bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of treadmill exercise on spatial learning memory and upregulation of reelin signaling pathway in autistic rats (884.29)
Authors: Baek Seung‐Soo , Ji Eun‐Sang , Lee Min‐Hee 
Published: June 2021

Reelin is an extracellular glycoprotein that is essential for neuronal migration and brain development. Neuroprotective effects of exercise on various brain insults are well documented, however, the effects of exercise on autism in relation with reelin expression are not clarified. In the present study, we investigated the effects of treadmill exercise on the functional recovery and on the expressions of reelin and its downstream molecules, phosphatidylinositol‐3‐kinase (PI3K), phosphorylated Akt (p‐Akt), phosphorylated extracellular signal‐regulated protein kinase 1 and 2(p‐ERK1/2), using autistic rats. The rat in the treadmill exercise groups were forced to run on a treadmill for 30 min once a day, five times a week for 4 weeks, starting postnatal day 28. To investigate autism‐like behaviors and memory deficit, open field, social interaction, and radial 8‐arm maze were performed. In the present results, treadmill exercise alleviated aggressive tendency and improved correct decision in the spatial learning memory in the autistic rats. Treadmill exercise increased neurogenesis and the expressions of reelin and its down‐stream molecules, PI3K, p‐Akt, and p‐ERK1/2, in the hippocampus of the autistic rats. The present study showed that treadmill exercise ameliorated aggressive behavior and improved spatial learning memory through activation of reeling signaling pathway in the valproic acid‐induced autistic rats.Grant Funding Source: This work was supported by the National Research Foundation
Exercise training combined with insulin attenuates cardiac mitochondrial dysfunctions in diabetic rats (884.9)
Authors: da Cunha Daise , da Silva Márcia , Natali Antonio , da Silva Edson , Teodoro Bruno , Drummond Lucas , Drummond Filipe , Moura Anselmo , Belfort Felipe , Oliveira Alessandro , Prímola‐Gomes Thales , Maldonado Izabel , Alberici Luciane 
Published: June 2021

Exercise training combined with insulin attenuates cardiac mitochondrial dysfunctions in diabetic rats Daise N.Q. Da Cunha1, Márcia F. da Silva3, Antonio J. Natali2, Edson da Silva3, Gilton G. Jesus2, Bruno G. Teodoro4, , Lucas R. Drummond2, Filipe R. Drummond2, Anselmo G. Moura2, Felipe G. Belfort2, Alessandro Oliveira5, Thales N. Prímola‐Gomes2, Izabel R.S.C. Maldonado3, Luciane C. Alberici4. Physical Education Department1, Veterinary Medicine Department2, General Biology Department3, Physics and Chemistry Department4, Nutrition and Health Department5. 1,2,3, and 5UFV, Viçosa, and 4USP, Ribeirão Preto, BrazilType 1 diabetes mellitus (T1DM) leads to cardiac mitochondrial dysfunction. We tested whether aerobic exercise training combined with insulin therapy attenuate the deleterious effects of T1DM on the cardiac mitochondrial function. T1DM was induced by Streptozotocin (IP, 60 mg/kg) in male Wistar rats. They were submitted to swimming training (90 min/day, 5 days/week, 5% body mass) and received daily insulin, 4 IU, for 8 weeks. Mitochondrial function was assessed in isolated cardiac mitochondria. Diabetes increased mitochondrial Ca2+ uptake and the susceptibility of the mitochondrial permeability transition pore (MPTP) opening, augmented resting respiration rates and reduced mitochondrial H2O2 release. Exercise training and insulin, singly, reduced the mitochondrial Ca2+ uptake; while the combination of both restored the susceptibility of MPTP opening, the rates of O2 consumption and H2O2 release in diabetic rats. In conclusion, aerobic swimming training associated with insulin therapy attenuated the disruptions of mitochondrial Ca2+ uptake, respiration rates, and H2O2 release in isolated cardiac mitochondria of rats with T1DM. We used FASEB Statement of Principles for the use of animals in research.Grant Funding Source: FAPEMIG
The crucial role of calcium sensing receptor for hypoxia‐induced pulmonary arterial hypertension in mice (889.2)
Authors: Tang Haiyang , Song Shanshan , Drennan Abigail , Fernandez Ruby , Chen Jiwang , Yuan Jason X.‐J. 
Published: June 2021

