bluuebunny/crossref_metadata_2025_split huggingface dataset:
Renal‐selective Snx5 gene silencing increases blood pressure and renal sodium transporters in mice
Authors: Wang Xiaoyan , Asico Laureano , Zheng Xiaoxu , Lin Hai , Jose Pedro A , Villar Van Anthony M 
Published: November 2023

We have reported that sorting nexin 5 (SNX5) plays an important role in the positive regulation of the renal dopamine receptor subtype 1 (D1R). siRNA‐mediated gene silencing of renal Snx5 results in anti‐natriuresis and increases further the elevated blood pressure (BP) of spontaneously hypertensive rats. We tested the hypothesis that the increased renal sodium transport and increased BP following Snx5 gene silencing is accompanied by changes in the expression of renal transporters in C57BL6/J mice. We infused subcapsularly the Snx5‐specific siRNA (3 μg/kg/day), or non‐silencing “mock” siRNA as control, for 7 days in 8 1‐year old, previously uninephrectomized male C57BL6 mice. A 24‐hour urine was collected from the mice housed in metabolic cages a day prior to the end of the siRNA infusion. Renal SNX5 protein expression was decreased by 60% with Snx5‐siRNA relative to control group. Renal SNX5‐depleted mice had elevated systolic (119±5.2 mm Hg, measured under anesthesia) and diastolic BPs (91.8±7.3 mm Hg) relative to control mice (systolic BP=101.5±0.5 mm Hg, diastolic BP=72±2.3 mm Hg). Urine sodium excretion tended to decrease in SNX5‐depleted mice (0.68±0.22 mmol/Cr mg) relative to controls (1.08±0.30 mmol/ Cr mg). Moreover, renal SNX5 depletion shifted the pressure natriuresis curve to the right. Food and water intake, body weight, urine volume, and heart rate were similar in the two groups. SNX5 is mainly located at the apical membrane of proximal tubules (PT), thick ascending limbs of loop of Henle (TAL) and distal convoluted tubules (DCT). SNX5 was observed via confocal microscopy to colocalize with NHE3, NKCC2 and NCC in C57Bl/6J mice under basal conditions. However, the co‐staining is strongest with NHE3 in the PT, relative to NKCC 2 and NCC which are expressed in TAL and DCT, respectively. The expression of renal NHE3 (172±29 % of control), NaPi2 (223±12%), NKCC2 (440±12%) and NCC (177±23%) were greater in SNX5‐depleted mice than in control mice. Renal protein expressions of α,β,γ‐ENaCs, Na+K+ATPase and actin were similar in the 2 groups. These findings suggest that inhibition of SNX5 expression with siRNA increases sodium transporters in proximal and distal nephron segments. This may lead to the inability of renal D1R to inhibit renal sodium transport and may be responsible for the increased BP in Snx5‐siRNA‐ treated mice.Support or Funding InformationThis work was supported in part by grants from the National Institutes of Health, R37HL023081, R01DK039308, P01HL068686, P01HL074940, and R01HL092196. Dr. Xiaoyan Wang was supported, in part, by National Kidney Foundation of Maryland (Professional Development Award, 2014).
