Role of inflammation in the aging bones.
*Models; Aging; Aging/*physiology; Animals; Biological; Bone adaptation; Bone and Bones/cytology/immunology/*physiopathology; Bone Marrow Cells/physiology; Bone resorption; Cell Differentiation/*physiology; Cumulative Trauma Disorders/physiopathology; Humans; Inflammation; Inflammation/*physiopathology; Macrophages; Macrophages/*physiology; Osteoblasts; Osteoblasts/*physiology; Osteoclasts; Osteoclasts/*physiology
Chronic inflammation in aging is characterized by increased inflammatory cytokines, bone loss, decreased adaptation, and defective tissue repair in response to injury. Aging leads to inherent changes in mesenchymal stem cell (MSC) differentiation, resulting in impaired osteoblastogenesis. Also, the pro-inflammatory cytokines increase with aging, leading to enhanced myelopoiesis and osteoclastogenesis. Bone marrow macrophages (BMMs) play pivotal roles in osteoblast differentiation, the maintenance of hematopoietic stem cells (HSCs), and subsequent bone repair. However, during aging, little is known about the role of macrophages in the differentiation and function of MSC and HSC. Aged mammals have higher circulating pro-inflammatory cytokines than young adults, supporting the hypothesis of increased inflammation with aging. This review will aid in the understanding of the potential role(s) of pro-inflammatory (M1) and anti-inflammatory (M2) macrophages in differentiation and function of osteoblasts and osteoclasts in relation to aging.
Abdelmagid Samir M; Barbe Mary F; Safadi Fayez F
Life sciences
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/10.1016/j.lfs.2014.11.011" target="_blank" rel="noreferrer noopener">10.1016/j.lfs.2014.11.011</a>
Mutation in osteoactivin decreases bone formation in vivo and osteoblast differentiation in vitro.
*Signal Transduction; Alkaline Phosphatase/metabolism; Animals; Apoptosis; Bone and Bones/metabolism/pathology; Cell Differentiation/genetics; Eye Proteins/*genetics; Inbred DBA; Male; Membrane Glycoproteins/*genetics; Mice; Mutation; Newborn; Osteoblasts/cytology/*physiology; Osteocalcin/*genetics; Osteogenesis/*genetics; Phenotype; Receptors; Transforming Growth Factor beta/metabolism
We have previously identified osteoactivin (OA), encoded by Gpnmb, as an osteogenic factor that stimulates osteoblast differentiation in vitro. To elucidate the importance of OA in osteogenesis, we characterized the skeletal phenotype of a mouse model, DBA/2J (D2J) with a loss-of-function mutation in Gpnmb. Microtomography of D2J mice showed decreased trabecular mass, compared to that in wild-type mice [DBA/2J-Gpnmb(+)/SjJ (D2J/Gpnmb(+))]. Serum analysis showed decreases in OA and the bone-formation markers alkaline phosphatase and osteocalcin in D2J mice. Although D2J mice showed decreased osteoid and mineralization surfaces, their osteoblasts were increased in number, compared to D2J/Gpnmb(+) mice. We then examined the ability of D2J osteoblasts to differentiate in culture, where their differentiation and function were decreased, as evidenced by low alkaline phosphatase activity and matrix mineralization. Quantitative RT-PCR analyses confirmed the decreased expression of differentiation markers in D2J osteoblasts. In vitro, D2J osteoblasts proliferated and survived significantly less, compared to D2J/Gpnmb(+) osteoblasts. Next, we investigated whether mutant OA protein induces endoplasmic reticulum stress in D2J osteoblasts. Neither endoplasmic reticulum stress markers nor endoplasmic reticulum ultrastructure were altered in D2J osteoblasts. Finally, we assessed underlying mechanisms that might alter proliferation of D2J osteoblasts. Interestingly, TGF-beta receptors and Smad-2/3 phosphorylation were up-regulated in D2J osteoblasts, suggesting that OA contributes to TGF-beta signaling. These data confirm the anabolic role of OA in postnatal bone formation.
Abdelmagid Samir M; Belcher Joyce Y; Moussa Fouad M; Lababidi Suzanne L; Sondag Gregory R; Novak Kimberly M; Sanyurah Afif S; Frara Nagat A; Razmpour Roshanak; Del Carpio-Cano Fabiola E; Safadi Fayez F
The American journal of pathology
2014
2014-03
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/10.1016/j.ajpath.2013.11.031" target="_blank" rel="noreferrer noopener">10.1016/j.ajpath.2013.11.031</a>
Mutation in Osteoactivin Promotes Receptor Activator of NFkappaB Ligand (RANKL)-mediated Osteoclast Differentiation and Survival but Inhibits Osteoclast Function.
*Mutation; Akt; Animals; bone; bone marrow; Bone Remodeling; Cell Differentiation/*physiology; Cell Survival/*physiology; Eye Proteins/*genetics; Inbred DBA; MAP kinases (MAPKs); Membrane Glycoproteins/*genetics; Mice; osteoactivin; osteoclast; Osteoclasts/*cytology; osteopetrosis; RANK Ligand/metabolism/*physiology; Signal Transduction; X-Ray Microtomography
We previously reported on the importance of osteoactivin (OA/Gpnmb) in osteogenesis. In this study, we examined the role of OA in osteoclastogenesis, using mice with a nonsense mutation in the Gpnmb gene (D2J) and wild-type controls (D2J/Gpnmb(+)). In these D2J mice, micro-computed tomography and histomorphometric analyses revealed increased cortical thickness, whereas total porosity and eroded surface were significantly reduced in D2J mice compared with wild-type controls, and these results were corroborated by lower serum levels of
Abdelmagid Samir M; Sondag Gregory R; Moussa Fouad M; Belcher Joyce Y; Yu Bing; Stinnett Hilary; Novak Kimberly; Mbimba Thomas; Khol Matthew; Hankenson Kurt D; Malcuit Christopher; Safadi Fayez F
The Journal of biological chemistry
2015
2015-08
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/10.1074/jbc.M114.624270" target="_blank" rel="noreferrer noopener">10.1074/jbc.M114.624270</a>
Cytometric study of the female Syrian hamster gallbladder epithelium following sex steroid administration.
Animals; Cell Count; Cholelithiasis/*chemically induced/pathology; Cricetinae; Cytoplasm/drug effects; Drug Administration Schedule; Epithelial Cells; Epithelium/drug effects; Estrogens/*pharmacology; Female; Gallbladder/cytology/*drug effects; Mesocricetus; Progesterone/*pharmacology
This report is a cytometric study of the female Syrian hamster gallbladder epithelium following 1-, 2-, and 3-month administration of female sex steroids. Nulliparous, multiparous, young, old and pregnant hamsters were used in this study. A 1 month treatment with estrogen alone significantly increases the nuclear volume of the gallbladder epithelial cells, while E + P treatment significantly affects the nuclear volume only after a 2 month treatment. On the other hand, E + P and P treatments significantly increase the cell volumes as compared to the E-treated groups, this effect is most striking following the 1 month period. Prolonged sex steroid treatment (2 and 3 month) does not appear to influence the gallbladder epithelial cell and nuclear volumes as dramatically as that observed following the 1 month treatment. The nulliparous, progesterone-treated hamsters appear to have a greater cytoplasmic volume than the multiparous group and this is substantiated by the bulging apices and the luminal cellular excrescences observed with scanning and transmission electron microscopy. These observations are similar to those reported in ovariectomized hamsters (Gilloteaux et al., 1992). Further, the gallbladder epithelial cells and nuclei of the older female hamsters demonstrate an accentuated response to a 1 month sex steroid treatment as compared to the younger hamsters for the same treatment duration. These results enable us to hypothesize that changes induced by a short term sex steroid treatment participate in the gallstone nucleation process, while longer duration of the treatments contribute to progressive enlargement and accumulation of gallbladder calculi.
Adamiec-Beyga E; Karkare S; Kelly T R; Gilloteaux J
Tissue & cell
1993
1993-08
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/10.1016/0040-8166(93)90006-7" target="_blank" rel="noreferrer noopener">10.1016/0040-8166(93)90006-7</a>
Activation of mechanosensitive ion channel TRPV4 normalizes tumor vasculature and improves cancer therapy.
Animals; Calcium Signaling/genetics; Carcinoma; Cell Line; Cell Proliferation/drug effects; Cisplatin/administration & dosage; Endothelium; Gene Expression Regulation; Humans; Leucine/administration & dosage/analogs & derivatives; Lewis Lung/drug therapy/*genetics/pathology; Mice; Neoplastic/drug effects; Neovascularization; Pathologic/drug therapy/*genetics/pathology; Sulfonamides/administration & dosage; TRPV Cation Channels/agonists/biosynthesis/*genetics; Tumor; Vascular Endothelial Growth Factor A/genetics; Vascular/drug effects/*pathology
Tumor vessels are characterized by abnormal morphology and hyperpermeability that together cause inefficient delivery of chemotherapeutic agents. Although vascular endothelial growth factor has been established as a critical regulator of tumor angiogenesis, the role of mechanical signaling in the regulation of tumor vasculature or tumor endothelial cell (TEC) function is not known. Here we show that the mechanosensitive ion channel transient receptor potential vanilloid 4 (TRPV4) regulates tumor angiogenesis and tumor vessel maturation via modulation of TEC mechanosensitivity. We found that TECs exhibit reduced TRPV4 expression and function, which is correlated with aberrant mechanosensitivity towards extracellular matrix stiffness, increased migration and abnormal angiogenesis by TEC. Further, syngeneic tumor experiments revealed that the absence of TRPV4 induced increased vascular density, vessel diameter and reduced pericyte coverage resulting in enhanced tumor growth in TRPV4 knockout mice. Importantly, overexpression or pharmacological activation of TRPV4 restored aberrant TEC mechanosensitivity, migration and normalized abnormal angiogenesis in vitro by modulating Rho activity. Finally, a small molecule activator of TRPV4, GSK1016790A, in combination with anticancer drug cisplatin, significantly reduced tumor growth in wild-type mice by inducing vessel maturation. Our findings demonstrate TRPV4 channels to be critical regulators of tumor angiogenesis and represent a novel target for anti-angiogenic and vascular normalization therapies.
