scholarly journals Identification of a physiological role for leptin in the regulation of ambulatory activity and wheel running in mice

2011 ◽  
Vol 300 (2) ◽  
pp. E392-E401 ◽  
Author(s):  
Gregory J. Morton ◽  
Karl J. Kaiyala ◽  
Jonathan D. Fisher ◽  
Kayoko Ogimoto ◽  
Michael W. Schwartz ◽  
...  
Keyword(s):  
Physical Activity ◽  
Wheel Running ◽  
Physiological Role ◽  
Dependent Manner ◽  
Wild Type ◽  
Dark Cycle ◽  
Ambulatory Activity ◽  
Spontaneous Physical Activity ◽  
Plasma Leptin ◽  
Dose Dependent

Mechanisms regulating spontaneous physical activity remain poorly characterized despite evidence of influential genetic and acquired factors. We evaluated ambulatory activity and wheel running in leptin-deficient ob/ob mice and in wild-type mice rendered hypoleptinemic by fasting in both the presence and absence of subcutaneous leptin administration. In ob/ob mice, leptin treatment to plasma levels characteristic of wild-type mice acutely increased both ambulatory activity (by 4,000 ± 200 beam breaks/dark cycle, P < 0.05) and total energy expenditure (TEE; by 0.11 ± 0.01 kcal/h during the dark cycle, P < 0.05) in a dose-dependent manner and acutely increased wheel running (+350%, P < 0.05). Fasting potently increased ambulatory activity and wheel running in wild-type mice (AA: +25%, P < 0.05; wheel running: +80%, P < 0.05), and the effect of fasting was more pronounced in ob/ob mice (AA: +400%, P < 0.05; wheel running: +1,600%, P < 0.05). However, unlike what occurred in ad libitum-fed ob/ob mice, physiological leptin replacement attenuated or prevented fasting-induced increases of ambulatory activity and wheel running in both wild-type and ob/ob mice. Thus, plasma leptin is a physiological regulator of spontaneous physical activity, but the nature of leptin's effect on activity is dependent on food availability.

scholarly journals Regulation of Reentrainment Function Is Dependent on a Certain Minimal Number of Intact Functional ipRGCs in rd Mice

2017 ◽  
Vol 2017 ◽  
pp. 1-8 ◽  
Author(s):  
Jingxue Zhang ◽  
Huaizhou Wang ◽  
Shen Wu ◽  
Qian Liu ◽  
Ningli Wang
Keyword(s):  
Wheel Running ◽  
Ganglion Cells ◽  
Survival Rates ◽  
Control Group ◽  
Dependent Manner ◽  
Retinal Ganglion ◽  
Dark Cycle ◽  
Visual Functions ◽  
Running System ◽  
Dose Dependent

Purpose. To investigate the effect of partial ablation of melanopsin-containing retinal ganglion cells (mcRGCs) on nonimage-forming (NIF) visual functions in rd mice lacking rods.Methods. The rd mice were intravitreally injected with different doses (100 ng/μl, 200 ng/μl, and 400 ng/μl) of immunotoxin melanopsin-SAP. And then, the density of ipRGCs was examined. After establishing the animal models with different degrees of ipRGC damage, a wheel-running system was used to evaluate their reentrainment response.Results. Intravitreal injection of melanopsin-SAP led to partial ablation of ipRGCs in a dose-dependent manner. The survival rates of ipRGCs in the 100 ng/μl, 200 ng/μl, and 400 ng/μl groups were 74.14% ± 4.15%, 39.25% ± 2.29%, and 38.38% ± 3.74%, respectively. The wheel-running experiments showed that more severe ipRGC loss was associated with a longer time needed for reentrainment. When the light/dark cycle was delayed by 8 h, the rd mice in the PBS control group took 4.67 ± 0.79 days to complete the synchronization with the shifted cycle, while those in the 100 ng/μl and 200 ng/μl groups required 7.90 ± 0.55 days and 11.00 ± 0.79 days to complete the synchronization with the new light/dark cycle, respectively.Conclusion. Our study indicates that the regulation of some NIF visual functions is dependent on a certain minimal number of intact functional ipRGCs.