Imbalanced Plasma ACE and ACE2 ratio in the Uremic Patients with Cardiovascular Diseases and Its Change during a Single Hemodialysis Session
Authors: Cho Ching‐Chang , Lu Li‐Che , Chang Chia‐Chu , Lin Chung‐I , Wang Guan‐Hua , Yang Chung‐Wei , Lin Chih‐Sheng 
Published: November 2023

BackgroundThe renin‐angiotensin system (RAS) has significant influences on heart and renal disease progression. Angiotensin converting enzyme (ACE) and angiotensin converting enzyme II (ACE2) are major peptidases of RAS components and play counteracting functions through classical angiotensin II (Ang II)/ATIR and non‐classical angiotensin‐(1–7) (Ang‐(1–7))/Mas axis, respectively. Based on crucial roles of RAS in the pathogenic development of chronic kidney disease (CKD), we tested the hypothesis whether plasma ACE and ACE2 levels might be significantly changed in the patients with end‐stage CKD (ESRK), i.e., uremic patients or HD patients.MethodsThis study included 372 uremic patients (aged 66.0 ± 13.4; 184 women; the mean hemodialysis (HD) therapy time was 7.5 years) who were on regular HD treatment and 50 healthy controls. The HD patients were grouped by the clinical symptoms or previous history of CVD (n = 122) and without CVD (n = 250). Hematological and biochemical parameters were determined by routine procedures. The plasma ACE and ACE2 levels were detected using fluorogenic substrates assay, and plasma Ang II and Ang‐(1–7) concentrations were determined by ELISA assay.ResultsThe clinical characteristics of the HD patients with CVD (n = 122) and without CVD (n = 250) were shown that few of the clinical determinants detected differs significantly between the HD patient subgroups. However, we compared pre‐HD levels of plasma ACE, ACE2, Ang II and Ang‐(1–7) in the HD patients with and without cardiovascular disease (CVD) to those of the controls. The HD patients, particularly those with CVD, showed a significant increase in the levels of plasma ACE and Ang II, whereas ACE2 and Ang‐(1–7) levels were lower than those in the healthy controls. Therefore, markedly loss of ACE and ACE2 correlation, i.e., imbalanced ACE/ACE2, was observed in the HD patients with CVD. In the course of a single HD session, the plasma ACE, ACE/ACE2 and Ang II levels in the HD patients with CVD were increased from pre‐HD to post‐HD. On the contrary, plasma ACE2 level were decreased after the HD session. These changes were not detected in the HD patients without CVD.ConclusionPathogenically imbalanced circulating ACE/ACE2 was detected in the HD patients, particularly those with CVD. HD session could increase ACE/Ang II/AT1R axis and decrease ACE2/Ang‐(1–7)/Mas axis activity in the circulation of HD patients with CVD. The imbalanced ACE/ACE2 due to a single HD session in the HD patients with CVD is required to further validate on its mechanism.
Acute Cyclooxygenase Inhibition and Baroreflex Sensitivity in Lean and Obese Adults
Authors: Al‐Khateeb Abdulrahman A , Limberg Jacqueline K , Barnes Jill N , Joyner Michael J , Charkoudian Nisha , Curry Timothy B 
Published: November 2023

PurposeObese adults exhibit increased levels of inflammation which may negatively affect blood pressure regulation. Based on existing literature, we hypothesized: 1) baroreflex sensitivity would be lower in obese adults when compared to lean adults and 2) acute ibuprofen (IBU, a cyclooxygenase inhibitor and nonsteroidal anti‐inflammatory agent) administration would increase baroreflex sensitivity in obese adults, with no effect in lean adults.MethodsSeven lean (4M, 3F; 25±2 yrs; 23±1 kg/m2) and six obese (5M, 1F; 30±3 yrs; 36±1 kg/m2) adults completed two visits randomized to control (CON) or IBU (800 mg oral). On each visit, blood pressure (intra‐arterial catheter), heart rate (electrocardiogram), and muscle sympathetic nerve activity (MSNA, microneurography) were measured continuously and venous blood was sampled for measures of systemic inflammation [C‐Reactive protein (CRP) and Interleukin‐6 (IL‐6)]. Sympathetic and cardiac baroreflex sensitivity were assessed using the modified Oxford technique, which consisted of a 5‐min resting period, followed by a 100 μg intravenous bolus of sodium nitroprusside. One minute later, subjects were administered a 150 μg intravenous bolus of phenylephrine HCl and data were collected for an additional 2‐min.ResultsCRP and IL‐6 were higher in obese adults when compared to lean adults, and tended to decrease with IBU (IL‐6: p<0.05; CRP: p=0.14). Cardiac baroreflex sensitivity was lower in obese adults (14±2 vs 24±2 ms/mmHg, p=0.02), whereas sympathetic baroreflex sensitivity was higher in obese adults (−3.6±0.5 vs −2.1±0.5 bursts/100 beats/mmHg, p=0.03) when compared to lean. There was no effect of IBU on cardiac or sympathetic baroreflex sensitivity in either group (p‐value range 0.20 – 0.71).ConclusionIn our present group of relatively healthy individuals with obesity, we observed lower cardiovagal baroreflex sensitivity but higher sympathetic baroreflex sensitivity in the obese group compared to lean controls. We found no effect of an acute dose of 800 mg ibuprofen on cardiac or sympathetic baroreflex sensitivity, suggesting that chronic effects of obesity‐related inflammation on baroreflex sensitivity may not be reversed by a single acute pharmacological anti‐inflammatory intervention.Support or Funding InformationNIH HL083947 (NC, MJJ), DK082424 (TBC), AG038067 (JNB), and UL1 TR000135 from the National Center for Advancing Translational Sciences (NCATS). AHA 0750036Z (NC) from the American Heart Association.
