Effects of Aging on Pressure-Induced Mapk Activation in the Rat Aorta

With age, the cardiovascular system experiences substantial alterations in cellular morphology and function. The factors regulating these changes are unknown; however, the mitogen activated protein kinase (MAPK) pathways have emerged as critical components for mediating numerous cellular responses including control of cell growth, differentiation and adaptation. Here we compare the expression, basal activation and the ability of increased pressure to activate the MAPK pathways in adult (6 month old), aged (30 month old) and very aged (36 month old) Fischer 344 x Brown Norway F1 Hybrid rats. Histochemical analysis demonstrated an age-related increase in tunica media thickness of approximately 11% and 21% in aortae from aged and very aged animals, respectively. Western blot analysis of the MAPK family extracellular signal-regulated kinase (ERK 1/2), p38, and c-Jun NH2 -terminal kinase (JNK) MAPKs showed differential expression and activation among these proteins with age. Expression of ERK 1/2, p38, and JNK were unchanged, slightly increased (10 ± 17.5%) or significantly increased (72.3 ± 27%), respectively, in very aged aortae. By comparison, basal activation levels of these proteins were reduced (-26.2 ± 7.4%), markedly increased (97.0 ± 16.8%) and slightly increased (14.4 ± 4.5%), respectively, in very aged versus 6-month rat aortae. An acute increase of aortic intraluminal pressure (200 mm Hg) indicated that ERK 1/2 regulation differed from p38 or JNK. Pressure loading-induced phosphorylation of ERK1/2 was unchanged or increased with aging while p38 and JNK phosphorylation was attenuated (P\u3c0.01). These observations confirm previous conclusions that MAPK proteins are mechanically regulated and expand these studies to suggest that MAPK expression and the control of activation are changed with aging

Efficacy of Female Rat Models in Translational Cardiovascular Aging Research

Cardiovascular disease is the leading cause of death in women in the United States. Aging is a primary risk factor for the development of cardiovascular disease as well as cardiovascular-related morbidity and mortality. Aging is a universal process that all humans undergo; however, research in aging is limited by cost and time constraints. Therefore, most research in aging has been done in primates and rodents; however it is unknown how well the effects of aging in rat models translate into humans. To compound the complication of aging gender has also been indicated as a risk factor for various cardiovascular diseases. This review addresses the systemic pathophysiology of the cardiovascular system associated with aging and gender for aging research with regard to the applicability of rat derived data for translational application to human aging

Effect of aging on cellular mechanotransduction

Aging is becoming a critical heath care issue and a burgeoning economic burden on society. Mechanotransduction is the ability of the cell to sense, process, and respond to mechanical stimuli and is an important regulator of physiologic function that has been found to play a role in regulating gene expression, protein synthesis, cell differentiation, tissue growth, and most recently, the pathophysiology of disease. Here we will review some of the recent findings of this field and attempt, where possible, to present changes in mechanotransduction that are associated with the aging process in several selected physiological systems, including musculoskeletal, cardiovascular, neuronal, respiratory systems and skin

Cerium oxide nanoparticles attenuate acute kidney injury induced by intra-abdominal infection in Sprague-Dawley rats

Background Intra-abdominal infection or peritonitis is a cause for great concern due to high mortality rates. The prognosis of severe intra-abdominal infection is significantly diminished in the presence of acute kidney injury (AKI) which is often characterized by renal tubular cell death that can lead to renal failure. The purpose of the current study is to examine the therapeutic efficacy of cerium oxide (CeO2) nanoparticles for the treatment of peritonitis-induced AKI by polymicrobial insult. Results A one-time administration of CeO2 nanoparticles (0.5 mg/kg) in the absence of antibiotics or other supportive care, attenuated peritonitis-induced tubular dilatation and the loss of brush border in male Sprague–Dawley rats. These improvements in renal structure were accompanied by decreases in serum cystatin-C levels, reduced renal oxidative stress, diminished Stat-3 phosphorylation and an attenuation of caspase-3 cleavage suggesting that the nanoparticle treatment improved renal glomerular filtration rate, diminished renal inflammation and reduced renal apoptosis. Consistent with these data, further analysis demonstrated that the CeO2 nanoparticle treatment diminished peritonitis-induced increases in serum kidney injury molecule-1 (KIM-1), osteopontin, β-2 microglobulin and vascular endothelial growth factor-A (VEGF-A) levels. In addition, the nanoparticle attenuated peritonitis-induced hyperglycemia along with increases in blood urea nitrogen (BUN), serum potassium and sodium. Conclusion CeO2 nanoparticles scavenge reactive oxygen species and attenuate polymicrobial insult induced increase in inflammatory mediators and subsequent AKI. Taken together, the data indicate that CeO2 nanoparticles may be useful as an alternative therapeutic agent or in conjunction with standard medical care for the treatment of peritonitis induced acute kidney injury

Cerium oxide nanoparticle aggregates affect stress response and function in Caenorhabditis elegans

