Medicine and Health Sciences Commons^™

Acetaminophen Improves Protein Translational Signaling In Aged Skeletal Muscle, Miaozong Wu, Hua Liu, Jacqueline Fannin, Anjaiah Katta, Yeling Wang, Ravi Kumar Arvapalli, Satyanarayana Paturi, Sunil K. Karkala, Kevin M. Rice, Eric R. Blough

Kevin M Rice

Background: Age-related muscle atrophy is characterized by increased oxidative stress, diminished Akt enzymatic function, and reduced phosphorylation of the mammalian target of rapamycin (mTOR), which can be attenuated by chronic acetaminophen ingestion. Here we hypothesize that age-related impairments in Akt/ mTOR function are associated with reduced protein translational signaling, and that these changes, if present, can be attenuated by acetaminophen treatment. Results: Compared to 6- and 27-month old animals, the expression of the mTOR-complex proteins raptor and GbL and the phosphorylation of tuberin/TSC2 (Thr1462) were reduced in the soleus muscles of very aged rats (33 months old). These changes in …

Diabetes Alters Vascular Mechanotransduction: Pressure-Induced Regulation Of Mitogen Activated Protein Kinases In The Rat Inferior Vena Cava, Kevin M. Rice, Devashish H. Desai, Sunil K. Kakarla, Anjaiah Katta, Deborah L. Preston, Paulette Wehner, Eric R. Blough

Kevin M Rice

Background Diabetes mellitus is an important risk factor for increased vein graft failure after bypass surgery. However, the cellular and molecular mechanism(s) underlying vessel attrition in this population remain largely unexplored. Recent reports have suggested that the pathological remodeling of vein grafts may be mediated by mechanically-induced activation of the mitogen activated protein kinase (MAPK) signaling pathways and the MAPK-related induction of caspase-3 activity. On the basis of these findings, we hypothesized that diabetes may be associated with alterations in how veins "sense" and "respond" to altered mechanical loading. Methods Inferior venae cavae (IVC) from the non-diabetic lean (LNZ) and …

Assembly And Function Of Myosin Ii On Ultraviolet/Ozone Patterned Trimethylchlorosilane Substrates, Hideyo Takatsuki, Madhukar Kolli, Kevin Rice, B. Day, Shinichi Asano, Mashiur Rahman, Yue Zhang, Ryoki Ishikawa, Kazuhiro Kohama, Eric Blough

Kevin M Rice

The study of biomolecular motors represents a rapidly and progressing field of nanobiotechnology. Here, we present a simple method for patterning myosin II on a microstructured surface. Our findings indicate that UV/ozone treatment can be used to alter the hydrophobicity of trimethyl-chloro-silane (TMCS) coated glass surfaces, to alter protein binding, and effectively produce localized motor activity. Taken together, these data suggest that photoreactive patterning may be useful for the selective localization of functional myosin II motor tracks.

Application Of Poly(Amidoamine) Dendrimers For Use In Bionanomotor Systems, Madhukar Babu Kolli, B. Scott Day, Hideyo Takatsuki, Siva Krishna Nalabotu, Kevin M. Rice, Kazuhiro Kohama, Murali K. Gadde, Anjaiah Katta, Eric R. Blough

Kevin M Rice

The study and utilization of bionanomotors represents a rapid and progressing field of nanobiotechnology. Here, we demonstrate that poly(amidoamine) (PAMAM) dendrimers are capable of supporting heavy meromyosin dependent actin motility of similar quality to that observed using nitrocellulose, and that microcontact printing of PAMAM dendrimers can be exploited to produce tracks of active myosin motors leading to the restricted motion of actin filaments across a patterned surface. These data suggest that the use of dendrimer surfaces will increase the applicability of using protein biomolecular motors for nanotechnological applications.

Altered Regulation Of Contraction-Induced Akt/Mtor/P70s6k Pathway Signaling In Skeletal Muscle Of The Obese Zucker Rat, Anjaiah Katta, Sunil K. Kakarla, Miaozong Wu, Satyanarayana Paturi, Murali K. Gadde, Ravi K. Arvapalli, Madhukar Babu Kolli, Kevin M. Rice, Eric R. Blough

Kevin M Rice

Increased muscle loading results in the phosphorylation of the 70 kDa ribosomal S6 kinase (p70S6k), and this event is strongly correlated with the degree of muscle adaptation following resistance exercise. Whether insulin resistance or the comorbidities associated with this disorder may affect the ability of skeletal muscle to activate p70S6k signaling following an exercise stimulus remains unclear. Here, we compare the contraction-induced activation of p70S6k signaling in the plantaris muscles of lean and insulin resistant obese Zucker rats following a single bout of increased contractile loading. Compared to lean animals, the basal phosphorylation of p70S6k (Thr389; 37.2% and Thr421/Ser424; 101.4%), …

