On the mechanisms of biliary flux.
The mechanism of transport of glandular secretions such as saliva, bile, and exocrine pancreatic juice is fundamental to their role in physiology. Recently, reports from two groups have rekindled the decades-old scientific debate on the mechanisms by which biliary fluid and biliary constituents exit the liver.(1-3) Bile acids (BAs) are secreted by the action of ATP-dependent transporter proteins to reach high concentrations in the liver canalicular network, but what transports them out of the canalicular network, into the bile ducts, and finally out of the liver? Conventional wisdom was in favor of an osmotically driven mechanism according to which the BAs and other solutes, such as glutathione, bilirubin and many other organic anions, secreted by hepatocytes, draw water into the bile canaliculi to create bulk canalicular fluid flow. In sharp contrast, work done by the present authors demonstrated the conspicuous lack of measurable flow in canaliculi.(1) Instead, BAs appear to move by molecular diffusion in a virtually stagnant canalicular fluid until they reach the bile ducts. Only in the ducts is fluid flow evident, caused by local inorganic ion secretion, drawing water from the cholangiocytes into the ductular lumen. Moreover, an osmotic potential generated by the high concentration of solutes diffusing from the canalicular network into the ducts may contribute to water influx from cholangiocytes into the ductular lumen, although this mechanism has not yet been directly proven. Therefore, the ducts, much more than the canaliculi, may represent the anatomical site where bile flow originates. Although this distinction in the anatomical site of origin of bile flow may seem like splitting hairs, it has important consequences for the understanding and development of therapy of various liver diseases. Solving this conundrum requires a multi-disciplinary excursion into fluid mechanics, molecular diffusion, and the development of new techniques that allow direct measurement of these processes in the biliary tract of intact functioning livers. After discussing the fundamental biophysical theory and presenting recently published data in this context, we here present a framework for bile flux and discuss its implications on pathophysiology and therapeutic developments.
Since the late 1950s, transport of bile in the liver has been described by the “osmotic concept,” according to which bile flows into the canaliculi toward the ducts, countercurrent to the blood flow in the sinusoids. However, because of the small size of canaliculi, it was so far impossible to observe, let alone to quantify this process. Still, “osmotic canalicular flow” was a sufficient and plausible explanation for the clearance characteristics of a wide variety of choleretic compounds excreted in bile. Imaging techniques have now been established that allow direct flux analysis in bile canaliculi of the intact liver in living organisms. In contrast to the prevailing osmotic concept these analyses strongly suggest that the transport of small molecules in canalicular bile is diffusion dominated, while canalicular flow is negligibly small. In contrast, with the same experimental approach, it could be shown that in the interlobular ducts, diffusion is augmented by flow. Thus, bile canaliculi can be compared to a standing water zone that is connected to a river. The seemingly subtle difference between diffusion and flow is of relevance for therapy of a wide range of liver diseases including cholestasis and NAFLD. Here, we incorporated the latest findings on canalicular solute transport, and align them with extant knowledge to present an integrated and explanatory framework of bile flux that will undoubtedly be refined further in the future.
Vartak N; Drasdo D; Geisler F; Itoh T; Oude Elferink RPJ; van de Graaf SFJ; Chiang J; Keitel Verena; Trauner M; Jansen P; Hengstler JG
Hepatology
2021
2021-06-23
Journal Article
<table width="91" style="border-collapse:collapse;width:68pt;"><colgroup><col width="91" style="width:68pt;" /></colgroup><tbody><tr style="height:15pt;"><td width="91" height="20" class="xl18" style="width:68pt;height:15pt;"><a href="http://doi.org/10.1002/hep.32027">http://doi.org/10.1002/hep.32027</a></td>
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The effect of manganese exposure in Atp13a2-deficient mice.
Female; Male; Animals; Mice; *Parkinson's disease; *Alpha-synuclein; Mice; Membrane Proteins/genetics/*metabolism; Motor Activity; *Lipofuscin; *Manganese; *Sensorimotor function; Behavior; Inbred C57BL; Animal; Knockout; Adenosine Triphosphatases/genetics/*metabolism; alpha-Synuclein/metabolism; Brain/*drug effects/*metabolism; Manganese/metabolism/*toxicity
Loss of function mutations in the P5-ATPase ATP13A2 are associated with Kufor-Rakeb Syndrome and Neuronal Ceroid Lipofuscinosis. While the function of ATP13A2 is unclear, in vitro studies suggest it is a lysosomal protein that interacts with the metals manganese (Mn) and zinc and the presynaptic protein alpha-synuclein. Loss of ATP13A2 function in mice causes sensorimotor deficits, enhanced autofluorescent storage material, and accumulation of alpha-synuclein. The present study sought to determine the effect of Mn administration on these same outcomes in ATP13A2-deficient mice. Wildtype and ATP13A2-deficient mice received saline or Mn at 5-9 or 12-19 months for 45days. Sensorimotor function was assessed starting at day 30. Autofluorescence was quantified in multiple brain regions and alpha-synuclein protein levels were determined in the ventral midbrain. Brain Mn, iron, zinc, and copper concentrations were measured in 5-9 month old mice. The results show Mn enhanced sensorimotor function, increased autofluorescence in the substantia nigra, and increased insoluble alpha-synuclein in the ventral midbrain in older ATP13A2-deficient mice. In addition, the Mn regimen used increased Mn concentration in the brain and levels were higher in Mn-treated mutants than controls. These results indicate loss of ATP13A2 function leads to increased sensitivity to Mn in vivo.
Fleming Sheila M; Santiago Nicholas A; Mullin Elizabeth J; Pamphile Shanta; Karkare Swagata; Lemkuhl Andrew; Ekhator Osunde R; Linn Stephen C; Holden John G; Aga Diana S; Roth Jerome A; Liou Benjamin; Sun Ying; Shull Gary E; Schultheis Patrick J
Neurotoxicology
2018
2018-01
<a href="http://doi.org/10.1016/j.neuro.2017.06.005" target="_blank" rel="noreferrer noopener">10.1016/j.neuro.2017.06.005</a>
Glycoprotein Nonmelanoma Clone B Regulates the Crosstalk between Macrophages and Mesenchymal Stem Cells toward Wound Repair.
Humans; Male; Animals; Mice; Cell Differentiation; Wound Healing/*physiology; Macrophages/*physiology; Diabetes Mellitus; Cells; Cultured; Inbred C57BL; Animal; Disease Models; Administration; Cutaneous; Cell Communication/*physiology; Eye Proteins/administration & dosage/genetics/*physiology; Membrane Glycoproteins/administration & dosage/genetics/*physiology; Mesenchymal Stem Cells/*physiology; Recombinant Proteins/administration & dosage/genetics/metabolism; Skin/*injuries/metabolism; Type 2/complications/pathology
The process of wound repair requires the coordinated participation of multiple types of cells, which are sequentially recruited during the healing process. In response to tissue injury, both macrophages and mesenchymal stem cells (MSCs) are recruited to the site of injury, where they participate in the repair process. Despite considerable understanding of the role of each cell type in the process of wound repair, the nature of the dynamic interplay between these two cell types and how this interaction influences the process of wound repair are not well understood. Here, using an in vivo model of cutaneous wound healing in mice, we provide evidence that GPNMB is functionally important in promoting the recruitment of MSCs to the site of skin injury, which in turn modulates inflammatory responses by directing the M2 polarization of macrophages in acute wound healing. Furthermore, we show that GPNMB activity is impaired in a diabetic wound environment, which is associated with impaired MSC recruitment that is reversed by the topical administration of recombinant GPNMB protein to the wounds of diabetic mice. Our study provides important insight into the crosstalk between macrophages and endogenous MSCs toward wound repair.
Yu Bing; Alboslemy Talib; Safadi Fayez; Kim Min-Ho
The Journal of investigative dermatology
2018
2018-01
<a href="http://doi.org/10.1016/j.jid.2017.08.034" target="_blank" rel="noreferrer noopener">10.1016/j.jid.2017.08.034</a>
Intestine farnesoid X receptor agonist and the gut microbiota activate G-protein bile acid receptor-1 signaling to improve metabolism.
Male; Animals; Mice; Random Allocation; Sensitivity and Specificity; *Signal Transduction; Lipid Metabolism; Bile Acids and Salts/*metabolism; GTP-Binding Proteins/*metabolism; Receptors; Inbred C57BL; Animal; Disease Models; G-Protein-Coupled/*metabolism; Gastrointestinal Microbiome/*drug effects; Glucagon-Like Peptide 1/metabolism; Cytoplasmic and Nuclear/*antagonists & inhibitors/pharmacology
Bile acids activate farnesoid X receptor (FXR) and G protein-coupled bile acid receptor-1 (aka Takeda G protein-coupled receptor-5 [TGR5]) to regulate bile acid metabolism and glucose and insulin sensitivity. FXR and TGR5 are coexpressed in the enteroendocrine L cells, but their roles in integrated regulation of metabolism are not completely understood. We reported recently that activation of FXR induces TGR5 to stimulate glucagon-like peptide-1 (GLP-1) secretion to improve insulin sensitivity and hepatic metabolism. In this study, we used the intestine-restricted FXR agonist fexaramine (FEX) to study the effect of activation of intestinal FXR on the gut microbiome, bile acid metabolism, and FXR and TGR5 signaling. The current study revealed that FEX markedly increased taurolithocholic acid, increased secretion of fibroblast growth factors 15 and 21 and GLP-1, improved insulin and glucose tolerance, and promoted white adipose tissue browning in mice. Analysis of 16S ribosomal RNA sequences of the gut microbiome identified the FEX-induced and lithocholic acid-producing bacteria Acetatifactor and Bacteroides. Antibiotic treatment completely reversed the
Pathak Preeti; Xie Cen; Nichols Robert G; Ferrell Jessica M; Boehme Shannon; Krausz Kristopher W; Patterson Andrew D; Gonzalez Frank J; Chiang John Y L
Hepatology (Baltimore, Md.)
2018
2018-10
<a href="http://doi.org/10.1002/hep.29857" target="_blank" rel="noreferrer noopener">10.1002/hep.29857</a>
Origins of spondyloarthropathy in Perissodactyla.
Animals; *Fossils; *Paleopathology; *Perissodactyla; Horse Diseases/history/*pathology; Horses; North America; Sacroiliac Joint/pathology; Spine/pathology; History; Ancient; Animal; Disease Models; Spondylitis; Ankylosing/history/*pathology
OBJECTIVE: Spondyloarthropathy has clearly been documented as not limited in occurrence to humans. Transmammalian in nature, it is of interest to understand the antiquity, and perhaps the origins, of this disorder in animal groups sufficiently represented in the skeletal record. METHODS: Fossil and recent skeletons of perissodactylae from North America were systematically examined to determine the occurrence and population frequency of spondyloarthropathy. RESULTS: Spondyloarthropathy was the most common form of arthritis recognized in the extant and fossil records. Common in extinct families such as Brontotheriidae and Chalicotheriidae, a progressive increase in the frequency of spondyloarthropathy was observed through geologic time in Equidae and Rhinocerotidae. CONCLUSION: Erosive arthritis of the spondyloarthropathy variety is now documented as not only persisting in Perissodactyla, but as actually increasing significantly in frequency (3-6 fold). Given the unusual evolutionary penetrance of this "disease," the possibility must be considered that its persistence provides evidence for some unknown benefit to the affected host.
Rothschild B M; Prothero D R; Rothschild C
Clinical and experimental rheumatology
2001
2001-12
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
Sex steroid induction of gallstones in the male Syrian hamster.