Adapala R K; Thoppil R J; Ghosh K; Cappelli H C; Dudley A C; Paruchuri S; Keshamouni V; Klagsbrun M; Meszaros J G; Chilian W M; Ingber D E; Thodeti C K
Oncogene
2016
2016-01
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/10.1038/onc.2015.83" target="_blank" rel="noreferrer noopener">10.1038/onc.2015.83</a>
PKCalpha mediates acetylcholine-induced activation of TRPV4-dependent calcium influx in endothelial cells.
Acetylcholine/*pharmacology; Animals; Calcium Signaling/*drug effects; Carbazoles/pharmacology; Cells; Cultured; Endothelial Cells/*drug effects/enzymology; Enzyme Activation; Inbred C57BL; Knockout; Male; Mesenteric Arteries/drug effects/enzymology; Mice; Mutation; Nitric Oxide Synthase Type III/metabolism; Phosphorylation; Protein Kinase C-alpha/genetics/*metabolism; Protein Kinase Inhibitors/pharmacology; Tetradecanoylphorbol Acetate/pharmacology; Time Factors; Transfection; TRPV Cation Channels/*agonists/deficiency/genetics/metabolism; Vasodilation/*drug effects; Vasodilator Agents/*pharmacology
Transient receptor potential vanilloid channel 4 (TRPV4) is a polymodally activated nonselective cationic channel implicated in the regulation of vasodilation and hypertension. We and others have recently shown that cyclic stretch and shear stress activate TRPV4-mediated calcium influx in endothelial cells (EC). In addition to the mechanical forces, acetylcholine (ACh) was shown to activate TRPV4-mediated calcium influx in endothelial cells, which is important for nitric oxide-dependent vasodilation. However, the molecular mechanism through which ACh activates TRPV4 is not known. Here, we show that ACh-induced calcium influx and endothelial nitric oxide synthase (eNOS) phosphorylation but not calcium release from intracellular stores is inhibited by a specific TRPV4 antagonist, AB-159908. Importantly, activation of store-operated calcium influx was not altered in the TRPV4 null EC, suggesting that
Adapala Ravi K; Talasila Phani K; Bratz Ian N; Zhang David X; Suzuki Makoto; Meszaros J Gary; Thodeti Charles K
American journal of physiology. Heart and circulatory physiology
2011
2011-09
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/10.1152/ajpheart.00142.2011" target="_blank" rel="noreferrer noopener">10.1152/ajpheart.00142.2011</a>
TRPV4 channels mediate cardiac fibroblast differentiation by integrating mechanical and soluble signals.
*Calcium Signaling; *Cell Differentiation; *Mechanotransduction; Animals; Cellular; Extracellular Matrix/metabolism/physiology; Fibroblasts/*physiology; Gene Knockdown Techniques; Male; Monoterpenes/pharmacology; Myocardium/cytology; Myofibroblasts/metabolism; Rats; RNA; Small Interfering/genetics; Sprague-Dawley; Transforming Growth Factor beta1/physiology; TRPM Cation Channels/antagonists & inhibitors/metabolism; TRPV Cation Channels/genetics/*metabolism
The phenotypic switch underlying the differentiation of cardiac fibroblasts into hypersecretory myofibroblasts is critical for cardiac remodeling following myocardial infarction. Myofibroblasts facilitate wound repair in the myocardium by secreting and organizing extracellular matrix (ECM) during the wound healing process. However, the molecular mechanisms involved in myofibroblast differentiation are not well known. TGF-beta has been shown to promote differentiation and this, combined with the robust mechanical environment in the heart, lead us to hypothesize that the mechanotransduction and TGF-beta signaling pathways play active roles in the differentiation of cardiac fibroblasts to myofibroblasts. Here, we show that the mechanosensitve ion channel TRPV4 is required for TGF-beta1-induced differentiation of cardiac fibroblasts into myofibroblasts. We found that the TRPV4-specific antagonist AB159908 and siRNA knockdown of TRPV4 significantly inhibited TGFbeta1-induced differentiation as measured by incorporation of alpha-SMA into stress fibers. Further, we found that
Adapala Ravi K; Thoppil Roslin J; Luther Daniel J; Paruchuri Sailaja; Meszaros J Gary; Chilian William M; Thodeti Charles K
Journal of molecular and cellular cardiology
2013
2013-01
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/10.1016/j.yjmcc.2012.10.016" target="_blank" rel="noreferrer noopener">10.1016/j.yjmcc.2012.10.016</a>
Immunohistochemical localization of substance P, somatostatin, enkephalin, and serotonin in the spinal cord of the northern leopard frog, Rana pipiens.
Animals; Enkephalins/analysis; Immunoenzyme Techniques; Male; Neuropeptides/*analysis; Rana pipiens/anatomy & histology/*metabolism; Serotonin/analysis; Somatostatin/analysis; Spinal Cord/*analysis; Substance P/analysis
Using the indirect antibody peroxidase-antiperoxidase method of Sternberger, we localized substance P (SP), somatostatin (SOM), enkephalin (ENK), and serotonin (5HT, 5-hydroxytryptamine) in the spinal cord of Rana pipiens. This is the first study to demonstrate all four substances in adjacent sections of frog spinal cord. The distribution patterns of ENK, SP, SOM, and 5HT in our study differ from that described for laminae I and II in amniotes. A high density of ENK, SP, and SOM fibers is present in a band ventral to the dorsal terminal field of cutaneous primary afferent fibers and slightly overlapping the ventral terminal field of muscle primary afferent fibers. However, a high density of 5HT fibers is present in the dorsal terminal field.
Adli D S; Rosenthal B M; Yuen G L; Ho R H; Cruce W L
The Journal of comparative neurology
1988
1988-09
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/10.1002/cne.902750109" target="_blank" rel="noreferrer noopener">10.1002/cne.902750109</a>
Obesity-associated decrease in growth hormone-releasing hormone gene expression: a mechanism for reduced growth hormone mRNA levels in genetically obese Zucker rats.
*Gene Expression; Animals; Blotting; Growth Hormone-Releasing Hormone/*genetics; Growth Hormone/blood/*genetics/metabolism; Male; Messenger/*metabolism; Northern; Obesity/*metabolism; Pituitary Gland/metabolism; Rats; RNA; Zucker
The secretion of growth hormone (GH) is impaired in the genetically obese Zucker rat where GH gene expression and plasma GH levels are depressed; however, the underlying mechanism of this abnormality remains unclear. We have evaluated the potential causative role of hypothalamic GH-releasing hormone (GHRH) and somatostatin (SRIH) gene expression in the onset of the decreased GH mRNA levels by studying both GHRH and SRIH mRNA and peptide levels in obese and lean rats at 5 weeks of age when the decrease in GH mRNA is first detected. At that age both GHRH content and GHRH mRNA were significantly reduced in obese rats as compared to lean controls; hypothalamic SRIH content was also decreased in obese rats, but SRIH mRNA levels did not differ. Since GHRH is capable of stimulating GH gene expression, the decreased GHRH mRNA level could be a critical factor in causing the attenuation in GH gene expression and consequent diminution of circulating plasma GH.
Ahmad I; Finkelstein J A; Downs T R; Frohman L A
Neuroendocrinology
1993
1993-09
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/10.1159/000126558" target="_blank" rel="noreferrer noopener">10.1159/000126558</a>
The analysis of RNA by in situ agarose gel hybridization is more sensitive than the equivalent northern blot analysis.
Animals; Rats; *Molecular Probe Techniques; *Nucleic Acid Hybridization; Growth Hormone/genetics; Northern; RNA; Zucker; *Blotting; Electrophoresis; Agar Gel; Messenger/*analysis
Ahmad I; Finkelstein J A; Steggles A W
BioTechniques
1990
1990-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
Developmental changes in levels of growth hormone mRNA in Zucker rats.
Aging/*metabolism; Animals; Blotting; Glyceraldehyde-3-Phosphate Dehydrogenases/genetics; Growth Hormone/blood/*genetics; Immunoblotting; Male; Messenger/*metabolism; Northern; Obesity/*genetics; Prolactin/genetics; Rats; RNA; Zucker
Levels of pituitary growth hormone (GH) messenger RNA (mRNA) were compared in groups of genetically obese (fa/fa) and lean (Fa/-) littermate male Zucker rats at four different ages, 3, 5, 9, and 11 weeks, in order to determine the earliest age at which a difference between the two groups could be detected. No difference was seen in three-week-old animals. Five weeks of age was the earliest time at which the level of GH mRNA was significantly decreased in the obese rats; this decrease was present at all subsequent ages. Mean serum growth hormone levels were lower in obese animals at all ages, but the differences were not statistically significant because of the large individual variation associated with the pulsatile nature of GH release. The earliest occurrence of differences in GH mRNA level is later than some of the obesity associated abnormalities present in adipose tissue. The earliest time of the GH mRNA differences can be associated with the time when decreased protein deposition is initially seen in the obese rats. Because of this association, decreased GH mRNA may enhance the development of obesity.
