bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cardioprotective Effects of the Ethanol Leaf Extract of Andrographis Paniculata in Isoproterenol‐induced Myocardial Infarction in Rats
Authors: Adedapo Adeolu Alex , Adeoye Bisi Olajumoke , Oyagbemi Ademola Adetokunbo , Omobowale Temidayo Olutayo , Yakubu Momoh Audu 
Published: November 2023

Andrographis paniculata commonly known as king of bitters is an annual ‐ branched, erect ‐ running 1/2 to 1 meter in height. The aerial parts of the plant (leaves and stems) are used to extract the active phytochemicals. It grows abundantly in south eastern Asia: India (and Sri Lanka), Pakistan and Indonesia ‐ but it is cultivated extensively in China and Thailand, the East and West Indies, and Mauritius. Modern pharmacological studies have demonstrated its hepatoprotective, antithrombotic, anti‐inflammatory, immunostimulant, antimalarial, antihyperglycemic and cardioprotective properties. Because of its well‐known medicinal properties, this study was designed to evaluate the cardioprotective effect of the Nigerian species of Andrographis paniculata (AP) ethanol leaf extracts in isoproterenol‐induced myocardial infarction in rats using electrocardiogram, blood pressure changes as well as anti‐oxidant status.Male rats were randomly divided into 7 groups of 7 animals per group. While group A served as control, group B was administered with Isoproterenol (ISO), group C was administered with Enalapril (10 mg/kg), but groups D, E and F were pretreated respectively with EEAP in three different doses (100, 200 and 400 mg/kg) orally for 7 days and group G was administered with 200 mg/kg EEAP post treatment with ISO. Myocardial infarction was induced intraperitoneally (i.p.) using isoproterenol (85 mg/kg) at interval of 24 h on 8th & 9th day in pretreated groups while on 1st & 2nd day in post treated group. The electrocardiogram, heart rate and blood pressure measurements were carried out on the 10th day in all groups and all animals were sacrificed afterwards and heart tissues were collected, homogenized, and centrifuged for anti‐oxidant studies.ISO injection (85 mg/kg i.p.) produced changes in ECG pattern including prolonged QT interval and notches. ISO injection also produced a significant decrease in SAP, DAP and MAP levels. Although the extract did not amend the changes in ECG to normal but significantly increased the hemodynamics parameters. The extract increased antioxidant enzymes (SOD, GPX, GST, and GSH) and reduced oxidative stress markers (MDA using lipid peroxidation, H2O2, PT and NPT).It could be concluded that the ethanol leaf extract of Andrographis paniculata exhibited cardioprotective effect in rats showing potent anti‐oxidant properties as well as improving the haemodynamic changes in the rats. This cardioprotective effect was similar to that of enalapril, an ACE inhibitor used in this study.Support or Funding InformationNational Research Foundation of the Tertiary Research Fund, Nigeria.
Heme oxygenase byproducts variably influences myocardial and autonomic dysfunctions induced by the cyclosporine/diclofenac regimen in female rats
Authors: Ibrahim Karim S , El‐Yazbi Ahmed F , El‐Gowelli Hanan M , El‐Mas Mahmoud M 
Published: November 2023

We recently reported that simultaneous exposure to cyclosporine (CSA) and diclofenac (DIC) causes hypertension and left ventricular (LV) and arterial baroreceptor dysfunction in conscious female rats. In this study we tested the hypothesis that these CSA effects could be mitigated by facilitated heme oxygenase (HO) signaling. Experiments were performed in female rats to assess the effects of 10‐day treatment with the CSA (25 mg/kg/day)/diclofenac (1 mg/kg/day) regimen on cardiovascular functions in the absence and presence of pharmacologic maneuvers that upregulate HO or its enzymatic products. The hypertensive effect of CSA/DIC and associated shift in cardiac sympathovagal balance towards parasympathetic dominance (i.e. reduced low‐frequency/high‐frequency spectral ratio) were blunted upon concurrent treatment with hemin (HO‐1 inducer), tricarbonyldichlororuthenium (II) dimer (CORM‐2, carbon monoxide‐releasing molecule), or bilirubin. Whereas none of the latter treatments affected the CSA/DIC‐evoked decreases in the isovolumic relaxation constant (Tau, τ, a measure of cardiac diastolic function), the increases in LV contractility (dP/dtmax) in CSA/DIC‐treated rats were abolished by bilirubin only. Further, measurement of arterial baroreflex activity by the vasoactive method showed that bilirubin reversed the attenuated reflex bradycardia in contrast to no effect for hemin or CORM‐2. Paradoxically, the attenuated reflex tachycardia caused by CSA/DIC treatment was improved in presence of hemin and CORM‐2, but not bilirubin. All the favorable effects of hemin disappeared in rats treated simultaneously with the NOS inhibitor L‐NAME. These finding highlights key and NOS‐dependent modulatory roles for HO and the products of its enzymatic activity in improving the worsened cardiovascular profile in CSA/DIC‐treated female rats.Support or Funding InformationSupported by the ALEX‐REP Grant Fund, Alexandria University, Egypt (Grant HLTH‐13‐01).
High Fat Feeding in Rats Alters Respiratory Parameters by a Mechanism that is Unlikely to be Mediated by Carotid Body Type I Cells
Authors: Rakoczy Ryan , Pye Richard L , Fayyad Tariq H , Santin Joseph M , Barr Barbara L , Wyatt Christopher N 
Published: November 2023