Male; Animals; Body Weight; Organ Size; Cricetinae; Drug Combinations; Estradiol/*pharmacology; Mesocricetus; Medroxyprogesterone/*pharmacology; Cholelithiasis/*etiology; Endoplasmic Reticulum/drug effects/ultrastructure; Gallbladder/*drug effects/ultrastructure; Golgi Apparatus/drug effects/ultrastructure; Animal; Disease Models
Light (LM), transmission (TEM) and scanning (SEM) electron microscopic techniques were used to characterize morphologic changes induced in the gallbladder of Syrian hamsters following a one-month estradiol (E) and estradiol + medroxyprogesterone (E+MP) treatment. The TEM results were correlated with the SEM findings. Compared to control (C), E-treated surface epithelial cells contain abundant RER, enlarged Golgi, multivesicular (foamy-heterophagosomes) bodies or lipofuscin inclusions. A 10-day E treatment showed large vesicles develop and, after longer E treatment, they could coalesce and create some of the large multivesicular bodies. Interestingly, E+MP epithelia are characterized by distinct bulging apices where a large number of apical granules accumulate, and contain an anionic mucous core. After a 4-week E+MP treatment, even though all the hamsters were fed a diet with trace cholesterol, significant increase in hamster liver weight, serum level of cholesterol and HDL were measured and, correspondingly, gallstones were found exclusively in E+MP-treated hamsters. Our results showed that not only does the Syrian hamster provide an appropriate model to study experimental lithogenesis without manipulating the diet. In addition, MP appears to induce morphologic changes associated with the formation of gallstones.
Gilloteaux J; Kosek E; Kelly T R
Journal of submicroscopic cytology and pathology
1993
1993-04
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
Gender differences in neurotoxicity of the nigrostriatal dopaminergic system: implications for Parkinson's disease.
Female; Humans; Male; Sex Factors; Sex Distribution; Estrogens/*pharmacology; Dopamine/metabolism; Postmenopause; Corpus Striatum/pathology/*physiopathology; Neurotoxins/*antagonists & inhibitors; Parkinson Disease/metabolism/pathology/*physiopathology; Substantia Nigra/pathology/*physiopathology; Animal; Disease Models
This article describes the progression of steps followed to demonstrate a gender difference associated with Parkinson's disease (PD) and to gain an understanding of the basis, mechanisms, and implications of this gender specificity. First, a review of the literature on PD shows a greater incidence in men. Next, data are presented from a series of laboratory studies in animal models of PD that suggest a basis for this gender difference: estrogen appears to act as a neuroprotectant of the striatal dopaminergic system. One mechanism for this effect may be that estrogen inhibits the uptake of neurotoxins capable of producing degeneration within dopaminergic neurons. Finally, some of the potential neurologic implications of manipulating estrogen in premenopausal and postmenopausal women are considered.
Dluzen D E; McDermott J L
The journal of gender-specific medicine : JGSM : the official journal of the Partnership for Women's Health at Columbia
2000
2000-10
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
Estrogen decreases corpus striatal neurotoxicity in response to
Female; Animals; Rats; Corpus Striatum/*drug effects; Dopamine/metabolism; Neurotoxins/*toxicity; Estradiol/*pharmacology; Oxidopamine/*toxicity; Parkinson Disease/*physiopathology; Sprague-Dawley; Animal; Disease Models; 3; 4-Dihydroxyphenylacetic Acid/metabolism
Ovariectomized rats treated or not with an estradiol pellet were subjected to an unilateral intrastriatal infusion of 6-hydroxydopamine (6-OHDA). Various parameters of nigrostriatal dopaminergic function as derived from measurements of dopamine and dihydroxyphenylacetic acid (DOPAC) concentrations were determined from the 6-OHDA lesioned and non-lesioned sides of the corpus striatum in these animals. Dopamine concentrations within the 6-OHDA lesioned striatum of estrogen-treated rats were significantly greater than non-estrogen-treated rats. There were no differences in striatal dopamine concentrations between estrogen- versus non-estrogen-treated rats on their non-lesioned side. In contrast to that of dopamine, no differences in DOPAC concentrations between estrogen and non-estrogen-treated rats were obtained within the 6-OHDA-lesioned side. The DOPAC concentrations on the non-lesioned side of the striatum were significantly greater in the non-estrogen-treated rats. These results demonstrate that estrogen significantly diminishes the depletion of striatal dopamine resulting from the neurotoxin 6-OHDA. The data obtained from the DOPAC determinations imply that this capacity of estrogen may be exerted through actions upon uptake processes of striatal dopaminergic neurons. Such findings suggest that estrogen may function as an important modulatory factor capable of attenuating degeneration within the corpus striatum, and in this way serve as a neuroprotectant of the nigrostriatal dopaminergic system.
Dluzen D
Brain research
1997
1997-09
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
Intrastrain variants of herpes simplex virus type 1 isolated from a neonate with fatal disseminated infection differ in the ICP34.5 gene, glycoprotein processing, and neuroinvasiveness.
Humans; Male; Animals; Mice; Amino Acid Sequence; *Genetic Variation; Base Sequence; Molecular Sequence Data; Polymerase Chain Reaction/methods; DNA; Deoxyribonuclease BamHI; Deoxyribonuclease EcoRI; Glycoproteins/metabolism; Viral Envelope Proteins/analysis; Viral Proteins/*genetics; Genes; Viral; Animal; Disease Models; Herpesvirus 1; Inbred BALB C; Amino Acid; Sequence Homology; Sequence Analysis; Nucleic Acid; Polymorphism; *Protein Processing; Post-Translational; Human/*genetics/growth & development/isolation & purification; Restriction Fragment Length
Two intrastrain variants of herpes simplex virus type 1 (HSV-1) were isolated from a newborn with fatal disseminated infection. A small-plaque-producing variant (SP7) was the predominant virus (\textgreater99%) in the brain, and a large-plaque-producing variant (LP5) was the predominant virus (\textgreater99%) in the lung and gastrointestinal tract. EcoRI and BamHI restriction fragment patterns indicated that SP7 and LP5 are related strains. The large-plaque variants produced plaques similar in size to those produced by HSV-1 KOS. Unlike LP5 or KOS, SP7 was highly cell associated and processing of glycoprotein C and glycoprotein D was limited to precursor forms in infected Vero cells. The large-plaque phenotype from KOS could be transferred into SP7 by cotransfection of plasmids containing the EK or JK EcoRI fragment or a 3-kb plasmid with the UL34.5 gene of HSV-1 KOS together with SP7 DNA. PCR analysis using primers from within the ICP34.5 gene indicated differences for SP7, LP5, and KOS. Sequencing data indicated two sets of deletions in the UL34.5 gene that distinguish SP7 from LP5. Both SP7 and LP5 variants were neurovirulent (lethal following intracranial inoculation of young BALB/c mice); however, the LP5 variant was much less able to cause lethal neuroinvasive disease (footpad inoculation) whereas KOS caused no disease. Passage of SP7 selected for viruses (SLP-5 and SLP-10) which were attenuated for lethal neuroinvasive disease, were not cell-associated, and differed in the UL34.5 gene. UL34.5 from SLP-5 or SLP-10 resembled that of KOS. These findings support a role for UL34.5 in promoting virus egress and for neuroinvasive disease.
Bower J R; Mao H; Durishin C; Rozenbom E; Detwiler M; Rempinski D; Karban T L; Rosenthal K S
Journal of virology
1999
1999-05
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
Functional outcome after anal sphincter injury and treatment with mesenchymal stem cells.
Female; Time Factors; Animals; Rats; Mesenchymal stem cells; Transfection; Recovery of Function; Fibrosis; *Mesenchymal Stem Cell Transplantation; *Regeneration; Anal Canal/injuries/metabolism/pathology/physiopathology/*surgery; Anal pressures; Anal sphincter; Fecal incontinence; Green Fluorescent Proteins/biosynthesis/genetics; i.v. infusion; Mesenchymal Stem Cells/metabolism; Pressure; Injections; Intralesional; Sprague-Dawley; Cells; Cultured; Animal; Disease Models; Infusions; Intravenous
This research demonstrates the regenerative effects of mesenchymal stem cells (MSCs) on the injured anal sphincter by comparing anal sphincter pressures following intramuscular and serial intravascular MSC infusion in a rat model of anal sphincter injury. Fifty rats were divided into injury (n = 35) and no injury (NI; n = 15) groups. Each group was further divided into i.m., serial i.v., or no-treatment (n = 5) groups and followed for 5 weeks. The injury consisted of an excision of 25% of the anal sphincter complex. Twenty-four hours after injury, 5 x 10(5) green fluorescent protein-labeled MSCs in 0.2 ml of phosphate-buffered saline (PBS) or PBS alone (sham) were injected into the anal sphincter for i.m. treatment; i.v. and sham i.v. treatments were delivered daily for 6 consecutive days via the tail vein. Anal pressures were recorded before injury and 10 days and 5 weeks after treatment. Ten days after i.m. MSC treatment, resting and peak pressures were significantly increased compared with those in sham i.m. treatment (p \textless .001). When compared with the NI group, the injury groups had anal pressures that were not significantly different 5 weeks after i.m./i.v. treatment. Both resting and peak pressures were also significantly increased after i.m./i.v. MSC treatment compared with treatment with PBS (p \textless .001), suggesting recovery. Statistical analysis was done using paired t test with Bonferroni correction. Marked decrease in fibrosis and scar tissue was seen in both MSC-treated groups. Both i.m. and i.v. MSC treatment after injury caused an increase in anal pressures sustained at 5 weeks, although fewer cells were injected i.m. The
Salcedo Levilester; Penn Marc; Damaser Margot; Balog Brian; Zutshi Massarat
Stem cells translational medicine
2014
2014-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.5966/sctm.2013-0157" target="_blank" rel="noreferrer noopener">10.5966/sctm.2013-0157</a>
Apolipoprotein A1 regulates coenzyme Q10 absorption, mitochondrial function, and infarct size in a mouse model of myocardial infarction.
