bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Oxygen Mirror‐J‐Curve: Mild Hyperoxia and Mild Hypoxia Induce Beneficial Adaptations
Authors: Lovrenčić Luka , Kovac Zdenko 
Published: April 2020

BackgroundMirror‐J‐response, named based on the shape of dose response curve, claims that physiological agents of living organism (including humans) when they deviate mildly from the reference range produce beneficial effects (e.g. glucose, calcium and osmolality, etc). A higher degree of deviations of those same agents produces harmful effects.HypothesisBoth mild hyperoxia and mild hypoxia may induce a positive adaptive response. Could the mirror‐J be substantiated for oxygen?MethodsObjective of this study was to search for a support of hypothesis in the published data.ResultsBeneficial effects of mild hypoxia have been shown both on cells and whole organisms. Cellular response to hypoxia consists of gene transcription modification and metabolic adaptations. These effects translate to adaptations of whole organisms. Animal studies show improved outcomes in both healthy subjects and disease models when challenged with hypoxia. Studies on healthy human subjects were mainly focused on physical activity performance, but have also shown decrease in inflammatory cytokines and glucose resistance. Studies on patients mostly focused on cardiovascular and neurologic diseases and show improvement in cardiorespiratory fitness similar to physical exercise.Mild hyperoxia animal studies demonstrated that ischemia improved tolerance following hyperoxia in myocardium, brain and kidney. Human studies focus primarily on exercise performance in healthy subjects and cardiovascular and neurological pathology, same as hypoxia research. Mild hyperoxia during exercise promoted fat oxidation, reduced sugar oxidation, and delayed time to exhaustion. Hyperoxia preconditioning reduced risk of heart surgery. Also, following traumatic brain injury, periods of hyperoxia can normalize oxidative metabolism markers in brain long after return to normoxia.Conclusion/DiscussionHypoxia and hyperoxia are in antithesis, but their effects are surprisingly similar. Both were shown to precondition various tissues to ischemia and to improve cardiorespiratory fitness. These similarities invoke a usage of a similar mechanism of action, as suggested for disarrangements in calcium, glucose and osmolality. Indeed, it was shown that both, mild hypoxia and mild hyperoxia induce production of reactive oxygen species which induce cellular adaptive response. Furthermore, studies have shown that both hypoxia and hyperoxia activate hypoxia inducible factor and promote erythropoietin production. Taken together, this data supports single unified cellular response to tipping oxygen balance. Those responses follow the mirror‐J nonlinearity. These adaptive responses appear to function on cellular level and level of organism as a whole and may improve functioning in normoxia.
The Effect of Different Magnesium Sources on Renal Magnesium Transporters in Rats Fed a High Fat Diet
Authors: Sahin Kazim , Yazgan Kubra , Tuzcu Mehmet , Orhan Cemal , Sahin Nurhan , Ojalvo Sara Perez , Sylla Sarah , Komorowski James R. 
Published: April 2020

Magnesium (Mg), which plays a role in many biochemical functions of the body, is the second most common cation in the cell. A high‐fat diet (HFD) intake causes hypomagnesemia, which is an electrolyte disorder. In this study, the molecular effects of Mg forms [magnesium oxide (MgO); magnesium picolinate (MgPic)] on renal Mg transporters (TRPM6, TRPM7, EGF, claudin‐16, claudin‐19, NCC) were investigated in HFD rats. For this purpose, 42 male Sprague‐Dawley (8 weeks old) rats were divided into 6 groups 1) Control; 2) MgO; 3) MgPic; 4) HFD; 5) HFD+MgO; 6) HFD+MgPic. Mg was supplemented at 500 mg of elemental Mg/kg diet. No effect on serum creatinine and urea levels of both Mg forms was detected (P >0.05). In HFD rats, kidney Mg levels were lower and kidney MDA levels were higher than other groups. However, the kidney Mg levels were increased and the kidney MDA levels were decreased by the Mg supplementation (P<0.001). The highest increase/decrease was obtained in the MgPic group. In addition, TRPM6, TRPM7, NCC, EGF, claudin16 and claudin19 Mg transporters were negatively affected by the HFD intake. However, it has been determined that Mg forms, especially MgPic, improved the levels of these proteins (P<0.001). As a result, MgPic may prevent oxidative stress and regulate Mg transporters in kidney including TRPM6, TRPM7, NCC, claudin16, and claudin19 in HFD ratsSupport or Funding InformationNutrition21, NY Firat Universitry ‐VF.18.02Turkish Academy of Science (KS)
Fetal Exposure to the Synthetic‐Progesterone Levonorgestrel (LNG) targets the brain resulting in hyperactive behavior using the Zebrafish (Danio rerio) as a model
Authors: Fuentes Austin K. , Ho-Shing Benjamin K. , Zamora Emily , Hinojosa Gabriella , Dearth Robert K. 