The carotid bodies (CB), the primary peripheral chemoreceptors, respond to changes in blood gases with neurotransmitter release, thereby increasing carotid sinus nerve firing frequency and ultimately correcting the pattern of breathing. It has previously been demonstrated that acute application of the adipokine leptin caused perturbations of intracellular calcium and membrane ion movement in isolated CB Type I cells (Pye et al, 2015) and blunted the response of the intact CB to hypoxia (Pye et al, 2016). This study's aim was to examine, in‐vivo, if elevated leptin modulated CB function and breathing.Rats were fed high‐fat chow or control chow for 16‐weeks. High‐fat fed (HFF) animals gained significantly more weight compared to control fed (CF) animals (n=18; p<.001; 512.56 g ± 14.70 g vs. 444.11 g ± 7.09 g). HFF animals also had significantly higher serum leptin levels compared to CF (n=18; p<.0001; 3.05 ng/mL ± 0.24 ng/mL vs. 1.29 ng/mL ± 0.12 ng/mL). Whole‐body plethysmography was used to test the acute hypoxic ventilatory response (HVR) in unrestrained, conscious animals. HFF animals had an attenuated 2nd‐phase of the HVR when compared to CF (n=18; p<.05; 710.1 ± 41.9 mL kg−1 min−1 vs. 855.4 ± 44.05 mL kg−1 min−1). CB Type I cells were isolated and intracellular calcium measured; no significant differences in the cellular hypoxic responses between groups were observed.These data show differences in the 2nd‐phase of the HVR caused by high fat feeding are unlikely to be caused by an action of leptin on the Type I cells. However the possibility remains that leptin may have in‐vivo postsynaptic effects on the carotid sinus nerve; this remains to be investigated.Support or Funding InformationThis work was funded by NIH grant RO1HL091836
Actin Polymerization Contributes to Augmented Basal Pulmonary Arterial Tone and Endothelin‐1‐Induced Vasoconstriction Following Chronic Hypoxia
Authors: Cross Laura Weise , Sands Michelle A. , Sheak Joshua R. , Snow Jessica B. , Gonzalez Bosc Laura V. , Jernigan Nikki L. , Walker Benjimen R. , Resta Thomas C. 
Published: November 2023

Chronic hypoxia increases pulmonary vascular resistance and promotes pulmonary hypertension through mechanisms that stimulate vasoconstriction and vascular remodeling. We have previously shown that chronic hypoxia augments pulmonary vasoconstrictor reactivity to endothelin‐1 (ET‐1) through reactive oxygen species generation and Rho kinase (ROCK)‐dependent Ca2+ sensitization.Because ROCK promotes actin polymerization and the actin cytoskeleton is important for tension generation in smooth muscle, we hypothesized that actin polymerization is required for both basal pulmonary arterial tone and enhanced ET‐1 dependent vasoconstriction following chronic hypoxia. To test this hypothesis, we applied the actin polymerization inhibitors cytochalasin B (10−6 M) and latrunculin A (5 × 10−7 M) to isolated, endothelium‐disrupted pulmonary arteries from control and chronically hypoxic (4 wk at 0.5 atm) rats that were exposed to increasing intraluminal pressure, and we monitored the development of tone. Arteries from each group were also exposed to increasing concentrations of ET‐1 (10−10 – 10−7 M) in the presence and absence of cytochalasin B. Consistent with our hypothesis, inhibition of actin polymerization reduced pressure‐dependent tone and attenuated ET‐1‐induced vasoconstriction in arteries from chronically hypoxic animals, while having no effect on arteries from control rats.To test whether chronic hypoxia directly alters the actin profile in pulmonary arteries, we measured filamentous (F) actin to globular (G) actin ratios by two methods: fluorescent labeling of F‐actin and G‐actin in fixed pulmonary artery segments, and actin sedimentation assays on homogenized pulmonary artery lysates. Results from both sets of experiments indicated that there is no significant difference in actin polymerization between pulmonary arteries from control and chronically hypoxic rats under baseline conditions, but that ET‐1 (10−8 M) stimulation significantly enhances actin polymerization in pulmonary arteries from rats exposed to chronic hypoxia. We conclude that actin polymerization contributes to pulmonary vasoreactivity following chronic hypoxia, under both pressure‐induced and ET‐1 stimulated conditions, but enhanced levels of actin polymerization following chronic hypoxia are only detected after stimulation with ET‐1.Support or Funding InformationNIH R01 HL132883AHA 16GRNT27700010K12 GM088021AHA 15GRNT25090039
PKCβ Signals Through Mitochondrial Reactive Oxygen Species Production in Pulmonary Arterial Smooth Muscle Cells of Neonatal Rats
Authors: Sheak Joshua R. , Jernigan Nikki L. , Walker Benjimen R. , Resta Thomas C. 
Published: November 2023