Male; Animals; Mice; Myocardium; Lipid Metabolism; Mitochondria; Heart/drug effects; Antioxidants/administration & dosage/*metabolism/pharmacokinetics/therapeutic use; Apolipoprotein A-I/blood/genetics/*metabolism; Cardiotonic Agents/administration & dosage/metabolism/pharmacokinetics/therapeutic use; Dietary Supplements; Electron Transport Complex II/chemistry/metabolism; Electron Transport Complex III/chemistry/metabolism; Electron Transport/drug effects; Hypoalphalipoproteinemias/physiopathology; Intestinal Absorption; Myocardial Infarction/etiology/metabolism/pathology/*therapy; Myocardial Reperfusion Injury/blood/metabolism/pathology/prevention & control; Myocardium/enzymology/*metabolism/pathology; Tissue Distribution; Ubiquinone/administration & dosage/*analogs & derivatives/metabolism/pharmacokinetics/therapeutic use; Injections; Biological; Models; Animal; Knockout; Intraperitoneal; *Disease Models; Heart/drug effects/enzymology/*metabolism; Proteins; Animal Studies; Apolipoproteins; Coenzyme Q; Proteins – Metabolism; Heart – Drug Effects; Myocardial Infarction – Therapy; Apolipoproteins – Blood; Apolipoproteins – Metabolism; Antioxidants – Administration and Dosage; Antioxidants – Metabolism; Antioxidants – Pharmacokinetics; Antioxidants – Therapeutic Use; Cardiotonic Agents – Administration and Dosage; Cardiotonic Agents – Metabolism; Cardiotonic Agents – Pharmacokinetics; Cardiotonic Agents – Therapeutic Use; Coenzyme Q – Administration and Dosage; Coenzyme Q – Metabolism; Coenzyme Q – Pharmacokinetics; Coenzyme Q – Therapeutic Use; Electron Transport – Drug Effects; Inborn Errors – Physiopathology; Mitochondria – Drug Effects; Mitochondria – Metabolism; Myocardial Infarction – Etiology; Myocardial Infarction – Metabolism; Myocardial Infarction – Pathology; Myocardial Reperfusion Injury – Blood; Myocardial Reperfusion Injury – Metabolism; Myocardial Reperfusion Injury – Pathology; Myocardial Reperfusion Injury – Prevention and Control; Myocardium – Metabolism; Myocardium – Pathology
HDL and apolipoprotein A1 (apoA1) concentrations inversely correlate with risk of death from ischemic heart disease; however, the role of apoA1 in the myocardial response to ischemia has not been well defined. To test whether apoA1, the primary HDL apolipoprotein, has an acute anti-inflammatory role in ischemic heart disease, we induced myocardial infarction via direct left anterior descending coronary artery ligation in apoA1 null (apoA1(-/-)) and apoA1 heterozygous (apoA1(+/-)) mice. We observed that apoA1(+/-) and apoA1(-/-) mice had a 52% and 125% increase in infarct size as a percentage of area at risk, respectively, compared with wild-type (WT) C57BL/6 mice. Mitochondrial oxidation contributes to tissue damage in ischemia-reperfusion injury. A substantial defect was present at baseline in the electron transport chain of cardiac myocytes from apoA1(-/-) mice localized to the coenzyme Q (CoQ) pool with impaired electron transfer (67% decrease) from complex II to complex III. Administration of coenzyme Q10 (CoQ10) to apoA1 null mice normalized the cardiac mitochondrial CoQ pool and reduced infarct size to that observed in WT mice. CoQ10 administration did not significantly alter infarct size in WT mice. These data identify CoQ pool content leading to impaired mitochondrial function as major contributors to infarct size in the setting of low HDL/apoA1. These data suggest a previously unappreciated mechanism for myocardial stunning, cardiac dysfunction, and muscle pain associated with low HDL and low apoA1 concentrations that can be corrected by CoQ10 supplementation and suggest populations of patients that may benefit particularly from CoQ10 supplementation.
Dadabayev Alisher R; Yin Guotian; Latchoumycandane Calivarathan; McIntyre Thomas M; Lesnefsky Edward J; Penn Marc S
The Journal of nutrition
2014
2014-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.3945/jn.113.184291" target="_blank" rel="noreferrer noopener">10.3945/jn.113.184291</a>
Early Evidence of Low Bone Density and Decreased Serotonergic Synthesis in the Dorsal Raphe of a Tauopathy Model of Alzheimer's Disease.
Female; Male; Animals; Mice; *Alzheimer's disease; Body Weight; Body Composition; Age Factors; Body Weight/genetics; Phosphorylation; Bone Density/*physiology; *Alzheimer Disease/complications/genetics/pathology; *bone density; *microtubule-associated protein; *serotonin; *tau proteins; *tauopathies; Body Composition/genetics; Bone Diseases/*etiology; Dorsal Raphe Nucleus/*pathology; Neurons/metabolism/pathology; Serotonin/*metabolism; tau Proteins/*genetics/metabolism; Tauopathies/complications/genetics; Tryptophan Hydroxylase/metabolism; Biological; Models; Inbred C57BL; Animal; Disease Models; Transgenic; Nerve Tissue Proteins; Neurodegenerative Diseases; Animal Studies; Alzheimer's Disease; Bone Density – Physiology; Nerve Tissue Proteins – Metabolism; Neurodegenerative Diseases – Complications; Alzheimer's Disease – Complications; Alzheimer's Disease – Pathology; Bone Diseases – Etiology; Brain Stem – Pathology; Neurons – Metabolism; Neurons – Pathology; Oxidoreductases – Metabolism; Serotonin – Metabolism
Reduced bone mineral density (BMD) and its clinical sequelae, osteoporosis, occur at a much greater rate in patients with Alzheimer's disease (AD), often emerging early in the disease before significant cognitive decline is seen. Reduced BMD translates to increased bone fracture risk, decreased quality of life, and increased mortality for AD patients. However, the mechanism responsible for this observation is unclear. We hypothesize that bone loss is an additional component of an AD prodrome-changes that emerge prior to dementia and are mediated by dysfunction of the central serotonergic pathways. We characterized the skeletal phenotype of htau mice that express human forms of the microtubule-associated protein tau that become pathologically hyperphosphorylated in AD. Using radiographic densitometry, we measured BMD in female and male htau mice from 2-6 months of age-time-points prior to the presence of significant tauopathy in the hippocampal/entorhinal regions characteristic of this model. We found a significantly reduced BMD phenotype in htau mice that was most pronounced in males. Using western blotting and immunofluorescence, we showed overall reduced tryptophan hydroxylase (TPH) protein in htau brainstem and a 70% reduction in
Dengler-Crish Christine M; Smith Matthew A; Wilson Gina N
Journal of Alzheimer's disease : JAD
2017
1905-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.3233/JAD-160658" target="_blank" rel="noreferrer noopener">10.3233/JAD-160658</a>
Thermoreversible gel for delivery of activin receptor-like kinase 5 inhibitor
Time Factors; Animals; Body Temperature; *Drug Delivery Systems; Temperature; Rabbits; Benzodioxoles/*administration & dosage/pharmacokinetics/toxicity; Delayed-Action Preparations; Drug Carriers/chemistry/toxicity; Fibroblasts/drug effects/metabolism; Filtering Surgery/*methods; Gels; Glaucoma/*surgery; Imidazoles/*administration & dosage/pharmacokinetics/toxicity; Poloxamer/chemistry/toxicity; Protein-Serine-Threonine Kinases/antagonists & inhibitors; Pyridines/*administration & dosage/pharmacokinetics/toxicity; Viscosity; Receptors; Receptor; Animal; Disease Models; Transforming Growth Factor-beta Type I; Transforming Growth Factor beta/antagonists & inhibitors
The purpose of this study is to investigate a thermoreversible gel using Pluronic
Sutariya Vijaykumar; Miladore Nicholas; Geldenhuys Werner; Bhatia Deepak; Wehrung Daniel; Nakamura Hiroshi
Pharmaceutical development and technology
2013
2013-08
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.3109/10837450.2011.647035" target="_blank" rel="noreferrer noopener">10.3109/10837450.2011.647035</a>
Selenium in the prevention and treatment of hepatocellular carcinoma.
Humans; Animals; Oxidative Stress; Anticarcinogenic Agents/*therapeutic use; Liver Neoplasms/chemically induced/*drug therapy/etiology/*prevention & control; Selenium/*therapeutic use; Carcinoma; Models; Animal; Hepatocellular/chemically induced/*drug therapy/etiology/*prevention & control
Hepatocellular carcinoma (HCC) happens to be one of the most lethal cancers in the world. Even though most cases occur in the developing world, reported cases in Western Europe as well as North America are on a steep rise. Human HCC etiology includes chronic liver disease, viral hepatitis, alcoholism, iron overload as well as dietary carcinogens such as aflatoxins and nitrosoamines. Surgical resection as well as liver transplants, which are currently used to treat HCC, is mostly ineffective. Consequently, there exists a decisive requirement to explore possible alternative chemopreventive and therapeutic strategies for HCC. Both oxidative stress and inflammatory mechanisms have been implicated in the pathophysiology of HCC. The use of dietary antioxidants and micronutrients has been proposed as an effective means for successful management of human HCC. Trace elements such as vanadium and selenium are involved in several major metabolic pathways as well as antioxidant defense systems. Selenium has been shown to be involved in the prevention of numerous chronic illnesses such as several specific cancers and neurodegenerative diseases. This review examines the potential role of selenium in the prevention and treatment of HCC. The in vivo and in vitro effects of selenium and the mechanisms involved in preclinical models of liver cancer are critically reviewed in this article. The chemopreventive and therapeutic effects of selenium are reviewed especially in relation to its antioxidant property. Future directions and potential challenges involved in the advance of selenium use in the prevention and treatment of liver cancer are also discussed.
Darvesh Altaf S; Bishayee Anupam
Anti-cancer agents in medicinal chemistry
2010
2010-05
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.2174/187152010791162252" target="_blank" rel="noreferrer noopener">10.2174/187152010791162252</a>
Novel models for assessing blood-brain barrier drug permeation.
Humans; Animals; Blood-Brain Barrier/*metabolism; *Capillary Permeability; Drosophila melanogaster/metabolism; Grasshoppers/metabolism; High-Throughput Screening Assays; Pharmaceutical Preparations/*metabolism; Zebrafish/metabolism; Models; Animal
INTRODUCTION: The blood-brain barrier (BBB) is a selectively permeable micro-vascular unit which prevents many central nervous system (CNS)-targeted compounds from reaching the brain. A significant problem in CNS drug development is the ability to model BBB permeability in a timely, reproducible and cost-effective manner. Through the years, several models have been used such as artificial membranes, cell culture and animal models. AREAS COVERED: In this focused review, the authors cover novel models which have been developed or are in the process of being developed which can be used in modeling BBB. These models can either be used to determine BBB permeability or whether a compound may be disrupting the BBB. Many of these models lend themselves to high-throughput screening. The main model organisms covered here are the grasshopper (Locusta migratoria), fruit fly (Drosophila melanogaster) and zebrafish (Danio rerio). EXPERT OPINION: Many of the models covered here have only recently been utilized for BBB studies and still needs to be fully studied for its impact on reducing costs during drug development. The strength of these models lay in the fact that a whole organism experiment can be done in high throughput fashion as compared with classical vertebrate models such as micro-dialysis.
Geldenhuys Werner J; Allen David D; Bloomquist Jeffrey R
Expert opinion on drug metabolism & toxicology
2012
2012-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1517/17425255.2012.677433" target="_blank" rel="noreferrer noopener">10.1517/17425255.2012.677433</a>
Salvianolic Acid B Alleviates Heart Failure by Inactivating ERK1/2/GATA4 Signaling Pathway after Pressure Overload in Mice.
Male; Animals; Mice; Phosphorylation/drug effects; Signal Transduction/*drug effects; Rats; Cell Line; Proto-Oncogene Proteins c-akt/metabolism; Benzofurans/chemistry/*pharmacology; Blood Pressure/drug effects; GATA4 Transcription Factor/metabolism; Heart Failure/metabolism/*pathology; Heart Ventricles/diagnostic imaging; Mitogen-Activated Protein Kinase 1/metabolism; Mitogen-Activated Protein Kinase 3/metabolism; Myocardium/metabolism/pathology; Drugs; Inbred C57BL; Animal; Disease Models; Myocytes; Aorta; Brain/blood; Natriuretic Peptide; Cardiac/cytology/drug effects/metabolism; Chinese Herbal/chemistry/pharmacology; Thoracic/surgery
BACKGROUND: Heart failure(HF) is a dangerous disease that affects millions of patients. Radix Salvia is widely used in Chinese clinics to treat heart diseases. Salvianolic acid B(SalB) is the major active component of Radix Salvia. This study investigated the mechanisms of action and effects of SalB on HF in an experimental mouse model of HF. METHODS: We created a mouse model of HF by inducing pressure overload with transverse aortic constriction(TAC) surgery for 2 weeks and compared among 4 study groups: SHAM group (n = 10), TAC group (n = 9), TAC+MET group (metprolol, positive drug treatment, n = 9) and TAC+SalB group (SalB, 240 mg*kg-1*day-1, n = 9). Echocardiography was used to evaluate the dynamic changes in cardiac structure and function in vivo. Plasma brain natriuretic peptide (BNP) concentration was detected by Elisa method. In addition, H9C2 rat cardiomyocytes were cultured and Western blot were implemented to evaluate the phosphorylation of ERK1/2, AKT, and protein expression of GATA4. RESULTS: SalB significantly inhibited the phosphorylation of Thr202/Tyr204 sites of ERK1/2, but not Ser473 site of AKT, subsequently inhibited protein expression of GATA4 and plasma BNP(P \textless 0.001), and then inhibited HF at 2 weeks after TAC surgery. CONCLUSIONS: Our data provide a mechanism of inactivating the ERK1/2/GATA4 signaling pathway for SalB inhibition of the TAC-induced HF.