Ahmad I; Steggles A W; Carrillo A J; Finkelstein J A
Journal of cellular biochemistry
1990
1990-05
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/10.1002/jcb.240430106" target="_blank" rel="noreferrer noopener">10.1002/jcb.240430106</a>
Obesity- and sex-related alterations in growth hormone messenger RNA levels.
Female; Male; Animals; Sex Characteristics; Rats; Nucleic Acid Hybridization; DNA Probes; Obesity/*genetics/metabolism; Prolactin/genetics; Somatomedins/*genetics; RNA; Messenger/metabolism; Zucker
The secretion of growth hormone (GH) is abnormal in genetically obese Zucker rats. Measurements of pulsatile GH release and circulating GH levels in lean (Fa/?) and obese (fa/fa) rats have shown that both are reduced in the latter. We have studied pituitary GH gene expression in order to understand the role of GH synthesis in this abnormality. Obese animals have lower pituitary GH mRNA levels than lean controls. Within each genotype a sex difference was observed with the female animals having lower GH mRNA levels than the males. It is unlikely that the GH abnormality is due to a generalized pituitary defect because prolactin mRNA levels were the same in all four groups of rats.
Ahmad I; Steggles A W; Carrillo A J; Finkelstein J A
Molecular and cellular endocrinology
1989
1989-08
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/10.1016/0303-7207(89)90170-6" target="_blank" rel="noreferrer noopener">10.1016/0303-7207(89)90170-6</a>
In situ hybridization study of obesity-associated alteration in growth hormone mRNA levels.
Male; Animals; Rats; *Gene Expression Regulation; Autoradiography; Growth Hormone/*genetics/metabolism; Nucleic Acid Hybridization; Obesity/*etiology/physiopathology; Pituitary Gland/*chemistry/metabolism; Northern; Blotting; RNA; Transcription; Genetic; Zucker; Messenger/*analysis
In order to investigate whether the impaired GH secretion associated with obesity is due to a pituitary disorder we studied GH mRNA levels by in situ hybridization in genetically obese and lean Zucker rats. The levels of GH mRNA were at least two fold lower in obese rats in comparison to that in lean controls as quantified by both the scanning of autoradiographs of tissue sections and Northern blot analysis. Quantification of somatotrophs revealed no significant difference in their number between lean and obese rat pituitaries. It is therefore likely that the attenuated GH mRNA levels in genetically obese Zucker rats are due to a decrease in GH transcripts per somatotroph rather than a result of a pituitary defect involving a preferential decrease in somatotroph population.
Ahmad I; Steggles A W; Finkelstein J A
International journal of obesity and related metabolic disorders : journal of the International Association for the Study of Obesity
1992
1992-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
Inhibition of cartilage degradation and suppression of PGE2 and MMPs expression by pomegranate fruit extract in a model of posttraumatic osteoarthritis.
*Phytotherapy; *Punicaceae; ACLT; Animal; Animals; Anterior Cruciate Ligament/drug effects/metabolism/pathology; Apoptosis; Cartilage/cytology/*drug effects/metabolism/pathology; Chondrocytes/drug effects/metabolism/pathology; Collagen Type II/genetics/metabolism; Dinoprostone/*metabolism; Disease Models; Disease Progression; Female; Fruit; Interleukins/metabolism; Joints/cytology/*drug effects/metabolism/pathology; Male; Messenger/metabolism; Metalloproteases/genetics/*metabolism; Mitogen-Activated Protein Kinases/metabolism; MMPs; NF-kappa B/metabolism; Osteoarthritis; Osteoarthritis/*drug therapy/etiology/metabolism/pathology; PGE(2); Plant Extracts/pharmacology/therapeutic use; Pomegranate; Rabbit; Rabbits; RNA; Synovial Fluid/metabolism
OBJECTIVE: Osteoarthritis (OA) is characterized by cartilage degradation in the affected joints. Pomegranate fruit extract (PFE) inhibits cartilage degradation in vitro. The aim of this study was to determine whether oral consumption of PFE inhibits disease progression in rabbits with surgically induced OA. METHODS: OA was surgically induced in the tibiofemoral joints of adult New Zealand White rabbits. In one group, animals were fed PFE in water for 8 wk postsurgery. In the second group, animals were fed PFE for 2 wk before surgery and for 8 wk postsurgery. Histologic assessment and scoring of the cartilage was per Osteoarthritis Research Society International guidelines. Gene expression and matrix metalloproteinases (MMP) activity were determined using quantitative reverse transcriptase polymerase chain reaction and fluorometric assay, respectively. Interleukin (IL)-1 beta, MMP-13, IL-6, prostaglandin (PG)E2, and type II collagen (COL2A1) levels in synovial fluid/plasma/culture media were quantified using enzyme-linked immunosorbent assay. Expression of active caspase-3 and poly (ADP-ribose) polymerase p85 was determined by immunohistochemistry. Effect of PFE and inhibitors of MMP-13, mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-kappaB was studied in IL-1 beta-stimulated rabbit articular chondrocytes. RESULTS: Safranin-O-staining and chondrocyte cluster formation was significantly reduced in the anterior cruciate ligament transaction plus PFE fed groups. Expression of MMP-3, MMP-9, and MMP-13 mRNA was higher in the cartilage of rabbits given water alone but was significantly lower in the animals fed PFE. PFE-fed rabbits had lower IL-6,
Akhtar Nahid; Khan Nazir M; Ashruf Omer S; Haqqi Tariq M
Nutrition (Burbank, Los Angeles County, Calif.)
2017
2017-01
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/10.1016/j.nut.2016.08.004" target="_blank" rel="noreferrer noopener">10.1016/j.nut.2016.08.004</a>
MicroRNA-602 and microRNA-608 regulate sonic hedgehog expression via target sites in the coding region in human chondrocytes.
Academic Medical Centers; Aged; Analysis of Variance; Animal; Animals; Anterior Cruciate Ligament/surgery; Blotting; Cells; Chondrocytes – Physiology; Chondrocytes/drug effects/*metabolism/pathology; Cultured; Disease Models; Female; Funding Source; Gene Expression Regulation/genetics/*physiology; Hedgehog Proteins/genetics/*metabolism; HEK293 Cells; Human; Humans; Immunohistochemistry; In Vitro Techniques; Interleukin-1beta/pharmacology; Knee/etiology/*metabolism/pathology; Male; Matrix Metalloproteinase 13/metabolism; MicroRNAs/genetics/*metabolism; Middle Age; Middle Aged; Ohio; Open Reading Frames/genetics/*physiology; Osteoarthritis; Osteoarthritis – Epidemiology; Osteoarthritis – Physiopathology; Polymerase Chain Reaction; Rabbits; Signal Transduction/genetics/physiology; T-Tests; Transfection; Up-Regulation/drug effects/genetics/physiology; Western
OBJECTIVE: Hedgehog (HH) signaling has recently been associated with cartilage degradation in osteoarthritis (OA). Because interleukin-1beta (IL-1beta) has been implicated as a principal instigator of OA, we sought to determine whether
Akhtar Nahid; Makki Mohammad S; Haqqi Tariq M
Arthritis & rheumatology (Hoboken, N.J.)
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/10.1002/art.38952" target="_blank" rel="noreferrer noopener">10.1002/art.38952</a>
Small heterodimer partner deletion prevents hepatic steatosis and when combined with farnesoid X receptor loss protects against type 2 diabetes in mice.
Animals; Body Weight/genetics; Cytoplasmic and Nuclear/*physiology; Diabetes Mellitus; Fatty Liver/*genetics; Knockout; Lipid Metabolism/genetics; Mice; Receptors; Type 2/*genetics
Nuclear receptors farnesoid X receptor (FXR) and small heterodimer partner (SHP) are important regulators of bile acid, lipid, and glucose homeostasis. Here, we show that global Fxr (-/-) Shp(-/-) double knockout (DKO) mice are refractory to weight gain, glucose intolerance, and hepatic steatosis when challenged with high-fat diet. DKO mice display an inherently increased capacity to burn fat and suppress de novo hepatic lipid synthesis. Moreover, DKO mice were also very active and that correlated well with the observed increase in phosphoenolpyruvate carboxykinase expression, type IA fibers, and mitochondrial function in skeletal muscle. Mechanistically, we demonstrate that liver-specific Shp deletion protects against fatty liver development by suppressing expression of peroxisome proliferator-activated receptor gamma 2 and lipid-droplet protein fat-specific protein 27 beta. CONCLUSION: These data suggest that Fxr and Shp inactivation may be beneficial to combat diet-induced obesity and uncover that hepatic SHP is necessary to promote fatty liver disease. (Hepatology 2017;66:1854-1865).
Akinrotimi Oludemilade; Riessen Ryan; VanDuyne Philip; Park Jung Eun; Lee Yoon-Kwang; Wong Lee-Jun; Zavacki Ann M; Schoonjans Kristina; Anakk Sayeepriyadarshini
Hepatology (Baltimore, Md.)
2017
2017-12
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/10.1002/hep.29305" target="_blank" rel="noreferrer noopener">10.1002/hep.29305</a>
Inhibition of monoamine oxidase by derivatives of piperine, an alkaloid from the pepper plant Piper nigrum, for possible use in Parkinson's disease.