Chronic hypoxia (CH)‐induced vasoconstriction has been implicated in the pathogenesis of pulmonary hypertension in infants with chronic cardiorespiratory disorders. Although mechanisms of pulmonary vasoconstriction resulting from neonatal CH are not well understood, preliminary studies from our group support a role for both PKCβ and reactive oxygen species (ROS) in this response. However, neither the signaling relationship between PKCβ and ROS nor the cellular source of ROS involved in this response has been previously addressed. Considering the importance of PKCβ in mitochondrial dysfunction and oxidative stress in neurodegenerative diseases, we hypothesized that PKCβ signals to induce mitochondrial ROS generation in neonatal pulmonary arterial smooth muscle cells. To test this hypothesis, we transiently cultured primary pulmonary arterial smooth muscle cells (PASMC) collected from neonatal normoxic control rats. The production of mitochondrial ROS was assessed using the mitochondrial selective fluorescent O2− indicator, mitoSOX (5 μM). We treated PASMC with PMA (10 μM), a phorbol ester known to activate PKC isoforms, including PKCβ, and observed PMA‐dependent increases in mitoSOX fluorescence that were prevented by selective PKCβ inhibition with LY‐333,531 (10 nM, p<0.05 vs. PMA alone, n=6 rats). Selectivity of mitoSOX for mitochondrial‐derived O2− was verified using the mitochondrial‐targeted O2− scavenger, mitoTEMPO (200 μM), which prevented PMA‐induced increases in mitoSOX fluorescence. Western blot analysis confirmed the expression of PKCβI and PKCβII splice variants in homogenates of isolated pulmonary arteries from neonatal normoxic control rats. We conclude that PKCβ stimulation leads to mitoROS production in PASMC from neonatal rats. Future studies are planned to evaluate the contribution of mitochondrial ROS to enhanced vasoconstrictor reactivity and associated pulmonary hypertension resulting from neonatal CH, and the cellular signaling mechanisms involved.Support or Funding InformationAwarded to Thomas C. Resta, PhD: NIH R01 HL132883 and AHA 16GRNT27700010. Awarded to Joshua R. Sheak: NIH F31 HL131334.
Regulation of Endothelial Cell Barrier Disruption in Acute Lung Injury by Autophagy
Authors: Spencer Spencer , Leonard Antony , Grose Valerie , Fazal Fabeha , Rahman Arshad 
Published: November 2023

Recent studies have implicated autophagy in many disorders including pulmonary diseases. However, the role of autophagy in endothelial cell (EC) barrier dysfunction and its relevance in the context of acute lung injury (ALI) remains uncertain. Here, we provide evidence that autophagy is a critical component of EC barrier disruption in ALI. Using an aerosolized bacterial lipopolysaccharide (LPS) inhalation mouse model of ALI, we found that administration of autophagy inhibitor 3‐methyladenine (3‐MA), either prophylactically or therapeutically, markedly reduced lung vascular leakage and tissue edema. Inhibiting autophagy by this approach also reduced the levels of proinflammatory mediators and lung neutrophil sequestration induced by LPS. To test the possibility that autophagy in EC could contribute to lung vascular injury, we addressed its role in the mechanism of EC barrier disruption. Pretreatment of cells with 3‐MA inhibited thrombin‐induced barrier disruption by inhibiting the cleavage and loss of VE‐cadherin at adherens junctions. 3‐MA was also effective in protecting against thrombin‐induced actin stress fiber formation. Together, these data reveal a novel role of autophagy in causing EC barrier dysfunction and lung microvascular permeability associated with ALI.Support or Funding InformationThis work was supported in part by National Heart, Lung, and Blood Institute Grants HL116632 and HL130870.
Methionine sulfoxide reductase as a neuroprotective mechanism in a model of anoxia tolerance: Trachemys scripta
Authors: Reiterer Melissa , Milton Sarah L. 
Published: November 2023