Yu Juan; Chen Renshan; Tan Yafang; Wu Jiashin; Qi Jianyong; Zhang Minzhou; Gu Weiwang
PloS one
2016
2016
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1371/journal.pone.0166560" target="_blank" rel="noreferrer noopener">10.1371/journal.pone.0166560</a>
Social vocalizations of big brown bats vary with behavioral context.
Animals; *Animal Communication; Chiroptera/*physiology; Electrocardiography; Acoustics; *Behavior; Animal
Bats are among the most gregarious and vocal mammals, with some species demonstrating a diverse repertoire of syllables under a variety of behavioral contexts. Despite extensive characterization of big brown bat (Eptesicus fuscus) biosonar signals, there have been no detailed studies of adult social vocalizations. We recorded and analyzed social vocalizations and associated behaviors of captive big brown bats under four behavioral contexts: low aggression, medium aggression, high aggression, and appeasement. Even limited to these contexts, big brown bats possess a rich repertoire of social vocalizations, with 18 distinct syllable types automatically classified using a spectrogram cross-correlation procedure. For each behavioral context, we describe vocalizations in terms of syllable acoustics, temporal emission patterns, and typical syllable sequences. Emotion-related acoustic cues are evident within the call structure by context-specific syllable types or variations in the temporal emission pattern. We designed a paradigm that could evoke aggressive vocalizations while monitoring heart rate as an objective measure of internal physiological state. Changes in the magnitude and duration of elevated heart rate scaled to the level of evoked aggression, confirming the behavioral state classifications assessed by vocalizations and behavioral displays. These results reveal a complex acoustic communication system among big brown bats in which acoustic cues and call structure signal the emotional state of a caller.
Gadziola Marie A; Grimsley Jasmine M S; Faure Paul A; Wenstrup Jeffrey J
PloS one
2012
1905-7
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1371/journal.pone.0044550" target="_blank" rel="noreferrer noopener">10.1371/journal.pone.0044550</a>
Diminished behavioral and neural sensitivity to sound modulation is associated with moderate developmental hearing loss.
Female; Male; Animals; Gerbillinae; *Attention; *Behavior; Neurons; Animal; Hearing Loss; Afferent/pathology; Conductive/pathology/*physiopathology
The acoustic rearing environment can alter central auditory coding properties, yet altered neural coding is seldom linked with specific deficits to adult perceptual skills. To test whether developmental hearing loss resulted in comparable changes to perception and sensory coding, we examined behavioral and neural detection thresholds for sinusoidally amplitude modulated (sAM) stimuli. Behavioral sAM detection thresholds for slow (5 Hz) modulations were significantly worse for animals reared with bilateral conductive hearing loss (CHL), as compared to controls. This difference could not be attributed to hearing thresholds, proficiency at the task, or proxies for attention. Detection thresholds across the groups did not differ for fast (100 Hz) modulations, a result paralleling that seen in humans. Neural responses to sAM stimuli were recorded in single auditory cortex neurons from separate groups of awake animals. Neurometric analyses indicated equivalent thresholds for the most sensitive neurons, but a significantly poorer detection threshold for slow modulations across the population of CHL neurons as compared to controls. The magnitude of the neural deficit matched that of the behavioral differences, suggesting that a reduction of sensory information can account for limitations to perceptual skills.
Rosen Merri J; Sarro Emma C; Kelly Jack B; Sanes Dan H
PloS one
2012
1905-7
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1371/journal.pone.0041514" target="_blank" rel="noreferrer noopener">10.1371/journal.pone.0041514</a>
Growth hormone injections improve bone quality in a mouse model of osteogenesis imperfecta.
Humans; Time Factors; Animals; Mice; Phenotype; Heterozygote; Body Weight/drug effects; Biomechanical Phenomena; Mutation; Bone and Bones/drug effects; Collagen Type I; Collagen/genetics; Densitometry; Femur/drug effects/pathology; Growth Hormone/*therapeutic use; Lumbar Vertebrae/drug effects; Osteoblasts/*drug effects/metabolism; Osteogenesis Imperfecta/*drug therapy; Inbred C57BL; Animal; Disease Models; Transgenic; Fractures; Bone/prevention & control
UNLABELLED: Systemic growth hormone injections increased spine and femur length in a mouse model of OI. Femur BMC, cross-sectional area, and BMD were increased. Smaller gains were produced in vertebral BMC and cross-sectional area. Biomechanical testing showed improvements to structural and material properties in the femur midshaft, supporting expanded testing of growth hormone therapy in children with OI. INTRODUCTION: Osteoblasts in heterozygous Cola2oim mutant mice produce one-half the normal amounts of the alpha2 strand of type I procollagen. The mice experience a mild osteogenesis imperfecta (OI) phenotype, with femurs and vertebrae that require less force than normal to break in a biomechanical test. MATERIALS AND METHODS: Subcutaneous injections of recombinant human growth hormone (rhGH) or saline were given 6 days per week to oim/+ mice between 3 and 12 weeks of age, in a protocol designed to simulate a trial on OI children. RESULTS: rhGH injections promoted significant weight gain and skeletal growth compared with saline-treated control animals. Femur and spine lengths were increased significantly. Significant increases at the femur midshaft in cortical BMD (2.2%), BMC (15.5%), and cross-sectional area (13%) were produced by rhGH treatment. Increases in the same cortical bone parameters were measured in the metaphyseal region of the femur and in tail vertebrae, but lumbar vertebrae showed significant increases in BMC (9.6%) and cross-sectional area (10.1%) of trabecular bone. Three-point bending testing documented functional improvements to the femur mid-shafts. GH treatment produced significant increases in bone stiffness (23.7%), maximum load (30.8%), the energy absorbed by the femurs to the point of maximum load (44.5%), and the energy to actual fracture (40.4%). The ultimate stress endured by the bone material was increased by 14.1%. CONCLUSIONS: Gains in bone length, cross-sectional area, BMD, BMC, structural biomechanical properties, and strength were achieved without directly addressing the genetic collagen defect in the mice. Results support expanded clinical testing of GH injections in children with OI.
King Donna; Jarjoura David; McEwen Heather A; Askew Michael J
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
2005
2005-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1359/JBMR.050108" target="_blank" rel="noreferrer noopener">10.1359/JBMR.050108</a>
Acute exercise attenuates phenylephrine-induced contraction of rabbit isolated aortic rings.
Animals; Rabbits; In Vitro Techniques; Phenylephrine/*pharmacology; Aorta/physiology; Muscle Contraction/*drug effects; Dose-Response Relationship; Drug; Muscle; Receptors; Animal; Smooth; Adrenergic; *Physical Conditioning; alpha/physiology; Vascular/*drug effects/physiology
Factors associated with a single bout of dynamic exercise (increased circulating catecholamines, increased body temperature, and decreased pH) are known to attenuate the vascular response to alpha-adrenergic receptor activation. Therefore, we postulate that an acute bout of dynamic exercise may decrease the vascular response to catecholamines. To test this hypothesis, we evaluated contractile responsiveness to phenylephrine (PE) in aortae of two groups of New Zealand white rabbits, a control group (no exercise) and an exercise group (treadmill running, 24m.min-1; 16 +/- 2.0 min). Aortic rings were prepared from age-matched control (N = 6) and exercise rabbits (N = 5) and mounted for isometric tension recording (in Krebs-Henseleit-bicarbonate solution, 37 degrees C, 1.5 g passive tension). After equilibration (2 h) a cumulative concentration-response curve to PE (10(-7) M-10(-2) M) was obtained. The results demonstrate that a single bout of dynamic exercise attenuates (P \textless 0.05) the maximal contractile tension (2,457 +/- 120 vs 3,620 +/- 321 mg tension.mg-1 ring wt), gain (602 +/- 31 vs 878 +/- 87 mg.M-1 PE), and rate of contraction (6.2 +/- 0.3 vs 4.7 +/- 0.3 mg tension.s-1). In addition, contraction threshold was significantly increased in exercise (2.6 +/- 0.4 x 10(-6) M) vs control aortae (1.03 +/- 0.4 x 10(-6) M). A single bout of dynamic exercise did not alter the contractile response to 70 mM KCl (3,555 +/- 270 vs 3,083 +/- 233 mg tension.mg-1 ring weight). These data suggest that an acute bout of dynamic exercise significantly attenuates alpha-adrenergic receptor-mediated contraction of vascular smooth muscle.
Howard M G; DiCarlo S E; Stallone J N
Medicine and science in sports and exercise
1992
1992-10
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1249/00005768-199210000-00006" target="_blank" rel="noreferrer noopener">10.1249/00005768-199210000-00006</a>
Cholesterol 7alpha-hydroxylase-deficient mice are protected from high-fat/high-cholesterol diet-induced metabolic disorders.
*bile acids and salt/metabolism; *cholesterol/diet; *lipids; *liver; Animal; Animals; Bile Acids and Salts/genetics/metabolism; Cholesterol 7-alpha-Hydroxylase/*genetics/metabolism; Cholesterol/*metabolism; Diet; Disease Models; Exhalation/genetics; Glucose/metabolism; High-Fat; Homeostasis; Humans; Lipid Metabolism/genetics; Liver/enzymology/pathology; Metabolic Diseases/*genetics/metabolism; Mice
Cholesterol 7alpha-hydroxylase (CYP7A1) is the first and rate-limiting enzyme in the conversion of cholesterol to bile acids in the liver. In addition to absorption and digestion of nutrients, bile acids play a critical role in the regulation of lipid, glucose, and energy homeostasis. We have backcrossed Cyp7a1(-/-) mice in a mixed B6/129Sv genetic background to C57BL/6J mice to generate Cyp7a1(-/-) mice in a near-pure C57BL/6J background. These mice survive well and have normal growth and a bile acid pool size approximately 60% of WT mice. The expression of the genes in the alternative bile acid synthesis pathway are upregulated, resulting in a more hydrophilic bile acid composition with reduced cholic acid (CA). Surprisingly, Cyp7a1(-/-) mice have improved glucose sensitivity with reduced liver triglycerides and fecal bile acid excretion, but increased fecal fatty acid excretion and respiratory exchange ratio (RER) when fed a high-fat/high-cholesterol diet. Supplementing chow and Western diets with CA restored bile acid composition, reversed the glucose tolerant phenotype, and reduced the RER. Our current study points to a critical role of bile acid composition, rather than bile acid pool size, in regulation of glucose, lipid, and energy metabolism to improve glucose and insulin tolerance, maintain metabolic homeostasis, and prevent high-fat diet-induced metabolic disorders.
Ferrell Jessica M; Boehme Shannon; Li Feng; Chiang John Y L
Journal of lipid research
2016
2016-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1194/jlr.M064709" target="_blank" rel="noreferrer noopener">10.1194/jlr.M064709</a>
Aldo-keto reductase 1B7 is a target gene of FXR and regulates lipid and glucose homeostasis.