Alkaloids/*chemistry/isolation & purification/pharmacology; Animals; Benzodioxoles/*chemistry/isolation & purification/pharmacology; Binding Sites; Blood-Brain Barrier/drug effects; Bovine/metabolism; Cattle; Humans; Hydrogen Bonding; Molecular Docking Simulation; Monoamine Oxidase Inhibitors/*chemistry/isolation & purification/pharmacology; Monoamine Oxidase/*chemistry/metabolism; Parkinson Disease/metabolism/pathology; Piper nigrum/*chemistry; Piperidines/*chemistry/isolation & purification/pharmacology; Polyunsaturated Alkamides/*chemistry/isolation & purification/pharmacology; Protein Binding; Protein Structure; Serum Albumin; Tertiary
A series of compounds related to piperine and antiepilepsirine was screened in a monoamine oxidase A and B assay. Piperine is an alkaloid from the source plant of both black and white pepper grains, Piper nigrum. Piperine has been shown to have a wide range of activity, including MAO inhibitory activity. The z-factor for the screening assay was found to be greater than 0.8 for both assays. Notably, the compounds tested were selective towards MAO-B, with the most potent compound having an IC(50) of 498 nM. To estimate blood-brain barrier (BBB) permeability, we used a PAMPA assay, which suggested that the compounds are likely to penetrate the BBB. A fluorescent bovine serum albumin (BSA) high-throughput screening (HTS) binding assay showed an affinity of 8 muM for piperine, with more modest binding for other test compounds. Taken together, the data described here may be useful in gaining insight towards the design of selective MAO-B inhibitory compounds devoid of MAO-A activity.
Al-Baghdadi Osamah B; Prater Natalie I; Van der Schyf Cornelis J; Geldenhuys Werner J
Bioorganic & medicinal chemistry letters
2012
2012-12
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/10.1016/j.bmcl.2012.09.056" target="_blank" rel="noreferrer noopener">10.1016/j.bmcl.2012.09.056</a>
Single low doses of MPTP decrease tyrosine hydroxylase expression in the absence of overt neuron loss.
1-Methyl-4-phenyl-1; 2; 3; 6-tetrahydropyridine/*administration & dosage; Animals; Catecholamines/metabolism; Cell Count; Corpus Striatum/*drug effects/metabolism; Dopamine; Dopamine transporter; Dopaminergic Neurons/*drug effects/metabolism; Inbred C57BL; Male; Mice; MPTP; MPTP Poisoning; Parkinsonian Disorders/*metabolism/*pathology; Stereology; Substantia Nigra/*drug effects/metabolism; Tyrosine 3-Monooxygenase/*metabolism; Tyrosine hydroxylase; Vesicular monoamine transporter
Parkinson's disease (PD) is the second most common age-related neurodegenerative disease. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a prototypical neurotoxicant used in mice to mimic primary features of PD pathology including striatal dopamine depletion and dopamine neuron loss in the substantia nigra pars compacta (SNc). In the literature, there are several experimental paradigms involving multiple doses of MPTP that are used to elicit dopamine neuron loss. However, a recent study reported that a single low dose caused significant loss of dopamine neurons. Here, we determined the effect of a single intraperitoneal injection of one of three doses of MPTP (0.1, 2 and 20mg/kg) on dopamine neurons, labeled by tyrosine hydroxylase (TH(+)), and total neuron number (Nissl(+)) in the SNc using unbiased stereological counting. Data reveal a significant loss of neurons in the SNc (TH(+) and Nissl(+)) only in the group treated with 20mg/kg MPTP. Groups treated with lower dose of MPTP (0.1 and 2mg/kg) only showed significant loss of TH(+) neurons rather than TH(+) and Nissl(+) neurons. Striatal dopamine levels were decreased in the groups treated with 2 and 20mg/kg MPTP and striatal terminal markers including, TH and the dopamine transporter (DAT), were only decreased in the groups treated with 20mg/kg MPTP. These data demonstrate that lower doses of MPTP likely result in loss of TH expression rather than actual dopamine neuron loss in the SN. This finding reinforces the need to measure both total neuron number along with TH(+) cells in determining dopamine neuron loss.
Alam Gelareh; Edler Melissa; Burchfield Shelbie L; Richardson Jason R
Neurotoxicology
2017
2017-05
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/10.1016/j.neuro.2017.03.008" target="_blank" rel="noreferrer noopener">10.1016/j.neuro.2017.03.008</a>
MPTP neurotoxicity is highly concordant between the sexes among BXD recombinant inbred mouse strains.
*QTL; *Recombinant inbred mice; *Sex Characteristics; *Sex differences; 1-Methyl-4-phenyl-1; 2; 3; 4-Dihydroxyphenylacetic Acid/metabolism; 6-tetrahydropyridine/pharmacology; Animal; Animals; Corpus Striatum/drug effects/*metabolism; Disease Models; Dopamine/metabolism; Female; Gene Expression Regulation/drug effects/*genetics; Glial Fibrillary Acidic Protein/*metabolism; Homovanillic Acid/metabolism; Inbred Strains; Male; Mice; MPTP Poisoning/chemically induced/*pathology; Serotonin/metabolism; Species Specificity; Tyrosine 3-Monooxygenase/metabolism
Continuing our previous work in which we showed wide-ranging strain differences in MPTP neurotoxicity in male mice among ten BXD recombinant inbred strains, we replicated our work in females from nine of the same strains. Mice received a single s.c. injection of 12.5mg/kg MPTP or saline. Forty-eight hours later the striatum was dissected for neurochemical analysis. Striatal dopamine (DA) and its metabolites, DOPAC and HVA, striatal serotonin (5-HT) and its metabolite, 5-HIAA, were analyzed using HPLC. Tyrosine hydroxylase (TH) and glial fibrillary acidic protein (GFAP), an astrocytic protein that increases during the astroglial response to neural injury, were measured using ELISA. There were wide genetic variations in the DA, DOPAC, HVA, TH and GFAP responses to MPTP. We also performed principal component analysis (PCA) on the difference values, saline minus MPTP, for DA, DOPAC, HVA and TH and mapped the dominant principal component to a suggestive QTL on chromosome 1 at the same location that we observed previously for males. Moreover, there were significant correlations between the sexes for the effect of MPTP on DA, HVA, and TH. Our findings suggest that the systems genetic approach as utilized here can help researchers understand the role of sex in individual differences. The same approach can pave the way to understand and pinpoint the genetic bases for individual differences in pathology attributable to toxicants. Such systems genetics approach has broad implications for elucidating gene-environment contributions to neurodegenerative diseases.
Alam Gelareh; Miller Diane B; O'Callaghan James P; Lu Lu; Williams Robert W; Jones Byron C
Neurotoxicology
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/10.1016/j.neuro.2016.04.008" target="_blank" rel="noreferrer noopener">10.1016/j.neuro.2016.04.008</a>
Time-dependent changes in norepinephrine-induced left ventricular dysfunction and histopathologic condition.
Female; Male; Animals; Rabbits; Myocardial Contraction/drug effects; Myocardial Infarction/chemically induced/pathology; Myocardium/pathology; Norepinephrine/*toxicity; Systole/drug effects/physiology; Ventricular Function; Dose-Response Relationship; Drug; Ventricular Dysfunction; Left/*chemically induced/pathology; Left/drug effects
BACKGROUND: Intense activation of the sympathetic nervous system or administration of high concentrations of catecholamines diminishes myocardial contractility and produces infarct-like lesions throughout the heart. This study was conducted to determine whether norepinephrine-induced left ventricular (LV) dysfunction reverses with time and whether the histopathologic condition and the cardiac dysfunction produced by high doses of norepinephrine are causally related. METHODS: Norepinephrine, 10 microg bolus followed by 2.5 microg/kg/min for 90 minutes, was administered to conscious New Zealand white rabbits. Control rabbits (n=8) received saline solution. LV function was evaluated either immediately (n=7), on day 4 (n=8), or on day 10 (n=7) after norepinephrine treatment. Transverse sections from the left ventricle were then prepared for light microscopic study. RESULTS: Animals studied immediately after norepinephrine treatment demonstrated severe LV dysfunction and a decrease in global LV compliance. In contrast, LV function and compliance were normal in rabbits studied on day 4, but tissue sections from the left ventricle showed diffuse areas of inflammation. By day 10 the inflammatory process had progressed, and substantial collagen deposition had occurred. LV systolic function was normal, but a decrease in LV compliance was evident at this time. CONCLUSIONS: The normal LV systolic function on days 4 and 10 in spite of multiple foci of inflammation suggests (1) that norepinephrine-induced LV systolic dysfunction is reversible and (2) that the histologic derangements and the LV dysfunction are not causally related.
Allman F D; Herold W; Bosso F J; Pilati C F
The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation
1998
1998-10
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
Effects of neonatal and prepubertal hormonal manipulations upon estrogen neuroprotection of the nigrostriatal dopaminergic system within female and male mice.