Lipid Homeostasis and Function
Authors: Riezman Howard , Hannich J. Thomas , Galih Agustinus , Santos Aline X.S. , Riezman Isabelle , Martinou Jean‐Claude , Gentina Sebastien 
Published: November 2023

We have developed a new approach to study lipid homeostasis and function which we call systematic lipidomics. It shows that the determined lipidome allows inferences about genetic background and has shown the tight relationship between the nutrient environment and lipid homeostasis. It represents therefore a new, rich source of biological information and has potential applications in medicine. We have recently focused on the role of ceramides in the response to anoxia after having isolated mutants in ceramide synthases that cause hypersensitivity or resistance to anoxia in worms. Using high resolution mass spectrometry we have shown that deoxyvceramides accumulate during anoxia and they seem to play a crucial role in determining the hypersensitivity to anoxia. Their mode of action seems to be through effects on mitochondria and the actin cytoskeleton. Our results would suggest that death after treatment under anoxic conditions involves generation of reactive oxygen species and therefore occurs during reoxygenation rather than during oxygen deprivation.Support or Funding InformationSwiss National Science Foundation, Swiss National Center of Competence in Research i (NCCR) n Chemical Biology
Determination of thermosensory pathways required for behavioural thermoregulation
Authors: Yahiro Takaki , Kataoka Naoya , Nakamura Yoshiko , Nakamura Kazuhiro 
Published: November 2023

Thermoregulatory behavior, represented by cold‐ and warm‐seeking behaviors in hot and cold environments, respectively, is utilized by animals to choose an optimal thermal environment. This voluntary behavior helps involuntary autonomous thermoregulatory mechanisms efficiently maintain body core temperature. Although many thermoregulatory behaviors are dependent on environmental temperature information transmitted from skin thermoreceptors to the brain, the afferent mechanism of the thermosensory transmission for behavioral thermoregulation has been unknown. In this study, we first examined the involvement of the well‐known spinothalamocortical thermosensory pathway in behavioral thermoregulation. The rat spinothalamocortical pathway was ablated by bilateral lesions of the ventral posteromedial and ventral posterolateral thalamic nuclei (VPM/VPL), a thalamic area receiving most thermal somatosensory signals from the spinal cord. The functional ablation of this pathway was confirmed with elimination of skin temperature‐dependent electroencephalographic responses recorded from the primary somatosensory cortex. To measure behavioral thermoregulation, we performed a two‐floor thermal plate preference test, in which control rats preferred a 28°C plate to a 15°C (cold) or 38°C (hot) plate, displaying cold‐ and heat‐avoidance thermoregulatory behaviors. Of note, the lesions of the VPM/VPL did not affect the thermoregulatory behaviors, indicating that the spinothalamocortical pathway is not involved in behavioral thermoregulation. We next investigated whether the lateral parabrachial nucleus (LPB), which mediates thermosensory signaling for autonomous thermoregulation, plays a role in behavioral thermoregulation. Inhibition of neurons in the LPB with bilateral nanoinjections of muscimol eliminated the cold‐ and heat‐avoidance thermoregulatory behaviors. These results indicate that an LPB‐mediated afferent pathway, but not the spinothalamocortical pathway, transmits the cutaneous thermosensory neural signals required for behavioral thermoregulation. This finding may contribute to future understanding of the central circuit mechanisms for the generation of thermal comfort and discomfort underlying thermoregulatory behavior.Support or Funding InformationFunding from Nagoya University School of Medicine (TY); KAKENHI, MEXT of Japan 16H05128 & 15H05932 (KN)