*Aldehyde Reductase/genetics/metabolism; Adenoviridae; Animal; Animals; Blood Glucose/*metabolism; Cholesterol/analysis; Cytoplasmic and Nuclear/genetics/*metabolism; Diabetes Mellitus/genetics/*metabolism/physiopathology; Disease Models; Fatty Liver/genetics/*metabolism/physiopathology; Gene Expression; Genetic Vectors; Gluconeogenesis/genetics; Homeostasis; Humans; Liver/*metabolism/physiopathology; Malondialdehyde/blood; Mice; Polymerase Chain Reaction; Receptors; Transfection; Transgenic; Triglycerides/analysis
Aldo-keto reductase 1B7 (AKR1B7) is proposed to play a role in detoxification of by-products of lipid peroxidation. In this article, we show that activation of the nuclear receptor farnesoid X receptor (FXR) induces AKR1B7 expression in the liver and intestine, and reduces the levels of malondialdehyde (MDA), the end product of lipid peroxidation, in the intestine but not in the liver. To determine whether AKR1B7 regulates MDA levels in vivo, we overexpressed AKR1B7 in the liver. Overexpression of AKR1B7 in the liver had no effect on hepatic or plasma MDA levels. Interestingly, hepatic expression of AKR1B7 significantly lowered plasma glucose levels in both wild-type and diabetic db/db mice, which was associated with reduced hepatic gluconeogenesis. Hepatic expression of AKR1B7 also significantly lowered hepatic triglyceride and cholesterol levels in db/db mice. These data reveal a novel function for AKR1B7 in lipid and glucose metabolism and suggest that AKR1B7 may not play a role in detoxification of lipid peroxides in the liver. AKR1B7 may be a therapeutic target for treatment of fatty liver disease associated with diabetes mellitus.
Ge Xuemei; Yin Liya; Ma Huiyan; Li Tiangang; Chiang John Y L; Zhang Yanqiao
Journal of lipid research
2011
2011-08
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1194/jlr.M015859" target="_blank" rel="noreferrer noopener">10.1194/jlr.M015859</a>
Turnover of histones and histone variants in postnatal rat brain: effects of alcohol exposure.
*2H2O-labeling; *Brain; *Genetic Variation; *Histone; *Mass spectrometry; *Post-translational modifications; *Postnatal alcohol exposure; *Turnover; Acetylation; Animal; Animals; Cell Proliferation; Disease Models; DNA Damage; Epigenesis; Female; Fetal Alcohol Spectrum Disorders/genetics/*metabolism; Genetic; Histones/*genetics/*metabolism; Humans; Post-Translational; Pregnancy; Protein Processing; Proteomics/*methods; Rats; Sprague-Dawley
BACKGROUND: Alcohol consumption during pregnancy is a significant public health problem and can result in a continuum of adverse outcomes to the fetus known as fetal alcohol spectrum disorders (FASD). Subjects with FASD show significant neurological deficits, ranging from microencephaly, neurobehavioral, and mental health problems to poor social adjustment and stress tolerance. Neurons are particularly sensitive to alcohol exposure. The neurotoxic action of alcohol, i.e., through ROS production, induces DNA damage and neuronal cell death by apoptosis. In addition, epigenetics, including DNA methylation, histone posttranslational modifications (PTMs), and non-coding RNA, play an important role in the neuropathology of FASD. However, little is known about the temporal dynamics and kinetics of histones and their PTMs in FASD. RESULTS: We examined the effects of postnatal alcohol exposure (PAE), an animal model of human third-trimester equivalent, on the kinetics of various histone proteins in two distinct brain regions, the frontal cortex, and the hypothalamus, using in vivo (2)H2O-labeling combined with mass spectrometry-based proteomics. We show that histones have long half-lives that are in the order of days. We also show that H3.3 and H2Az histone variants have faster turnovers than canonical histones and that acetylated histones, in general, have a faster turnover than unmodified and methylated histones. Our work is the first to show that PAE induces a differential reduction in turnover rates of histones in both brain regions studied. These alterations in histone turnover were associated with increased DNA damage and decreased cell proliferation in postnatal rat brain. CONCLUSION: Alterations in histone turnover might interfere with histone deposition and chromatin stability, resulting in deregulated cell-specific gene expression and therefore contribute to the development of the neurological disorders associated with FASD. Using in vivo (2)H2O-labeling and mass spectrometry-based proteomics might help in the understanding of histone turnover following alcohol exposure and could be of great importance in enabling researchers to identify novel targets and/or biomarkers for the prevention and management of fetal alcohol spectrum disorders.
Rachdaoui Nadia; Li Ling; Willard Belinda; Kasumov Takhar; Previs Stephen; Sarkar Dipak
Clinical epigenetics
2017
1905-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1186/s13148-017-0416-5" target="_blank" rel="noreferrer noopener">10.1186/s13148-017-0416-5</a>
TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy.
*Alzheimers disease; *Immunity; *Inflammation; *Tauopathy; *TREM2; Animal; Animals; Disease Models; Humans; Immunologic/*deficiency; Inbred C57BL; Membrane Glycoproteins/*deficiency; Mice; Microglia/metabolism; Protein Kinases/*metabolism; Receptors; Signal Transduction/physiology; tau Proteins/*metabolism; Tauopathies/metabolism/*pathology; Transgenic
BACKGROUND: Genetic variants of the Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) confer increased risk of developing late-onset Alzheimer's Disease (LOAD) and other neurodegenerative disorders. Recent studies provided insight into the multifaceted roles of TREM2 in regulating extracellular beta-amyloid (Abeta) pathology, myeloid cell accumulation, and inflammation observed in AD, yet little is known regarding the role of TREM2 in regulating intracellular microtubule associated protein tau (MAPT; tau) pathology in neurodegenerative diseases and in AD, in particular. RESULTS: Here we report that TREM2 deficiency leads to accelerated and exacerbated hyperphosphorylation and aggregation of tau in a humanized mouse model of tauopathy. TREM2 deficiency also results, indirectly, in dramatic widespread dysregulation of neuronal stress kinase pathways. CONCLUSIONS: Our results suggest that deficiency of microglial TREM2 leads to heightened tau pathology coupled with widespread increases in activated neuronal stress kinases. These findings offer new insight into the complex, multiple roles of TREM2 in regulating Abeta and tau pathologies.
Bemiller Shane M; McCray Tyler J; Allan Kevin; Formica Shane V; Xu Guixiang; Wilson Gina; Kokiko-Cochran Olga N; Crish Samuel D; Lasagna-Reeves Cristian A; Ransohoff Richard M; Landreth Gary E; Lamb Bruce T
Molecular neurodegeneration
2017
2017-10
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1186/s13024-017-0216-6" target="_blank" rel="noreferrer noopener">10.1186/s13024-017-0216-6</a>
Reduced AMPK activation and increased HCAR activation drive anti-inflammatory response and neuroprotection in glaucoma.
AMP-activated protein kinase; AMP-Activated Protein Kinases/*metabolism; Animal; Animals; Biological; Calcium Binding Proteins – Metabolism; Calcium-Binding Proteins/metabolism; Cells – Drug Effects; Cells – Pathology; Diet; Disease Models; Eye Proteins/genetics; Female; G-Protein-Coupled – Metabolism; G-Protein-Coupled/*metabolism; Glaucoma; Glaucoma – Complications; Glaucoma – Pathology; Glaucoma/*complications/pathology; Impact of Events Scale; Inbred DBA; Inflammation – Etiology; Inflammation – Prevention and Control; Inflammation hydroxycarboxylic acid receptor; Inflammation/*etiology/*prevention & control; Ketogenic diet; Ketogenic/methods; Male; Membrane Glycoproteins; Membrane Glycoproteins/genetics; Mice; Microfilament Proteins – Metabolism; Microfilament Proteins/metabolism; Microglia/drug effects/pathology; Models; Mutation; Mutation/genetics; Neuroprotection/drug effects/*physiology; NLR Family; Optic Nerve – Pathology; Optic Nerve/pathology; Phosphotransferases – Metabolism; Proteins; Pyrin Domain-Containing 3 Protein/genetics/metabolism; Receptors; Retina – Drug Effects; Retina – Pathology; Retinal Ganglion Cells/drug effects/*pathology; Transgenic
BACKGROUND: Glaucoma is a chronic degenerative disease for which inflammation is considered to play a pivotal role in the pathogenesis and progression. In this study, we examined the impact of a ketogenic diet on the inflammation evident in glaucoma as a follow-up to a recent set of experiments in which we determined that a ketogenic diet protected retinal ganglion cell structure and function. METHODS: Both sexes of DBA/2J (D2) mice were placed on a ketogenic diet (keto) or standard rodent chow (untreated) for 8 weeks beginning at 9 months of age. DBA/2J-Gpnmb(+) (D2G) mice were also used as a non-pathological genetic control for the D2 mice. Retina and optic nerve (ON) tissues were micro-dissected and used for the analysis of microglia activation, expression of pro- and anti-inflammatory molecules, and lactate- or ketone-mediated anti-inflammatory signaling. Data were analyzed by immunohistochemistry, quantitative RT-PCR, ELISA, western blot, and capillary tube-based electrophoresis techniques. RESULTS: Microglia activation was observed in D2 retina and ON as documented by intense microglial-specific Iba1 immunolabeling of rounded-up and enlarged microglia. Ketogenic diet treatment reduced Iba1 expression and the activated microglial phenotype. We detected low energy-induced AMP-activated protein kinase (AMPK) phosphorylation in D2 retina and ON that triggered NF-kappaB p65 signaling through its nuclear translocation. NF-kappaB induced pro-inflammatory TNF-alpha,
Harun-Or-Rashid Mohammad; Inman Denise M
Journal of neuroinflammation
2018
2018-11
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1186/s12974-018-1346-7" target="_blank" rel="noreferrer noopener">10.1186/s12974-018-1346-7</a>
Genetically enhancing the expression of chemokine domain of CX3CL1 fails to prevent tau pathology in mouse models of tauopathy.
Alzheimer's disease; Animal; Animals; Antigens; Biological; Calcium Binding Proteins – Metabolism; Calcium-Binding Proteins/metabolism; Cells – Drug Effects; Cells – Metabolism; Cells – Pathology; Chemokine CX3CL1/*genetics/metabolism; Cognition Disorders – Etiology; Cognition Disorders/etiology; CX3CL1; CX3CR1; Cytokines; Cytokines – Metabolism; Cytokines/metabolism; Differentiation/genetics/metabolism; Disease Models; Gene Expression Regulation/drug effects/*genetics; Genes; Genes – Drug Effects; Learning; Lipopolysaccharides; Lipopolysaccharides/toxicity; Maze Learning; Mice; Microfilament Proteins – Metabolism; Microfilament Proteins/metabolism; Microglia; Microglia/drug effects/*metabolism/pathology; Models; Mutation; Mutation/genetics; Nerve Tissue Proteins; Nerve Tissue Proteins – Metabolism; Neurodegenerative Diseases; Neurodegenerative Diseases – Complications; Neurodegenerative Diseases – Pathology; Neuroinflammation; Surface; Surface – Metabolism; Tau; tau Proteins/genetics/metabolism; Tauopathies; Tauopathies/complications/genetics/*pathology; Transgenic
BACKGROUND: Fractalkine (CX3CL1) and its receptor (CX3CR1) play an important role in regulating microglial function. We have previously shown that Cx3cr1 deficiency exacerbated tau pathology and led to cognitive impairment. However, it is still unclear if the chemokine domain of the ligand CX3CL1 is essential in regulating neuronal tau pathology. METHODS: We used transgenic mice lacking endogenous Cx3cl1 (Cx3cl1(-/-)) and expressing only obligatory soluble form (with only chemokine domain) and lacking the mucin stalk of CX3CL1 (referred to as Cx3cl1(105Delta) mice) to assess tau pathology and behavioral function in both lipopolysaccharide (LPS) and genetic (hTau) mouse models of tauopathy. RESULTS: First, increased basal tau levels accompanied microglial activation in Cx3cl1(105Delta) mice compared to control groups. Second, increased CD45(+) and F4/80(+) neuroinflammation and tau phosphorylation were observed in LPS, hTau/Cx3cl1(-/-), and hTau/Cx3cl1(105Delta) mouse models of tau pathology, which correlated with impaired spatial learning. Finally, microglial cell surface expression of CX3CR1 was reduced in Cx3cl1(105Delta) mice, suggesting enhanced fractalkine receptor internalization (mimicking Cx3cr1 deletion), which likely contributes to the elevated tau pathology. CONCLUSIONS: Collectively, our data suggest that overexpression of only chemokine domain of CX3CL1 does not protect against tau pathology.
