Effect of ageing on cyclic AMP output by renal medullary cells in response to arginine vasopressin in vitro in C57BL/Icrfat mice

1984 ◽  
Vol 103 (2) ◽  
pp. 133-139 ◽  
Author(s):  
C. Goddard ◽  
Y. S. Davidson ◽  
B. B. Moser ◽  
I. Davies ◽  
E. B. Faragher
Keyword(s):  
Cyclic Amp ◽  
Arginine Vasopressin ◽  
Age Related ◽  
Camp Metabolism ◽  
The Right ◽  
Old Mice ◽  
Effect Of Age ◽  
Urine Concentrating Ability ◽  
Medullary Cells

ABSTRACT The effect of age on the cyclic AMP (cAMP) response to increases in the concentration of arginine vasopressin in the presence of isobutyl methylxanthine (100 μmol/l) was studied in an in-vitro renal cell suspension prepared from C57BL/Icrfat mice at 6, 12, 18, 24, 29 and 35 months of age. Comparison of the response of the preparation to vasopressin, calcitonin and parathyroid hormone suggested that it was enriched with renal medullary cells. Basal cAMP output was similar throughout but the threshold dose of vasopressin increased from 1 × 10−11 mol/l (6, 12 and 18 months of age) to 1 × 10−10 mol/l (24, 29 and 35 months of age). The dose–response curve in 35-month-old mice was shifted to the right with the concentration of vasopressin required to give half maximal cAMP increased from 9·4 ± 0·37 × 10−11 mol/l (6 months) to 3·5±1·6 × 10−10 mol/l (35 months). Maximum cAMP output at 1 × 10 −9 mol/l was also reduced in the same animals (stimulated:basal ratio, 51·22±19·12 at 6 months; 11·50 ± 6·02 at 35 months). The results suggest that the lack of renal response to vasopressin in terms of cAMP metabolism may play a role in the well-documented age-related decline in urine-concentrating ability in experimental animals and elderly people. J. Endocr. (1984) 103, 133–139

scholarly journals Neuroinflammation in Aged Brain: Impact of the Oral Administration of Ellagic Acid Microdispersion

2020 ◽  
Vol 21 (10) ◽  
pp. 3631 ◽  
Author(s):  
Raffaella Boggia ◽  
Federica Turrini ◽  
Alessandra Roggeri ◽  
Guendalina Olivero ◽  
Francesca Cisani ◽  
...  
Keyword(s):  
Oral Administration ◽  
Ellagic Acid ◽  
Ex Vivo ◽  
Behavioral Skills ◽  
Aged Mice ◽  
Age Related ◽  
The Central Nervous System ◽  
The Impact ◽  
Old Mice

The immune system and the central nervous system message each other to preserving central homeostasis. Both systems undergo changes during aging that determine central age-related defects. Ellagic acid (EA) is a natural product which is beneficial in both peripheral and central diseases, including aging. We analyzed the impact of the oral administration of a new oral ellagic acid micro-dispersion (EAm), that largely increased the EA solubility, in young and old mice. Oral EAm did not modify animal weight and behavioral skills in young and old mice, but significantly recovered changes in “ex-vivo, in vitro” parameters in old animals. Cortical noradrenaline exocytosis decreased in aged mice. EAm administration did not modify noradrenaline overflow in young animals, but recovered it in old mice. Furthermore, GFAP staining was increased in the cortex of aged mice, while IBA-1 and CD45 immunopositivities were unchanged when compared to young ones. EAm treatment significantly reduced CD45 signal in both young and old cortical lysates; it diminished GFAP immunopositivity in young mice, but failed to affect IBA-1 expression in both young and old animals. Finally, EAm treatment significantly reduced IL1beta expression in old mice. These results suggest that EAm is beneficial to aging and represents a nutraceutical ingredient for elders.