Lean And Obese Zucker Rats Exhibit Different Patterns Of P70s6 Kinase Regulation In The Tibialis Anterior Muscle In Response To High-Force Muscle Contraction, Anjaiah Katta, Sunil K. Karkala, Miaozong Wu, Sarath Meduru, Devashish H. Desai, Kevin M. Rice, Eric R. Blough

Kevin M Rice

Increased phosphorylation of the 70-kDa ribosomal S6 kinase (p70S6k) signaling is strongly correlated with the degree of muscle adaptation following exercise. Herein we compare the phosphorylation of p70S6k, Akt, and mammalian target of rapamycin (mTOR) in the tibialis anterior (TA) muscles of lean and obese Zucker rats following a bout of eccentric exercise. Exercise increased p70S6k (Thr389) phosphorylation immediately after (33.3 ± 7.2%) and during [1 h (24.0 ± 14.9%) and 3 h (24.6 ± 11.3%)] recovery in the lean TA and at 3 h (33.5 ± 8.0%) in the obese TA Zucker rats. mTOR (Ser2448) phosphorylation was elevated in …

Diabetes Alters Contraction-Induced Mitogen Activated Protein Kinase Activation In The Rat Soleus And Plantaris, Anjaiah Katta, Deborah L. Preston, Sunil K. Kakarla, Shinichi Asano, Sarath Meduru, Sriram P. Mupparaju, Ellie Yokochi, Kevin M. Rice, Devashish H. Desai, Eric R. Blough

Kevin M Rice

The prescription of anaerobic exercise has recently been advocated for the management of diabetes; however exercise-induced signaling in diabetic muscle remains largely unexplored. Evidence from exercise studies in nondiabetics suggests that the extracellular-signal-regulated kinases (Erk1/2), p38, and c-JUN NH2-terminal kinase (Jnk) mitogen-activated protein kinases (MAPKs) are important regulators of muscle adaptation. Here, we compare the basal and the in situ contraction-induced phosphorylation of Erk1/2- p38- and Jnk-MAPK and their downstream targets (p90rsk and MAPKAP-K2) in the plantaris and soleus muscles of normal and obese (fa/fa) Zucker rats. Compared to lean animals, the time course and magnitude of Erk1/2, p90rsk and …

Iron-Induced Cardiac Damage: Role Of Apoptosis And Deferasirox Intervention, Yeling Wang, Miaozong Wu, Rabaa Al-Rousan, Hua Liu, Jacqueline Fannin, Satyanarayana Paturi, Ravi Arvapalli, Anjaiah Katta, Sunil Kakarla, Kevin Rice, William Triest, Eric Blough

Kevin M Rice

Excess cardiac iron levels are associated with cardiac damage and can result in increased morbidity and mortality. Here, we hypothesize that elevations in tissue iron can activate caspase-dependent signaling, which leads to increased cardiac apoptosis and fibrosis, and that these alterations can be attenuated by iron chelation. Using an iron-overloaded gerbil model, we show that increased cardiac iron is associated with reduced activation of Akt (Ser473 and Thr308), diminished phosphorylation of the proapoptotic regulator Bad (Ser136), and an increased Bax/Bcl-2 ratio. These iron-overload-induced alterations in Akt/Bad phosphorylation and Bax/Bcl-2 ratio were coupled with increased activation of the downstream caspase-9 (40/38- …

Acetaminophen Combinations Protect Against Iron-Induced Cardiac Damage In Gerbils, Ernest M. Walker Jr., Ryan G. Morrison, Lucy Dornon, Joseph P. Laurino, Sandra M. Walker, Mark Studeny, Paulette S. Wehner, Kevin M. Rice, Miaozong Wu, Eric R. Blough

Kevin M Rice

This study tested if acetaminophen, N-methyl-D-glucamine dithiocarbamate (NMGDTC), deferoxamine, and combinations of these agents reduce excess iron content, prevent iron-induced pathology, reduce cardiac arrhythmias, and reduce mortality in iron-overloaded gerbils. Eight groups of 16 gerbils received iron dextran injections (ferric hydroxide dextran complex, 120 mg/kg, ip) or saline solution (controls) twice/wk for 8 wk. The 8 groups were treated every Monday, Wednesday, and Friday with one of the following: saline control, acetaminophen, 150 mg/kg, ip), acetaminophen (150 mg/kg, po), deferoxamine, 83 mg/kg, ip), NMGDTC (200 mg/kg, ip), or combinations of acetaminophen (75 mg/kg) with deferoxamine (42 mg/kg, each ip, separately) …

Fluprostenol-Induced Mapk Signaling Is Independent Of Aging In Fischer 344/Nniahsd X Brown Norway/Binia Rat Aorta, Kevin M. Rice, Ernest M. Walker, Sunil K. Kakarla, Satyanarayana Paturi, Miaozong Wu, Sumit Narula, Eric R. Blough