*Sex Characteristics; Aging/metabolism; Animal; Animals; Disease Models; Dopamine/metabolism; Estrogens/metabolism/*pharmacology; Female; Gonads/growth & development/metabolism; Male; Methamphetamine/antagonists & inhibitors/toxicity; Mice; Neostriatum/*drug effects/metabolism/physiopathology; Neural Pathways/drug effects/metabolism/physiopathology; Neuroprotective Agents/metabolism/*pharmacology; Newborn; Orchiectomy; Ovariectomy; Sexual Maturation/physiology; Substantia Nigra/*drug effects/metabolism/physiopathology; Testosterone/metabolism/*pharmacology
Estrogen (E) can function as a neuroprotectant of the nigrostriatal dopaminergic (NSDA) system against methamphetamine (MA) neurotoxicity in female, but not male, mice. In the present report we examined whether the organizational effects of gonadal steroid hormones, as exerted in the early postnatal period, or developmental effects, as exerted during the pubertal period, would contribute to this sexually dimorphic neuroprotectant action of E. Neonatal gonadectomy and treatment with testosterone of female mice, retained the ability to show an E neuroprotectant response when tested as adults. However, females not treated with gonadal steroids failed to show an E-dependent neuroprotectant response. Neonatal gonadectomy of male mice, failed to result in the display of an E neuroprotectant response when tested as adults. Prepubertal gonadectomy of female mice, with or without testosterone treatment, abolished the capacity for E to produce neuroprotection against MA-induced NSDA neurotoxicity. Nor did prepubertal gonadectomy enable male mice to show an E neuroprotectant response. Taken together these results demonstrate that none of the manipulations performed within male mice enabled them to show an E-dependent neuroprotective response against MA-induced neurotoxicity of the NSDA system when tested as adults. For the female, it appears that the presences of gonadal steroids at these two developmental periods are needed for the display of an E-dependent neuroprotectant response within the adult.
Anderson L I; Leipheimer R E; Dluzen D E
Neuroscience
2005
1905-06
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/10.1016/j.neuroscience.2004.09.033" target="_blank" rel="noreferrer noopener">10.1016/j.neuroscience.2004.09.033</a>
TRPA1 ion channel stimulation enhances cardiomyocyte contractile function via a CaMKII-dependent pathway.
[Ca2+]i; *Myocardial Contraction; Animals; Calcium-Calmodulin-Dependent Protein Kinase Type 2/*metabolism; CaMKII; Cardiac/*metabolism; cardiomyocytes; contractility; Inbred C57BL; Knockout; Mice; Myocytes; TRPA1; TRPA1 Cation Channel/deficiency/*metabolism
RATIONALE: Transient receptor potential channels of the ankyrin subtype-1 (TRPA1) are non-selective cation channels that show high permeability to calcium. Previous studies from our laboratory have demonstrated that TRPA1 ion channels are expressed in adult mouse ventricular cardiomyocytes (CMs) and are localized at the z-disk, costamere and intercalated disk. The functional significance of TRPA1 ion channels in the modulation of CM contractile function have not been explored. OBJECTIVE: To identify the extent to which TRPA1 ion channels are involved in modulating CM contractile function and elucidate the cellular mechanism of action. METHODS AND RESULTS: Freshly isolated CMs were obtained from murine heart and loaded with Fura-2 AM. Simultaneous measurement of intracellular free Ca(2+) concentration ([Ca(2+)]i) and contractility was performed in individual CMs paced at 0.3 Hz. Our findings demonstrate that TRPA1 stimulation with AITC results in a dose-dependent increase in peak [Ca(2+)]i and a concomitant increase in CM fractional shortening. Further analysis revealed a dose-dependent acceleration in time to peak [Ca(2+)]i and velocity of shortening as well as an acceleration in [Ca(2+)]i decay and velocity of relengthening. These effects of TRPA1 stimulation were not observed in CMs pre-treated with the TRPA1 antagonist, HC-030031 (10 micromol/L) nor in CMs obtained from TRPA1(-/-) mice. Moreover, we observed no significant increase in cAMP levels or PKA activity in response to TRPA1 stimulation and the PKA inhibitor peptide (PKI
Andrei Spencer R; Ghosh Monica; Sinharoy Pritam; Dey Souvik; Bratz Ian N; Damron Derek S
Channels (Austin, Tex.)
2017
2017-11
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/10.1080/19336950.2017.1365206" target="_blank" rel="noreferrer noopener">10.1080/19336950.2017.1365206</a>
TRPA1 is functionally co-expressed with TRPV1 in cardiac muscle: Co-localization at z-discs, costameres and intercalated discs.
Animals; Ca2+; Calcium/physiology; Cardiac/*physiology; cardiomyocytes; Inbred C57BL; Male; Mice; Myocytes; Transient Receptor Potential Channels/genetics/*physiology; TRPA1; TRPA1 Cation Channel; TRPV Cation Channels/genetics/*physiology; TRPV1; Z-disc
Transient receptor potential channels of the ankyrin subtype-1 (TRPA1) and vanilloid subtype-1 (TRPV1) are structurally related, non-selective cation channels that show a high permeability to calcium. Previous studies indicate that TRP channels play a prominent role in the regulation of cardiovascular dynamics and homeostasis, but also contribute to the pathophysiology of many diseases and disorders within the cardiovascular system. However, no studies to date have identified the functional expression and/or intracellular localization of TRPA1 in primary adult mouse ventricular cardiomyocytes (CMs). Although TRPV1 has been implicated in the regulation of cardiac function, there is a paucity of information regarding functional expression and localization of TRPV1 in adult CMs. Our current studies demonstrate that TRPA1 and TRPV1 ion channels are co-expressed at the protein level in CMs and both channels are expressed throughout the endocardium, myocardium and epicardium. Moreover, immunocytochemical localization demonstrates that both channels predominantly colocalize at the Z-discs, costameres and intercalated discs. Furthermore, specific TRPA1 and TRPV1 agonists elicit dose-dependent, transient rises in intracellular free calcium concentration ([Ca(2+)]i) that are abolished in CMs obtained from TRPA1(-/-) and TRPV1(-/-) mice. Similarly, we observed a dose-dependent attenuation of the TRPA1 and TRPV1 agonist-induced increase in [Ca(2+)]i when WT CMs were pretreated with increasing concentrations of selective TRPA1 or TRPV1 channel antagonists. In summary, these findings demonstrate functional expression and the precise ultrastructural localization of TRPA1 and TRPV1 ion channels in freshly isolated mouse CMs. Crosstalk between TRPA1 and TRPV1 may be important in mediating cellular signaling events in cardiac muscle.
Andrei Spencer R; Sinharoy Pritam; Bratz Ian N; Damron Derek S
Channels (Austin, Tex.)
2016
2016-09
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/10.1080/19336950.2016.1185579" target="_blank" rel="noreferrer noopener">10.1080/19336950.2016.1185579</a>
The large protein 'L' of Peste-des-petits-ruminants virus exhibits RNA triphosphatase activity, the first enzyme in mRNA capping pathway.
Acid Anhydride Hydrolases/*metabolism; Animals; Baculoviridae/genetics; Cercopithecus aethiops; Cloning; Conventional mRNA capping; Enzyme Activation; Gene Expression; Genetic Vectors/genetics; Messenger/*genetics/*metabolism; Molecular; Morbillivirus; mRNA capping; Peste-des-petits-ruminants virus L protein; Peste-des-petits-ruminants virus/*physiology; Peste-des-Petits-Ruminants/*virology; PPRV; RNA; RNA Caps/*metabolism; RNA triphosphatase; Vero Cells; Viral Proteins/*metabolism
Peste-des-petits-ruminants is a highly contagious and fatal disease of goats and sheep caused by non-segmented, negative strand RNA virus belonging to the Morbillivirus genus-Peste-des-petits-ruminants virus (PPRV) which is evolutionarily closely related to Rinderpest virus (RPV). The large protein 'L' of the members of this genus is a multifunctional catalytic protein, which transcribes and replicates the viral genomic RNA as well as possesses mRNA capping, methylation and polyadenylation activities; however, the detailed mechanism of mRNA capping by PPRV L protein has not been studied. We have found earlier that the L protein of RPV has RNA triphosphatase (RTPase), guanylyltransferase (GTase) and methyltransferase activities, and unlike vesicular stomatitis virus (VSV), follows the conventional pathway of mRNA capping. In the present work, using a 5'-end labelled viral RNA as substrate, we demonstrate that PPRV L protein has RTPase activity when present in the ribonucleoprotein complex of purified virus as well as recombinant L-P complex expressed in insect cells. Further, a minimal domain in the C-terminal region (aa1640-1840) of the L protein has been expressed in E. coli and shown to exhibit RTPase activity. The RTPase activity of PPRV L protein is metal-dependent and functions with a divalent cation, either magnesium or manganese. In addition, RTPase associated nucleotide triphosphatase activity (NTPase) of PPRV L protein is also demonstrated. This work provides the first detailed study of RTPase activity and identifies the RTPase domain of PPRV L protein.
Ansari Mohammad Yunus; Singh Piyush Kumar; Rajagopalan Deepa; Shanmugam Purnima; Bellur Asutosh; Shaila Melkote Subbarao
Virus Genes
2019
2019-02
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/10.1007/s11262-018-1617-5" target="_blank" rel="noreferrer noopener">10.1007/s11262-018-1617-5</a>
An interspecific analysis of relative jaw-joint height in primates.