Oxytocin affects apical sodium conductance in rabbit cortical collecting duct

1993 ◽  
Vol 265 (4) ◽  
pp. F487-F503 ◽  
Author(s):  
T. Inoue ◽  
M. Naruse ◽  
M. Nakayama ◽  
K. Kurokawa ◽  
T. Sato
Keyword(s):  
Receptor Antagonist ◽  
Collecting Duct ◽  
Rat Kidney ◽  
Physiological Role ◽  
Free Calcium ◽  
Second Phase ◽  
Dependent Manner ◽  
Cortical Collecting Duct ◽  
Acetoxymethyl Ester ◽  
Dose Dependent

The physiological role of oxytocin (OT) in the kidney is still unclear, although autoradiographic data have shown the existence of OT receptors in the rat kidney. We examined the effect of OT in the microperfused rabbit cortical collecting duct (CCD) by using conventional cable analysis and microscope photometry. On addition of 10(-9) M OT to the bath, the lumen-negative transepithelial voltage (VT) transiently increased and the transepithelial resistance (RT) and the fractional resistance of the apical membrane (FRA) (1st phase) both decreased. After this initial change, the lumen-negative VT gradually decreased below its baseline level and RT and FRA (second phase) both increased. These electrical changes were dose dependent and were prevented by the addition of 10(-5) M amiloride to the lumen. Although responses to OT were not prevented by 10(-9) M arginine vasopressin (AVP) or 10(-6) M of a V1-receptor antagonist (OPC-21268) or V2-receptor antagonist (OPC-31260), they were inhibited by the addition of the specific OT antagonist des-Gly-NH2-[d(CH2)3,Tyr(Me),Thr]OVT. Additional studies of intracellular free calcium ([Ca2+]i) revealed that 10(-8)-10(-6) M OT caused an increase in [Ca2+]i in CCD in a dose-dependent manner. Also, pretreatment with 2 x 10(-8) M bis-(aminophenoxy)ethane-tetraacetic acid-acetoxymethyl ester, an intracellular Ca2+ chelator, abolished the electrical and [Ca2+]i responses to OT. Pretreatment with 5 x 10(-4) M 8-(4-chlorophenylthio)-adenosine 3',5'-cyclic monophosphate (CPT-cAMP) partially prevented the electrical responses to OT, thus reducing the decrease in lumen-negative VT below its basal level and the increase in RT after the 1st phase. These data show that OT affects the apical Na+ conductance of collecting duct cells through OT receptors distinct from the AVP receptors and that the effect of OT may, at least in part, be brought about by a mechanism(s) dependent on the increase in [Ca2+]i and cAMP production.

scholarly journals Lipopolysaccharide biosynthesis-related genes are required for colony pigmentation of Porphyromonas gingivalis

Microbiology ◽  
2009 ◽  
Vol 155 (4) ◽  
pp. 1282-1293 ◽  
Author(s):  
Keiko Sato ◽  
Nobuo Kido ◽  
Yukitaka Murakami ◽  
Charles I. Hoover ◽  
Koji Nakayama ◽  
...  
Keyword(s):  
Cell Surface ◽  
Porphyromonas Gingivalis ◽  
Dependent Manner ◽  
Wild Type ◽  
Gene Encoding ◽  
Lipopolysaccharide Biosynthesis ◽  
Ladder Pattern ◽  
Surface Polysaccharides ◽  
Culture Supernatants ◽  
Dose Dependent

The periodontopathic bacterium Porphyromonas gingivalis forms pigmented colonies when incubated on blood agar plates as a result of accumulation of μ-oxo haem dimer on the cell surface. Gingipain–adhesin complexes are responsible for production of μ-oxo haem dimer from haemoglobin. Non-pigmented mutants (Tn6-5, Tn7-1, Tn7-3 and Tn10-4) were isolated from P. gingivalis by Tn4351 transposon mutagenesis [Hoover & Yoshimura (1994), FEMS Microbiol Lett 124, 43–48]. In this study, we found that the Tn6-5, Tn7-1 and Tn7-3 mutants carried Tn4351 DNA in a gene homologous to the ugdA gene encoding UDP-glucose 6-dehydrogenase, a gene encoding a putative group 1 family glycosyltransferase and a gene homologous to the rfa gene encoding ADP heptose-LPS heptosyltransferase, respectively. The Tn10-4 mutant carried Tn4351 DNA at the same position as that for Tn7-1. Gingipain activities associated with cells of the Tn7-3 mutant (rfa) were very weak, whereas gingipain activities were detected in the culture supernatants. Immunoblot and mass spectrometry analyses also revealed that gingipains, including their precursor forms, were present in the culture supernatants. A lipopolysaccharide (LPS) fraction of the rfa deletion mutant did not show the ladder pattern that was usually seen for the LPS of the wild-type P. gingivalis. A recombinant chimera gingipain was able to bind to an LPS fraction of the wild-type P. gingivalis in a dose-dependent manner. These results suggest that the rfa gene product is associated with biosynthesis of LPS and/or cell-surface polysaccharides that can function as an anchorage for gingipain–adhesin complexes.

