bluuebunny/crossref_metadata_2025_split huggingface dataset:
IBUPROFEN IMPROVES POSTOPERATIVE SPATIAL RECOGNITION
Authors: Schoemaker Regien G , Hovens Iris B , de Haan Jacco J , van Leeuwen Barbara L 
Published: November 2023

BackgroundTen percent of older surgical patients experience prolonged dementia‐like symptoms after major surgery. This postoperative cognitive dysfunction (POCD) appears to be mediated by surgery‐induced (neuro)inflammation. We aimed to investigate the feasibility of acute anti‐inflammatory treatment prior to surgery as preventive therapy against POCD.MethodsYoung (3 mo, n=16) and aged (23 mo, n=16) male Wistar rats were subjected to major abdominal surgery. Before surgery, rats were fasted overnight and received ibuprofen (15 mg/kg i.p.; IBU) 30 minutes before surgery or no treatment. In the second postoperative week cognitive performance was assessed with the novel object (NO) and novel location (NL) test, and training, probe trials, and reversal training in the Morris water maze (MWM). Brains were collected two weeks after surgery and processed for immunohistochemical analyses of microglial activity and neurogenesis in the hippocampus.ResultsNO recognition was not affected by age nor by IBU. Whereas spatial learning and reversal learning were impaired with age but not affected by IBU, in young, but not in old rats IBU improved spatial recognition in the NL test. This was accompanied by increased hippocampal neurogenesis in young, but not in old rats. Surprisingly, hippocampal microglial activity after ibuprofen treatment appeared concomitantly increased.ConclusionImproved spatial recognition accompanied by increased hippocampal neurogenesis, but higher microglial activity suggest mixed effects of preoperative anti‐inflammatory treatment with ibuprofen.Support or Funding InformationResearch was funded by the University Medical enter Groningen
Disruption of Adenylyl Cyclase Type 5 Induces Anti‐Depressive Behavior
Authors: Trifiolis Taylor Lyn , Guers John , Buchholz Bruno , Vatner Dorothy , Vatner Stephen , Gelpi Ricardo 
Published: November 2023

It is generally thought that increases in cyclic AMP signaling will induce depressive behavior. We examined the extent to which behavior was modified by disruption of adenylyl cyclase type 5 (AC5), which reduces cyclic AMP levels, and which is prevalent in most organs, including the brain. Accordingly, we assessed behavior using traditional tests, i.e., locomotor activity using an open field, examining total distance traveled, rest time and vertical activity, which were all recorded and analyzed for AC5 knock out (KO) mice and their wild type (WT) littermates. The AC5 KO mice were significantly more active in all aspects of the open field test in comparison to the wild type mice. The average total distance traveled by AC5 KO mice over a two hour testing period was (7,584 ± 749 cm) while WT average total distance was (1,764 ± 99 cm; p<0.05). Rest time was less in AC5 KO. AC5 KO only rested for (3,884 ± 172 s) while AC5 WT remained inactive for (5,745 ± 86 s; p<0.05). AC5 KO moved vertically more often (1008 ± 117 counts) than AC5 WT (125 ± 11 counts; p <0.05). These data, in contrast to most of the literature, indicate that AC5 KO mice, which have lower cAMP signaling, actually exhibit increased locomotion and strongly suggesting an anti‐depressive behavior. Translating this concept to the clinics would be a novel therapeutic approach for patients with depression.Support or Funding InformationThis study is supported by NIH grant: R01 HL106511.
Immunohistochemical Localization of Neuropeptide Arginine Vasopressin and Morphometric Study of Domestic Cat Amygdala
Authors: Kaur Gagandeep , Tang Karena , Seelman Amanda , Shahriar Farshid , Khamas Wael 
Published: November 2023