Necrotizing enterocolitis is associated with recruitment of Lysozyme M positive myeloid cells in the intestinal submucosa via NF‐κB‐dependent upregulation of adhesion molecules
Authors: Managlia Elizabeth , Yan Xiaocai , Liu Xueli , De Plaen Isabelle 
Published: November 2023

Necrotizing enterocolitis (NEC) is a devastating disease of the neonatal intestine. It predominantly affects premature infants and results in high mortality and morbidity. The pathogenesis of NEC is incompletely understood. We previously found that NEC is associated with a macrophage‐rich infiltrate and that blocking NF‐κB in LysM‐myeloid cells protects against experimental NEC. Furthermore, our previous data suggest that LysM‐myeloid cells are mainly present in intestinal monocytes in dam fed pups, but present in both monocytes and inflammatory macrophages in pups exposed to a NEC protocol in an NF‐κB‐dependent manner. Here, we sought to investigate whether Lysozyme (Lys) M‐myeloid cells infiltrate the intestine during NEC using our well‐established neonatal mouse model. To do so, we quantified by immunohistochemistry LysM+ cells present in the villi and submucosa of IKKβ floxed or WT mice with LysM expressing cre‐recombinase crossed with GFP cre‐reporter (mT/mG) mice. We found that NEC induction was associated with an increase in LysM+ (= GFP +) cells in the submucosa (14.78±1.1 vs controls 9.47±0.07 cells/HPF; p<0.01) but not the villi ((10.03±1.03 vs controls 6.5±0.88) in NF‐κB‐sufficient pups, but not in NF‐κB‐deficient pups. Furthermore, many of the GFP+ cells were located outside the intestinal vasculature, while they were located predominantly intravascularly in the NF‐κB‐deficient pups. Interestingly, we found that expression of L‐selectin and alpha 4‐integrin of isolated intestinal inflammatory myeloid cells, which were significantly increased during NEC when assessed by PCR, was significantly attenuated in NF‐κB‐deficient pups. This suggests, that, in NEC, inflammatory macrophages are recruited into intestinal tissue via expression of adhesion molecules, which is dependent on NF‐κB activation in myeloid cells.Support or Funding InformationSupported by NIH grant RO1HD060876 and Ann & Robert H. Lurie Children's Hospital of Chicago Foundation
The role of HIF‐1α in a single bout of heavy exercise induced intestinal barrier dysfunction
Authors: Wu Die , Luo Beibei , Chen Peijie , Xiang Dao , Shi Yue 
Published: November 2023

Intestinal epithelial cells are positioned between an anaerobic lumen and a highly metabolic lamina propria, affected by reduced blood flow and tissue hypoxia. Heavy exercise induces tissue blood flow redistribution by which the blood flow is decreased in the splanchnic circulation. The redistribution significantly reduces blood flow to the gut, leading to hypoperfusion and GI compromise. The hypoxia‐inducible factor (HIF) 1α is pivotal in the transcriptional response to oxygen flux. Therefore, we hypothesize that HIF‐1α plays an important role in heavy exercise induced intestinal barrier dysfunction. Two heavy exercise models were used in this study. (1) Long‐time exercise: mice voluntarily swam for 3 hours (or till exhaustion) in warm water (37 ± 1°C). (2) High‐intensity exercise: mice were subjected to weight‐loaded forced swim (7.5% of the body weight) for 1 hour. The noninvasive in vivo bioluminescence imaging was applied to monitor HIF‐1α expression after exercise in ROSA26 ODD‐Luc/+ mouse model (ODD‐Luc) that ubiquitously expresses a bioluminescent reporter consisting of firefly luciferase fused to a region of HIF‐1α. We found that one session of heavy swimming exercise markedly increases in vivo HIF‐1α in the gastrointestinal system. Next, we developed Vil‐Cre mediated, intestinal specific deletions of HIF‐1α (Vil‐Hif1a−/−) mouse model to verify the role of HIF‐1α in heavy exercise induced intestinal barrier dysfunction. Intestine segments were excised and stained with hematoxylin and eosin (HE) and alcian