Analysis of Variance; Animals; Female; Haplorhini/*anatomy & histology; Male; Phylogeny; Posture/*physiology; Regression Analysis; Skull/anatomy & histology; Strepsirhini/*anatomy & histology; Temporomandibular Joint/*anatomy & histology
Jaw-joint height (JJH) above the occlusal plane is thought to be influenced by cranial base angle (CBA) and facial angulation during growth. To better understand how JJH relates to midline craniofacial form, we test the hypothesis that relative increases in JJH are correlated with increasing CBA flexion and facial kyphosis (i.e., ventral bending) across primates. We compared JJH above the occlusal plane to CBA and the angle of facial kyphosis (AFK) across adults from 82 species. JJH scales with positive allometry relative to a skull geometric mean in anthropoids and most likely strepsirrhines. Anthropoid regressions for JJH are elevated above strepsirrhines, whereas catarrhines exhibit a higher slope than platyrrhines. Semipartial correlations between relative JJH and both CBA and AFK show no association across a small strepsirrhine sample, limited associations among catarrhines and anthropoids, but strong correlations in platyrrhines. Contrary to our hypothesis, however, increases in relative JJH are correlated with relatively less flexed basicrania and more airorhynch faces (i.e., reduced ventral bending) in platyrrhines. The mosaic pattern of relationships involving JJH across primate clades points to multiple influences on JJH across primates. In clades showing little association with basicranial and facial angles, such as strepsirrhines, the potential morphological independence of JJH may facilitate a relative freedom for evolutionary changes related to masticatory function. Finally, failure to associate relative JJH and basicranial flexion in most clades suggests that the relatively taller JJH and more flexed basicrania of anthropoids compared to strepsirrhines may have evolved as an isolated event during the origin of anthropoids.
Armfield Brooke A; Vinyard Christopher J
American journal of physical anthropology
2010
2010-08
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/10.1002/ajpa.21251" target="_blank" rel="noreferrer noopener">10.1002/ajpa.21251</a>
The role of NMDA receptors in long-term potentiation (LTP) and depression (LTD) in rat visual cortex.
*Cortical Spreading Depression/drug effects; 2-Amino-5-phosphonovalerate/pharmacology; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Calcium Chloride/pharmacology; Electric Stimulation; Evoked Potentials/drug effects; Ibotenic Acid/analogs & derivatives/pharmacology; In Vitro Techniques; Kainic Acid/pharmacology; Magnesium/pharmacology; N-Methyl-D-Aspartate/drug effects/*physiology; Quinoxalines/pharmacology; Rats; Receptors; Synapses/physiology; Time Factors; Visual Cortex/drug effects/*physiology
The purpose of the present study was to improve our understanding of the role of NMDA receptors in neocortical synaptic plasticity. In slices of rat visual cortex the field potential elicited in layer III in response to white matter stimulation consisted of two components with peak latencies at 5-8 ms (EPSP1) and 12-19 ms (EPSP2). EPSP2 appeared to be polysynaptic since it did not follow stimulation at 0.5 Hz. EPSP1 consisted of both kainate/AMPA and NMDA receptor activity, as revealed by bath application of DNQX and APV. EPSP2 displayed a variable sensitivity to bath-applied APV. Tetanic stimulation of the white matter in normal medium consistently induced long-term potentiation of EPSP1. In the presence of APV, LTP of EPSP1 was induced only when EPSP2 was still present, while there was no change, or LTD was induced, when EPSP2 was completely blocked by APV. In rat visual cortex, blockade of NMDA receptor participation in the postsynaptic response to tetanic stimulation reduces the probability for LTP induction but does not necessarily prevent LTP; synaptic strength may still change in either direction depending, in part, on factors affecting the magnitude of postsynaptic depolarization during tetanus.
Aroniadou V A; Teyler T J
Brain research
1991
1991-10
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/10.1016/0006-8993(91)91197-9" target="_blank" rel="noreferrer noopener">10.1016/0006-8993(91)91197-9</a>
Induction of NMDA receptor-independent long-term potentiation (LTP) in visual cortex of adult rats.
Animals; Electric Stimulation; Evoked Potentials/physiology; In Vitro Techniques; N-Methyl-D-Aspartate/antagonists & inhibitors/drug effects/*physiology; Neuronal Plasticity/drug effects/*physiology; Rats; Receptors; Synapses/physiology; Visual Cortex/*physiology
The aim of this study was to examine: (1) whether long-term potentiation (LTP) can be induced in slices from adult rat visual cortex under conditions where inhibition is not antagonized, and (2) the role of N-methyl-D-aspartate (NMDA) receptors in its induction. The field potential elicited in layer III in response to stimulation of the subcortical white matter consisted of a component with peak latency 5-8 ms (N1) and, in most slices, a second component with peak latency
Aroniadou V A; Teyler T J
Brain research
1992
1992-07
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/10.1016/0006-8993(92)90891-c" target="_blank" rel="noreferrer noopener">10.1016/0006-8993(92)90891-c</a>
Don't let the bedbugs bite: the Cimicidae debacle and the denial of healthcare and social justice.
*Bedbugs; *Healthcare Disparities/ethics; *Social Justice; Animals; Bedbugs; Delivery of Health Care/ethics; Ectoparasitic Infestations – Prevention and Control; Ectoparasitic Infestations/prevention & control; Health Care Delivery – Ethical Issues; Health Services Accessibility – Ethical Issues; Health Services Accessibility/ethics; Healthcare Disparities – Ethical Issues; Insect Control; Pest Control; Resource Allocation – Ethical Issues; Resource Allocation/ethics; Social Justice; Special Populations; Vulnerable Populations
Although bedbug infestation is not a new public health problem, it is one that is becoming more alarming among healthcare professionals, public health officials, and ethicists given the magnitude of patients who may be denied treatment, or who are unable to access treatment, especially those underserved populations living in low income housing. Efforts to quarantine and eradicate Cimicidae have been and should be made, but such efforts require costly interventions. The alternative, however, can further exacerbate the already growing problems of injustice, i.e., unfair treatment of patients, inaccessibility of needed resources. In the following paper, I examine the ramifications of denying access to medical care, among other healthcare justice dilemmas surrounding bedbug infestations. I also explore the value of health, and how healthcare professionals and public officials often feel as though bedbugs are not a priority because they, themselves, are not diseases, regardless of the fact they cause physical and mental problems that affect a person's health. I propose recommendations for improving the health and well-being of those vulnerable populations who are facing a difficult and growing public health problem that is currently being ignored in medical and public health ethics literature, regardless of increased media attention and unusual habitats of localized infestations, e.g., Statue of Liberty, New York City.
Aultman Julie M
Medicine, health care, and philosophy
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/10.1007/s11019-012-9404-x" target="_blank" rel="noreferrer noopener">10.1007/s11019-012-9404-x</a>
Beyond thermoregulation: metabolic function of cetacean blubber in migrating bowhead and beluga whales.
*Lipid Metabolism; Adipose Tissue/*metabolism; Aging/metabolism; Amino Acid Sequence; Animals; Base Sequence; Beluga Whale/*physiology; Blubber; Body Temperature Regulation; Bowhead whale; Bowhead Whale/*physiology; Development; Female; Humans; Inbred C57BL; Leptin; Leptin/genetics; Leptin/genetics/metabolism; Lipase/genetics; Long-Evans; Male; Metabolic activity; Mice; Rats; Receptors; Seasons
The processes of lipid deposition and utilization, via the gene leptin (Lep), are poorly understood in taxa with varying degrees of adipose storage. This study examines how these systems may have adapted in marine aquatic environments inhabited by cetaceans. Bowhead (Balaena mysticetus) and beluga whales (Delphinapterus leucas) are ideal study animals-they possess large subcutaneous adipose stores (blubber) and undergo bi-annual migrations concurrent with variations in food availability. To answer long-standing questions regarding how (or if) energy and lipid utilization adapted to aquatic stressors, we quantified variations in gene transcripts critical to lipid metabolism related to season, age, and blubber depth. We predicted leptin tertiary structure conservation and assessed inter-specific variations in Lep transcript numbers between bowheads and other mammals. Our study is the first to identify seasonal and age-related variations in Lep and lipolysis in these cetaceans. While Lep transcripts and protein oscillate with season in adult bowheads reminiscent of hibernating mammals, transcript levels reach up to 10 times higher in bowheads than any other mammal. Data from immature bowheads are consistent with the hypothesis that short baleen inhibits efficient feeding. Lipolysis transcripts also indicate young Fall bowheads and those sampled during Spring months limit energy utilization. These novel data from rarely examined species expand the existing knowledge and offer unique insight into how the regulation of Lep and lipolysis has adapted to permit seasonal deposition and maintain vital blubber stores.
Ball H C; Londraville R L; Prokop J W; George John C; Suydam R S; Vinyard C; Thewissen J G M; Duff R J
Journal of comparative physiology. B, Biochemical, systemic, and environmental physiology
2017
2017-01
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/10.1007/s00360-016-1029-6" target="_blank" rel="noreferrer noopener">10.1007/s00360-016-1029-6</a>
Methods and insights from the characterization of osteoprogenitor cells of bats (Mammalia: Chiroptera).