Published: April 2020

Anxiety‐related disorders are a rising health concern in adolescent and young adults. Evidence suggests that disrupting normal neuronal development (neurogenesis) in the fetal brain could play a role in the manifestation of mental health disorders later in life. Growing literature suggests a role in hormone receptor (HR)‐regulated brain development, particularly in the hypothalamus, the neuroendocrine section of the brain and part of the limbic center. Yet, this link has not been thoroughly investigated. Levonorgestrel (LNG), a synthetic steroid used in contraceptive pills in adults, may also pose a threat to the developing brain by targeting HRs. Furthermore, this endocrine disrupting chemical (EDC) has been found at physiologically relevant levels in potable water sources worldwide providing an alternative route of exposure for unknowing individuals. Therefore, we investigated the effects embryonic exposure to LNG had on neurogenesis and hyperactivity using the zebrafish (Danio rerio) as neurobiological model. First, computational modeling using Quantitative structure‐activity relationships (QSAR), determined the predicted bioavailability, physiological half‐life and overall potential efficacy of LNG as a neuroendocrine disruptor. Next, Zebrafish were bred and fertilized embryos were collected and individually placed in 96‐well plates. Embryos were exposed to LNG levels (at doses ranging from 5–1000ng/L) or a vehicle control starting at 3 hours post fertilization (hpf) to 5 days pf (dpf), the time encompassing neurogenesis. There were no observable differences in fertilization ratios, hatching or morphology between LNG treated groups and vehicle controls. On 5 dpf, all treated and controls were assayed for changes in locomotor activity (i.e. hyperactivity busts). Larval movement were analyzed using computational locomotor activity software. Interestingly, the 5ng dose of LNG significantly (p<0.05) increased hyperactive behavior compared to vehicle controls. HR expression and neuronal marker α‐HuC were used to document neurogenesis. Our data suggests that the observed LNG‐induced hyperactivity represents anxiety‐like behavior as a manifestation of aberrant neurogenesis. This is the first study to show that exposure to low environmentally relevant levels of LNG causes hyperactivity and thus, potentially alters HR regulated neuronal development increasing the risk of other mental issues later in life.Support or Funding InformationThis project was supported in part by UTRGV College of Science (COS) Research Enhancement Seed Grants Program to RKD, the UTRGV Presidential Graduate Research Fellowship to AF and GH, the UTRGV COS Dean's Fellowship to EZ, and the UTRGV Engaged Scholars Award to BHS.
Contributions of Creatine Kinase to Mucosal Immune Responses in Colitis
Authors: Lanis Jordi M. , Lee J. Scott , Cartwright Ian , Hall Carrie , Colgan Sean P. 