scholarly journals Inflamma-miR-21 Negatively Regulates Myogenesis during Ageing

Antioxidants ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 345 ◽  
Author(s):  
Maria Borja-Gonzalez ◽  
Jose C. Casas-Martinez ◽  
Brian McDonagh ◽  
Katarzyna Goljanek-Whysall
Keyword(s):  
Skeletal Muscle ◽  
Satellite Cells ◽  
Muscle Regeneration ◽  
Muscle Hypertrophy ◽  
Myogenic Potential ◽  
Age Related ◽  
Primary Myoblasts ◽  
Muscle Homeostasis ◽  
Old Mice

Ageing is associated with disrupted redox signalling and increased circulating inflammatory cytokines. Skeletal muscle homeostasis depends on the balance between muscle hypertrophy, atrophy and regeneration, however during ageing this balance is disrupted. The molecular pathways underlying the age-related decline in muscle regenerative potential remain elusive. microRNAs are conserved robust gene expression regulators in all tissues including skeletal muscle. Here, we studied satellite cells from adult and old mice to demonstrate that inhibition of miR-21 in satellite cells from old mice improves myogenesis. We determined that increased levels of proinflammatory cytokines, TNFα and IL6, as well as H2O2, increased miR-21 expression in primary myoblasts, which in turn resulted in their decreased viability and myogenic potential. Inhibition of miR-21 function rescued the decreased size of myotubes following TNFα or IL6 treatment. Moreover, we demonstrated that miR-21 could inhibit myogenesis in vitro via regulating IL6R, PTEN and FOXO3 signalling. In summary, upregulation of miR-21 in satellite cells and muscle during ageing may occur in response to elevated levels of TNFα and IL6, within satellite cells or myofibrillar environment contributing to skeletal muscle ageing and potentially a disease-related decline in potential for muscle regeneration.

scholarly journals AGE-ASSOCIATED INCREASE IN KYNURENINE INHIBITS AUTOPHAGY AND PROMOTES SENESCENCE IN BONE MARROW STEM CELLS

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S956-S956
Author(s):  
Dmitry Kondrikov ◽  
Ahmed Elmansi ◽  
Xing-ming Shi ◽  
Sadanand Fulzele ◽  
Meghan mcGee-Lawrence ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Cell Lines ◽  
Free Radical Oxidation ◽  
Autophagic Flux ◽  
Galactosidase Activity ◽  
Activity Increase ◽  
Age Related ◽  
Old Mice

Abstract Aging is characterized by progressive decline of tissue functionality and age-related accumulation of cellular and molecular damage leading to multiple pathological conditions including osteoporosis and increased fracture rates. Bone marrow mesenchymal stem cells (BMSCs) play an essential role in bone development and regeneration with their ability to undergo differentiation into osteogenic, chondrogenic, myogenic, and adipogenic cell lines cell lines. Proliferation rate of MSC is declined with ages leading to misbalance between bone resorption and osteogenesis. A recently identified age-related change in bone and bone marrow is an accumulation of tryptophan metabolite, kynurenine (KYN), catalyzed by indoleamine-2,3-dioxygenase (IDO) or free-radical oxidation. We previously reported that KYN suppresses autophagy in BMSC. We now investigated the effect of KYN on BMSC cellular function. In vitro treatment of murine BMSC isolated from 18 month old mice with kynurenine disrupted autophagy suppressing autophagic flux. KYN treatment also induces senescence in BMSC marked by increase in SA-beta-galactosidase activity as well as, increased expression of senescence marker p21. Inhibition of Aryl Hydrocarbon Receptor (AhR) by AhR inhibitors significantly reduced β-galactosidase activity increase and blocked p21 expression elevation suggesting that KYN induces senescence in BMSC through the AhR pathway. Interestingly, KYN treatment failed to up-regulate beta-gal activity in BMSC isolated from 6 month-old mice suggesting that KYN induction of senescence maybe potentiated with aging. Together those data support the idea that KYN shifts the homeostatic balance of BMSC during prolonged stress or in aging through downregulating survival autophagic pathway in favor of driving BMSCs to senescence.