Animals; Bone Marrow Cells/cytology; Cell Differentiation/genetics; Cell Proliferation; Cells; Cellular Reprogramming; Chiroptera; Core Binding Factor Alpha 1 Subunit/genetics/metabolism; Cultured; Inbred C57BL; Mice; Osteoblasts/cytology/*metabolism; Osteocalcin/genetics/metabolism; Osteogenesis/*genetics; Real-Time Polymerase Chain Reaction; Stem Cells/*cytology/metabolism; Transcription Factors/genetics/metabolism
Osteoprogenitor cells contribute to the development and maintenance of skeletal tissues. Bats are unique model taxa whose cellular processes are poorly understood, especially in regards to skeletal biology. Forelimb bones of bats, unlike those of terrestrial mammals, bend during flight and function in controlled deformation. As a first step towards understanding the molecular processes governing deposition of this flexible bone matrix, we provide the first method for isolation and differentiation of cell populations derived from the bone marrow and cortical bone of bats, and compare results with those harvested from C57BL/6J mice. Osteogenic capacity of these cells was assessed via absolute quantitative real-time PCR (qPCR) and through quantification of in vitro mineral deposition. Results indicate the differentiated bone cells of bats display significantly lower gene expression of known osteogenic markers (Runt-related transcription factor (RUNX2), osteocalcin (BGLAP) and osterix (SP7)), and deposit a less-mineralized matrix compared with murine controls. By characterizing the in vitro performance of osteoprogenitor cells throughout differentiation and matrix production, this study lays the ground work for in vitro manipulations of bat stem and osteoprogenitor cells and extends our understanding of the cellular diversity across mammals that occupy different habitats.
Ball H C; Moussa F M; Mbimba T; Orman R; Safadi F F; Cooper L N
Stem cell 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/10.1016/j.scr.2016.05.009" target="_blank" rel="noreferrer noopener">10.1016/j.scr.2016.05.009</a>
Comparative metabolomics of aging in a long-lived bat: Insights into the physiology of extreme longevity.
Animals; *Metabolomics; Chiroptera/*physiology; Feces/*chemistry; Longevity/*physiology
Vespertilionid bats (Mammalia: Order Chiroptera) live 3-10 times longer than other mammals of an equivalent body size. At present, nothing is known of how bat fecal metabolic profiles shift with age in any taxa. This study established the feasibility of using a non-invasive, fecal metabolomics approach to examine age-related differences in the fecal metabolome of young and elderly adult big brown bats (Eptesicus fuscus) as an initial investigation into using metabolomics for age determination. Samples were collected from captive, known-aged big brown bats (Eptesicus fuscus) from 1 to over 14 years of age: these two ages represent age groups separated by approximately 75% of the known natural lifespan of this taxon. Results showed 41 metabolites differentiated young (n = 22) and elderly (n = 6) Eptesicus. Significant differences in metabolites between young and elderly bats were associated with tryptophan metabolism and incomplete protein digestion. Results support further exploration of the physiological mechanisms bats employ to achieve exceptional longevity.
Ball Hope C; Levari-Shariati Shiva; Cooper Lisa Noelle; Aliani Michel
PloS one
2018
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.0196154" target="_blank" rel="noreferrer noopener">10.1371/journal.pone.0196154</a>
Seasonal and Ontogenetic Variation in Subcutaneous Adipose Of the Bowhead Whale (Balaena mysticetus).
*Biological Evolution; *Seasons; Adaptation; Adipocytes/*cytology; adipose; Age Factors; Animals; Autopsy; blubber; bowhead; Bowhead Whale/*anatomy & histology/psychology; Cell Size; Feeding Behavior; Female; Male; ontogeny; Physiological; seasonal variation; Subcutaneous Fat/*cytology
Cetacean evolution was shaped by an extraordinary land-to-sea transition in which the ancestors of whales became fully aquatic. As part of this transition, these mammals evolved unusually thick blubber which acts as a metabolic reservoir as well as an insulator and provides buoyancy and streamlining. This study describes blubber stratification and correlates it to seasonal variation, feeding patterns, and ontogeny in an arctic-adapted mysticete, the bowhead whale (Balaena mysticetus). Bowheads are unique among mammals for possessing the largest known blubber stores. We found that adipocyte numbers in bowheads, like other mammals, do not vary with season or feeding pattern but that adipocyte size and structural fiber densities do vary with blubber depth.
Ball Hope C; Stavarz Madeline; Oldaker Jonathan; Usip Sharon; Londraville Richard L; George John C; Thewissen Johnannes G M; Duff Robert Joel
Anatomical record (Hoboken, N.J. : 2007)
2015
2015-08
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/10.1002/ar.23125" target="_blank" rel="noreferrer noopener">10.1002/ar.23125</a>
Maturation of the Coordination Between Respiration and Deglutition with and Without Recurrent Laryngeal Nerve Lesion in an Animal Model.
*Animal model; *Deglutition; *Development; *Infant; *Recurrent laryngeal nerve; *Respiration; *Sensorimotor; Animal; Animal Population Groups; Animals; Biological; Deglutition – Physiology; Deglutition Disorders; Deglutition/*physiology; Disease Models; Humans; Laryngeal Nerves – Injuries; Laryngeal Nerves – Physiology; Larynx – Physiology; Larynx/*physiology; Models; Newborn; Questionnaires; Recurrent Laryngeal Nerve Injuries/*complications; Recurrent Laryngeal Nerve/physiology; Respiration; Swine
The timing of the occurrence of a swallow in a respiratory cycle is critical for safe swallowing, and changes with infant development. Infants with damage to the recurrent laryngeal nerve, which receives sensory information from the larynx and supplies the intrinsic muscles of the larynx, experience a significant incidence of dysphagia. Using our validated infant pig model, we determined the interaction between this nerve damage and the coordination between respiration and swallowing during postnatal development. We recorded 23 infant pigs at two ages (neonatal and older, pre-weaning) feeding on milk with barium using simultaneous high-speed videofluoroscopy and measurements of thoracic movement. With a complete linear model, we tested for changes with maturation, and whether these changes are the same in control and lesioned individuals. We found (1) the timing of swallowing and respiration coordination changes with maturation; (2) no overall effect of RLN lesion on the timing of coordination, but (3) a greater magnitude of maturational change occurs with RLN injury. We also determined that animals with no surgical intervention did not differ from animals that had surgery for marker placement and a sham procedure for nerve lesion. The coordination between respiration and swallowing changes in normal, intact individuals to provide increased airway protection prior to weaning. Further, in animals with an RLN lesion, the maturation process has a larger effect. Finally, these results suggest a high level of brainstem sensorimotor interactions with respect to these two functions.
Ballester Ashley; Gould Francois; Bond Laura; Stricklen Bethany; Ohlemacher Jocelyn; Gross Andrew; DeLozier Katherine R; Buddington Randall; Buddington Karyl; Danos Nicole; German Rebecca
Dysphagia
2018
2018-10
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/10.1007/s00455-018-9881-z" target="_blank" rel="noreferrer noopener">10.1007/s00455-018-9881-z</a>
Moth tails divert bat attack: evolution of acoustic deflection.
*Biological Evolution; *Chiroptera; Animal Structures/anatomy & histology/*physiology; Animals; antipredator defense; bat-moth interactions; Food Chain; Lepidoptera; Moths/*physiology; Saturniidae
Adaptations to divert the attacks of visually guided predators have evolved repeatedly in animals. Using high-speed infrared videography, we show that luna moths (Actias luna) generate an acoustic diversion with spinning hindwing tails to deflect echolocating bat attacks away from their body and toward these nonessential appendages. We pit luna moths against big brown bats (Eptesicus fuscus) and demonstrate a survival advantage of approximately 47% for moths with tails versus those that had their tails removed. The benefit of hindwing tails is equivalent to the advantage conferred to moths by bat-detecting ears. Moth tails lured bat attacks to these wing regions during 55% of interactions between bats and intact luna moths. We analyzed flight kinematics of moths with and without hindwing tails and suggest that tails have a minimal role in flight performance. Using a robust phylogeny, we find that long spatulate tails have independently evolved four times in saturniid moths, further supporting the selective advantage of this anti-bat strategy. Diversionary tactics are perhaps more common than appreciated in predator-prey interactions. Our finding suggests that focusing on the sensory ecologies of key predators will reveal such countermeasures in prey.
Barber Jesse R; Leavell Brian C; Keener Adam L; Breinholt Jesse W; Chadwell Brad A; McClure Christopher J W; Hill Geena M; Kawahara Akito Y
Proceedings of the National Academy of Sciences of the United States of America
2015
2015-03
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/10.1073/pnas.1421926112" target="_blank" rel="noreferrer noopener">10.1073/pnas.1421926112</a>
Fetal lung epithelial ion channels relocate in the cell membrane during late gestation.
Animals; Blotting; Caveolin 1/*metabolism; Cell Membrane/*metabolism; Cl transport; Cystic Fibrosis Transmembrane Conductance Regulator/*metabolism; distal lung fluid absorption; Epithelial Sodium Channels/*metabolism; Epithelium/embryology/*metabolism; Female; fetal lung development; Fetus/*metabolism; Gestational Age; Guinea Pigs; IL-1beta; Immunoprecipitation; Interleukin-1beta/metabolism; Ion Channels/metabolism; Lung/embryology/*metabolism; Na transport; Western
Near the end of gestation, the direction of ion and fluid flow across the alveolar epithelium rapidly changes from secretion to absorption. Thus, the relative cell membrane location of epithelial Na channels (ENaCs) and cystic fibrosis transmembrane regulator (CFTR) Cl channels during late fetal lung development and after maternal interleukin-1beta (IL-1beta) pretreatment was the focus of our study. Western blot analysis after sucrose gradient separation of caveolin-1-(Cav-1)-rich membrane regions (CRR) and Cav-1-poor membrane (non-CRR) revealed primary CRR ENaC localization at gestation day (GD) 61 in guinea pigs. Correlating with the natural induction of distal lung fluid absorption, ENaC appeared in the non-CRR cell membrane regions at GD68. Conversely, CFTR was present in the non-CRR cell membrane regions at GD61 and in the CRRs at GD68.