Published: April 2020

Intestinal epithelial cells facilitate nutrient transport as well as protect against invasion of luminal bacteria and microbial products. Disruption of the intestinal epithelial barrier is a hallmark of IBD. The regulation of intestinal epithelial barrier is made possible by junctional complexes including tight junctions and adherens junctions that are supported by the actin cytoskeleton. Maintenance of the actin cytoskeleton is an energy demanding process and intestinal epithelial cells shuttle energy to the locations of the cellular junctions through the creatine‐ATP energy circuit. Within the cell, creatine and its associated enzyme(s) creatine kinase(s) (CK) facilitate the shuttling of high energy phosphates in the form of phosphocreatine between sites of ATP generation. Work in our lab has shown that CK contributes to apical junction assembly in vitro and that supplementation with creatine in murine colitis models is protective. Further studies have shown that mice lacking the brain and mitochondrial isoforms of CK (CK dKO) are significantly more susceptible to DSS‐induced colitis as measured by multiple disease parameters, including disease activity, weight loss, intestinal permeability and by histological assessment. In addition to impaired barrier function, mice lacking CK showed defective inflammatory responses underscored by nearly non‐existent levels of colonic IFNγ. Flow cytometry from splenocytes and MLNs of CK dKO mice showed that T cells produced less IFNγ upon stimulation in vitro, and this finding was confirmed in human PBMC treated with the CK inhibitor cyclocreatine. These results implicate a CK‐dependent regulation of IFNγ in protective innate immune responses during mucosal inflammation, and ongoing studies are focused on elucidating the mechanism of CK activity on T cell signaling.Support or Funding InformationCrohn's and Colitis Foundation RFA #546183
Transient silencing of transforming growth factor‐β1 expression restores nitric oxide generation in diabetic hematopoietic stem/progenitor cells: Role of thrombospondin‐1.
Authors: Jahan Jesmin , Miguel Duran , Quiroz Julio , Gracia Charles , Bartelmez Stephen , Jarajapu Yagna 
Published: April 2020

Adult hematopoietic stem/progenitor cells (HSPCs) participate in the cardiovascular repair by stimulating regeneration and angiogenic functions of endothelium. Long‐term diabetes is associated with impaired vasoprotective functions of HSPCs. Transforming growth factor β (TGFβ1) is pleiotropic regulator of HSPC functions. Previous studies have shown that transient silencing of TGFβ1 expression improves in vivo migratory functions of diabetic HSPCs partly by restoring nitric oxide (NO) generation. This study tested the hypothesis that restoration of NO by TGFβ1‐silencing is mediated by thrombospondin‐1 (TSP1)/CD47 pathway. TSP1 is known to attenuate NO generation via inhibition of endothelial nitric oxide synthase (eNOS). HSPCs were isolated from peripheral blood samples obtained from either male or female healthy (n=25) or diabetic (both type 1 and type 2) (n=27) individuals (50–80 years of age) by immunomagnetic enrichment. TGFβ1 expression was transiently blocked by using TGFβ1‐antisense delivered in the form of phosphorodiamidate morpholino oligomer (PMO‐TGFβ1). TGFβ1 and TSP1 gene expressions were determined in HSPCs treated with either PMO‐control or PMO‐TGFβ1. NO generation induced by stromal‐derived factor‐1α (SDF) was determined by DAF‐FM flow cytometry. Diabetic cells have higher expression of TGFβ1 or TSP1 compared to that observed in cells derived from healthy individuals (n=10). Treatment with TGFβ1‐PMO decreased the expression of TGFβ1, which was associated with decreased TSP1 expression. CD47 expression is similar in healthy or diabetic individuals. NO generation by SDF is attenuated in diabetic compared to healthy cells (P<0.01, n=5). PMO‐TGFβ1‐treated diabetic cells showed increased generation of NO in response to SDF compared to PMO‐control‐treatment (P<0.01, n=5). Future studies will determine the effect of TSP1 on SDF/NO generation in cells with or without CD47‐siRNA, to further support the hypothesis. Collectively, these studies indicate the involvement of TGFβ1/TSP1/CD47/eNOS pathway in diabetic impairment of NO generation however involvement of other pathways cannot be ruled out.Support or Funding InformationThis study is partly supported by funding from NIH National Institute of Aging (AG056681).