Rationale: An increase in cytosolic free Ca2+ in pulmonary arterial smooth muscle cells (PASMC) is not only a major trigger for pulmonary vasoconstriction but also an important stimulus for PASMC proliferation. Our previous data showed that the extracellular calcium sensing receptor (CaSR) expression and function were both enhanced in PASMC from idiopathic PAH patients. However, the implication of CaSR in the development of PAH remains elusive.Methods: CaSR and parathyroid hormone double knockout (DK) mice were used to test the hypothesis that CaSR modulates pulmonary vascular tone and the response to hypoxia. Wild type (WT) and DK mice were exposed to 10% oxygen for up to three weeks. Pulmonary vascular remodeling was evaluated using tissue morphometrics. Right ventricle systolic pressures (RVSP) and right ventricular hypertrophy by, RV/(LV+S) ratios, were measured to evaluate pulmonary hypertensive development. We also isolated PASMC from WT or DK mice, followed with cell proliferation assay and cytosolic Ca2+ concentration ([Ca2+]cyt) measurement.Results: WT and DK mice displayed normal systemic and pulmonary arterial pressure under normoxic conditions. However, compared to WT mice, DK mice had significantly lower RVSP, RV/LV+S ratios, and displayed less pulmonary vascular remodeling when exposed to hypoxia. Extracellular Ca2+ caused an increase in [Ca2+]cyt in PASMC isolated from hypoxic WT mice. However, restoration of extracellular Ca2+ had little effect on [Ca2+]cyt in DK mice. Additionally, a decrease in store‐operated Ca2+ entry (SOCE) was observed in PASMC from DK mice, as compared to SOCE in PASMC from WT mice.Conclusion: These data indicate that CaSR plays an important role in the development and progression of pulmonary vascular remodeling in mice with PH. CaSR deletions prevent the development of hypoxia‐induced PAH in mice via its modulation of extracellular Ca2+ entry in PASMC, suggesting that CaSR may be a novel therapeutic candidate for the treatment of PAH.Grant Funding Source: Supported by NIH (HL066012; HL115014)
Pre‐existing hypoxia sensitizes the kidney to an ischemia‐reperfusion insult (890.10)
Authors: Pihl Liselotte , Nangaku Masaomi , Inagi Reiko , Liss Per , Palm Fredrik , Nordquist Lina 
Published: June 2021

Hypoxia plays an important role in progression of kidney disease. Indeed, diabetic kidney develops pronounced hypoxia and is sensitive to an ischemia‐reperfusion (IR) insult. However, diabetes is also characterized by hyperglycemia and oxidative stress. It is therefore important to delineate the role hypoxia per se. We therefore developed a protocol to induce intrarenal tissue hypoxia independently of the diabetic condition using the mitochondrial uncoupler dinitrophenol (DNP).Rats with and without DNP‐induced hypoxia were subjected to 40 min of kidney ischemia and function measured 4 weeks thereafter.IR to DNP‐treated rats resulted in 30% lower glomerular filtration rate, whereas it did not affect kidney function in untreated rats.The aim of this project was to investigate if pre‐existing tissue hypoxia sensitizes the kidney to an IR insult independently of hyperglycemia and oxidative stress.Pre‐existing intrarenal hypoxia sensitizes the kidney to an IR insult. It may therefore be beneficial to target kidney hypoxia as a strategy to prevent or reduce the often detrimental effect of an IR insult to the diabetic kidney.
Hyperaldosteronism in KCa1.1 channel β2‐subunit KO mice (892.15)
Authors: Larsen Casper , Sorensen Mads , Praetorius Helle , Leipziger Jens 
Published: June 2021

Whole body K+ homeostasis depends on matching K+ excretion to the daily K+ intake. K+ is excreted via the colon and the kidney, the latter handling the majority of the total K+ excretion. Aldosterone is an important regulator of both renal and colonic K+ excretion. Renal K+ secretion depends on 2 apical K+ channels, ROMK and KCa1.1, while colonic K+ secretion depends on apical KCa1.1 channels. We have acquired a novel global knockout mouse for the β2‐subunit of the KCa1.1 channel, which is the only KCa1.1 β‐subunit expressed in murine colonic epithelium.The β2 KO mice have increased plasma aldosterone. Primary hyperaldosteronism is characterized by low plasma K+, low renin and hypertension. β2 KO mice have normokalemia and low renin, indicating a secondary cause of hyperaldosteronism. The low renin in β2 KO mice indicates that a K+ handling deficiency, rather than hypotension, is causing the hyperaldosteronism.BK channel‐dependent colonic K+ secretion was not disturbed in β2 KO mice In contrast, urinary K+ excretion was reduced in β2 KO mice (P=0.06, n=5), suggesting that β2 KO mice have a reduced capacity for renal K+ secretion. mRNA expression of the β2 subunit has previously been found in rabbit cortical collecting ducts, where expression is increased by K+ loading and reduced by K+ depletion. These data indicate an important function of the β2 subunit of the KCa1.1 in renal K+ excretion.Grant Funding Source: Supported by The Lundbeck Foundation
Acute inhibition of calcineurin using cyclosporine activates renal salt transporters (892.31)
Authors: Blankenstein Katharina , Borschewski Aljona , Ellison David , Bachmann Sebastian , Mutig Kerim 
Published: June 2021

