bluuebunny/crossref_metadata_2025_split huggingface dataset:
α1A‐Subtype Adrenergic Agonist Therapy for Failing Right Ventricle
Authors: Cowley Patrick M , Wang Guanying , Swigart Philip M , Lovett David H , Simpson Paul C , Baker Anthony J 
Published: November 2023

Experimental and clinical evidence suggests that signaling by α1‐adrenergic receptors (α1‐ARs) is increased in heart failure and that this increase is beneficial. In a mouse model of failing right ventricle (RV) we found that the α1‐AR inotropic (contractile) response was increased. Of the two predominant α1‐AR subtypes on cardiac myocytes (α1A and α1B), we found that the increased inotropic response was mediated solely by the α1A‐subtype. Our recent studies find that in a mouse model of RV failure, chronic stimulation of the α1A‐subtype with the selective agonist A61603 has multiple beneficial effects, including decreased necrosis, and increased myofilament force. The mechanisms for these beneficial effects are unknown.GoalDetermine the mechanisms for the beneficial effects of chronic α1A‐subtype stimulation on the failing RV.MethodsWe used a mouse model of RV failure induced by tracheal instillation of the fibrogenic antibiotic bleomycin to cause pulmonary fibrosis, pulmonary hypertension, and RV failure within 2 wk. Mice were treated concurrently using osmotic mini‐pump chronic infusion of a low dose of A61603 (10ng/kg/day) or saline (control).ResultsCompared to non‐failing RV, the bleomycin model of RV failure resulted in decreased RV fractional shortening in‐vivo, increased cardiac fibrosis, increased serum levels of cardiac TnI, and decreased contraction strength of cardiac myofilaments. These changes were abolished by chronic treatment with A61603. Compared to non‐failing RV, the bleomycin model of RV failure was associated with increased levels of the oxidative‐stress mediated protein adduct 4‐HNE (4‐Hydroxynonenal), and increased levels of the oxidant‐producing enzyme NOX‐2. These changes were abolished by chronic treatment with A61603. Moreover, chronic treatment with A61603 increased the level of the endogenous antioxidant superoxide disumutase‐1 (SOD1). Oxidative stress is known to activate transcription of matrixmetalloproteinase‐2 (MMP‐2) that can result in both extracellular and intracellular dysfunctional remodeling. Levels of MMP‐2 were increased in the bleomycin model of RV failure, and this increase was abolished by chronic treatment with A61603, which may have contributed to better preservation of myofilament integrity and force production with A61603 treatment.Summary and ConclusionsChronic treatment of failing RV with A61603 reduces oxidative stress injury, possibly by reducing oxidant production and increasing antioxidant SOD1 levels. Reduced oxidative stress due to chronic A61603 treatment may result in decreased oxidative‐stress‐activation of MMP‐2, leading to decreased dysfunctional remodeling. Stimulation of the α1A‐subtype is a novel therapy for RV failure.Support or Funding InformationThis work was supported by Department of Veterans Affairs Merit Review Awards I01BX000740 (AJB), I01BX001970 (PCS), National Heart, Lung and Blood Institute Grant HL31113 (PCS) and the American Heart Association (AJB)
Indices of autophagy are unaltered by quercetin consumption in hearts of Mdx/Utrn+/− mice
Authors: Quindry John C , Quindry Tiffany S , Ballmann Christopher G , Selsby Joshua T 
Published: November 2023

A significant percentage of Duchenne muscular dystrophy (DMD) is associated with progressive cardiac damage and heart failure. The extent to which autophagy is altered in the dystrophic myocardium with advanced disease is unknown. DMD countermeasures, and prevention of resultant cardiomyopathy, may correct disease‐related autophagic dysfunction. Using mouse models, our lab has demonstrated previously that long‐term consumption of the flavonol quercetin benefits physiologic, biochemical, and histological outcomes in dystrophic hearts. The purpose of this investigation was to determine the extent to which 1) autophagy is dysregulated in dystrophic hearts with advanced disease, and 2) whether indices of autophagic dysfunction are corrected by oral quercetin administration. Hearts harvested from untreated 10‐month old C57, Mdx/Utro+/‐ (heterozygous for a utrophin knockout), and Mdx/Utro+/− treated with a 0.2% quercetin enriched diet from 2–10 months of age. In these hearts we have previously reported widespread dystrophic injury that was largely corrected by the quercetin intervention. Using a western blot approach, dependent measures included relative abundance of key autophagic markers including Atg5, Atg7, beclin‐1, LC3II/I, and p62. Results indicate that Atg5 (p=0.779), Atg7 (p=0.895), beclin‐1 (p=0.251), and p62 (p=0.064) were similar between groups. The LC3II/I ratio was similarly unaffected by 8 months of quercetin treatment, although a strain‐dependent effect (p=0.038) was observed with Mdx/Utrn+/−Q and Mdx/Utrn+/− being 44% and 56% lower than C57, respectively. Based on these preliminary findings, disease‐related injury is independent of changes in autophagic signaling. Moreover, quercetin‐mediated protection appears to be unrealated to alterations to the autophagic process. Additional metrics of autophagic flux and examination using other animal models are needed to confirm the current findings.Support or Funding InformationFunded by: Duchenne Alliance and its member foundations
Ammonia Promotes Endothelial Cell Survival via the Heme Oxygenase‐1‐Mediated Release of Carbon Monoxide
Authors: Durante William , Liu Xiao‐ming , Peyton Kelly J. 
Published: November 2023