Bemiller Shane M; Maphis Nicole M; Formica Shane V; Wilson Gina N; Miller Crystal M; Xu Guixiang; Kokiko-Cochran Olga N; Kim Ki-Wook; Jung Steffen; Cannon Judy L; Crish Samuel D; Cardona Astrid E; Lamb Bruce T; Bhaskar Kiran
Journal of neuroinflammation
2018
2018-09
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1186/s12974-018-1310-6" target="_blank" rel="noreferrer noopener">10.1186/s12974-018-1310-6</a>
Qualitative skeletal correlates of wing shape in extant birds (Aves: Neoaves).
*Flight; Animal; Animal/*anatomy & histology/physiology; Animals; Biological Evolution; Birds/*anatomy & histology/classification/*physiology; Bone and Bones/anatomy & histology; Feathers; Fossils; Phylogeny; Wings
BACKGROUND: Among living fliers (birds, bats, and insects), birds display relatively high aspect ratios, a dimensionless shape variable that distinguishes long and narrow vs. short and broad wings. Increasing aspect ratio results in a functional tradeoff between low induced drag (efficient cruise) and increased wing inertia (difficult takeoff). Given the wide scope of its functional effects, the pattern of aspect ratio evolution is an important factor that contributes to the substantial ecological and phylogenetic diversity of living birds. However, because the feathers that define the wingtip (and hence wingspan and aspect ratio) often do not fossilize, resolution in the pattern of avian wing shape evolution is obscured by missing information. Here I use a comparative approach to investigate the relationship between skeletal proxies of flight feather attachment and wing shape. RESULTS: An accessory lobe of the internal index process of digit II-1, a bony correlate of distal primary attachment, shows weak but statistically significant relationships to aspect ratio and mass independent of other skeletal morphology. The dorsal phalangeal fossae of digit II-1, which house distal primaries VIII and IX, also show a trend of increased prominence with higher aspect ratio. Quill knobs on the ulna are examined concurrently, but do not show consistent signal with respect to wing shape. CONCLUSIONS: Although quill knobs are cited as skeletal correlates of flight performance in birds, their relationship to wing shape is inconsistent among extant taxa, and may reflect diverging selection pressures acting on a conserved architecture. In contrast, correlates of distal primary feather attachment on the major digit show convergent responses to increasing aspect ratio. In light of the diversity of musculoskeletal and integumentary mophology that underlies wing shape in different avian clades, it is unlikely that a single skeletal feature will show consistent predictive power across Neoaves. Confident inference of wing shape in basal ornithurine birds will require multiple lines of evidence, together with an understanding of clade-specific evolutionary trends within the crown.
Hieronymus Tobin L
BMC evolutionary biology
2015
2015-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1186/s12862-015-0303-7" target="_blank" rel="noreferrer noopener">10.1186/s12862-015-0303-7</a>
Suppression of acute proinflammatory cytokine and chemokine upregulation by post-injury administration of a novel small molecule improves long-term neurologic outcome in a mouse model of traumatic brain injury.
Animal; Animals; Brain Injuries/blood/epidemiology/genetics/*physiopathology; Cerebral Cortex/physiopathology; Chemokine CCL2/genetics/physiology; Chemokines/*genetics; Cytokines/*antagonists & inhibitors; Disease Models; Hippocampus/physiopathology; Inflammation/genetics/*physiopathology; Interleukin-1beta/genetics/physiology; Interleukin-6/genetics/physiology; Male; Mice; Tumor Necrosis Factor-alpha/genetics/physiology; United States/epidemiology; Up-Regulation
BACKGROUND: Traumatic brain injury (TBI) with its associated morbidity is a major area of unmet medical need that lacks effective therapies. TBI initiates a neuroinflammatory cascade characterized by activation of astrocytes and microglia, and increased production of immune mediators including proinflammatory cytokines and chemokines. This inflammatory response contributes both to the acute pathologic processes following TBI including cerebral edema, in addition to longer-term neuronal damage and cognitive impairment. However, activated glia also play a neuroprotective and reparative role in recovery from injury. Thus, potential therapeutic strategies targeting the neuroinflammatory cascade must use careful dosing considerations, such as amount of drug and timing of administration post injury, in order not to interfere with the reparative contribution of activated glia. METHODS: We tested the hypothesis that attenuation of the acute increase in proinflammatory cytokines and chemokines following TBI would decrease neurologic injury and improve functional neurologic outcome. We used the small molecule experimental therapeutic, Minozac (Mzc), to suppress TBI-induced up-regulation of glial activation and proinflammatory cytokines back towards basal levels. Mzc was administered in a clinically relevant time window post-injury in a murine closed-skull, cortical impact model of TBI. Mzc effects on the acute increase in brain cytokine and chemokine levels were measured as well as the effect on neuronal injury and neurobehavioral function. RESULTS: Administration of Mzc (5 mg/kg) at 3 h and 9 h post-TBI attenuates the acute increase in proinflammatory cytokine and chemokine levels, reduces astrocyte activation, and the longer term neurologic injury, and neurobehavioral deficits measured by Y maze performance over a 28-day recovery period. Mzc-treated animals also have no significant increase in brain water content (edema), a major cause of the neurologic morbidity associated with TBI. CONCLUSION: These results support the hypothesis that proinflammatory cytokines contribute to a glial activation cycle that produces neuronal dysfunction or injury following TBI. The improvement in long-term functional neurologic outcome following suppression of cytokine upregulation in a clinically relevant therapeutic window indicates that selective targeting of neuroinflammation may lead to novel therapies for the major neurologic morbidities resulting from head injury, and indicates the potential of Mzc as a future therapeutic for TBI.
Lloyd Eric; Somera-Molina Kathleen; Van Eldik Linda J; Watterson D Martin; Wainwright Mark S
Journal of neuroinflammation
2008
2008-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1186/1742-2094-5-28" target="_blank" rel="noreferrer noopener">10.1186/1742-2094-5-28</a>
Mitochondrial morphology differences and mitophagy deficit in murine glaucomatous optic nerve.
*Disease Models; Adenosine Triphosphate/metabolism; Age Factors; Animal; Animals; autophagosome; Axons/pathology; Electron; Inbred DBA; Mice; Microscopy; mitochondria; Mitochondria/*pathology; Mitochondrial Degradation/*physiology; mitophagy; Myelinated/pathology; Nerve Fibers; Optic Nerve/*pathology
PURPOSE: Decreased ATP correlates with intraocular pressure exposure in the optic nerves of mice with glaucoma. To understand what underlies this energy deficit, we examined mitochondria in the myelinated optic nerve axons of the DBA/2J mouse, a model of glaucoma secondary to iris pigment disease, and the DBA/2(wt-gpnmb) control strain. METHODS: Mitochondrial length, width, surface area, and health status were measured in 30 electron microscopic fields within the myelinated portion of optic nerves from DBA/2J and DBA/2(wt-gpnmb) mice at 3, 6, and 10 months of age. Protein was isolated from optic nerve for analysis of PINK1, Parkin, LC3-I and -II, and lysosome-associated membrane protein 1 (LAMP1) by Western blot. RESULTS: The number of mitochondria in DBA/2J optic nerve was increased, and they had significantly smaller surface area. Mitochondria in DBA/2J were closer to the axolemma, more spatially isolated, and their cristae were more disrupted at every age group as compared to DBA/2(wt-gpnmb). Autophagosomes were significantly increased in DBA/2J optic nerve at all ages. Protein analysis showed higher LC3-II to LC3-I ratio in aged DBA/2J optic nerve than in DBA/2(wt-gpnmb). PINK1 and Parkin levels were not statistically different across age groups. LAMP1 was significantly decreased in the aged DBA/2J optic nerve. CONCLUSIONS: Decreased surface area, combined with reduced oxidative capacity in mitochondria from the aged DBA/2J axon, indicate that mitochondrial pathology may contribute to the energy deficit in glaucomatous optic nerve. Though autophagosomes were increased in DBA/2J optic nerve, the increased mitochondria and decreased LAMP1 suggest deteriorating mitochondria are not being efficiently recycled by mitophagy.
Coughlin Lucy; Morrison Richard S; Horner Philip J; Inman Denise M
Investigative ophthalmology & visual science
2015
2015-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1167/iovs.14-16126" target="_blank" rel="noreferrer noopener">10.1167/iovs.14-16126</a>
Adrenal epinephrine increases alveolar liquid clearance in a canine model of neurogenic pulmonary edema.
Adrenal Glands/*metabolism; Adrenalectomy; Adrenergic beta-Agonists/blood/*pharmacology/therapeutic use; Adrenergic beta-Antagonists/therapeutic use; Amiloride/therapeutic use; Animal; Animals; Blood; Blood Pressure; Brain Diseases/chemically induced/*complications; Central Nervous System Agents/adverse effects; Cisterna Magna; Disease Models; Diuretics/therapeutic use; Dogs; Epinephrine/blood/*physiology/therapeutic use; Extravascular Lung Water/chemistry/*metabolism; Female; Hypertension; Injections; Male; Propanolamines/therapeutic use; Proteins/analysis; Pulmonary Alveoli/*metabolism; Pulmonary Artery; Pulmonary Edema/etiology/*metabolism/prevention & control; Pulmonary/prevention & control; Sodium Channel Blockers; Veratrine/adverse effects
Case reports of neurogenic pulmonary edema (NPE) often indicate that the edema resolves quickly. Because plasma epinephrine concentration may be elevated in NPE, and epinephrine has been shown to increase the rate of alveolar liquid clearance (ALC), we determined if ALC was increased in a canine model of NPE produced by the intracisternal administration of veratrine. ALC was determined by instilling autologous plasma into a lower lung lobe and using the increase in instillate protein concentration after 4 h to calculate the volume of fluid cleared from the airspaces by mass balance. To prevent pulmonary hypertension and edema, which would confound the mass balance analysis, carotid arterial blood was allowed to drain into a reservoir as pulmonary arterial pressure started to rise after veratrine administration. ALC in animals administered veratrine (n = 6) was 30.4 +/- 1.6 (SE)% of the instilled volume compared with 14.1 +/- 2.1% observed in control animals. The increase in ALC could be inhibited by adrenalectomy, beta2-adrenergic blockade using ICI 118,551, or sodium channel blockade using amiloride and could be duplicated by infusing epinephrine to increase plasma epinephrine concentration to levels observed in NPE. These data indicate that the increased ALC was mediated by adrenal epinephrine and suggest that edema resolution in patients with NPE might be accelerated by endogenous epinephrine.
Lane S M; Maender K C; Awender N E; Maron M B
American journal of respiratory and critical care medicine
1998
1998-09
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1164/ajrccm.158.3.9802031" target="_blank" rel="noreferrer noopener">10.1164/ajrccm.158.3.9802031</a>
Absence of type VI collagen paradoxically improves cardiac function, structure, and remodeling after myocardial infarction.