Inflation-associated increases in lung polyamine uptake: role of altered pulmonary vascular flow

1989 ◽  
Vol 257 (5) ◽  
pp. E729-E735 ◽  
Author(s):  
H. W. Karl ◽  
L. A. Russo ◽  
D. E. Rannels
Keyword(s):  
Flow Rate ◽  
Metabolic Response ◽  
Left Lung ◽  
Pulmonary Flow ◽  
Vascular Flow ◽  
Isolated Lung ◽  
Wide Range ◽  
Camp Metabolism ◽  
The Right

Unilateral pneumonectomy in rats leads to rapid compensatory growth of the remaining lung. Previous studies showed that postoperative increases in lung mass are preceded by enhanced uptake of exogenous polyamines and by alterations in adenosine 3',5'-cyclic monophosphate (cAMP) metabolism. These effects are both mimicked in lungs of intact animals subjected to increased inflation in vitro. Partial pneumonectomy also leads to increased flow to the contralateral lung associated with reduced pulmonary vascular resistance. This raises the possibility that the postoperative metabolic response is initiated by changes in pulmonary artery pressure (Pa) or flow, rather than altered inflation. The present studies were designed to investigate this issue. Uptake of exogenous [14C]spermidine by isolated perfused rat lungs was examined over a wide range (greater than 4-fold) of pulmonary flow and ventilation at fixed PaS. Assessment of tissue metabolism from rates of protein synthesis suggested stability of the isolated lung preparations. Apnea (0 ventilation) had no effect on spermidine uptake or flow rate, compared with lungs evaluated under normal conditions of ventilation (inspiratory pressure, 15 cmH2O; positive end expiratory pressure, 2 cmH2O; rate, 70 breaths/min). At both high and low Pa (at a flow rate of 37 +/- 1 and 11 +/- 2 ml/min, respectively, with 0 ventilation), removal of the left lung from the perfusion circuit increased specific right lung flow rate greater than 30% but had no effect on spermidine uptake. Similar alterations in flow rate to the right or both apneic lungs had no effect on the tissue content of cAMP.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Alteration of Platelet Cyclic AMP (cAMP) by Ethanol

1977 ◽  
Author(s):  
D.H. Cowan ◽  
M. Kikta ◽  
D. Baunach
Keyword(s):  
Cyclic Amp ◽  
Platelet Function ◽  
Inhibitory Effect ◽  
Human Platelets ◽  
Platelet Dysfunction ◽  
Camp Metabolism ◽  
Subnormal Level ◽  
Camp Levels ◽  
Stimulation Of

Studies of cAMP in human platelets exposed to ethanol were done to assess one possible mechanism for ethanol-related platelet dysfunction. Ingestion of ethanol by 3 subjects produced blood ethanol levels from 65-76 mM. Thrombocytopenia occurred in 1 subject and impaired platelet function occurred in all. Platelet cAMP decreased 36,51, and 59% below control levels. Infusion of ethanol to 2 normals produced blood ethanol levels of 43 mM and decreased platelet cAMP by 15% and 22%. Incubation of normal platelets with 86 mM ethanol in vitro decreased cAMP from 13.8 ± 2.9 (1 SD) to 9.4 ± 3.5 (p<0.02). By contrast, ethanol did not impair the increase in cAMP that occurred with 1.3 μM PGE1. Further, ethanol enhanced the increase in cAMP produced by 2.0 mM papaverine (Pap) by 160-220% and that produced by Pap + PGE1 by 58%. Dopamine, 0.1 mM, caused a 23% decrease in the basal level of cAMP, a 31% decrease below the subnormal level of cAMP seen with ethanol alone, and a 41% reduction in the increased level of cAMP produced by Pap + ethanol. The effect of ethanol on platelet cAMP metabolism is complex. Ethanol reduces basal levels of cAMP, does not decrease elevated levels that result from PGE1 stimulation of adenylate cyclase, and augments the inhibitory effect of Pap on platelet phosphodiesterase (PDE). Despite causing a decrease in basal cAMP levels, ethanol may impair platelet function by potentiating the effect of agents or other conditions which increase cAMP. The effect of ethanol on Pap-stimulated PDE activity may be blocked by dopamine, a neuropharmacologic agent that is actively accumulated by platelets.