blue‐periodic acid Schiff (AB‐PAS). Intestinal permeability was quantified with FITC‐dextran. Bacterial translocation was determined by quantification of colony forming units (CFU) in cultured mesenteric lymph nodes, livers, kidneys and spleens. Gene expression profiling experiments were performed on mouse intestine cDNA samples from each group using RT2 Profiler PCR Arrays including over 84 genes related to antimicrobial responses. We found no significant differences between Vil‐Hif1a−/− and control Hif1aloxp mice in intestinal histology and mucus layer structure. However, the antimicrobial responses related genes expression were significantly different (P<0.001) between Vil‐Hif1a−/− and Hif1aloxp mice, including Il12a, Irak3, Irf5, Lbp, Lyz2, Nlrp1a, Ticam2, Tlr4, Tlr9 and Tnf. In conclusion, these results demonstrate an important role of HIF‐1α in the regulation of intestinal barrier functions related genes expression after one session of heavy exercise.Support or Funding InformationThe National Natural Science Foundation of China (31471135).
α2‐Adrenergic Blockade as a Novel Drug Therapy for Obstructive Sleep Apnea
Authors: Song Gang , Poon Chi‐Sang 
Published: November 2023

RationaleDecreased noradrenergic excitation of hypoglossal motoneurons during sleep causing atonia of pharyngeal dilator muscles is a major contributor to the pathogenesis of obstructive sleep apnea (OSA), a widespread disease for which effective drug treatment is currently lacking. Previous drug candidates for OSA aiming to restore hypoglossal motoneuron excitability and upper airway dilator muscle tone have proved largely ineffective in animal studies and clinical trials. Episodic airway obstruction is known to induce a long‐lasting noradrenergic‐dependent increase in hypoglossal activity called hypoglossal long‐term facilitation (hLTF) in animal models. We hypothesized that (1) the pathogenesis of OSA may involve not only decreased hypoglossal motoneuron excitability but also impaired hLTF during sleep; (2) therapeutic drugs targeting endogenous noradrenergic drive rather than hypoglossal motoneurons per se may prove more effective in restoring baseline hypoglossal activity and hLTF in defense against OSA.ObjectivesTo examine the efficacy and mechanism of action (MOA) of a clinically well‐tested α2‐adrenoceptor antagonist (yohimbine) as a potential drug candidate for OSA in an animal model.MethodshLTF was induced by episodic airway occlusion simulating obstructive apnea and by episodic optogenetic stimulation of central noradrenergic neurons in urethane‐anesthetized rats. Efficacy of yohimbine therapy in restoring baseline hypoglossal activity and hLTF was studied during spontaneous or cholinergic‐induced REM sleep.Measurements and Main Results(1) Baseline hypoglossal activity and hLTF were markedly depressed during spontaneous or cholinergic‐induced REM sleep in urethane‐anesthetized rats. (2) These adverse effects of REM sleep on the first‐and second‐line motor defenses against OSA were promptly reversed by systemic (i.v.) administration of yohimbine. (3) Rats exposed to episodic airway occlusion demonstrated increased c‐Fos expression in pontine A7 and A5 neurons but not A6 (locus coeruleus and sub‐coeruleus) neurons, suggesting possible involvement of these noradrenergic neurons in the induction of hLTF. (4) Episodic optogenetic activation of pontine A7 or A5 noradrenergic neurons effectively induced hLTF post‐stimulation. (5) Microinjection of yohimbine into bilateral A7 and A5 regions resulted in significant augmentations of baseline hypoglossal activity and hLTF similar to systemic yohimbine administration, whereas microinjection of clonidine (an α2‐adrenoceptor agonist) into these regions produced the opposite effects.ConclusionResults suggest that disinhibition of A7 and A5 noradrenergic neurons by α2‐adrenergic blockade with yohimbine constitutes a viable drug therapy for OSA.Support or Funding InformationHL093225, HL127258 and NS094178