scholarly journals Choline Induces Transcriptional Repression and Proteasomal Degradation of the Malarial Phosphoethanolamine Methyltransferase

2007 ◽  
Vol 6 (9) ◽  
pp. 1618-1624 ◽  
Author(s):  
William Harold Witola ◽  
Choukri Ben Mamoun
Keyword(s):  
Transcriptional Repression ◽  
Morphological Changes ◽  
Transcriptional Level ◽  
Dependent Manner ◽  
Wild Type ◽  
Active Synthesis ◽  
Rapid Multiplication ◽  
Gene And Protein Expression ◽  
Transgenic Parasites ◽  
Dose Dependent

ABSTRACT During its intraerythrocytic life cycle, the malaria parasite Plasmodium falciparum undergoes dramatic metabolic and morphological changes and multiplies to produce up to 36 new daughter parasites. This rapid multiplication of the parasite requires an active synthesis of new membranes. The major component of these membranes, phosphatidylcholine, is synthesized via two metabolic routes, the CDP-choline pathway, which uses host choline as a precursor, and the plant-like serine decarboxylase-phosphoethanolamine methyltransferase (SDPM) pathway, which uses host serine as a precursor. Here we provide evidence indicating that the activity of the SDPM pathway is regulated by the CDP-choline precursor, choline. We show that the phosphoethanolamine methyltransferase, Pfpmt, a critical enzyme in the SDPM pathway, is down-regulated at the transcriptional level as well as targeted for degradation by the proteasome in the presence of choline. Transcript analysis revealed that PfPMT transcription is repressed by choline in a dose-dependent manner. Immunoblotting, pulse-chase experiments, and immunoprecipitation studies demonstrated that Pfpmt degradation occurs not only in wild-type but also in transgenic parasites constitutively expressing Pfpmt. The proteasome inhibitor bortezomib inhibited choline-mediated Pfpmt degradation. These data provide the first evidence for metabolite-mediated transcriptional and proteasomal regulation in Plasmodium and will set the stage for the use of this system for conditional gene and protein expression in this organism.

Physical activity is associated with bone geometry of premenarcheal girls in a dose-dependent manner

Metabolism ◽  
2013 ◽  
Vol 62 (12) ◽  
pp. 1811-1818 ◽  
Author(s):  
Maria Michalopoulou ◽  
Antonis Kambas ◽  
Diamanda Leontsini ◽  
Athanasios Chatzinikolaou ◽  
Dimitrios Draganidis ◽  
...  
Keyword(s):  
Physical Activity ◽  
Bone Geometry ◽  
Dependent Manner ◽  
Dose Dependent

scholarly journals Genetic or Enzymatic Disruption of Aromatase Inhibits the Growth of Ectopic Uterine Tissue

2002 ◽  
Vol 87 (7) ◽  
pp. 3460-3466 ◽  
Author(s):  
Zongjuan Fang ◽  
Sijun Yang ◽  
Bilgin Gurates ◽  
Mitsutoshi Tamura ◽  
Evan Simpson ◽  
...  
Keyword(s):  
Enzyme Activity ◽  
Mouse Model ◽  
Lesion Size ◽  
Dependent Manner ◽  
Wild Type ◽  
Uterine Tissue ◽  
Abdominal Organs ◽  
Letrozole Treatment ◽  
Key Enzyme ◽  
Dose Dependent