Osmoregulation of vasopressin in diabetic ketoacidosis

1990 ◽  
Vol 259 (5) ◽  
pp. E723-E728
Author(s):  
J. A. Durr ◽  
W. H. Hoffman ◽  
J. Hensen ◽  
A. H. Sklar ◽  
T. el Gammal ◽  
...  
Keyword(s):  
Correlation Analysis ◽  
Diabetic Ketoacidosis ◽  
Arginine Vasopressin ◽  
Plasma Osmolality ◽  
Cell Permeability ◽  
Plasma Sodium ◽  
Two Dimensional ◽  
The Right

Osmoregulation of arginine vasopressin (AVP) is altered in diabetic ketoacidosis (DKA). With hyperglycemia, the AVP-plasma sodium (PNa) curve is displaced to the left, whereas the AVP-osmolality (Posm) curve is displaced to the right. The shift in the Na curve is explained by either resetting of the Na set point or by glucose acting as a nonpermeable solute, substituting for Na. Conversely, putative unmeasured solutes that, like urea, fail to affect AVP have been postulated to account for the right shift in the AVP-Posm curve. Therefore the respective roles of Posm = sigma [Xi] and plasma tonicity (Pton = sigma [sigmaiXi]), i.e., the sum of concentrations of all solutes [Xi] corrected (Pton) or not (Posm) for their relative cell permeability (sigma i), were studied in DKA. Indeed, Posm = sigma [Xi] exceeds Pton = sigma [sigma iXi] in DKA, since sigma i less than 1 for glucose. Potential determinants of AVP release (Posm, Pton, and PNa) were monitored in 7 patients with DKA. Conventional correlation analysis and two-dimensional (2D) graphs reproduced the paradox of an opposite shift in PNa and Posm set points for AVP release. However, by using the concept of tonicity instead of osmolality, 3D plots instead of 2D graphs, and multiple regressions instead of correlations, the AVP-PNa and AVP-Pton curves did not appear displaced. The concept of tonicity resolved the paradox of both osmolality and Na thresholds reset in opposite directions. Indeed, in states where a solute like glucose (with sigma less than 1) contributes substantially to plasma osmolality, Posm measured in vitro by the osmometer greatly exceeds Pton perceived in vivo by the osmoreceptor.

scholarly journals Reversal of Age-Related Neuronal Atrophy by α5-GABAA Receptor Positive Allosteric Modulation

2020 ◽  
Author(s):  
Thomas D Prevot ◽  
Akiko Sumitomo ◽  
Toshifumi Tomoda ◽  
Daniel E Knutson ◽  
Guanguan Li ◽  
...  
Keyword(s):  
Working Memory ◽  
Beneficial Effect ◽  
Frontal Cortex ◽  
Cortical Neurons ◽  
Gaba A ◽  
Age Related ◽  
Dendritic Branching ◽  
Old Mice ◽  
Separate Cohort