Renal tubular transport processes are essential for systemic water and salt homeostasis and blood pressure control. The renal distal cation‐chloride cotransporters NKCC2 and NCC play a pivotal role in volume regulation. Increased activity of these transporters may cause salt retention and hypertension. Both NKCC2 and NCC are activated by N‐terminal phosphorylation. We recently showed that chronic administration of a calcineurin inhibitor tacrolimus was associated with increased NCC phosphorylation suggesting a role of the phosphatase in deactivation of the distal transporters. In this study we test acute effects of another calcineurin inhibitor, cyclosporine A (CsA) on NKCC2 and NCC in vivo and in cultured cells. The expression of cyclophilins, interacting with CsA during calcineurin inhibition, has been localized to the distal nephron using in situ hybridization and immunohistochemistry. Administration of CsA (25 mg/kg) to normal rats for 4 h led to marked increases of phosphorylated NKCC2 (3 fold) and NCC (6 fold). The concomitant analysis of total NKCC2 or NCC abundance revealed no significant changes. To exclude potential systemic influences, cultured rat TAL cells were treated with CsA for 4 h, which led to a substantial increase of NKCC2 phosphorylation. Our data suggest that phosphorylation of NKCC2 and NCC is acutely regulated by CsA at posttranscriptional level. Considering the broad clinical application of CsA and its renal side effects such as hypertension and electrolyte disorders, understanding of mechanisms of its side effects has clinical implications.Grant Funding Source: DFG 88126042
Aldosterone enhances urine flow in mice on a low Na, high K diet (892.7)
Authors: Cornelius Ryan , Wen Donghai , Sansom Steve 
Published: June 2021

Mice on a low Na, high K diet (LNaHK) are able to excrete excess K and maintain K homeostasis by increasing tubular fluid flow in the distal nephron of the kidney. High tubular fluid flow increases K secretion by activating BK‐α/β4 channels in the collecting duct, which are regulated by aldosterone (aldo). The effect of aldo on tubular fluid flow has not yet been investigated. We hypothesized that aldosterone enhances tubular fluid flow in mice on LNaHK. C57BL/6 mice underwent adrenalectomy (ADX) or sham surgery and were given either LNaHK or control diet. ADX LNaHK received aldo replacement, via osmotic pump, at low dose (L‐Aldo; analogous to sham control diet mice) or high dose (H‐Aldo; analogous to sham LNaHK mice). Plasma [aldo] was higher in L‐Aldo (728 pg/ml) compared to sham control diet mice (287 pg/ml), while H‐Aldo (1754 pg/ml) was lower than sham LNaHK (3630 pg/ml). L‐Aldo exhibited a urine flow (UV) of 1.4 ml/day, a UKV of 1005 μmol/day, and a luminal [K] of 125 mM. H‐Aldo demonstrated an increased UV and UKV of 5.0 ml/day and 2714 μmol/day, respectively, whereas the luminal [K] was not significantly different (125 mM). The results demonstrate that L‐Aldo enhances K secretion in mice on LNaHK by increasing K secretion in the distal nephron, while H‐Aldo further increases K secretion by enhancing distal flow. This indicates that high levels of aldo is needed in mice on LNaHK to enhance UV enough to excrete the excess K.Grant Funding Source: Supported by AHA Predoctoral Fellowship 11PRE7530018
TRPV4 deficiency protects myocardium following myocardial infarction and transverse aortic constriction (893.11)
Authors: Cappelli Holly , Adapala Ravi , Thoppil Roslin , Ohanyan Vahagn , Luli Jordan , Luther Daniel , Paruchiri Sailaja , Meszaros J. Gary , Chilian William , Thodeti Charles 
Published: June 2021