Aromatase P450 (P450arom) is the key enzyme for the biosynthesis of estrogen that is essential for the growth of human endometriosis, a pathology characterized by endometrium-like tissue on the peritoneal surfaces of abdominal organs manifest by pelvic pain and infertility. Surgically transplanted autologous uterine tissue to ectopic sites on the peritoneum in mice has been used as an animal model to study endometriosis. Using this mouse model, we evaluated the roles of the P450arom gene and aromatase enzyme activity in the growth of endometriosis represented by ectopic uterine tissues in mice. Endometriosis was induced surgically in the following groups of mice: 1) untreated transgenic mice with disrupted P450arom gene (ArKO); 2) ArKO mice treated with systemic estrogen; 3) untreated wild-type (WT) mice; 4) WT mice treated with estrogen; 5) WT mice treated with the aromatase inhibitor, letrozole; and 6) WT mice treated with letrozole and estrogen. Each group contained eight mice; +/+ littermates of ArKO mice were used as WT controls. Treatment with estrogen increased the size of ectopic uterine tissues in ArKO and WT mice significantly. The ectopic uterine lesions in untreated and estrogen-treated ArKO mice were strikingly smaller than those in untreated and estrogen-treated WT controls, respectively. Systemic treatment of WT mice with letrozole significantly decreased the lesion size in a dose-dependent manner. The addition of estrogen to letrozole treatment increased the ectopic lesion size, although these lesions were significantly smaller than those in mice treated with estrogen only. As tissue controls, the effects of these conditions on normally located (eutopic) uterine tissue were evaluated. The effects of disruption of the P450arom gene and treatments with letrozole and estrogen seemed to be more profound on ectopic tissues, suggesting that ectopic tissues might be more sensitive to estrogen for growth. We conclude that both an intact P450arom gene and the presence of aromatase enzyme activity are essential for the growth of ectopic uterine tissue in a mouse model of endometriosis.

Platelet endothelial cell adhesion molecule-1 is a negative regulator of platelet-collagen interactions

Blood ◽  
2001 ◽  
Vol 98 (5) ◽  
pp. 1456-1463 ◽  
Author(s):  
Karen L. Jones ◽  
Sascha C. Hughan ◽  
Sacha M. Dopheide ◽  
Richard W. Farndale ◽  
Shaun P. Jackson ◽  
...  
Keyword(s):  
Cell Adhesion Molecule ◽  
Collagen Matrix ◽  
Negative Regulator ◽  
Dependent Manner ◽  
Wild Type ◽  
Platelet Endothelial Cell Adhesion ◽  
Cell Adhesion Molecule 1 ◽  
Dose Dependent ◽  
Deficient Mice ◽  
Endothelial Cell Adhesion

The functional importance of platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) in platelets is unclear. Because PECAM-1 represents a newly assigned immunoglobulin–ITIM superfamily member expressed on the surface of platelets, it was hypothesized that it may play an important regulatory role in modulating ITAM-bearing receptors such as collagen (GP)VI receptor and FcγRIIA. To examine the functional role of PECAM-1 in regulating platelet-collagen interactions, 2 different approaches were applied using recombinant human PECAM-1–immunoglobulin chimeras and platelets derived from PECAM-1–deficient mice. Stimulation of platelets by collagen-, (GP)VI-selective agonist, collagen-related peptide (CRP)–, and PECAM-1–immunoglobulin chimera induced tyrosine phosphorylation of PECAM-1 in a time- and dose-dependent manner. Activation of PECAM-1 directly through the addition of soluble wild-type PECAM-1–immunoglobulin chimera, but not mutant K89A PECAM-1–immunoglobulin chimera that prevents homophilic binding, was found to inhibit collagen- and CRP-induced platelet aggregation. PECAM-1–deficient platelets displayed enhanced platelet aggregation and secretion responses on stimulation with collagen and CRP, though the response to thrombin was unaffected. Under conditions of flow, human platelet thrombus formation on a collagen matrix was reduced in a dose-dependent manner by human PECAM-1–immunoglobulin chimera. Platelets derived from PECAM-1–deficient mice form larger thrombi when perfused over a collagen matrix under flow at a shear rate of 1800 seconds−1 compared to wild-type mice. Collectively, these results indicate that PECAM-1 serves as a physiological negative regulator of platelet-collagen interactions that may function to negatively limit growth of platelet thrombi on collagen surfaces.

scholarly journals Spontaneous Physical Activity Downregulates Pax7 in Cancer Cachexia