Neuropeptide arginine vasopressin (AVP) is known to modulate social behavior in several species. The AVP and its receptors are broadly distributed in the limbic system, with several studies documenting their involvement in behavior regulation. However, the role of AVP in feline behavior is unknown, due to lack of studies and possible species differences. Here, as the first step, we investigated the presence of AVP in the domestic cat amygdala by using immunohistochemistry on freely‐floating brain tissue sections. The amygdala is an important component of the circuitry underlying social behavior and emotions. Therefore, we also characterized the neuronal morphology of domestic cat amygdala using cresyl violet stained 30μm serial sections. Our results show the presence of AVP immunoreactive neurons in the domestic cat amygdala (4 males, 1 female). The average neuronal diameter was 10.7±0.3μm in the lateral nucleus, 14.2±0.6μm in the medial nucleus, 11.1±0.8μm in the central nucleus, and 14.3±1.4μm in the basal nucleus, within the amygdala. The rostrocaudal length of the amygdala ranged from 6.7 – 7.3mm (3 males, 1 female). Variations in neuronal diameters did not translate to AVP immunoreactivity. This study is the first demonstration of the presence of neuropeptide AVP in the domestic cat amygdala. This might suggest a potential role of AVP in regulating social behavior in domestic cats. The morphometric findings of neuronal diameter might complement the physiological findings, implementing different roles in behavior for different subnuclei. Such studies will lay foundation for future research in feline behavior to improve feline health and welfare.Support or Funding InformationWestern University of Health Sciences, Pomona, CA
Chronic, complete cervical6‐7 cord injury: distinct autonomic, cardiac and vascular deficits
Authors: Lujan Heidi L. , Mulder Rebecca A. , DiCarlo Stephen E 
Published: November 2023

Spinal cord injury (SCI) resulting in tetraplegia is a devastating, life‐changing injury causing paralysis and sensory impairment as well as autonomic dysfunction that triggers compromised cardiovascular, bowel, bladder and sexual activity. Life becomes a battle for independence as even routine bodily functions and the smallest activity of daily living become a major challenge. The human physiology, mind and spirit are wonderfully adaptable as individuals with tetraplegia find ways to adjust. However, addressing autonomic losses and cardiovascular consequences would greatly improve the quality of life for individuals living with tetraplegia. Virtually all pre‐clinical investigations of autonomic losses and cardiovascular consequences following SCI induce lesions in the thoracic region. However, cervical lesions produce distinct autonomic, cardiac and vascular deficits and result in the most dramatic autonomic outcomes and cardiovascular consequences. Specifically, although cardiovascular disease (CVD) is the leading cause of morbidity and mortality for individuals living with SCI, the magnitude of CVD risk is dependent on the level of SCI, whereby individuals with tetraplegia have a 16% greater risk of all‐cause CVD than individuals with paraplegia. Accordingly, there is a critical need for a chronic pre‐clinical model of tetraplegia. In this report, we compare resting cardiac sympathetic and parasympathetic tonus, reflex sympathetic effects (heart rate responses to sodium nitroprusside), tonic autonomic effects (responses to autonomic ganglionic blockade), cardiac responses to beta‐adrenergic stimulation and the response to angiotensin‐converting enzyme inhibition in 6 rats with chronic (4 week) complete C6‐7 transection and 6 intact sham‐transected rats. Histological examination of the heart and stellate ganglia support the profound and distinct autonomic and cardiac deficits and reliance on angiotensin to maintain cardiovascular stability following chronic, complete cervical6‐7 cord transection.Support or Funding InformationR01HL122223
Identification of Inflammatory Biomarkers for Hypertension from Isolated Human Monocytes
Authors: Norlander Allison Elizabeth , Galindo Cristi L , Elijovich Fernando , Laffer Cheryl L , Montaniel Kim Ramil Contreras , Gnecco Juan S , Madhur Meena S 
Published: November 2023

Individuals on traditional hypertensive treatments are still more likely to develop cardiovascular and kidney complications, including occurrences of myocardial infarction and chronic kidney disease, than normotensive individuals. In recent years, our laboratory has demonstrated a role for inflammation, while specifically characterizing the contribution of monocytes and dendritic cells, in the development of hypertension. We embarked on the current study in attempts to determine, through an unbiased approach, if individuals on conventional hypertensive therapies have altered monocytic gene expression compared to normotensive humans that could help to explain the maintenance of increased cardiovascular risk. We used next generation RNA sequencing to profile monocytes isolated from the peripheral blood of 5 normotensive and 7 hypertensive subjects. We identified 60 transcripts that were significantly differentially expressed. Regression analysis was performed on these transcripts in order to correlate them with mean arterial pressure (MAP). After multivariate analyses, two genes, LTF (r=0.99, p<0.0001) and PGLYRP1 (r=0.99, p<0.005) significantly correlated with MAP in normotensive individuals. GZMH (r=0.88, p<0.01) significantly correlated with MAP in hypertensive individuals. While, IL18RAP significantly correlated with MAP in normotensive (r=0.93, p<0.03) and hypertensive (r=0.78, p<0.04) humans. Finally, we examined transcript expression of the four genes identified in the regression analyses in combination with several other candidate genes identified as significantly differentially expressed in the original analysis using quantitative RT‐PCR in a separate cohort of 6 normotensive and 9 hypertensive subjects. We were able to validate 6 out of 8 transcripts tested; expression of LTF (3.13 fold, p=0.0128), MMP8 (3.78 fold, p=0.044), ARG1 (1.39 fold, p=0.0248), PGLYRP1 (4.62 fold, p=0.0332), and IL18RAP (2.1 fold, p=0.038) all significantly increased in hypertensives while expression of VSIG4 (1.7 fold, p=0.0248) significantly decreased in hypertensives. These data demonstrate that monocytes from treated hypertensive patients exhibit a pro‐inflammatory gene signature which could potentially serve as biomarkers for disease severity and may explain the residual cardiovascular risk in these individuals.Support or Funding InformationNIH T32 Training Grant; F31 Predoctoral Individual National Research Service Award; AHA Strategically Focused Prevention Research Network Grant; NIH NHLBI K08 Award
Hydrogen sulfide controls CBS‐CTH feedback regulation by inducing miR‐133a and suppressing SP1 in a dose dependent manner in cardiomyocytes
Authors: Nandi Shyam Sundar , Mishra Paras Kumar 
Published: November 2023