Beard LaMonta L; Li Tianbo; Hu Yang; Folkesson Hans G
Anatomical record (Hoboken, N.J. : 2007)
2011
2011-09
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/10.1002/ar.21363" target="_blank" rel="noreferrer noopener">10.1002/ar.21363</a>
Extracellular Molecular Markers and Soma Size of Inhibitory Neurons: Evidence for Four Subtypes of GABAergic Cells in the Inferior Colliculus.
Female; GABA; Male; Animals; auditory; Guinea Pigs; plasticity; Auditory Pathways/cytology/*physiology; Biomarkers; Cell Size; Extracellular Space/*physiology; gamma-Aminobutyric Acid/*physiology; Glutamate Decarboxylase/metabolism; Inferior Colliculi/cytology/*physiology; inhibition; Neuronal Plasticity/physiology; Neurons/*physiology/ultrastructure; perineuronal net; Vesicular Glutamate Transport Protein 2/metabolism; VGLUT2
UNLABELLED: Inhibition plays an important role in shaping responses to stimuli throughout the CNS, including in the inferior colliculus (IC), a major hub in both ascending and descending auditory pathways. Subdividing GABAergic cells has furthered the understanding of inhibition in many brain areas, most notably in the cerebral cortex. Here, we seek the same understanding of subcortical inhibitory cell types by combining staining for two types of extracellular markers–perineuronal nets (PNs) and perisomatic rings of terminals expressing vesicular glutamate transporter 2 (VGLUT2)–to subdivide IC GABAergic cells in adult guinea pigs. We found four distinct groups of GABAergic cells in the IC: (1) those with both a PN and a VGLUT2 ring; (2) those with only a PN; (3) those with only a VGLUT2 ring; and (4) those with neither marker. In addition, these four GABAergic subtypes differ in their soma size and distribution among IC subdivisions. Functionally, the presence or absence of VGLUT2 rings indicates differences in inputs, whereas the presence or absence of PNs indicates different potential for plasticity and temporal processing. We conclude that these markers distinguish four GABAergic subtypes that almost certainly serve different roles in the processing of auditory stimuli within the IC. SIGNIFICANCE STATEMENT: GABAergic inhibition plays a critical role throughout the brain. Identification of subclasses of GABAergic cells (up to 15 in the cerebral cortex) has furthered the understanding of GABAergic roles in circuit modulation. Inhibition is also prominent in the inferior colliculus, a subcortical hub in auditory pathways. Here, we use two extracellular markers to identify four distinct groups of GABAergic cells. Perineuronal nets and perisomatic rings of glutamatergic boutons are present in many subcortical areas and often are associated with inhibitory cells, but they have rarely been used to identify inhibitory subtypes. Our results further the understanding of inhibition in the inferior colliculus and suggest that these extracellular molecular markers may provide a key to distinguishing inhibitory subtypes in many subcortical areas.
Beebe Nichole L; Young Jesse W; Mellott Jeffrey G; Schofield Brett R
The Journal of neuroscience : the official journal of the Society for Neuroscience
2016
2016-04
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1523/JNEUROSCI.0217-16.2016" target="_blank" rel="noreferrer noopener">10.1523/JNEUROSCI.0217-16.2016</a>
Alternative microglial activation is associated with cessation of progressive dopamine neuron loss in mice systemically administered lipopolysaccharide.
Animals; Astrocytes/immunology/pathology; Cell Death/physiology; Corpus Striatum/immunology/pathology; Cytokines/metabolism; Disease Progression; Dopaminergic Neurons/*immunology/pathology; Inbred C57BL; Inflammation/pathology/physiopathology; Lipopolysaccharides/*toxicity; Male; Messenger/metabolism; Mice; Microglia/*immunology/pathology; Nerve Degeneration/*immunology/pathology; Neurodegenerative Diseases/immunology/pathology; Neuroimmunomodulation/physiology; Random Allocation; RNA; Time Factors
Inflammation arising from central and/or peripheral sources contributes to the pathogenesis of multiple neurodegenerative diseases including Parkinson's disease (PD). Emerging data suggest that differential activation of glia could lead to the pathogenesis and progression of PD. Here, we sought to determine the relationship between lipopolysaccharide (LPS) treatment, loss of dopaminergic neurons and differential activation of glia. Using a model of repeated injections with LPS (1mg/kg, i.p. for 4days), we found that LPS induced a 34% loss of dopamine neurons in the substantia nigra 19days after initiation of treatment, but no further cell loss was observed at 36days. LPS induced a strong pro-inflammatory response with increased mRNA expression of pro-inflammatory markers, including tumor necrosis factor-alpha (4.8-fold), inducible nitric oxide synthase (2.0-fold), interleukin-1 beta (8.9-fold), interleukin-6 (10.7-fold), and robust glial activation were observed at 1day after final dose of LPS. These pro-inflammatory genes were then reduced at 19days after treatment, when there was a rise in the anti-inflammatory genes Ym1 (1.8-fold) and arginase-1 (2.6-fold). Additionally, 36days after the last LPS injection there was a significant increase in interleukin-10 (2.1-fold) expression. The qPCR data results were supported by protein data, including cytokine measurements, western blotting, and immunofluorescence in brain microglia. Taken together, these data demonstrate that progressive neurodegeneration in the substantia nigra following LPS is likely arrested by microglia shifting to an anti-inflammatory phenotype. Thus, strategies to promote resolution of neuroinflammation may be a promising avenue to slow the progressive loss of dopamine neurons in PD.
Beier Eric E; Neal Matthew; Alam Gelerah; Edler Melissa; Wu Long-Jun; Richardson Jason R
Neurobiology of disease
2017
2017-12
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/10.1016/j.nbd.2017.08.009" target="_blank" rel="noreferrer noopener">10.1016/j.nbd.2017.08.009</a>
Augmentation of Muscle Blood Flow by Ultrasound Cavitation Is Mediated by ATP and Purinergic Signaling.
Adenosine Triphosphate – Metabolism; Adenosine Triphosphate/*metabolism; Animal Studies; Animals; contrast echocardiography; Equipment and Supplies; Hemodynamics; Humans; Inbred C57BL; Male; Mice; microbubbles; Microbubbles; microcirculation; Muscle; Neurotransmitter Agents – Metabolism; perfusion; Purinergic Agents/*metabolism; Signal Transduction; Skeletal – Blood Supply; Skeletal/*blood supply; Ultrasonography – Methods; Ultrasonography/*methods
BACKGROUND: Augmentation of tissue blood flow by therapeutic ultrasound is thought to rely on convective shear. Microbubble contrast agents that undergo ultrasound-mediated cavitation markedly amplify these effects. We hypothesized that purinergic signaling is responsible for shear-dependent increases in muscle perfusion during therapeutic cavitation. METHODS: Unilateral exposure of the proximal hindlimb of mice (with or without ischemia produced by iliac ligation) to therapeutic ultrasound (1.3 MHz, mechanical index 1.3) was performed for 10 minutes after intravenous injection of 2x10(8) lipid microbubbles. Microvascular perfusion was evaluated by low-power contrast ultrasound perfusion imaging. In vivo muscle ATP release and in vitro ATP release from endothelial cells or erythrocytes were assessed by a luciferin-luciferase assay. Purinergic signaling pathways were assessed by studying interventions that (1) accelerated ATP degradation; (2) inhibited P2Y receptors, adenosine receptors, or KATP channels; or (3) inhibited downstream signaling pathways involving endothelial nitric oxide synthase or prostanoid production (indomethacin). Augmentation in muscle perfusion by ultrasound cavitation was assessed in a proof-of-concept clinical trial in 12 subjects with stable sickle cell disease. RESULTS: Therapeutic ultrasound cavitation increased muscle perfusion by 7-fold in normal mice, reversed tissue ischemia for up to 24 hours in the murine model of peripheral artery disease, and doubled muscle perfusion in patients with sickle cell disease. Augmentation in flow extended well beyond the region of ultrasound exposure. Ultrasound cavitation produced an approximately 40-fold focal and sustained increase in ATP, the source of which included both endothelial cells and erythrocytes. Inhibitory studies indicated that ATP was a critical mediator of flow augmentation that acts primarily through either P2Y receptors or adenosine produced by ectonucleotidase activity. Combined indomethacin and inhibition of endothelial nitric oxide synthase abolished the effects of therapeutic ultrasound, indicating downstream signaling through both nitric oxide and prostaglandins. CONCLUSIONS: Therapeutic ultrasound using microbubble cavitation to increase muscle perfusion relies on shear-dependent increases in ATP, which can act through a diverse portfolio of purinergic signaling pathways. These events can reverse hindlimb ischemia in mice for \textgreater24 hours and increase muscle blood flow in patients with sickle cell disease. CLINICAL TRIAL REGISTRATION: URL: http://clinicaltrials.gov. Unique identifier: NCT01566890.
Belcik J Todd; Davidson Brian P; Xie Aris; Wu Melinda D; Yadava Mrinal; Qi Yue; Liang Sherry; Chon Chae Ryung; Ammi Azzdine Y; Field Joshua; Harmann Leanne; Chilian William M; Linden Joel; Lindner Jonathan R
Circulation
2017
2017-03
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/CIRCULATIONAHA.116.024826" target="_blank" rel="noreferrer noopener">10.1161/CIRCULATIONAHA.116.024826</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>
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>