Animal; Animals; Apoptosis/physiology; Cardiac/pathology/physiology; Collagen Type VI/*genetics/*metabolism; Disease Models; Echocardiography; Extracellular Matrix/metabolism/pathology; Fibrosis/genetics/pathology/physiopathology; Knockout; Male; Mice; Myocardial Infarction/diagnostic imaging/*genetics/*physiopathology; Myocytes; Ventricular Remodeling/*physiology
RATIONALE: We previously reported that type VI collagen deposition increases in the infarcted myocardium in vivo. To date, a specific role for this nonfibrillar collagen has not been explored in the setting of myocardial infarction (MI). OBJECTIVE: To determine whether deletion of type VI collagen in an in vivo model of post-MI wound healing would alter cardiac function and remodeling in the days to weeks after injury. METHODS AND RESULTS: Wild-type and Col6a1(-/-) mice were subjected to MI, followed by serial echocardiographic and histological assessments. At 8 weeks after MI, infarct size was significantly reduced, ejection fraction was significantly preserved (43.9% +/- 3.3% versus 29.1% +/- 4.3% for wild-type), and left ventricular chamber dilation was attenuated in the Col6a1(-/-) MI group (25.8% +/- 7.9% increase versus 62.6% +/- 16.5% for wild-type). The improvement in cardiac remodeling was evident as early as 10 days after MI in the Col6a1(-/-) mice. Myocyte apoptosis within the infarcted zones was initially greater in the Col6a1(-/-) group 3 days after MI, but by day 14 this was significantly reduced. Collagen deposition also was reduced in the infarcted and remote areas of the Col6a1(-/-) hearts. The reductions in chronic myocyte apoptosis and fibrosis are critical events leading to improved long-term remodeling and functional outcomes. CONCLUSIONS: These unexpected results demonstrate for the first time that deletion of type VI collagen in this knockout model plays a critical protective role after MI by limiting infarct size, chronic apoptosis, aberrant remodeling, and fibrosis, leading to preservation of cardiac function.
Luther Daniel J; Thodeti Charles K; Shamhart Patricia E; Adapala Ravi K; Hodnichak Cheryl; Weihrauch Dorothee; Bonaldo Paolo; Chilian William M; Meszaros J Gary
Circulation research
2012
2012-03
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1161/CIRCRESAHA.111.252734" target="_blank" rel="noreferrer noopener">10.1161/CIRCRESAHA.111.252734</a>
Induction of vascular progenitor cells from endothelial cells stimulates coronary collateral growth.
*Collateral Circulation; *Coronary Circulation; Animal; Animals; Biomarkers/metabolism; Cell Differentiation; Cell Lineage; Cells; Coronary Occlusion/genetics/metabolism/pathology/physiopathology/*surgery; Coronary Vessels/metabolism/pathology/*physiopathology; Cultured; Developmental; Disease Models; Endothelial Cells/metabolism/pathology/*transplantation; Epigenesis; Gene Expression Profiling; Gene Expression Regulation; Genetic; Induced Pluripotent Stem Cells/metabolism/*transplantation; Mice; Muscle; Myocytes; Neovascularization; Physiologic; Rats; Regenerative Medicine/methods; Regional Blood Flow; Reverse Transcriptase Polymerase Chain Reaction; SCID; Smooth; Smooth Muscle/metabolism/pathology/*transplantation; Sprague-Dawley; Teratoma/metabolism/pathology; Time Factors; Transcription Factors/genetics/metabolism; Transduction; Vascular/metabolism/pathology/*physiopathology
RATIONALE: A well-developed coronary collateral circulation improves the morbidity and mortality of patients following an acute coronary occlusion. Although regenerative medicine has great potential in stimulating vascular growth in the heart, to date there have been mixed results, and the ideal cell type for this therapy has not been resolved. OBJECTIVE: To generate induced vascular progenitor cells (iVPCs) from endothelial cells, which can differentiate into vascular smooth muscle cells (VSMCs) or endothelial cells (ECs), and test their capability to stimulate coronary collateral growth. METHODS AND RESULTS: We reprogrammed rat ECs with the transcription factors Oct4, Klf4, Sox2, and c-Myc. A population of reprogrammed cells was derived that expressed pluripotent markers Oct4, SSEA-1, Rex1, and AP and hemangioblast markers CD133, Flk1, and c-kit. These cells were designated iVPCs because they remained committed to vascular lineage and could differentiate into vascular ECs and VSMCs in vitro. The iVPCs demonstrated better in vitro angiogenic potential (tube network on 2-dimensional culture, tube formation in growth factor reduced Matrigel) than native ECs. The risk of teratoma formation in iVPCs is also reduced in comparison with fully reprogrammed induced pluripotent stem cells (iPSCs). When iVPCs were implanted into myocardium, they engrafted into blood vessels and increased coronary collateral flow (microspheres) and improved cardiac function (echocardiography) better than iPSCs, mesenchymal stem cells, native ECs, and sham treatments. CONCLUSIONS: We conclude that iVPCs, generated by partially reprogramming ECs, are an ideal cell type for cell-based therapy designed to stimulate coronary collateral growth.
Yin Liya; Ohanyan Vahagn; Pung Yuh Fen; Delucia Angelo; Bailey Erin; Enrick Molly; Stevanov Kelly; Kolz Christopher L; Guarini Giacinta; Chilian William M
Circulation research
2012
2012-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1161/CIRCRESAHA.111.250126" target="_blank" rel="noreferrer noopener">10.1161/CIRCRESAHA.111.250126</a>
Isolation of canine coronary sinus musculature from the atria by radiofrequency catheter ablation prevents induction of atrial fibrillation.
*Catheter Ablation; Acetylcholine; Action Potentials; Animal; Animal Studies; Animals; Artificial; atrial fibrillation; Atrial Fibrillation – Etiology; Atrial Fibrillation – Physiopathology; Atrial Fibrillation – Prevention and Control; Atrial Fibrillation/etiology/physiopathology/*prevention & control; Biological; Body Surface Potential Mapping; Cardiac Pacing; catheter ablation; Catheter Ablation; coronary sinus; Coronary Sinus/physiopathology/*surgery; Coronary Vessels – Physiopathology; Coronary Vessels – Surgery; Disease Models; Dogs; Heart Atria/physiopathology/surgery; Heart Atrium – Physiopathology; Heart Atrium – Surgery; Male; Models; optical Vm mapping; Time Factors
BACKGROUND: The junction between the coronary sinus (CS) musculature and both atria contributes to initiation of atrial tachyarrhythmias. The current study investigated the effects of CS isolation from the atria by radiofrequency catheter ablation on the induction and maintenance of atrial fibrillation (AF). METHODS AND RESULTS: Using an optical mapping system, we mapped action potentials at 256 surface sites in 17 isolated and arterially perfused canine atrial tissues containing the entire musculature of the CS, right atrial septum, posterior left atrium, left inferior pulmonary vein, and vein of Marshal. Rapid pacing from each site before and after addition of acetylcholine (0.5 mumol/L) was applied to induce AF. Epicardial radiofrequency catheter ablation at CS-atrial junctions isolated the CS from the atria. Rapid pacing induced sustained AF in all tissues after acetylcholine. Microreentry within the CS drove AF in 88% of preparations. Reentries associated with the vein of Marshall (29%), CS-atrial junctions (53%), right atrium (65%), and pulmonary vein (76%) (frequently with 2-4 simultaneous circuits) were additional drivers of AF. Radiofrequency catheter ablation eliminated AF in 13 tissues before acetylcholine (P\textless0.01) and in 5 tissues after acetylcholine. Radiofrequency catheter ablation also abbreviated the duration of AF in 12 tissues (P\textless0.01). CONCLUSIONS: CS and its musculature developed unstable reentry and AF, which were prevented by isolation of CS musculature from atrial tissue. The results suggest that CS can be a substrate of recurrent AF in patients after pulmonary vein isolation and that CS isolation might help prevent recurrent AF.
Morita Hiroshi; Zipes Douglas P; Morita Shiho T; Wu Jiashin
Circulation. Arrhythmia and electrophysiology
2014
2014-12
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1161/CIRCEP.114.001578" target="_blank" rel="noreferrer noopener">10.1161/CIRCEP.114.001578</a>
Mitochondrial oxidative stress corrupts coronary collateral growth by activating adenosine monophosphate activated kinase-alpha signaling.
AMP-Activated Protein Kinases/*metabolism; Animal; Animals; Body Weight/physiology; Cells; collateral circulation; coronary circulation; Coronary Vessels/cytology/*enzymology; Cultured; Disease Models; Endothelial Cells/cytology/*enzymology; Humans; Inbred WKY; Ischemia/metabolism/pathology; mitochondria; Mitochondria/drug effects/*metabolism; Myocardium/enzymology/pathology; Oxidative Stress/*physiology; Rats; reactive oxygen species; Rotenone/pharmacology; Signal Transduction/*physiology; TOR Serine-Threonine Kinases/metabolism; Uncoupling Agents/pharmacology
OBJECTIVE: Our goal was to determine the mechanism by which mitochondrial oxidative stress impairs collateral growth in the heart. APPROACH AND RESULTS: Rats were treated with rotenone (mitochondrial complex I inhibitor that increases reactive oxygen species production) or sham-treated with vehicle and subjected to repetitive ischemia protocol for 10 days to induce coronary collateral growth. In control rats, repetitive ischemia increased flow to the collateral-dependent zone; however, rotenone treatment prevented this increase suggesting that mitochondrial oxidative stress compromises coronary collateral growth. In addition, rotenone also attenuated mitochondrial complex I activity and led to excessive mitochondrial aggregation. To further understand the mechanistic pathway(s) involved, human coronary artery endothelial cells were treated with 50 ng/mL vascular endothelial growth factor, 1 micromol/L rotenone, and rotenone/vascular endothelial growth factor for 48 hours. Vascular endothelial growth factor induced robust tube formation; however, rotenone completely inhibited this effect (P\textless0.05 rotenone versus vascular endothelial growth factor treatment). Inhibition of tube formation by rotenone was also associated with significant increase in mitochondrial superoxide generation. Immunoblot analyses of human coronary artery endothelial cells with rotenone treatment showed significant activation of adenosine monophosphate activated kinase (AMPK)-alpha and inhibition of mammalian target of rapamycin and p70 ribosomal S6 kinase. Activation of AMPK-alpha suggested impairments in energy production, which was reflected by decrease in O2 consumption and bioenergetic reserve capacity of cultured cells. Knockdown of AMPK-alpha (siRNA) also preserved tube formation during rotenone, suggesting the negative effects were mediated by the activation of AMPK-alpha. Conversely, expression of a constitutively active AMPK-alpha blocked tube formation. CONCLUSIONS: We conclude that activation of AMPK-alpha during mitochondrial oxidative stress inhibits mammalian target of rapamycin signaling, which impairs phenotypic switching necessary for the growth of blood vessels.
Pung Yuh Fen; Sam Wai Johnn; Stevanov Kelly; Enrick Molly; Chen Chwen-Lih; Kolz Christopher; Thakker Prashanth; Hardwick James P; Chen Yeong-Renn; Dyck Jason R B; Yin Liya; Chilian William M
Arteriosclerosis, thrombosis, and vascular biology
2013
2013-08
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1161/ATVBAHA.113.301591" target="_blank" rel="noreferrer noopener">10.1161/ATVBAHA.113.301591</a>
Resolution of mitochondrial oxidative stress rescues coronary collateral growth in Zucker obese fatty rats.