Previously we reported that hydrogen sulfide (H2S) donor can mitigate hyperhomocysteinemia (HHcy)‐mediated cardiomyocyte hypertrophy by upregulating miR‐133a. However, the dose dependent effect of Hcy and H2S on miR‐133a level, the effect of homocysteine metabolizing enzyme cystathionine‐β‐synthase (CBS) on cystathionine‐ϒ‐lyase (CTH) (a precursor enzyme for H2S biosynthesis), and the role of H2S in CBS and CTH regulation in cardiomyocytes, are poorly understood. We hypothesized that H2S and homocysteine (Hcy) influence CBS and CTH expression in a dose dependent manner, and H2S controls CBS‐CTH feedback regulation by inducing miR‐133a and suppressing SP1, a transcriptional activator of CTH promoter, in cardiomyocytes. We treated HL1 cardiomyocytes with 0, 5, 25, 50, 75 and 100 μmL−1 doses of Hcy or H2S donor Na2S for 24 hours. Our results demonstrated that 50 μmL−1 Na2S upregulates miR‐133a and downregulates CTH, whereas 25 μmL−1 Hcy downregulates miR‐133a and upregulates CTH. To determine the in vivo effect of CBS on CTH, we measured the cardiac levels of CBS and CTH in CBS+/− mice, a model for HHcy. We found that in CBS+/− hearts, CBS is downregulated but CTH is upregulated, suggesting a negative feedback regulation between CBS and CTH. To assess the effect of H2S on CTH, we measured the levels of SP1 in Na2S‐treated cardiomyocytes. Our results revealed that Na2S treatment suppresses SP1 in a dose dependent manner, suggesting that H2S may downregulate CTH by inhibiting SP1. Moreover, our luciferase reporter assay on CTH 3′UTR demonstrated that miR‐133a targets CTH. Since H2S upregulates miR‐133a, it could be an indirect mechanism for H2S‐mediated regulation of CTH. In conclusion, H2S and Hcy regulate CBS and CTH in a dose dependent manner. CBS negatively regulates CTH. H2S upregulates CBS but downregulates CTH, possibly by suppressing SP1 and inducing miR‐133a in cardiomyocytes.Support or Funding InformationAmerican Heart Association Postdoctoral fellowship award 16POST30180003 and National Institute of Health grants HL‐113281 and HL‐116205
The impact of severe burn injury on cardiac mitochondrial function
Authors: Guillory Ashley Nicole , Clayton Robert Patrick , Prasai Anesh , El Ayadi Amina , Bhattarai Nisha , Herndon David N , Porter Craig , Finnerty Celeste C 
Published: November 2023