Although endothelial cells (ECs) produce substantial amounts of ammonia (NH3) during cell metabolism, the physiologic role of this gas in these cells is not known. In this study, we investigated if NH3 regulates the expression of heme oxygenase‐1 (HO‐1), and if this enzyme influences the biological actions of NH3 on ECs. Exogenously administered NH3, given as ammonium chloride or ammonium hydroxide, or endogenously generated NH3 stimulated HO‐1 protein expression in cultured human and murine ECs. Dietary supplementation of NH3 also increased HO‐1 expression in mouse arteries. The induction of HO‐1 protein by NH3 in ECs was associated with an elevation in HO‐1 mRNA, enhanced production of reactive oxygen species (ROS), and increased expression and activity of the transcription factor Nrf2. NH3 also activated the HO‐1 promoter and this was blocked by mutating the antioxidant responsive elements of the promoter, or by overexpressing dominant‐negative Nrf2. The induction of HO‐1 by NH3 was dependent on ROS formation and prevented by N‐acetyl‐L‐cysteine or rotenone. Significantly, prior treatment of ECs with NH3 inhibited tumor necrosis factor‐α‐mediated cell death. However, silencing HO‐1 expression abrogated the protective action of NH3, and this was reversed by the administration of carbon monoxide (CO) but not bilirubin or iron. In conclusion, this study demonstrates that NH3 stimulates the expression of HO‐1 via the ROS‐Nrf2 pathway, and that the induction of HO‐1 contributes to the cytoprotective action of NH3 by generating CO. Moreover it identifies NH3 as a novel modulator of EC survival and reveals new critical regulatory and functional interactions between signaling gases in the vasculature.Support or Funding InformationSupported by grants from the NIH (R01HL59976) and AHA (15GRNT25250015).
Neuroprotective Effect of Low Dose Alcohol Consumption Against Transient Focal Cerebral Ischemia
Authors: McCarter Kimberly DeShon , Sun Hong , Li Chun 
Published: November 2023

BackgroundIschemic stroke, which accounts for 87% of diagnosed strokes, is a leading cause of long‐term disability and mortality worldwide. Chronic alcohol abuse is a risk factor for ischemic stroke and worsens the prognosis of ischemic stroke. On the other hand, increasing evidence suggest that chronic low‐dose alcohol consumption (LAC) reduces the incidence of ischemic stroke and improves the functional outcome of ischemic stroke. Our goal is to delineate the molecular basis whereby LAC alters the incidence and prognosis of ischemic stroke. We hypothesize that LAC protects the brain against its ischemia/reperfusion (I/R) injury by suppressing postischemic inflammation.MethodsMale Sprague‐Dawley rats were divided into 3 groups, an ethanol group, a wine group, and a control group and fed with ethanol, wine (Castle Rock Pinot Noir), or volume‐matched water via gavage for 8 weeks. Ethanol and wine consumption was 1.4g/kg/day. The animals were then subjected to a 2‐hour middle cerebral artery occlusion (MCAO) and sacrificed at 24 hours of reperfusion after neurological evaluation. Cerebral I/R injury, microglial activation and neutrophil infiltration were evaluated by TTC staining and immunohistochemical staining, respectively. Expression of adhesion molecules were analyzed using western blot analysis. Pro‐inflammatory molecules were measured using ELISA.ResultsCerebral infarct volume is significantly reduced in ethanol‐ and wine‐fed rats compared to control rats. There is no significant difference in infarct volume between ethanol‐fed and wine‐fed rats. Sensory‐motor functions were significantly improved in ethanol‐fed rats when compared to control rats. Transient focal cerebral ischemia increased neutrophil infiltration, microglial activation and the expression of adhesion molecules such as intercellular adhesion molecule (ICAM), vascular cellular adhesion molecule (VCAM), E‐selectin and P‐selectin. However, the magnitude of microglial activation and ICAM and E‐selectin expression was significantly reduced in ethanol‐fed rats while neutrophil infiltration and the magnitude of the increased expression of P‐selectin were significantly reduced in wine‐fed rats when compared to control rats. VCAM expression after ischemia was significantly increased in ethanol fed rats when compared to control rats.ConclusionsOur findings suggest that LAC may protect the brain against its I/R injury by suppressing postischemic inflammation.Support or Funding InformationNational Institute of Health Grant; Malcolm Feist PreDoctoral Award (Center for Cardiovascular Diseases, LSU Health Sciences Shreveport)
The Protective Role of NHERF1 in Cisplatin‐Induced Acute Kidney Injury
Authors: Bushau‐Sprinkle Adrienne M , Sherwood Amanda R , Conklin Caryl A , Barati Michelle T , Dupre Tess , Siskind Leah , Gagnon Kenneth B , Khundmiri Syed J , Lederer Eleanor D 
Published: November 2023