Abstract Aging is associated with reduced brain volume, altered neural activity, and neuronal atrophy in cortical-like structures, comprising the frontal cortex and hippocampus, together contributing to cognitive impairments. Therapeutic efforts aimed at reversing these deficits have focused on excitatory or neurotrophic mechanisms, although recent findings show that reduced dendritic inhibition mediated by α5-subunit containing GABA-A receptors (α5-GABAA-Rs) occurs during aging and contributes to cognitive impairment. Here, we aimed to confirm the beneficial effect on working memory of augmenting α5-GABAA-R activity in old mice and tested its potential at reversing age-related neuronal atrophy. We show that GL-II-73, a novel ligand with positive allosteric modulatory activity at α5-GABAA-R (α5-PAM), increases dendritic branching complexity and spine numbers of cortical neurons in vitro. Using old mice, we confirm that α5-PAM reverses age-related working memory deficits and show that chronic treatment (3 months) significantly reverses age-related dendritic shrinkage and spine loss in frontal cortex and hippocampus. A subsequent 1-week treatment cessation (separate cohort) resulted in loss of efficacy on working memory but maintained morphological neurotrophic effects. Together, the results demonstrate the beneficial effect on working memory and neurotrophic efficacy of augmenting α5-GABAA-R function in old mice, suggesting symptomatic and disease-modifying potential in age-related brain disorders.

scholarly journals Incidence and severity of G6PI-induced arthritis are not increased in genetically distinct mouse strains upon aging

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Nico Andreas ◽  
Sylvia Müller ◽  
Nicole Templin ◽  
Paul M. Jordan ◽  
Harald Schuhwerk ◽  
...  
Keyword(s):  
Immune Cell ◽  
Ex Vivo ◽  
Wild Type Mouse ◽  
Mouse Strains ◽  
Functional Difference ◽  
Susceptible Mouse ◽  
Age Related ◽  
Th Cell ◽  
Old Mice

Abstract Background The incidence of rheumatoid arthritis is correlated with age. In this study, we analyzed the association of the incidence and severity of glucose-6-phosphate isomerase (G6PI)-induced arthritis with age in two different mouse strains. Methods Young and very old mice from two different arthritis-susceptible wild-type mouse strains were analyzed after a single subcutaneous injection of G6PI s.c. The metabolism and the function of synoviocytes were analyzed in vitro, the production of bioactive lipid mediators by myeloid cells and synoviocytes was assessed in vitro and ex vivo by UPLC-MS-MS, and flow cytometry was used to verify age-related changes of immune cell composition and function. Results While the severity of arthritis was independent from age, the onset was delayed in old mice. Old mice showed common signs of immune aging like thymic atrophy associated with decreased CD4+ effector T cell numbers. Despite its decrease, the effector T helper (Th) cell compartment in old mice was reactive and functionally intact, and their Tregs exhibited unaltered suppressive capacities. In homeostasis, macrophages and synoviocytes from old mice produced higher amounts of pro-inflammatory cyclooxygenase (COX)-derived products. However, this functional difference did not remain upon challenge in vitro nor upon arthritis reactions ex vivo. Conclusion While old mice show a higher baseline of inflammatory functions, this does not result in increased reaction towards self-antigens in arthritis-susceptible mouse strains. Together, our data from two different mouse strains show that the susceptibility for G6PI-induced arthritis is not age-dependent.

scholarly journals Effect of age on susceptibility to Salmonella Typhimurium infection in C57BL/6 mice

2009 ◽  
Vol 58 (12) ◽  
pp. 1559-1567 ◽  
Author(s):  
Zhihong Ren ◽  
Raina Gay ◽  
Adam Thomas ◽  
Munkyong Pae ◽  
Dayong Wu ◽  
...  
Keyword(s):  
Immune Response ◽  
Ex Vivo ◽  
The Elderly ◽  
Mesenteric Lymph ◽  
Age Related ◽  
Serovar Typhimurium ◽  
Lymph Node Cells ◽  
Old Mice ◽  
Effect Of Age ◽  
Young Mice