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Dario Coletti ◽  
Paola Aulino ◽  
Eva Pigna ◽  
Fabio Barteri ◽  
Viviana Moresi ◽  
...  
Keyword(s):  
Physical Activity ◽  
Cancer Cachexia ◽  
Wheel Running ◽  
Voluntary Exercise ◽  
Acute Injury ◽  
Muscle Stem Cells ◽  
Positive Effects ◽  
Tumor Bearing ◽  
Spontaneous Physical Activity ◽  
Carcinoma Tumor

Emerging evidence suggests that the muscle microenvironment plays a prominent role in cancer cachexia. We recently showed that NF-kB-induced Pax7 overexpression impairs the myogenic potential of muscle precursors in cachectic mice, suggesting that lowering Pax7 expression may be beneficial in cancer cachexia. We evaluated the muscle regenerative potential after acute injury in C26 colon carcinoma tumor-bearing mice and healthy controls. Our analyses confirmed that the delayed muscle regeneration observed in muscles form tumor-bearing mice was associated with a persistent local inflammation and Pax7 overexpression. Physical activity is known to exert positive effects on cachectic muscles. However, the mechanism by which a moderate voluntary exercise ameliorates muscle wasting is not fully elucidated. To verify if physical activity affects Pax7 expression, we hosted control and C26-bearing mice in wheel-equipped cages and we found that voluntary wheel running downregulated Pax7 expression in muscles from tumor-bearing mice. As expected, downregulation of Pax7 expression was associated with a rescue of muscle mass and fiber size. Our findings shed light on the molecular basis of the beneficial effect exerted by a moderate physical exercise on muscle stem cells in cancer cachexia. Furthermore, we propose voluntary exercise as a physiological tool to counteract the overexpression of Pax7 observed in cancer cachexia.

scholarly journals Computational Modeling for Antiarrhythmic Drugs for Atrial Fibrillation According to Genotype

2021 ◽  
Vol 12 ◽  
Author(s):  
Inseok Hwang ◽  
Je-Wook Park ◽  
Oh-Seok Kwon ◽  
Byounghyun Lim ◽  
Myunghee Hong ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Computational Modeling ◽  
Antiarrhythmic Drugs ◽  
Dominant Frequency ◽  
Dependent Manner ◽  
Ion Currents ◽  
Wild Type ◽  
Wave Dynamic ◽  
Phase Singularities ◽  
Dose Dependent

Background: The efficacy of antiarrhythmic drugs (AAD) can vary in patients with atrial fibrillation (AF), and the PITX2 gene affects the responsiveness of AADs. We explored the virtual AAD (V-AAD) responses between wild-type and PITX2+/−-deficient AF conditions by realistic in silico AF modeling.Methods: We tested the V-AADs in AF modeling integrated with patients' 3D-computed tomography and 3D-electroanatomical mapping, acquired in 25 patients (68% male, 59.8 ± 9.8 years old, 32.0% paroxysmal type). The ion currents for the PITX2+/− deficiency and each AAD (amiodarone, sotalol, dronedarone, flecainide, and propafenone) were defined based on previous publications.Results: We compared the wild-type and PITX2+/− deficiency in terms of the action potential duration (APD90), conduction velocity (CV), maximal slope of restitution (Smax), and wave-dynamic parameters, such as the dominant frequency (DF), phase singularities (PS), and AF termination rates according to the V-AADs. The PITX2+/−-deficient model exhibited a shorter APD90 (p &lt; 0.001), a lower Smax (p &lt; 0.001), mean DF (p = 0.012), PS number (p &lt; 0.001), and a longer AF cycle length (AFCL, p = 0.011). Five V-AADs changed the electrophysiology in a dose-dependent manner. AAD-induced AFCL lengthening (p &lt; 0.001) and reductions in the CV (p = 0.033), peak DF (p &lt; 0.001), and PS number (p &lt; 0.001) were more significant in PITX2+/−-deficient than wild-type AF. PITX2+/−-deficient AF was easier to terminate with class IC AADs than the wild-type AF (p = 0.018).Conclusions: The computational modeling-guided AAD test was feasible for evaluating the efficacy of multiple AADs in patients with AF. AF wave-dynamic and electrophysiological characteristics are different among the PITX2-deficient and the wild-type genotype models.

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