Cardiac remodeling is triggered by a cascade of events following myocardial injury, including the differentiation of cardiac fibroblasts (CFs) into myofibroblasts. Myofibroblasts are hypersecretory and highly contractile cells, however, in excess, can lead to cardiac dysfunction and eventual heart failure. Recently, our lab has shown, in vitro, that TRPV4, a mechanosensitive ion channel, integrates mechanical and soluble signals to aid in the differentiation process of CFs. Our current study aims to investigate physiological role of TRPV4 during the remodeling process by subjecting wild type (WT) and TRPV4 knockout (KO) mice to myocardial infarction (MI) or transverse aortic constriction (TAC). Assessment of the post‐surgery survival and cardiac function found the TRPV4 KO mice to have improved survival rates and preserved ejection fraction. Cardiac fibrosis was examined using picrosirius red staining which revealed that the TRPV4 KO mice had significantly less fibrosis than their WT counterparts. Furthermore, a comparison of gene expression in the whole heart tissue allowed analysis of pro‐fibrotic genes, such as col1A2, α‐SMA, N‐FAT, TGF‐β1, and mechanosensitive transcription factor MRTF‐a, and found a reduction in the expression of these genes in the TRPV4 KO mice pre‐ and post‐cardiac injury. Altogether, our findings suggest that the absence of TRPV4 improves the cardiac function and remodeling following myocardial injury, and could lead to a novel therapeutic target for cardiac fibrosis.Grant Funding Source: Supported by NIH‐1R15HL106442‐01
All‐trans‐retinoic acid ameliorates hepatic steatosis by activating Hes6, a novel transcriptional repressor in mice (901.2)
Authors: Kim Chun‐Ki , Kim Seongchul , Axe David , Cook Aaron , Lee Mikang , Lee Yoon Kwang 
Published: June 2021

Mice deficient orphan nuclear receptor Small Heterodimer Partner (SHP) are protected from diet‐induced hepatic steatosis due to increased fatty acid oxidation and decreased lipogenesis. Especially the mice exhibited very low expression of peroxisome proliferator activated receptor gamma 2 (Pparγ2), a potent adipogenic transcription factor, in the liver after long‐term western diet (WestD) regimen. We have identified a hairy and enhancer split 6 (Hes6), a novel transcriptional repressor, as an important mediator for the regulation of Pparγ2 expression by SHP using Illumina Beadchip array and realtime PCR analysis in the RNAs isolated from livers of SHP‐/‐ and SHP‐overexpressing mice. The repression of Pparγ2 expression by Hes6 is achieved via its direct repression of hepatocyte nuclear factor 4 alpha (Hnf4α) transcriptional activity. The Hes6 promoter is specifically activated by the retinoic acid receptor (RAR) in response to its natural agonist all‐trans retinoic acid (atRA), and is repressed by SHP. Treatment of atRA or adenovirus‐mediated RARα overexpression in obese mice increased Hes6 mRNA levels and significantly reduced hepatic fat accumulation along with the decreased expression of Pparγ2 and its downstream target gene, fat specific protein 27 (Fsp27). Furthermore, adenovirus‐mediated Hes6 overexpression significantly reduced triglyceride concentration and the expression of Pparγ2 and Fsp27 in the livers of WestD‐fed mice. The current study identifies a novel transcriptional regulatory cascade controlling lipid metabolism and provides insights into new therapeutic approaches to fatty liver diseases.Grant Funding Source: This study is supported by NIH grant R01DK093774.
Regulation of intestinal calcium absorption appears to be different in dogs and man (908.9)
Authors: Dobenecker Britta , Schmitt Stephanie , Mack Julia , Kienzle Ellen , Alexander Lucille , Morris Penelope 
Published: June 2021

The dog is used as a model for human skeletal research, with the assumption that calcium (Ca) and phosphorus (P) metabolism are similar between species. A prior meta‐analysis of Ca intake and faecal excretion suggested that adult dogs are unable to adapt their Ca digestibility to Ca intake, meaning dogs lack the ability to increase Ca digestibility when dietary Ca is low. We wanted to test this hypothesis in vivo with diets reflective of normal feeding.Apparent Ca digestibility and selected Ca metabolism and safety markers were determined at baseline and every 6 weeks for 6 months of low Ca feeding (~60 mg Ca/kg BW^0.75 = Minimum Requirement (MR), Ca/P=0.6) in 11 adult dogs. During low Ca feeding there was no decrease in faecal Ca excretion and apparent Ca digestibility was negative. Markers of bone resorption increased. This study confirmed the results of the meta‐analysis: dogs fed Ca at MR exhibit negative apparent Ca digestibility and increased bone resorption suggesting that Ca regulation in the dog does not utilize changes in Ca digestibility. These data show that Ca homeostasis of the dog differs from human, and thus the dog should not be used as a model animal for human skeletal research.
Reproductive effects of phoenixin (911.8)
Authors: Tullock Chloe , Samson Willis 
Published: June 2021