Ageing is associated with a decline in immune function, which predisposes the elderly to a higher incidence of infections. Information on the mechanism of the age-related increase in susceptibility to Salmonella enterica serovar Typhimurium (S. Typhimurium) is limited. In particular, little is known regarding the involvement of the immune response in this age-related change. We employed streptomycin (Sm)-pretreated C57BL/6 mice to develop a mouse model that would demonstrate age-related differences in susceptibility and immune response to S. Typhimurium. In this model, old mice inoculated orally with doses of 3×108 or 1×106 c.f.u. S. Typhimurium had significantly greater S. Typhimurium colonization in the ileum, colon, Peyer's patches, spleen and liver than young mice. Old mice had significantly higher weight loss than young mice on days 1 and 2 post-infection. In response to S. Typhimurium infection, old mice failed to increase ex vivo production of IFN-γ and TNF-α in the spleen and mesenteric lymph node cells to the same degree as observed in young mice; this was associated with their inability to maintain the presence of neutrophils and macrophages at a ‘youthful’ level. These results indicate that Sm-pretreated C57BL/6 old mice are more susceptible to S. Typhimurium infection than young mice, which might be due to impaired IFN-γ and TNF-α production as well as a corresponding change in the number of neutrophils and macrophages in response to S. Typhimurium infection compared to young mice.

scholarly journals Use of forskolin to study the relationship between cyclic AMP formation and bone resorption in vitro

1986 ◽  
Vol 240 (2) ◽  
pp. 529-539 ◽  
Author(s):  
U H Lerner ◽  
B B Fredholm ◽  
M Ransjö
Keyword(s):  
Bone Resorption ◽  
Cyclic Amp ◽  
Phosphodiesterase Inhibitor ◽  
Inhibitory Effect ◽  
Cyclic Amp Accumulation ◽  
The Relationship ◽  
Dose Dependent ◽  
Old Mice ◽  
45Ca Release

The effect of the adenylate cyclase activator forskolin on bone resorption and cyclic AMP accumulation was studied in an organ-culture system by using calvarial bones from 6-7-day-old mice. Forskolin caused a rapid and fully reversible increase of cyclic AMP, which was maximal after 20-30 min. The phosphodiesterase inhibitor rolipram (30 mumol/l), enhanced the cyclic AMP response to forskolin (50 mumol/l) from a net cyclic AMP response of 1234 +/- 154 pmol/bone to 2854 +/- 193 pmol/bone (mean +/- S.E.M., n = 4). The cyclic AMP level in bones treated with forskolin (30 mumol/l) was significantly increased after 24 h of culture. Forskolin, at and above 0.3 mumol/l, in the absence and the presence of rolipram (30 mumol/l), caused a dose-dependent cyclic AMP accumulation with an calculated EC50 (concentration producing half-maximal stimulation) value at 8.3 mumol/l. In 24 h cultures forskolin inhibited spontaneous and PTH (parathyroid hormone)-stimulated 45Ca release with calculated IC50 (concentration producing half-maximal inhibition) values at 1.6 and 0.6 mumol/l respectively. Forskolin significantly inhibited the release of 3H from [3H]proline-labelled bones stimulated by PTH (10 nmol/l). The inhibitory effect by forskolin on PTH-stimulated 45Ca release was significant already after 3 h of culture. In 24 h cultures forskolin (3 mumol/l) significantly inhibited 45Ca release also from bones stimulated by prostaglandin E2 (1 mumol/l) and 1 alpha-hydroxycholecalciferol (0.1 mumol/l). The inhibitory effect of forskolin on spontaneous and PTH-stimulated 45Ca release was transient. A dose-dependent stimulation of basal 45Ca release was seen in 120 h cultures, at and above 3 nmol of forskolin/l, with a calculated EC50 value at 16 nmol/l. The stimulatory effect of forskolin (1 mumol/l) could be inhibited by calcitonin (0.1 unit/ml), but was insensitive to indomethacin (1 mumol/l). Forskolin increased the release of 3H from [3H]proline-labelled bones cultured for 120 h and decreased the amount of hydroxyproline in bones after culture. Forskolin inhibited PTH-stimulated release of Ca2+, Pi, beta-glucuronidase and beta-N-acetylglucosaminidase in 24 h cultures. In 120 h cultures forskolin stimulated the basal release of minerals and lysosomal enzymes.(ABSTRACT TRUNCATED AT 400 WORDS)

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