Acute kidney injury (AKI), an abrupt loss of kidney function which carries a high mortality and confers an increased risk of chronic kidney disease, develops in 30% of patients who receive cisplatin, a widely used and potent chemotherapeutic agent. The sodium hydrogen regulatory factor isoform 1 (NHERF1) is a scaffolding protein that anchors multiple membrane proteins, including the sodium‐phosphate cotransporter (NPT2a) in renal proximal tubules. NHERF1‐deficient proximal tubule cells show slower growth, abnormal transport properties, and aberrant localization of BBM proteins in intracellular compartments. We hypothesize that NHERF1‐deficiency increases susceptibility to AKI through a well‐defined cellular response to conditions of metabolic stress. To test this hypothesis, we used the Opossum kidney (OK) proximal tubule cell line and their NHERF1‐deficient (OKH) cells maintained in minimal essential medium supplemented with 10% FBS and 1% Pen/Strep in humidified 95% O2/5% CO2 incubator. Activated PERK and GRP78 was measured by WB to determine the presence of ER stress. We also used the in vivo model of cisplatin‐induced AKI in C57BL/6 wild type (WT) and NHERF1 knock out (NHERF1‐KO) mice. Male and female WT and NHERF1‐KO mice were treated with vehicle or cisplatin (20 mg/kg dose IP) to induce AKI. After 72 hours, blood samples were collected from these mice to measure blood urea nitrogen (BUN) levels and were sacrificed. The kidneys were analyzed by immunohistochemistry. Hematoxylin and eosin and periodic acid‐schiff staining of the kidney cortex of cisplatin‐treated NHERF1‐KO mice showed greater proximal tubular injury manifested by BBM sloughing, tubular cell detachment and vacuolization. Statistically significant differences were observed in blood urea nitrogen (BUN) levels between cisplatin‐treated WT and NHERF1‐KO male mice (p<0.01) (n= 6/group). NHERF1‐KO mice (n=2/group) treated with cisplatin also demonstrated decreased expression of GRP78, a pro‐survival ER chaperone that is upregulated during ER stress. Female cisplatin‐treated NHERF1‐KO mice (n=2/group) show a decrease in expression of p‐eIF2α/eIF2α total, a translation initiation factor that is phosphorylated in times of ER stress, when compared to male cisplatin‐treated NHERF1‐KO mice. We also observed an increased p‐PERK activity (an eIF2α kinase) in OKH to OK cells. We conclude that NHERF1‐deficiency is associated with an underlying ER stress which in turn may confer enhanced susceptibility to cisplatin‐induced AKI.Support or Funding InformationFunding for this research was provided by Robley Rex Veterans Affairs Medical Center and University of Louisville School of Medicine (to EDL).
The host engulfment pathway in enteroids is linked to intestinal inflammation following bacterial infection
Authors: Das Soumita , Lim Eileen , Suarez Katherine , Ernst Peter B , Barrett Kim E 
Published: November 2023