Phoenixin is a peptide hormone identified by our group to be produced in the neuroendocrine hypothalamus and pituitary gland (J Neuroendocrinol 25:206,2013). We have demonstrated a direct pituitary action of phoenixin to augment GnRH‐stimulated LH secretion and that compromise of endogenous phoenixin production in hypothalamus delayed the onset of estrus in female rats, suggesting an important role for the peptide in reproductive function. We report here that phoenixin mRNA levels are significantly elevated in hypothalamus and anterior pituitary on diestrous day one when estrogen levels are at their lowest during the rat estrous cycle. In cultures of an immortalized mouse gonadotroph cell line, LβT2, phoenixin treatment for two hours increases Luteinizing Hormone β‐chain mRNA, as determined by real time polymerase chain reaction. Treatment of the cells with estradiol benzoate abrogates this effect. Additionally, ovariectomized animals treated with estradiol benzoate also show a trend toward a decrease in phoenixin gene expression in hypothalamus and anterior pituitary gland. These data demonstrate that phoenixin production and action may be controlled by ambient, gonadal steroid levels, and further support a physiologically relevant role for endogenous phoenixin in the control of gonadotropin release.Grant Funding Source: SLU President's Research Fund
Efficient in vivo gene transfer to murine renal cells using AAV9 vectors (912.7)
Authors: Konkalmatt Prasad , Asico Laureano , Feranil Jun , Jose Pedro , Armando Ines 
Published: June 2021

Adeno‐associated viral (AAV) vectors provide sustained long‐term gene expression with minimal immunological consequences. Therefore AAV vector systems are useful gene‐transfer tools in translational, as well as in basic research studies. Systemic administration of AAV9 vector transduces various tissues efficiently but provides very low transduction in kidney, compared to other organs such as liver, heart, and skeletal muscle. We hypothesized that the administration of AAV9 vector by retrograde infusion via the ureter can provide efficient gene transfer to renal cells and minimize off‐target gene expression. AAV9 vector (1e+11 viral genome particles/100 μl), encoding firefly luciferase (AAVCMVLuc) or eGFP (AAVCMVeGFP) under the control of CMV promoter, was infused into the left kidney via the ureter and held for a period of 15 minutes. Non‐invasive bioluminescence imaging (IVIS‐200, Xenogen Corporation) of the mice treated with AAVCMVLuc after one week showed that the signal was limited to the left kidney. Three weeks following vector administration, the magnitude and distribution of gene expression was measured by luciferase activity assay and immunohistochemistry, respectively. Luciferase activity was 4.6‐fold (n=3, P<0.05) higher in the kidney infused with AAVCMVLuc than the liver. Immunohistochemical analyses of AAVCMVeGFP‐treated mice showed gene expression in renal distal, as well as proximal tubular epithelial cells. These studies show that AAV9 gene transfer via the ureter is a highly efficient method for gene transfer and gene rescue studies in mouse kidney.Grant Funding Source: 1R01DK090918‐01A1
COLIIA1 overexpression with low level laser therapy after experimental injury (914.5)
Authors: Jacomo Alfredo , Teodoro Walcy , Saleh Samir , Martinez Carlos , Ribeiro Marcelo , Hojaij Flávio , Andrade Mauro , Akamatsu Flávia 
Published: June 2021

BACKGROUND: Calcaneous tendon injuries are commonly seen as consequences of sports trauma and costly in terms of surgery and rehabilitation. Low Level Laser Therapy (LLLT) has been used to accelerate healing process and avoid tissue adhesions. We investigated the response of experimental lesions of the calcaneous tendon in rats after LLLT therapy.METHODS AND MATERIAL: Thirty adult male Wistar rats weighing 250 to 300 g were surgically submitted to bilateral partial transverse section of the calcaneous tendon. The right tendon was treated with LLLT whereas the left tendon served as control. On the third postoperative day, the rats were divided into three experimental groups consisting of ten rats each which were treated with LLLT ( Konf, Aculas ‐ HB 750), 780nm and 80mW for 20 seconds, three times/week for 7, 14 and 28 days. Collagen I, II, and III gene expression were studied.RESULTS: Increased collagen II gene expression was observed in all experimental groups.CONCLUSION: mRNA gene expression for COLIIA1 is confirmed with immunolocalization of type II collagen and suggests that it could give support to the interstitial tissues on healing process of the calcaneous tendon. Further studies are needed to confirm LLLT role in tendon healing.