Respiratory Dysfunction in a novel mouse model of Duchenne Muscular Dystrophy.
Authors: McCall Angela L. , Bailey Aidan M. , Pucci Logan A. , Dhindsa Justin S. , Strickland Laura M. , Robinson-Hamm Jacqueline , Gersbach Charles A. , ElMallah Mai K. 
Published: April 2020

Duchenne muscular dystrophy (DMD) is the most common genetic disease in adolescent males. It is caused by a loss of dystrophin protein, necessary for skeletal and cardiac muscle fiber membrane integrity, linking the sarcolemma to the extracellular matrix. Without dystrophin, muscle fibers are unable to maintain structure, with each contraction and relaxation leading to progressive muscle weakness. Weakness of the diaphragm results in respiratory failure for patients in early adulthood. For over 30 years, the mdx mouse which lacks dystrophin expression has served as a relevant model for DMD. However, the genotype of the mdx mouse does not reflect that of the patient population.Recently, a new mouse model harboring a human mutation in the dystrophin gene (DMD) was introduced into the mdx mouse (hDMD/Δ52;mdx) to better recapitulate a common genotype in patients. Since respiratory pathology is a significant cause of morbidity and mortality in DMD, this study sought to characterize the respiratory pathology in a novel DMD model – the hDMD/Δ52;mdx ‐ and further investigate the mdx mouse, using C57BL/6J mice as wildtype controls. The hypothesis driving this work is that the hDMD/Δ52;mdx mouse has greater respiratory deficiency compared to the mdx mouse. Whole body plethysmography (WBP) was used to assess respiration at baseline and during a challenge with hypercapnic and hypoxic conditions (FiCO2: 0.07, FiO2: 0.10; nitrogen balance). While exposed to normoxic air (FiO2: 0.21; nitrogen balance) the hDMD/Δ52;mdx was indistinguishable from either control at each time point. However, during the respiratory challenge the hDMD/Δ52;mdx mice had reduced frequency and minute ventilation by 6 months, which continued to decline at 12 months compared to the C57B/6J mice. Post mortem immunohistochemical studies of the neuromuscular junctions within the diaphragm showed that hDMD/Δ52;mdx and mdx mice had reduced overlap between presynaptic and postsynaptic endplates. Myofiber atrophy, fibrosis, and myofiber regeneration were also observed in the diaphragms of both mouse models. In conclusion, the hDMD/Δ52;mdx exhibits moderate respiratory pathology, and serves as a relevant animal model to study the impact of novel therapies on respiratory function.Support or Funding InformationDuke Department of Pediatrics Derfner Grant; R01 HD099486‐01; 1R21NS098131‐01
Arterial Stiffening and Calcification Associated with Abnormal Lysosomal Positioning and Exosome Secretion in Mice Lacking Mucolipin 1 Gene
Authors: Bhat Owais M. , Yuan Xinxu , Camus Sarah , Salloum Fadi , Li Pin-Lan 
Published: April 2020

Arterial calcification is a highly regulated cellular process that is characterized by the pathological mineral deposition leading to reduced arterial compliance. The aim of the present study was to investigate whether mucolipin 1 gene contributes to lysosomal positioning and exosome secretion which may results in phenotype change in SMCs during arterial medial calcification (AMC). In mucolipin 1 gene knock out (KO) mice, a high dose of Vit D (500,000 IU/kg/day) resulted in increased aortic calcification compared to their wild type littermates, which was accompanied by downregulation of SM22‐a and upregulation of RUNX2 and osteopontin in the arotic media, indicating phenotypic switch to osteogenic. Furthermore, we observed decreased colocalization of lysosome marker (Lamp‐1) with lysosome coupling marker (Rab 7 and ALG‐2) in the arterial wall of mucolipin 1 KO mice as compared to their wild type littermates. In addition, mucolipin 1 KO mice showed increased expression of exosome markers, CD63 and annexin‐II (AnX2), in the arterial medial wall, which was associated with reduced co‐localization of lysosome marker (Lamp‐1) with multivesicular body (MVB) marker (VPS16). This suggests reduction of the lysosome‐MVB interactions. Furthermore, we found significantly increased exosomes in the plasma of mucolipin 1 KO mice as compared to the wild type littermates. Functionally, in mucolipin 1 KO mice pulse wave velocity (PWV) significantly increased and Vit D treatment further enhance such stiffening. All these data indicate that mucolipin‐1 gene deletion leads to abnormal lysosome positioning and exosome secretion in the arterial wall, which may contribute to the arterial stiffness during the development of AMC.Support or Funding Information(Supported by NIH grants HL057244, HL075316 and DK120491)
Nicotinamide mononucleotide (NMN) treatment attenuates oxidative stress and rescues angiogenic capacity in aged cerebromicrovascular endothelial cells: a potential mechanism for the prevention of vascular cognitive impairment.