Hypermetabolism, hypercatabolism, inflammation, and muscle wasting are all key characteristics of the pathophysiological response to severe burn injury. Severe burn injury also induces an exaggerated and prolonged release of catecholamines. These catecholamines include norepinephrine and epinephrine, which activate β‐adrenergic receptors (β‐ARs). The over‐activation of β‐ARs leads to increased resting heart rate and cardiac work, which is associated with morbidity and increased risk of mortality. We have previously shown that severe burn injury causes mitochondrial dysfunction in skeletal muscle, which persists for more than a year after injury. We hypothesized that cardiac mitochondrial function would also be altered by burn injury.We tested this hypothesis using a rat model of 60% of total body surface area scald burn. Hearts were excised at three days and seven days post‐burn. Mitochondrial respiration was determined in saponin‐permeabilized myofiber bundles. Statistical analysis was performed by one‐way ANOVA followed by Tukey's post‐hoc test. Significance was accepted at p<0.05.Respiration coupled to ATP production was significantly decreased at 3 days post‐burn compared to both the control and 7 days post‐burn groups (control: 194±35 pmol/s/mg; 3 days: 104±53 pmol/s/mg; 7 days: 164±40 pmol/s/mg; p=0.003). The respiratory control ratio for ADP was also significantly decreased 3 days post‐burn but was comparable to controls by 7 days post‐burn (control: 2.79±0.50; 3 days: 1.76±0.57; 7 days: 2.46±0.37; p=0.004). However, the flux control ratio was significantly higher 3 days post‐burn compared to the other groups (control: 0.85±0.06; 3 days: 1.01±0.15; 7days: 0.84±0.05; p=0.009).Our data verifies that severe burn injury has a significant impact on cardiac mitochondrial function. Respiratory control and thus capacity for ATP production is lost at 3 days post burn. Interestingly, these effects appear temporal.Support or Funding InformationThis study was supported by grants from the National Institutes of Health (P50‐GM60338, R01GM056687, R01GM112936), Shriners Hospitals for Children (80100, 84291, 80500, 84202, 84090, 85410,87300), and the ‘Remembering the 15’ Research Education Endowment Fund.
Identity and Function of a Cardiac Mitochondrial Small Conductance Ca2+‐Activated K+ Channel Splice variant
Authors: Yang Meiying , Camara Amadou K.S. , Kwok Wai‐Meng , Aldakkak Mohammed , Stowe David F 
Published: November 2023

Small conductance Ca2+‐activated K+ channels (SKCa) have three isoforms, SK1, 2 and 3, with small unit conductance of 3–30 pS; Ca2+ binding to calmodulin initiates opening of SKCa channels. SKCa channel activator DCEBIO protects against ischemia and reperfusion (IR) injury in isolated hearts but protection is abolished by reactive O2 species scavenger MnTBAP, indicating SKCa channels play an important role in mitochondrial function during IR injury. Here we provide further evidence by showing that: SKCa channel opening via i.v. infusion in intact rats reduces regional infarct size induced by coronary artery occlusion and reperfusion; agonists of SKCa channels improve mitochondrial respiration after IR injury; and CaCl2 applied to isolated mitochondria (m) increases K+ influx. Moreover, we confirm the presence of mSKCa isoform 3 (mSK3) in heart mitochondria of guinea pig, rat and human using Western blotting of inner mitochondrial membrane proteins, immunocytochemical staining of cardiomyocytes, and immunogold labeling of isolated mitochondria. We identify mSK3 splice variants in guinea pig (SK3.1, aka SK3a) and human ventricular cells (SK3.2). Overexpression of full length, N‐terminal truncated and C‐terminal truncated guinea pig SK3.1 in HL‐1 cells demonstrated that N‐terminus is not required for mitochondrial trafficking but the C‐terminus beyond the Ca2+ calmodulin binding domain is required for Ca2+ sensing to induce mK+ influx and to promote mitochondrial localization. Silencing of SK3.1 with siRNA in HL‐1 cells induced a greater fall in membrane potential (DYm), and enhanced cell death with simulated IR injury. Together, these molecular and physiological experiments support the presence of, and a prominent role for, SKCa channel splice variants in mitochondria that afford cardiac protection against oxidative stress injury.Support or Funding InformationThis research study was supported in part by the Veterans Administration (BX‐002539‐01) and the National Institutes of Health (R01 HL089514 and P01‐GM066730).
Stress‐induced Nitration of the Voltage‐Dependent Anion Channel and its Dissociation from Hexokinase and Adenine Nucleotide Translocase: Implications in Cardiac Injury
Authors: Yang Meiying , Camara Amadou KS , Kwok Wai‐Meng , Stowe David F 
Published: November 2023

