No abstract

Peppler WT, Anderson ZG, Sutton CD, Rector RS, Wright DC. Voluntary wheel running attenuates lipopolysaccharide-induced liver inflammation in mice. Am J Physiol Regul Integr Comp Physiol 310: R934 -R942, 2016. First published February 17, 2016 doi:10.1152/ajpregu.00497.2015.-Sepsis induces an acute inflammatory response in the liver, which can lead to organ failure and death. Given the anti-inflammatory effects of exercise, we hypothesized that habitual physical activity could protect against acute sepsis-induced liver inflammation via mechanisms, including heat shock protein (HSP) 70/72. Male C57BL/6J mice (n ϭ 80, ϳ8 wk of age) engaged in physical activity via voluntary wheel running (VWR) or cage control (SED) for 10 wk. To induce sepsis, we injected (2 mg/kg ip) LPS or sterile saline (SAL), and liver was harvested 6 or 12 h later. VWR attenuated increases in body and epididymal adipose tissue mass, improved glucose tolerance, and increased liver protein content of PEPCK (P Ͻ 0.05). VWR attenuated increases in LPS-induced IL-6 signaling and mRNA expression of other inflammatory markers (TNF-␣, chemokine C-C motif ligand 2, inducible nitric oxide synthase, IL-10, IL-1␤) in the liver; however, this was not reflected at the whole body level, as systemic markers of inflammation were similar between SED and VWR. Insulin tolerance was greater in VWR compared with SED at 6 but not 12 h after LPS. The protective effect of VWR occurred in parallel with increases in the liver protein content of HSP70/72, a molecular chaperone that can protect against inflammatory challenges. This study provides novel evidence that physical activity protects against the inflammatory cascade induced by LPS in the liver and that these effects may be mediated via HSP70/72. lipopolysaccharide; inflammation; liver; physical activity; exercise SEPSIS IS A CONTINUUM OF CLINICAL events defined by the presence of infection and systemic inflammation (18). The worldwide incidence of sepsis was recently estimated at 437 cases per 100,000 person years between 2003 and 2015, with an associated fatality rate of 17% (11). This puts a significant burden on the health care system, and in the United States alone, the direct hospital costs associated with sepsis are over $24 billion (17).The infiltration of a host with both gram-negative and gram-positive bacterial species is often considered to be the cause of acute sepsis (34). LPS from Escherichia coli, a component of gram-negative bacteria, is often used to produce these effects in rodent models. Upon exposure to LPS, an inflammatory cascade is activated both systemically and at a tissue-specific level (1). Initial signaling involves a Toll-like receptor 4 (TLR4)-myeloid differentiation primary response gene 88 (MyD88) interaction that then propagates the inflammatory response (24). Increases in circulating inflammatory factors, such as TNF-␣, IL-6, and IL-1␤, occur rapidly and are regulated by the dose and duration of exposure (21,29,40). Clearance of inflammatory markers begins as early as 8 h post...

5'-AMP-activated protein kinase (AMPK) is activated as a consequence of lipolysis and has been shown to play a role in regulation of adipose tissue mitochondrial content. Conversely, the inhibition of lipolysis has been reported to potentiate the induction of protein kinase A (PKA)-targeted genes involved in the regulation of oxidative metabolism. The purpose of the current study was to address these apparent discrepancies and to more fully examine the relationship between lipolysis, AMPK, and the β-adrenergic-mediated regulation of gene expression. In 3T3-L1 adipocytes, the adipose tissue triglyceride lipase (ATGL) inhibitor ATGListatin attenuated the Thr(172) phosphorylation of AMPK by a β3-adrenergic agonist (CL 316,243) independent of changes in PKA signaling. Similarly, CL 316,243-induced increases in the Thr(172) phosphorylation of AMPK were reduced in adipose tissue from whole body ATGL-deficient mice. Despite reductions in the activation of AMPK, the induction of PKA-targeted genes was intact or, in some cases, increased. Similarly, markers of mitochondrial content and respiration were increased in adipose tissue from ATGL knockout mice independent of changes in the Thr(172) phosphorylation of AMPK. Taken together, our data provide evidence that AMPK is not required for the regulation of adipose tissue oxidative capacity in conditions of reduced fatty acid release.

The attached Final Report "Highway Bridge Vibration Studies" is submitted as a summary of the extensive research conducted on this project. The research has provided considerable new information and clearer understanding of the bridge vibration problem and advanced capability toward the use of a dynamic-based design criterion for highway bridges. Such use should provide more effectively for the comfort of users of bridges in an economic and beneficial manner.This research in our opinion has been very productive and we are hopeful the State Highway Department can utilize some of the findings in designing and building a highway bridge and that further confirmation of the findings of this project can be the subject of a new research project on such implementation.The acceptance of this report as fulfilling the objectives of the Study will terminate this research. The general objectives of this research have been to obtain a better understanding of the dynamic performance of highway bridges and of the vibrations sensed by bridge users in order to aid in the development and implementation of a dynamic-based design criterion which can more effectively ensure the comfort of pedestrians, maintenance workers, cyclists, etc. Because the human body is primarily sensitive to changes in motion, the investigations have focused on accelerations.Special purpose computer programs were used for parametric studies of the bridge vehicle system. Significant parameters were found to be span length, weight and speed of the vehicle, and the roughness of the bridge deck. Maximum accelerations were only moderately increased by reductions in girder stiffness.Dynamic responses of some 62 steel and concrete beam bridges under actual highway traffic were measured in the field. Bridges were instrumented with midspan accelerometers and one deflection transducer, all mounted on the curbes of the deck.Differentiated deflection records were used to check corresponding acceleration records. More than 900 crossing records were analyzed for maximum deflection, velocity, acceleration, jerk, and frequency content. Only 5 of the crossing records contained accelerations which exceeded the comfort limit proposed by Wright and Walker.

Mutations in the dopamine transporter gene (SLC6A3) have been implicated in many human diseases. Among these is the infantile parkinsonism-dystonia known as Dopamine Transporter Deficiency Syndrome (DTDS). Afflicted individuals have minimal to no functional dopamine transporter protein. This is primarily due to retention of misfolded disease-causing dopamine transporter variants. This results in a variety of severe motor symptoms in patients and the disease ultimately leads to death in adolescence or young adulthood. Though no treatment is currently available, pharmacological chaperones targeting the dopamine transporter have been shown to rescue select DTDS disease-causing variants. Previous work has identified two DAT pharmacological chaperones with moderate potency and efficacy: bupropion and ibogaine. In this study, we carried out structure-activity relationships (SARs) for bupropion and ibogaine with the goal of identifying the chemical features required for pharmacological chaperone activity. Our results show that the isoquinuclidine substituent of ibogaine and its analogs is an important feature for pharmacological chaperone efficacy. For bupropion, the secondary amine group is essential for pharmacological chaperone activity. Lastly, we describe additional ibogaine and bupropion analogs with varying chemical modifications and variable pharmacological chaperone efficacies at the dopamine transporter. Our results contribute to the design and refinement of future dopamine transporter pharmacological chaperones with improved efficacies and potencies.