Intestinal homeostasis is maintained through regulated interactions between epithelial cells, innate immune cells and the microbiota. The immune homeostasis is lost following interaction of the host with enteric pathogens that generate inflammation. Microbes are recognized by specific receptors such as Pattern Recognition Receptors (PRRs). PRRs can bind pathogens as well as commensals, but in most cases inflammation is generated only from pathogenic encounters. Previously, we identified Brain Angiogenesis Inhibitor 1 (BAI1) as a PRR that recognizes bacterial lipopolysaccharide (LPS). BAI1 binds Engulfment and Cell Motility Protein‐1 (ELMO1), which facilitates the engulfment of bacteria by host cells. We have shown that ELMO1 in phagocytes regulates the entry of bacteria and subsequent intestinal inflammation. Cytokine arrays and ELISA showed reduced release of pro‐inflammatory cytokines, including TNF‐α, monocyte chemoattractant protein (MCP‐1) and IL‐1β, from ELMO1‐depleted macrophages. Interestingly, higher expression of ELMO1 in biopsy specimens from inflammatory bowel disease patients correlates with the expression of MCP‐1 and TNF‐a. We developed enteroid‐derived monolayers (EDMs) that mimic the architecture and cell populations of the in‐vivo intestinal epithelium. Here we show that human as well as murine enteroids express ELMO1. We used Salmonella as well as adherent‐invasive E. coli as enteric pathogens. We found a significant reduction of bacterial internalization and pro‐inflammatory cytokines in EDMs generated from ELMO1 knockout mice compared to WT mice. EDMs infected with enteric bacteria generate MCP‐1 in an ELMO1‐dependent manner that attracts monocyte at the site of inflammation. The expression of MCP‐1 is higher in several inflammatory diseases including the atherosclerosis and inflammatory bowel diseases. Therefore, elevated expression of MCP‐1 via ELMO1 may be an early biomarker in inflammatory diseases. Our work also uncovers a central role of ELMO1 in the induction of inflammatory cytokines in non‐phagocytic cells.Support or Funding InformationUCSD, Academic Senate (Das), NIH‐NIDDK R01 (Das)Clinical and Transitional Research Institute/NIH‐NCATS (Das)
The Effects of Conjugated Linoleic Acid and Berberine Supplementation on Markers of Oxidative Stress in Broiler Chickens
Authors: Dartigue Vincent , Klandorf Hillar , Falkenstein Elizabeth , Barnes Kimberly , Van Dyke Knox 
Published: November 2023

Reactive oxidative species (ROS) are oxygen base molecules that are leaked from the electron transport chain during mitochondrial cellular respiration. They are kept in balance by endogenous and exogenous antioxidants, which may include conjugated linoleic acid (CLA) and a plant root extract called berberine. A redox shift towards oxidants causes a state called oxidative stress, which is detrimental if prolonged. A ten week study examined the effect CLA and berberine supplementation on markers of oxidative stress in broiler birds. Broilers (n=60) were divided into six groups; the diet of group four to six included allopurinol (25mg/kg body weight) which induced an oxidative stress state. Pen 1(P1) served as the control, P2 CLA oil (50% substitution), P3 berberine supplementation (20g/kg feed), P4 allopurinol alone, P5 CLA oil + allopurinol and P6 berberine + allopurinol. Body weight, plasma uric acid as a marker of oxidative stress, blood glucose, lipid peroxidation via TBARs assay of serum, and relative gene expression of five endogenous liver antioxidants were measured during the course of the study. The addition of allopurinol to the diet induced an oxidative stress state when compared to the baseline groups as observed by a significant reduction in plasma uric acid. In P5 and P6 treatment we observed on average a 10 fold increase in the relative mRNA expression of superoxide dismutase 2 and 3 as well as glutathione 3 and 7. Notably, CLA increased the expression of uncoupling protein 34 fold compared to control while the addition of allopurinol blocked these changes; in contrast there was a slight increase in the berberine+allopurinol treatment. No significant changes were measured in blood glucose and TBARS. Despite the increase in mRNA expression of the antioxidants genes, the result of the uric acids assay suggest that at the dosages administered CLA and berberine were not effective in reversing the oxidative stress induced by allopurinol.Support or Funding InformationWVU Hatch
Nicorandil reduces lipoperoxidation in stimulated and non‐stimulated atrophied muscle
Authors: Sanchez‐Perez Alina , Padilla‐Maldonado Paulina , Sanchez‐Duarte Elizabeth , Cortes‐Rojo Christian , Saavedra‐Molina Alfredo , Gomez‐Barroso Mariana , Montoya‐Perez Rocio 
Published: November 2023