Animal; Animals; Antioxidants/*pharmacology; Collateral Circulation/*drug effects/physiology; Coronary Vessels/drug effects/*growth & development; Disease Models; Heart/*drug effects/physiology; Lipid Peroxidation/drug effects/physiology; Lipid Peroxides/metabolism; Male; Metabolic Syndrome/*metabolism/physiopathology; Mitochondria; Mitochondrial Proteins/metabolism; Obesity/*metabolism/physiopathology; Organophosphorus Compounds/pharmacology; Oxidative Stress/*drug effects/physiology; Piperidines/pharmacology; Rats; Reactive Oxygen Species/metabolism; Ubiquinone/pharmacology; Zucker
OBJECTIVE: We have previously found abrogated ischemia-induced coronary collateral growth in Zucker obese fatty (ZOF) rats compared with Zucker lean (ZLN) rats. Because ZOF rats have structural abnormalities in their mitochondria suggesting dysfunction and also show increased production of O(2), we hypothesized that mitochondrial dysfunction caused by oxidative stress impairs coronary collateral growth in ZOF. METHODS AND RESULTS: Increased levels of reactive oxygen species were observed in aortic endothelium and smooth muscle cells in ZOF rats compared with ZLN rats. Reactive oxygen species levels were decreased by the mitochondria-targeted antioxidants MitoQuinone (MQ) and MitoTempol (MT) as assessed by MitoSox Red and dihydroethidine staining. Lipid peroxides (a marker of oxidized lipids) were increased in ZOF by approximately 47% compared with ZLN rats. The elevation in oxidative stress was accompanied by increased antioxidant enzymes, except glutathione peroxidase-1, and by increased uncoupling protein-2 in ZOF versus ZLN rats. In addition, elevated respiration rates were also observed in the obese compared with lean rats. Administration of MQ significantly normalized the metabolic profiles and reduced lipid peroxides in ZOF rats to the same level observed in lean rats. The protective effect of MQ also suppressed the induction of uncoupling protein-2 in the obese rats. Resolution of mitochondrial oxidative stress by MQ or MT restored coronary collateral growth to the same magnitude observed in ZLN rats in response to repetitive ischemia. CONCLUSIONS: We conclude that mitochondrial oxidative stress and dysfunction play a key role in disrupting coronary collateral growth in obesity and the metabolic syndrome, and elimination of the mitochondrial oxidative stress with MQ or MT rescues collateral growth.
Pung Yuh Fen; Rocic Petra; Murphy Michael P; Smith Robin A J; Hafemeister Jennifer; Ohanyan Vahagn; Guarini Giacinta; Yin Liya; Chilian William M
Arteriosclerosis, thrombosis, and vascular biology
2012
2012-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1161/ATVBAHA.111.241802" target="_blank" rel="noreferrer noopener">10.1161/ATVBAHA.111.241802</a>
Hepatic hepatocyte nuclear factor 4alpha is essential for maintaining triglyceride and cholesterol homeostasis.
Adenoviridae/genetics; Animal; Animals; Cells; Cholesterol; Cholesterol/*metabolism; Cultured; Fatty Liver/metabolism/physiopathology; HDL/metabolism; Hepatocyte Nuclear Factor 4/drug effects/genetics/*physiology; Hepatocytes/cytology/*metabolism; Homeostasis/genetics/*physiology; Inbred C57BL; Lipid Metabolism/genetics/physiology; Mice; Models; RNA; Small Interfering/genetics/pharmacology; Triglycerides/*metabolism; VLDL/metabolism
OBJECTIVE: Loss-of-function mutations in human hepatocyte nuclear factor 4alpha (HNF4alpha) are associated with maturity-onset diabetes of the young and lipid disorders. However, the mechanisms underlying the lipid disorders are poorly understood. In this study, we determined the effect of acute loss or augmentation of hepatic HNF4alpha function on lipid homeostasis. METHODS AND RESULTS: We generated an adenovirus expressing LacZ (Ad-shLacZ) or short hairpin RNA of Hnf4alpha (Ad-shHnf4alpha). Tail vain injection of C57BL/6J mice with Ad-shHnf4alpha reduced hepatic Hnf4alpha expression and resulted in striking phenotypes, including the development of fatty liver and a \textgreater80% decrease in plasma levels of triglycerides, total cholesterol, and high-density lipoprotein cholesterol. These latter changes were associated with reduced hepatic lipogenesis and impaired very-low-density lipoprotein secretion. Deficiency in hepatic Hnf4alpha did not affect intestinal cholesterol absorption despite decreased expression of genes involved in bile acid synthesis. Consistent with the loss-of-function data, overexpression of Hnf4alpha induced numerous genes involved in lipid metabolism in isolated primary hepatocytes. Interestingly, many of these HNF4alpha-regulated genes were not induced in wild-type mice that overexpressed hepatic Hnf4alpha. Because of selective gene regulation, mice overexpressing hepatic Hnf4alpha had unchanged plasma triglyceride levels and decreased plasma cholesterol levels. CONCLUSIONS: Loss of hepatic HNF4alpha results in severe lipid disorder as a result of dysregulation of multiple genes involved in lipid metabolism. In contrast, augmentation of hepatic HNF4alpha activity lowers plasma cholesterol levels but has no effect on plasma triglyceride levels because of selective gene regulation. Our data indicate that hepatic HNF4alpha is essential for controlling the basal expression of numerous genes involved in lipid metabolism and is indispensable for maintaining normal lipid homeostasis.
Yin Liya; Ma Huiyan; Ge Xuemei; Edwards Peter A; Zhang Yanqiao
Arteriosclerosis, thrombosis, and vascular biology
2011
2011-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1161/ATVBAHA.110.217828" target="_blank" rel="noreferrer noopener">10.1161/ATVBAHA.110.217828</a>
The mechanistic basis for the disparate effects of angiotensin II on coronary collateral growth.
Angiotensin; Angiotensin II/*physiology; Animal; Animals; Coronary Occlusion/drug therapy/*physiopathology; Disease Models; Hemorheology; Ischemia/drug therapy/*physiopathology; Male; Neovascularization; Oxidative Stress/*physiology; Physiologic/*physiology; Rats; Reactive Oxygen Species/adverse effects/metabolism; Receptor; Type 1/*drug effects/physiology; Vasoconstrictor Agents/pharmacology
OBJECTIVE: We hypothesize that controversial effects of angiotensin II (Ang II) are attributable to its regulation of reactive oxygen species (ROS) and
Reed Ryan; Kolz Christopher; Potter Barry; Rocic Petra
Arteriosclerosis, thrombosis, and vascular biology
2008
2008-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1161/ATVBAHA.107.154294" target="_blank" rel="noreferrer noopener">10.1161/ATVBAHA.107.154294</a>
LEAPS Vaccine Incorporating HER-2/neu Epitope Elicits Protection That Prevents and Limits Tumor Growth and Spread of Breast Cancer in a Mouse Model.
*Cancer Vaccines/genetics/immunology/therapeutic use; Animal; Animals; Breast Neoplasms/genetics/immunology/prevention & control/therapy; CD8-Positive T-Lymphocytes/immunology; Cell Line; Cytotoxic/immunology; Disease Models; Disease Progression; Epitopes; erbB-2; Experimental/immunology/pathology/*prevention & control/*therapy; Female; Genes; Immunoglobulin G/blood; Inbred BALB C; Mammary Neoplasms; Mice; Neoplasm Metastasis/prevention & control; Proof of Concept Study; T-Lymphocyte/immunology; T-Lymphocytes; Tumor
The prototype J-LEAPS T cell vaccine for HER-2/neu breast cancer (J-HER) consists of the murine HER-2/neu66-74 H-2(d) CD8 T cell epitope covalently attached through a triglycine linker to the J-immune cell binding ligand (ICBL) (human beta2 microglobulin38-50 peptide). The J-ICBL was chosen for its potential to promote Th1/Tc1 responses. In this proof-of-concept study, the ability of J-HER to prevent or treat cancer was tested in the TUBO cell-challenged BALB/c mouse model for HER-2/neu-expressing tumors. The J-HER vaccine was administered as an emulsion in Montanide ISA-51 without the need for a more potent adjuvant. When administered as a prophylactic vaccination before tumor challenge, J-HER protected against tumor development for at least 48 days. Despite eliciting protection, antibody production in J-HER-immunized, TUBO-challenged mice was less than that in unimmunized mice. More importantly, therapeutic administration of
Rosenthal Ken S; Stone Sarah; Koski Gary; Zimmerman Daniel H
Journal of immunology research
2017
1905-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1155/2017/3613505" target="_blank" rel="noreferrer noopener">10.1155/2017/3613505</a>
Weighted Lin-Wang tests for crossing hazards.
*Survival Analysis; Algorithms; Animal; Animals; Computer Simulation; Data Interpretation; Disease Models; Humans; Kaplan-Meier Estimate; Leukemia/drug therapy; Mice; Models; Reproducibility of Results; Statistical
Lin and Wang have introduced a quadratic version of the logrank test, appropriate for situations in which the underlying survival distributions may cross. In this note, we generalize the Lin-Wang procedure to incorporate weights and investigate the performance of Lin and Wang's test and weighted versions in various scenarios. We find that weighting does increase statistical power in certain situations; however, none of the procedures was dominant under every scenario.
Koziol James A; Jia Zhenyu
Computational and mathematical methods in medicine
2014
1905-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1155/2014/643457" target="_blank" rel="noreferrer noopener">10.1155/2014/643457</a>
Frequency organization and responses to complex sounds in the medial geniculate body of the mustached bat.
*Brain Mapping; Animal; Animals; Auditory Cortex/*physiology; Auditory Perception/*physiology; Chiroptera/*physiology; Electrophysiology/methods; Geniculate Bodies/*physiology; Neurons/*physiology; Pitch Discrimination/*physiology; Reaction Time; Ultrasonics; Vocalization
The auditory cortex of the mustached bat (Pteronotus parnellii) displays some of the most highly developed physiological and organizational features described in mammalian auditory cortex. This study examines response properties and organization in the medial geniculate body (MGB) that may contribute to these features of auditory cortex. About 25% of 427 auditory responses had simple frequency tuning with single excitatory tuning curves. The remainder displayed more complex frequency tuning using two-tone or noise stimuli. Most of these were combination-sensitive, responsive to combinations of different frequency bands within sonar or social vocalizations. They included FM-FM neurons, responsive to different harmonic elements of the frequency modulated (FM) sweep in the sonar signal, and H1-CF neurons, responsive to combinations of the bat's first sonar harmonic (H1) and a higher harmonic of the constant frequency (CF) sonar signal. Most combination-sensitive neurons (86%) showed facilitatory interactions. Neurons tuned to frequencies outside the biosonar range also displayed combination-sensitive responses, perhaps related to analyses of social vocalizations. Complex spectral responses were distributed throughout dorsal and ventral divisions of the MGB, forming a major feature of this bat's analysis of complex sounds. The auditory sector of the thalamic reticular nucleus also was dominated by complex spectral responses to sounds. The ventral division was organized tonotopically, based on best frequencies of singly tuned neurons and higher best frequencies of combination-sensitive neurons. Best frequencies were lowest ventrolaterally, increasing dorsally and then ventromedially. However, representations of frequencies associated with higher harmonics of the FM sonar signal were reduced greatly. Frequency organization in the dorsal division was not tonotopic; within the middle one-third of MGB, combination-sensitive responses to second and third harmonic CF sonar signals (60-63 and 90-94 kHz) occurred in adjacent regions. In the rostral one-third, combination-sensitive responses to second, third, and fourth harmonic FM frequency bands predominated. These FM-FM neurons, thought to be selective for delay between an emitted pulse and echo, showed some organization of delay selectivity. The organization of frequency sensitivity in the MGB suggests a major rewiring of the output of the central nucleus of the inferior colliculus, by which collicular neurons tuned to the bat's FM sonar signals mostly project to the dorsal, not the ventral, division. Because physiological differences between collicular and MGB neurons are minor, a major role of the tecto-thalamic projection in the mustached bat may be the reorganization of responses to provide for cortical representations of sonar target features.
Wenstrup J J
Journal of neurophysiology
1999
1999-11
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1152/jn.1999.82.5.2528" target="_blank" rel="noreferrer noopener">10.1152/jn.1999.82.5.2528</a>