The voltage‐dependent anion channel (VDAC1) is the main conduit for transport of metabolites, substrates, and ions across the outer membrane of mitochondria (OMM). It is also a receptor for pro‐ and anti‐apoptotic proteins. Thus, as a channel and a receptor, VDAC1 plays key roles in modulating mitochondrial function and determining cell fate. We have previously reported on the nitration of VDAC1 following cardiac ischemia‐reperfusion injury. In the current study, we identified and investigated the impact of specific stress‐induced VDAC1 nitrated tyrosine residues on cell survival, and the consequence of stress on VDAC1 association with hexokinase II (HKII), an anti‐apoptotic protein, and with the adenine nucleotide translocase (ANT1) on the inner mitochondrial membrane. Proteomic analysis by LC‐MS/MS using an LQT Orbitrap Velos analyzer identified tyrosine nitration of Y62, Y67 and Y225 on VDAC1 enriched from mitochondria that were isolated from guinea pig hearts subjected to 35 min ischemia + 20 min reperfusion (IR). Transient overexpression of VDAC1 mutants (where tyrosine was substituted by phenylalanine to prevent nitration) in HL‐1 cells revealed that Y225F did not protect against hypoxia‐reoxygenation as measured by LDH release. In contrast, a double mutant of Y62F+Y67F significantly reduced LDH release, indicative of cytoprotection against hypoxia‐reoxygenation. Furthermore, mitochondria isolated from hearts exposed to the IR protocol showed reduced association of VDAC1 and ANT1, as determined by immuno‐precipitation. In another set of experiments, isolated mitochondria that were exposed to peroxynitrite (ONOO−) resulted in decreased association of VDAC1 with HKII. ONOO− treatment also led to an increase in cytochrome c release, which was attenuated by DIDS, a putative VDAC blocker. Our results show that nitration of specific tyrosine residues leads to cell death. Furthermore, stress induced dissociation of VDAC1 from ANT1 can potentially result in the derangement of metabolite transport and the inability of mitochondria to efficiently deliver ATP under pathophysiological conditions. Dissociation of HKII from VDAC1 would also promote cell death. These events are also associated with an increase in OMM permeability via VDAC1. Thus, stress‐induced nitration of VDAC1 likely impairs metabolite transport and promotes dissociation of proteins from VDAC1 that are key to cell function and survival.Support or Funding InformationThis study was supported in part by the Veterans Administration (BX‐002539‐01) and the National Institutes of Health (R01 HL089514 and P01‐GM066730).
Testing the Potential for Nitric Oxide Treatment to Prevent Disuse Atrophy in Muscle During Suspension
Authors: Anderson Judy E , Zhu Antonia , Craig Paige , Letourneau Lucien 
Published: November 2023

Disuse atrophy in muscle is progressively debilitating in obesity and exacerbates age‐related atrophy. Effective treatment is challenging in both conditions, and prevention is the best approach to avoiding progressive weakness. Since a nitric‐oxide (NO) stimulus activates muscle stem cells, we tested the hypothesis that treatment with a NO‐donor drug, isosorbide dinitrate (ISDN), during hind limb suspension for 18 days, can alleviate muscle atrophy (UM protocol F11‐029). Muscles in unloaded lower and weight‐bearing upper limbs were weighed to study muscle loss. Western blots were used to measure protein levels in experimental (suspended, ISDN‐suspended) and age‐matched control groups of young (3wk) and young‐adult (6–8wk) mice. Protein levels of atrogin‐1, myostatin, and myosin heavy chain isoforms (MyHCs) were analyzed (relative to beta‐actin) for changes expected with muscle atrophy. Analysis of variance was used to determine if changes were statistically significant. Unloaded muscles (quadriceps and soleus) in suspended mice showed atrophy compared to control. In ISDN‐suspended mice, the weight of these 2 muscles tended to increase toward control. In the unloaded quadriceps of suspended mice, ISDN significantly decreased atrogin‐1, a negative regulator of muscle mass (p<0.05) and myostatin precursor, an inhibitor of myogenesis (p<0.05). ISDN also increased the levels of MyHC‐1 and MyHC‐2b in unloaded muscles of suspended young‐adult mice compared to the untreated suspended group. There were no changes in vascular density in quadriceps or pectoralis major as a result of suspension or ISDN treatment, although density was higher in the 6–8 wk than the 3wk group (p<0.05). Suspension resulted in fatty‐liver changes in the 6–8wk group, and ISDN treatment significantly attenuated that increase (p<0.05). Results suggest that NO treatment has the potential to attenuate muscle‐disuse atrophy, with possible significance to preventing atrophy during aging or space travel.Support or Funding InformationSupported by the University of Manitoba Research Grant Program (JEA) and NSERC Undergraduate Student Research Award (AZ)