Authors: Kiss Tamas , Tarantini Stefano , Yabluchanskiy Andriy , Csipo Tamas , Balasubramanian Priya , Lipecz Agnes , Reglodi Dora , Farkas Eszter , Zhang Xin , Bari Ferenc , Csiszar Anna , Ungvari Zoltan 
Published: April 2020

Age‐related impairment of angiogenesis likely has a critical role in cerebromicrovascular rarefaction and development of vascular cognitive impairment and dementia (VCID) in the elderly. Recently, we demonstrated that aging is associated with NAD+ depletion in the vasculature and that administration of NAD+ precursors exerts potent anti‐aging vascular effects, rescuing endothelium‐mediated vasodilation in the cerebral circulation and improving cerebral blood supply. The present study was designed to elucidate how treatment with nicotinamide mononucleotide (NMN), a key NAD+ intermediate, impacts age‐related impairment of endothelial angiogenic processes. Using cerebromicrovascular endothelial cells (CMVECs) isolated from young and aged F344xBN rats, we demonstrated that compared with young cells, aged CMVECs exhibit impaired proliferation, cellular migration (measured by a wound‐healing assay using electric cell‐substrate impedance sensing [ECIS] technology), impaired ability to form capillary‐like structures, and increased oxidative stress. NMN treatment in aged CMVECs significantly improved angiogenic processes and attenuated H2O2 production. We also found that pre‐treatment with EX‐527, a pharmacological inhibitor of SIRT1, prevented NMN‐mediated restoration of angiogenic processes in aged CMVECs. Collectively, we find that normal cellular NAD+ levels are essential for normal endothelial angiogenic processes, suggesting that age‐related cellular NAD+ depletion and consequential SIRT1 dysregulation may be a potentially reversible mechanism underlying impaired angiogenesis and cerebromicrovascular rarefaction in aging. We recommend that pro‐angiogenic effects of NAD+ boosters should be considered in both preclinical and clinical studies.Support or Funding InformationThis work was supported by grants the Oklahoma Center for the Advancement of Science and Technology, the Oklahoma Shared Clinical and Translational Resources (OSCTR) program funded by the National Institute of General Medical Sciences (GM104938), the NIA‐supported Geroscience Training Program in Oklahoma (T32AG052363), the Oklahoma Nathan Shock Center (P30AG050911), the Cellular and Molecular GeroScience CoBRE (1P20GM125528, sub#5337), and the NIGMS supported Center of Biomedical Research Excellence (CoBRE).