Diaphragm Muscle Activity Following High Cervical Spinal Cord Injury (SCI) in Rats
Authors: Bezdudnaya Tatiana , DeFinis Jaclyn , Marchenko Vitaliy , Lane Michael A 
Published: November 2023

Diaphragm dysfunction occurs following high cervicall spinal cord injury (SCI). As the diaphragm is a primary respiratory muscle its dysfunction often necessitates assited‐ventiation, dramatically impacting quality of life and increasing risk of mortality in injured individuals. Despite these devastating outcomes, functional plasticity and recovery of diaphragm activity, albeit limited, can occur spontaneously over the time. Understanding of the mechanisms underlying this recovery will facilitate developing new therapeutic strategies to treat respiratory impairment post‐SCI. In the current study, a C2 cervical spinal cord hemisection (C2Hx) was used to explore spontaneous plasticity ‐ known as the spontaneous crossed phrenic phenomenon – in awake behaving animals. While previous studies have assessed functional under anesthesia, the present study monitored changes in diaphragm activity using chronically implanted diaphragm EMG electrodes in behaving rats up to 8 weeks. Our EMG recording data show that recovery of diaphragm activity in awake animal occurs in one‐two weeks post injury, but inspiratory bursts on the injured side differ from the contralateral. Even when the amplitude of ipsilateral bursts is comparable with uninjured side, intraburst spike frequency is significantly lower especially during quiet breathing. Recording diaphragm EMG activity under anesthesia (isoflurane or ketamine) can eliminate ipsilateral diaphragm activity up to 100% indicating that recovery seen in behaving rats is mostly attributed to NMDA receptor activation. Ongoing studies are assessing this progressive functional recovery in more detail.Support or Funding InformationSupported by Conquer Paralysis Now (CPN) and the Edward Jekkal Muscular Dystrophy Association Fellowship (Drexel).
Epigenetic‐Modification of Adult Fibroblast Cells into OCT4+ and VEGFR‐2+ Angiogenic Cells
Authors: Wary Anita , Wary Neil , Baruah Jugajyoti , Wary Kishore 
Published: November 2023

RationaleThe epigenome of fibroblast cells is plastic. Here, we address the hypothesis that fibroblast cells can be epigenetically modified into blood vessel forming cells.Methods and ResultsHuman adult dermal fibroblast cells (hADFCs) were treated with optimal concentrations of chromatin‐modifying agents 5‐aza‐2′‐deoxycytidine (5‐Aza) and trichostatin A (TSA), thereafter subjected to activation of canonical Wnt signaling. We provide evidence that these epigenetically modified hADFCs increasingly expressed β‐catenin, pluripotency factor octamer‐binding transcription factor‐4 (OCT4, also known as POU5F1), and endothelial cell (EC) marker called vascular endothelial growth factor receptor‐2 (VEGFR‐2) and Lipid Phosphate Phosphatase‐3 (LPP3). Staining and microscopic analysis showed differential localization of β‐catenin and OCT4 proteins in epigenetically modified hADFCs. Accordingly, in a chromatin immunoprecipitation (ChIP) assay, OCT4 bound to the VEGFR‐2/FLK1 promoter. Finally, these modified hADFCs also transduced Wnt signaling. Importantly, on a three‐dimensional (3D) Matrigel, a subset of modified cells formed branching point network‐like structures in VEGF‐dependent manner.SummaryThe epigenome of adult fibroblast cells is amenable to epigenetic modification, and has significant implications for the use of epigenetically modified cells to promote angiogenesis in vivo.Support or Funding InformationStudies were supported by the RO1‐HL079356 and (GRNT25710129) and by the University of Illinois at Chicago Center for Clinical and Translation Science Award (UL1RR029879) to K.K.W. J.B was supported by AHA pre‐doctoral fellowship Mid‐West affiliate (15PRE22760004) and CCTS‐PECTs (1UL1TR002003). The UIC, RRC Core Imaging Facility, at the University of Illinois Chicago.