The damaging effects of oxidative stress caused by the accumulation of Reactive Oxygen Species (ROS) have been linked to several neurodegenerative diseases as well as aging and senescence. Mammals and especially humans are extremely susceptible to this damage as can be observed following an ischemic stroke when blood flow is restored and oxygen is reintroduced. ROS damage lipids, proteins, and DNA, and thus can induce further cell death beyond that caused by the ischemia. However, some organisms can withstand extended anoxia and reoxygenation without damage, including the freshwater turtle Trachemys scripta.To cope with potential oxidative stress, the freshwater turtle possesses high endogenous levels of antioxidants and can also inhibit ROS production. One potential antioxidant mechanism is the Methionine Sulfoxide Reductase System (Msr) that catalyzes the reduction of oxidized Methionine (Met) residues. Methionine residues are easily oxidized amino acids; oxidized Met is associated with decreased protein activity and Msr may restore function to damaged proteins; it has also been shown to scavenge ROS and thus ameliorates cellular damage.The present study investigated the role and regulation of MsrA in turtle neuronal cultures exposed to 4 hours of anoxia/4 hours of reoxygenation by altering the expression of MsrA. As FOXO3a has been shown to regulate MsrA levels in other animal models, we also induced its expression by transfecting a FOXO3a plasmid into the cells. We found that knock down of MsrA expression with target specific siRNA resulted in decreased cell viability; and induction of FOXO3a showed protection against cell death. Furthermore, treatment of cells with Epigallocatechin gallate (EGCG), an extract found in green tea that has antioxidant properties, results in increased expression of FOXO3a. These results suggest that MsrA may play an important role in protection against anoxia and oxidative stress in the turtle brain, and may prove to be a target to treat diseases of ischemia.Support or Funding InformationFlorida Atlantic University GRIP Grant (2015–2016)John Nambu Scholarship for Molecular Biology (FAU‐ 2016)Andrew Todd Auster Alumni Scholarship (FAU‐2016)
Comparative physiology of hypoxia tolerance in intertidal sculpins
Authors: Richards Jeffrey , Lau Gigi 
Published: November 2023

The goal of our work is to characterize the underlying factors that result in variation in hypoxia tolerance among organisms. At that heart of hypoxia tolerance is the ability to effectively acquire and utilized environmental oxygen at the mitochondria to sustain aerobic function even when exposed to oxygen limitations. In order to elucidate the factors that explains variation in hypoxia tolerance among organisms, we use a well‐described, phylogenetically informed comparative system involving several species of marine fish from the family Cottidae (sculpins) that show a strong habitat zonation along the near‐shore environment. Sculpins from the intertidal zone experience daily fluctuations in O2 with species located in the higher intertidal oscillating between ~0 to 400% air saturation and are hypoxia tolerant, whereas subtidal species rarely experience hypoxia and are not as hypoxia tolerant. These interspecific differences in hypoxia tolerance is reflected in modifications to various steps in the oxygen transport cascade, whereby hypoxia tolerant sculpins show higher gill surface area, better hemoglobin O2 binding affinity, and an overall lower oxygen consumption rate. In the present study, we focus on the mitochondria and the terminal protein of the oxygen transport cascade, cytochrome c oxidase (COX), to determine if oxygen use by the mitochondria differs among sculpin species that vary in hypoxia tolerance. Hypoxia tolerant species showed higher COX oxygen binding affinity (measured as a lower apparent Km for O2) in both brain and liver, and a higher overall COX capacity. In order to provide a mechanistic hypothesis to explain the putatively adaptive changes in COX Km for O2, we performed in silico protein analyses of the deduced amino acid sequence of the mitochondrial‐encoded COX3 subunit, which is postulated as the entry point for O2 and protons into the COX protein. Our analysis suggests that variation in two amino acid residues (positions 55 and 224) on COX3 may affect cardiolipin binding and O2 movement, thus contributing to the variation in COX Km for O2. As such, we provide evidence for adaptive variation in COX function across sculpins that vary in hypoxia tolerance.Support or Funding InformationThis work was funded by an NSERC Discovery Grant to Jeffrey Richards.
Metabolic Rate and Hypoxia Tolerance Are Effected by Group Interactions and Sex in the Fruit Fly (Drosophila melanogaster): New Data and a Meta‐Analysis
Authors: Burggren Warren , Souder BriAnna , Ho Dao 
Published: November 2023

