nerves below the diaphragm, resulted in loss of capsular mesothelial acetylcholine esterase staining and a significant reduction in splenic mass, which was not additive. Our data indicate that oral NaHCO3 activates the cholinergic anti‐inflammatory pathway and provides evidence that the signals that mediate this response are transmitted to the spleen via a novel neuronal like function of mesothelial cells.Support or Funding InformationThis work was supported by grants to Paul O'Connor (NIH DK099548 and 1P01HL134604)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Fluorescent Based Tracing of Sensory Nerve Subtypes in Vagal Ganglia and Lung
Authors: Kim Seol‐Hee , Taylor‐Clark Thomas 
Published: June 2021

Cell bodies of airway afferent nerves originate from vagal ganglia and vagal afferent nerves project to the respiratory tract. The inputs from these nerves converge at the brainstem to regulate respiratory reflexes. These vagal afferent nerves can be classified into various subtypes based on the origins of cell bodies in vagal ganglia, conduction velocity, size and stimuli required for activation. The polymodal nature of vagal afferent nerves complicates the study of respiratory reflexes. Transient receptor potential vanilloid 1 (TRPV1) is one of the ion channels expressed in bronchopulmonary C‐fibers. Tachykinin 1 (Tac1) encodes for a neuropeptide, Substance P, which is released from sensory nerve terminals in jugular originated afferent nerves. 5HT3 is expressed in nodose originated nociceptive C‐fibers. In the present study, we focused on defining afferent nerves subtypes in vagal ganglia based on ion channel/receptor expression as well as innervation into respiratory tract using a transgenic mouse model.The Cre‐LoxP reporter system was used to target specific populations of afferent nerve subtypes and to control red fluorescent protein (tdTomato) expression. Trpv1‐Cre, Tac1‐Cre and 5ht3‐Cre strains were bred with Floxed Ai9 ROSA tdTomato; thus, expressing red fluorescent in Trpv1, Tac1 and 5ht3 positive neurons. Mice (6 to 8‐week‐old) were euthanized and tissues were collected. Lungs were inflated with 3 % low‐melting agarose solution and sectioned at 100 μm using a vibratome. Immunohistochemistry was done using anti‐E‐Cadherin and anti‐dsRed antibodies. Vagal ganglia were dissected and cryo‐sectioned at 20 μm. Immunohistochemistry was done using anti‐Trpv1 antibody to compare with native tdTomato expression. Images were taken using Olympus FV1200 confocal microscope.Native tdTomato expression for Trpv1 positive afferent nerves were seen in both jugular and nodose ganglia. tdTomato tagged for Tac1 positive afferent nerves were mostly expressed in jugular and some in nodose ganglia, while 5ht3 positive afferent nerves were exclusively in nodose ganglia. The native tdTomato expression of 5ht3 positive afferent nerves did not completely overlap with anti‐TRPV1 staining. We further visualized the nerve endings that projected from vagal ganglia into lung and the tdTomato expression patterns of the nerve endings were different depending on strains. With Trpv1 strain, nerve endings spread out in all the lobes and those nerve endings resided in the epithelial layer, mainly around the bronchi.Overall, we were able to identify the distinct locations of cell bodies in vagal ganglia and nerve endings in lung of various subsets of airway afferent nerves using Cre‐LoxP reporter system. This information may be valuable to investigate the highly complicated mechanism of respiratory reflexes.Support or Funding InformationNIH Common Fund SPARC OT2This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
One Cause of Sensorineural Hearing Loss for Meniere's disease, Otosyphilis, and Enlarged Vestibular Aqueduct Syndrome from MR findings
Authors: Tanioka Hisaya 
Published: June 2021

Objectives/HypothesisTo evaluate conditions of the endolymphatic duct and sac of normal subjects, Meniere's disease (MD), late congenital otosyphilis, and enlarged vestibular aqueduct syndrome (EVAS) from high‐resolution MR imaging. Although these diseases present similar clinical symptoms, the basic etiology is veiled. Comparing their pathological evidence with these MR features results in one hypothesis of the causes of MD, late congenital otosyphilis, and EVAS.Study DesignRetrospective studyMaterials and Method10 normal ears, 10 unilateral MD, 1 unilateral EVAS, and 1 late congenital Otosyphilis underwent 1.5T MR scanner. The scan sequences were as follows; SE (T1‐W, Proton Density, and T2‐W), FISP (T2‐W) and FLASH (Proton Density).ResultsAlthough the normal endolymphatic duct and sac were depicted relatively low signal in all sequences, the rugose portion of the sac was imaged as a low signal constriction. In MD, there were two patterns imaging. One lacked imaging of the endolymphatic duct. In the other, there was stenosis in the part of the rugose portion. In EVAS, the endolymphatic duct and sac showed enlargement with high signal fluid on T2‐WI. In the late congenital syphilis, the enlarged endolymphatic duct and sac compounded with the soft tissue irregular intensified substances were depicted.ConclusionsUnder normal conditions, the normal endolymphatic duct and sac are depicted in low signal intensity by all MR imaging sequences. That is, if a certain part will be depicted as a high signal, the lesion will be considered as an abnormality. Hence, in EVAS, this fact indicates that the high signal endolymphatic and duct in T2‐WI are abnormal status. This condition will be caused by stagnation of the endolymph. The stagnation is the inhibition of the endolymphatic flow itself. The symptoms of otosyphilis will be caused that the endolymphatic duct and sac are occluded by the microgummata and fibrotic substances, and the endolymphatic flow is obstructed. However, In MD, the causes are complicated in this study. There are two possible obstructive lesions in the endolymphatic duct and sac. One seems to be deeper than the sinus in the proximal part of the endolymphatic duct, because the endolymphatic duct cannot be depicted in MR imaging. The other will be at the rugose portion of the sac. In the later pattern, the endolymphatic duct may be imaged at parts with high intensified spot on T2‐WI. Any patient with unexplained sudden deafness should be screened for syphilis.Support or Funding InformationConflict of InterestThe author of this manuscript declares no relationship with any companies, whose products or services may be related the subject matter of the articlcle. Funding: The author states that this work has not received any fundings.