Muscle atrophy is characterized by a reduction of muscle mass through protein degradation resulting in a reduction of strength development. There is evidence that the opening of the ATP sensitive potassium channels (KATP) causes a protective effect in muscle against deterioration. Thus, the aim of the present study was to explore the effect of nicorandil on lipoperoxidation in stimulated and non‐stimulated atrophied muscle. C57BL/6 male mice 14–16 weeks‐old were used for the experimental basis; these animals were separated in 4 groups: 1) Control, 2) Nicorandil, 3) Atrophy and 4) Atrophy treated with Nicorandil. Atrophy was induced by hindlimb unloading by the tail method. Nicorandil was purveying in 40 mg/kg by intramuscular injection during 14 days. Once finished the treatment, the animals were sacrificed by cervical dislocation and the hindlimb were used lipoperoxidation measurement. In the stimulated muscles, a decrease in membrane damage in the group treated with nicorandil was observed 47.3% (0.157 ± 0.0124 nmol/mg prot), the damage increased to 256.3% (0.85 ± 0.0327 nmol/mg prot) during atrophy; reducing this levels to 128% (0.426 ± 0.0299 nmol/mg prot) in atrophied treated with nicorandil. In non‐stimulated muscles, there was a decrease in membrane damage 56.1% (0.184 ± 0.0.0025 nmol/mg prot) in the group treated with nicorandil, after which the damage increased to 247% (0.81 ± 0.0.0047 nmol/mg prot) during atrophy and decreased to 119.5% (0.392 ± 0.0097 nmol/mg prot). The results suggest that nicorandil decreases lipoperoxidation in stimulated and non‐stimulated soleus muscle during muscle possible through the opening of the ATP sensitive potassium channel.Support or Funding InformationWe thank Universidad Michoacana de San Nicolás de Hidalgo (UMSNH). We acknowledge the partial financing to Coordinación de la Investigación Científica of UMSNH: CCR‐CIC1821440; ASM‐CIC‐2.16; RMP‐CIC 182171.
Chronic Electronic Cigarette Vapor Inhalation Induces Renal Injury and Functional Decline in Female Mice
Authors: Drummond Christopher , Alexander Laura E Crotty , Tian Jiang 
Published: November 2023

Clinical studies indicate that combustible cigarette smoke increases renal and cardiac tissue injury progression and functional decline in the setting of chronic kidney disease (CKD). Novel nicotine delivery devices like electronic (e)‐cigarettes are used by over 10% of the population and produce vapor which may also induce renal injury. To establish whether e‐cigarette vapor inhalation induced renal injury in the form of fibrosis and decreased renal injury our current study utilized a nose‐only inhalation exposure system to induce 8 week‐old female mice to inhale e‐cigarette vapor containing 24mg/mL of nicotine suspended in a solution of 50% propylene glycol and 50% vegetable glycerin using the following parameters: 12 seconds of vapor exposure every 60 seconds for 60 minutes five days per week for 1‐, 3‐ and 6‐months. Following e‐cigarette exposure, assessment of renal fibrosis, glomerular filtration rate, and expression of the antifibrotic microRNA miR‐29b‐3p were evaluated. Mice exposed to e‐cigarette vapor suffered a 31% decline in renal tissue expression of miR‐29b‐3p vs air‐exposed controls (p<0.05). Additionally, mRNA targets of miR‐29b‐3p that regulate fibrosis formation or are part of fibrosis were also significantly increased in the kidneys of e‐cigarette exposed mice versus air controls, i.e., Collagen 1A1 (increased 98%; p<0.05); Collagen 3A1 (129% increase; p<0.05); Collagen 4a1 (72% increase; p<0.05); Integrin beta 1 (58% increase; p<0.05); and Fibrillin 1 (100% increase; p<0.05). Additionally, we observed a significant increase in renal fibrosis at the 3‐ and 6‐month time points as assessed by Trichrome staining in these animals. Lastly, following 3‐months of exposure to e‐cigarette vapor renal function was significantly reduced by 21% versus air exposed controls (p=0.017). These data are the first to indicate that e‐cigarettes induce renal fibrosis and functional decline. In addition, these data suggest a novel miR‐29b‐3p mediated mechanism linking e‐cigarette vapor exposure and renal injury and functional decline.Support or Funding InformationThis work was supported by the National Institutes of Health (1F32DK104615‐01 to CAD and HL‐105649 to JT. Additional support was from a Veterans Affairs BLR&D Career Development Award (1IK2BX001313 to LCA), AHA Beginning Grant‐in‐aid (16BGIA27790079 to LCA), and O'Brien Center Daniel O'Connor Memorial Pilot Award to LCA. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.