Population density and associated behavioral adjustments are potentially important in regulating physiological performance in many animals. In r‐selected species like the fruit fly (Drosophila), where population density rapidly shifts in unpredictable and unstable environments, density‐dependent physiological adjustments may aid survival of individuals living in a social environment. Yet, how population density (and associated social behaviors) affects physiological functions like metabolism is poorly understood in insects. Additionally, insects often show marked sexual dimorphism (larger females). Thus, in this study on D. melanogaster, we characterized the effects of fly density and sex on both mass‐specific routine oxygen consumption (VO2) and hypoxia tolerance (PCrit). Females had significantly lower routine VO2 (~4 μl O2·mg−1·h−1) than males (~6 μl O2·mg−1·h−1) at an average fly density of 28 flies·respirometer chamber−1. However, VO2 was also inversely related to respirometer chamber fly density in males, with values ranging from 4 to 11 μl O2·mg−1·h−1 at a density of 10 and 40 flies·chamber−1, respectively (r2=0.58, P<0.001). Female flies showed a similar but less pronounced effect, with a VO2 of 4 and 7 μl O2·mg−1·h−1 at a density of 10 and 40 flies·chamber−1, respectively (r2=0.43, P<0.001). PCrit (~5.5 to 7.5 kPa) varied significantly with density in male (r2=0.50, P<0.01) but not female (r2=0.02, P>0.5) flies, with higher fly densities having lower PCrits. A meta‐analysis of ~30 metabolic studies on fruit flies revealed a similar inverse relationship between fly density and oxygen consumption. We conclude that future studies on insect metabolism should control for, and report on, both of these factors.Support or Funding InformationNational Science Foundation Grant IOS1543301
Oxytocin Receptors are expressed on Neurons within the Prefrontal Cortex that Control Preference for Social Novelty
Authors: Tan Yalun , Singhal Sarthak , Hiller Helmut , Nguyen Dan‐Tam , Colon‐Perez Luis M. , Febo Marcelo , Wang Lei , de Kloet Annette D. , Frazier Charles J. , Krause Eric G. 
Published: November 2023

Oxytocin is a promising therapeutic for social impairments associated with neuropsychiatric conditions; however, the precise brain circuits influenced by oxytocin remain unknown. The prefrontal cortex (PFC), which exerts top‐down control over various subcortical regions, densely expresses oxytocin receptors (OTR) that may mediate the effects of oxytocin on social behavior. Here, we use the Cre‐LoxP system in mice with anatomical, electrophysiological, imaging and optogenetic approaches to discern how ‘oxytocin sensitive’ neurons in the PFC may influence social behaviors. Male mice with expression of Cre recombinase driven by the promoter for the OTR gene (OTR‐Cre mice) were delivered Cre‐inducible adeno associated virus producing channel rhodopsin‐2 and enhanced yellow fluorescent protein (AAV‐ChR2‐eYFP) into the PFC. Viral delivery revealed that 54% and 27% of OTR‐expressing neurons in the PFC were glutamatergic or GABAergic, respectively. Retrograde tract‐tracing, in conjunction with in vitro optogenetics, found that OTR‐expressing PFC neurons sent glutamatergic projections to the nucleus accumbens, bed nucleus of the stria terminalis and basolateral amygdala (BLA). Functional magnetic resonance imaging confirmed that in vivo photo‐stimulation of OTR‐expressing neurons evoked increased activation of the PFC and downstream subcortical regions including the BLA. To assess the function of OTR‐expressing PFC neurons, OTR‐Cre mice were administered AAV‐ChR2‐eYFP or control virus and chronically implanted with fiber optics targeting the PFC. Subsequently, mice were evaluated in the social interaction (SI) and social novelty paradigms, novel object recognition test, elevated plus maze (EPM) and open field (OF). In vivo optogenetic stimulation of OTR‐expressing PFC neurons abolished preference for social novelty (n=6 per group; Control: P<0.01; ChR2: P=0.4), but had no effect on anxiety‐like behavior in the EPM, OF, or SI test. Locomotor activity and novel object recognition were also not affected. Collectively, our results suggest that excitation of OTR‐expressing neurons in the PFC exerts top‐down control over brain circuits controlling preference for social novelty.Support or Funding InformationNational Heart, Lung, and Blood Institute Grant HL122494 (Eric G Krause); National Institute of Mental Health Grant MH104641 (Charles J Frazier)