Transport of Degraded Ferric Enterobactin by Fiu
Authors: Yang Taihao , Newton Salete M. , Klebba Phillip 
Published: April 2020

Under iron deficient conditions, Gram‐negative bacteria like Escherichia coli secrete enterobactin, a catecholate siderophore that complexes and solubilizes iron in the extracellular environment. Ferric enterobactin (FeEnt) is the most avid natural or synthetic iron complex. It may be glucosylated (FeGEnt), and it is also subject to both chemical degradation and oxidation (FeEnt*). Neverthless, bacterial outer membrane transporters acquire FeEnt, FeGEnt and FeEnt*. For example, the E. coli Fiu protein is known to catalyze the uptake of monomeric catecholate iron complexes, and using siderophore nutrition tests and radioisotopic iron accumulation experiments, we found that Fiu preferentially recognizes and transports FeEnt*. To further analyze the specificity of the FeEnt* uptake process, we created Cys substitutions in the external surface loops of Fiu and labeled them with fluorescein maleimide (FM). During binding of ferric siderophores, the surface loops undergo conformational motion that quenches attached fluorophores, allowing quantitative determinations of affinity and specificity. We measured the affinity of Fiu‐FM for different ferric catecholate compounds: FeEnt*, FeEnt, and FeGEnt produced Kd values of 0.46, 20, and 0.5 μM, respectively. Thus, Fiu manifests specificity for the degradation products of FeEnt, but also mediates the uptake of FeEnt and FeGEnt, identifying it as an important component of bacterial iron acquisition systems that are essential to bacterial survival.Support or Funding InformationNational Institutes of Health
Mitochondria Amplify TRPV4‐dependent Calcium Dynamics within the Pulmonary Microvascular Endothelium
Authors: Knighten Jennifer , Phillips Vantel , Taylor Mark , Townsley Mary , Francis Christopher Michael 
Published: April 2020

Acute respiratory distress syndrome (ARDS) is an inflammatory lung disease common in critically ill patients marked by diffuse alveolar damage and increased pulmonary endothelial barrier permeability. A large body of evidence supports the role of mitochondrial dysfunction in ARDS, which has been shown to mediate endothelial permeability. For example, in cultured rat pulmonary microvascular endothelial cells (PMVECs), the mitochondrial complex I inhibitor rotenone increases endothelial permeability and in isolated perfused lung studies, rotenone increases the pulmonary vascular filtration coefficient. In both cell culture and isolated perfused lungs, the amphipathic quinone coenzyme Q1 (CoQ1) rescues rotenone‐dependent increases in endothelial permeability by bypassing complex I to restore mitochondrial bioenergetics.The transient receptor potential vanilloid protein 4 (TRPV4), a mechanically gated calcium channel, has also been implicated in mediating endothelial permeability by increasing intracellular calcium in response to high pressure ventilation. The phorbol ester 4α‐phorbol‐12,13‐didecanoate (4αPDD) provides a pharmacological means of TRPV4 activation and stimulates endothelial permeability responses in both cell culture and animal models of lung injury. Given that mitochondria actively participate in calcium buffering, we hypothesized that TRPV4‐dependent calcium signals may be compartmentalized by mitochondria. To test this hypothesis, we used confocal microscopy to measure calcium signals in PMVECs in response to TRPV4 activation via 4αPDD (5 μM) after treatment with vehicle, rotenone (0.5 μM), or rotenone in combination with CoQ1 (10 μM), and developed a sensitive, automated technique for intracellular calcium signal transient analysis.Using our novel analysis approach, we found that rotenone significantly decreased the number of calcium signal transients stimulated by 4αPDD over a 15 minute interval (mean ± SEM: 22 ± 4 rotenone vs 96 ± 14 vehicle, p <0.01), and that CoQ1 in combination with rotenone reversed this effect (60 ± 15, p = n.s. vs vehicle). Rotenone also dampened the amplitude of calcium responses to TRPV4, an effect that was partially restored by CoQ1. These findings support the hypothesis that mitochondria regulate TRPV4‐mediated calcium dynamics by amplifying calcium signals, and that mitochondrial dysfunction impairs this phenomenon. This suggests that mitochondrial regulation of endothelial calcium signaling is essential to the maintenance of barrier integrity and provides a possible therapeutic target in ARDS.Support or Funding InformationNIH K25HL136869 and NIH P01 HL066299‐17