Objective: The continual increase in production and disposal of nanomaterials raises concerns regarding the safety of nanoparticles on the environmental and human health. Recent studies suggest that cerium oxide (CeO2) nanoparticles may possess both harmful and beneficial effects on biological processes. The primary objective of this study is to evaluate how exposure to different concentrations (0.17–17.21 µg/mL) of aggregated CeO2 nanoparticles affects indices of whole animal stress and survivability in Caenorhabditis elegans. Methods: Caenorhabditis elegans were exposed to different concentrations of CeO2 nanoparticles and evaluated. Results: Our findings demonstrate that chronic exposure of CeO2 nanoparticle aggregates is associated with increased levels of reactive oxygen species and heat shock stress response (HSP-4) in Caenorhabditis elegans, but not mortality. Conversely, CeO2 aggregates promoted strain-dependent decreases in animal fertility, a decline in stress resistance as measured by thermotolerance, and shortened worm length. Conclusion: The data obtained from this study reveal the sublethal toxic effects of CeO2 nanoparticle aggregates in Caenorhabditis elegans and contribute to our understanding of how exposure to CeO2 may affect the environment

LOWER LEG MORPHOLOGY AND STRETCH-SHORTENING CYCLE PERFORMANCE IN YOUNG AND ELDERLY MALES

The purpose of this investigation was to examine bone and muscle characteristics of the lower leg and stretch-shortening cycle capabilities of the ankle in young (22.3 ± 1.3 yrs) and elderly (67.5 ± 3.3 yrs) males. Peripheral quantitiative computed tomography (pQCT) was utilized to assess bone stress-strain index, bone ultimate fracture load, muscle density, muscle cross-sectional area (CSA), fat CSA and muscle+bone CSA. Maximal voluntary isometric plantarflexion (MVIP) force and force-velocity measurments during a countermovement hop (CMH) and drop hops from 20, 30 and 40 cm (DH20, DH30, DH40) were also measured. Bone stress-strain index was significantly higher in young males as well as muscle density, muscle CSA and muscle+bone CSA in comparison to elderly males. MVIP peak force and rate of force development was significantly higher in young males in comparsion to elderly males as well. An analysis of the force-velocity curves indicated that young males had significanlty higher levels of force and velocity in both the eccentric and concentric phase during the CMH, DH20, DH30 and DH40 in comparsion to elderly males. The data from this investigation indicate that aging potentially negatively influences lower leg bone and muscle strength and this may be reflected in lower stretch-shortening cycle capabilities of the ankle

Uniaxial stretch-induced regulation of mitogen-activated protein kinase, Akt and p70S6 kinase in the ageing Fischer 344 × Brown Norway rat aorta

The effects of ageing on the cardiovascular system contribute to substantial alterations in cellular morphology and function. The variables regulating these changes are unknown; however, one set of signalling molecules that may be of particular importance in mediating numerous cellular responses, including control of cell growth, differentiation and adaptation, are the proteins associated with the mitogen-activated protein kinase (MAPK) signalling systems. The MAPKs, in conjunction with the p70 S6k signalling cascade, have emerged as critical components for regulating numerous mechanotransduction-related cellular responses. Here we investigate the ability of uniaxial stretch to activate the MAPK and p70 S6k pathways in adult (6-month-old), aged (30-month-old) and very aged (36-month-old) Fischer 344/NNiaHSd × Brown Norway/BiNia (FBN) rats. Western blotting of the MAPK family proteins extracellular signal-regulated kinase (Erk) 1/2, p38- and c-Jun NH2-terminal kinase (Jnk)-MAPKs showed differential expression and activation between these proteins with age. An acute 15 min interval of 20% uniaxial stretch using an ex vivo aortic preparation demonstrated similar regulation of Erk1/2, p38- and Jnk-MAPK. However, ageing altered uniaxial induced p70 S6k pathway signalling. These observations confirm previous data demonstrating that MAPK proteins are mechanically regulated and also suggest that p70 S6k signalling expression and activation are controlled differently with ageing. Taken together, these data may help to explain, in part, the age-related changes in vascular morphology, function and response to injury

Fingerprinting Noncanonical and Tertiary RNA Structures by Differential SHAPE Reactivity

Many RNA structures are comprised of simple secondary structure elements linked by a few, critical, tertiary interactions. SHAPE chemistry has made interrogation of RNA dynamics at single-nucleotide resolution straightforward. However, de novo identification of nucleotides involved in tertiary interactions remains a challenge. Here we show that nucleotides that form non-canonical or tertiary contacts are detected by comparing information obtained using two SHAPE reagents, N-methylisatoic anhydride (NMIA) and 1-methyl-6-nitroisatoic anhydride (1M6). Nucleotides that react preferentially with NMIA exhibit slow local nucleotide dynamics and preferentially adopt the less common C2′-endo ribose conformation. Experiments and first-principle calculations show 1M6 reacts preferentially with nucleotides in which one face of the nucleobase allows an unhindered stacking interaction with the reagent. Differential SHAPE reactivities were used to detect non-canonical and tertiary interactions in four RNAs with diverse structures and to identify pre-formed non-canonical interactions in partially folded RNAs. Differential SHAPE reactivity analysis will enable experimentally concise, large-scale identification of tertiary structure elements and ligand binding sites in complex RNAs and in diverse biological environments