Kevin M Rice

The factors that regulate vascular mechanotransduction and how this process may be altered with aging are poorly understood and have not been widely studied. Recent data suggest that increased tissue loading can result in the release of prostaglandin F2 alpha (PGF2α) and other reports indicate that aging diminishes the ability of the aged aorta to activate mitogen activated protein kinase (MAPK) signaling in response to increased loading. Using ex vivo incubations, here we investigate whether aging affects the ability of the aorta to induce phosphorylation of extracellular signal-regulated kinase 1/2 (ERK½-MAPK), p38-MAPK, and Jun N-terminal kinase (JNK-MAPK) activation following stimulation …

Age-Associated Changes In Hearts Of Male Fischer 344/Brown Norway F1 Rats, Ernest M. Walker Jr., Michael S. Nillas, Elsa I. Mangiarua, Sylvestre Cansino, Ryan G. Morrison, Romaine R. Perdue, William E. Triest, Gary L. Wright, Mark Studeny, Paulette Wehner, Kevin M. Rice, Eric R. Blough

Kevin M Rice

Aging is associated with left ventricular hypertrophy, dilatation, and fibrosis of the heart. The Fischer 344/Brown Norway F1 (F344/BNF1) rat is recommended for age-related studies by the National Institutes on Aging because this hybrid rat lives longer and has a lower rate of pathological conditions than inbred rats. However, little is known about age-associated changes in cardiac and aortic function and structure in this model. This study evaluated age-related cardiac changes in male F344/BNF1 rats using ECHO, gross, and microscopic examinations. Rats aged 6-, 30-, and 36-mo were anesthetized and two-dimensional ECHO measurements, two-dimensional guided M-mode, Doppler M-mode, and other …

Intratracheal Instillation Of Cerium Oxide Nanoparticles Induces Hepatic Toxicity In Male Sprague-Dawley Rats, Siva Krishna Nalabotu, Madhukar Babu Kolli, William E. Triest, Jane Y. Ma, Nandini Dpk Manne, Anjaiah Katta, Hari S. Addagarla, Kevin M. Rice, Eric R. Blough

Kevin M Rice

Background: Cerium oxide (CeO2) nanoparticles have been posited to have both beneficial and toxic effects on biological systems. Herein, we examine if a single intratracheal instillation of CeO2 nanoparticles is associated with systemic toxicity in male Sprague-Dawley rats. Methods and results: Compared with control animals, CeO2 nanoparticle exposure was associated with increased liver ceria levels, elevations in serum alanine transaminase levels, reduced albumin levels, a diminished sodium-potassium ratio, and decreased serum triglyceride levels (P < 0.05). Consistent with these data, rats exposed to CeO2nanoparticles also exhibited reductions in liver weight (P < 0.05) and dose-dependent hydropic degeneration, hepatocyte enlargement, sinusoidal dilatation, and …

Aging-Associated Dysfunction Of Akt/Protein Kinase B: S-Nitrosylation And Acetaminophen Intervention, Miaozong Wu, Anjaiah Katta, Murali K. Gadde, Hua Liu, Sunil K. Kakarla, Jacqueline Fannin, Satyanarayana Paturi, Ravi K. Arvapalli, Kevin M. Rice, Yeling Wang, Eric R. Blough

Kevin M Rice

Background: Aged skeletal muscle is characterized by an increased incidence of metabolic and functional disorders, which if allowed to proceed unchecked can lead to increased morbidity and mortality. The mechanism(s) underlying the development of these disorders in aging skeletal muscle are not well understood. Protein kinase B (Akt/PKB) is an important regulator of cellular metabolism and survival, but it is unclear if aged muscle exhibits alterations in Akt function. Here we report a novel dysfunction of Akt in aging muscle, which may relate to S-nitrosylation and can be prevented by acetaminophen intervention.

Principal Findings: Compared to 6- and 27-month rats, …

Effect Of Aging On Cellular Mechanotransduction, Miaozong Wu, Jacqueline Fannin, Kevin M. Rice, Bin Wang, Eric R. Blough

Kevin M Rice

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, …

Effects Of Aging On Pressure-Induced Mapk Activation In The Rat Aorta, Kevin M. Rice

Kevin M Rice

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% …

Aortic Aging In The Fischer 344 / Nniahsd × Brown Norway / Binia Rat, Kevin Rice, Miaozong Wu, Eric Blough

Kevin M Rice

Aging is now recognized as one of major risk factors for cardiovascular disease (CVD). It is well documented that elderly populations show increased incidence of CVD symptomology but whether these changes are directly related to aging is not well understood since the possibility exists that other age-associated pathologies in different organ systems could impact on cardiovascular function. Hence, the development of an aging model with reduced systemic illness could invigorate efforts to understand the direct role of aging in CVD progression. The Fischer 344 / NNIaHSD × Brown Norway / BiNia rat (F344BN) has been proposed as a potential model …