Serum Concentrations of Losartan Metabolites Correlate With Improved Physical Function in a Pilot Study of Prefrail Older Adults.

Losartan is an oral antihypertensive agent that is rapidly metabolized to EXP3174 (angiotensin-subtype-1-receptor blocker) and EXP3179 (peroxisome proliferator-activated receptor gamma [PPARγ] agonist), which was shown in animal studies to reduce inflammation, enhance mitochondrial energetics, and improve muscle repair and physical performance. We conducted an exploratory pilot study evaluating losartan treatment in prefrail older adults (age 70-90 years, N = 25). Participants were randomized to control (placebo) or treatment (daily oral losartan beginning at 25 mg per day and increasing every 8 weeks) for a total of 6 months.

Plasma levels of corticosterone, tumor necrosis factor receptor 1 and interleukin 6 are influenced by age, sex and chronic inflammation in mice treated with acute temperature stress.

Resiliency is the ability to respond to, adapt to and recover from stressors. Deterioration of resiliency in older adults has been hypothesized to be regulated by age-related changes in stress response systems, including the Hypothalamic Pituitary Adrenal (HPA) axis and the innate immune system response. Although age-related chronic inflammation is strongly related to lack of resiliency, the impact of chronic inflammation on acute stress response is unclear.

Impaired mitochondrial degradation by autophagy in the skeletal muscle of the aged female interleukin 10 null mouse.

Mitochondrial dysfunction, chronic inflammation and muscle aging are closely linked. Mitochondrial clearance is a process to dampen inflammation and is a critical pre-requisite to mitobiogenesis. The combined effect of aging and chronic inflammation on mitochondrial degradation by autophagy is understudied.

Combined effects of aging and inflammation on renin-angiotensin system mediate mitochondrial dysfunction and phenotypic changes in cardiomyopathies.

Although the effects of aging and inflammation on the health of the cardiac muscle are well documented, the combined effects of aging and chronic inflammation on cardiac muscle are largely unknown. The renin-angiotensin system (RAS) has been linked independently to both aging and inflammation, but is understudied in the context of their collective effect. Thus, we investigated localized cardiac angiotensin II type I and type II receptors (AT(1)R, AT(2)R), downstream effectors, and phenotypic outcomes using mouse models of the combination of aging and inflammation and compared it to a model of aging and a model of inflammation.

A large community outbreak of blastomycosis in Wisconsin with geographic and ethnic clustering.

Background: Blastomycosis is a potentially life-threatening infection caused by the soil-based dimorphic fungus Blastomyces dermatitidis, which is endemic throughout much of the Midwestern United States. We investigated an increase in reported cases of blastomycosis that occurred during 2009-2010 in Marathon County, Wisconsin.

Methods: Case detection was conducted using the Wisconsin Electronic Disease Surveillance System (WEDSS).

VEGF and Angiopoietin-1 exert opposing effects on cell junctions by regulating the Rho GEF Syx.

Vascular endothelial growth factor (VEGF) and Ang1 (Angiopoietin-1) have opposing effects on vascular permeability, but the molecular basis of these effects is not fully known. We report in this paper that VEGF and Ang1 regulate endothelial cell (EC) junctions by determining the localization of the RhoA-specific guanine nucleotide exchange factor Syx. Syx was recruited to junctions by members of the Crumbs polarity complex and promoted junction integrity by activating Diaphanous.

Activation of serum/glucocorticoid-induced kinase 1 (SGK1) is important to maintain skeletal muscle homeostasis and prevent atrophy.

Maintaining skeletal muscle mass is essential for general health and prevention of disease progression in various neuromuscular conditions. Currently, no treatments are available to prevent progressive loss of muscle mass in any of these conditions. Hibernating mammals are protected from muscle atrophy despite prolonged periods of immobilization and starvation.

Impaired skeletal muscle regeneration in the absence of fibrosis during hibernation in 13-lined ground squirrels.

Skeletal muscle atrophy can occur as a consequence of immobilization and/or starvation in the majority of vertebrates studied. In contrast, hibernating mammals are protected against the loss of muscle mass despite long periods of inactivity and lack of food intake. Resident muscle-specific stem cells (satellite cells) are known to be activated by muscle injury and their activation contributes to the regeneration of muscle, but whether satellite cells play a role in hibernation is unknown.

Losartan restores skeletal muscle remodeling and protects against disuse atrophy in sarcopenia.

Sarcopenia, a critical loss of muscle mass and function because of the physiological process of aging, contributes to disability and mortality in older adults. It increases the incidence of pathologic fractures, causing prolonged periods of hospitalization and rehabilitation. The molecular mechanisms underlying sarcopenia are poorly understood, but recent evidence suggests that increased transforming growth factor-β (TGF-β) signaling contributes to impaired satellite cell function and muscle repair in aged skeletal muscle.

Syx, a RhoA guanine exchange factor, is essential for angiogenesis in Vivo.

Rho GTPases play an important and versatile role in several biological processes. In this study, we identified the zebrafish ortholog of the mammalian Rho A guanine exchange factor, synectin-binding guanine exchange factor (Syx), and determined its in vivo function in the zebrafish and the mouse. We found that Syx is expressed specifically in the vasculature of these organisms.

The neuronal RhoA GEF, Tech, interacts with the synaptic multi-PDZ-domain-containing protein, MUPP1.

Tech is a RhoA guanine nucleotide exchange factor (GEF) that is highly enriched in hippocampal and cortical neurons. To help define its function, we have conducted studies aimed at identifying partner proteins that bind to its C-terminal PDZ ligand motif. Yeast two hybrid studies using the Tech C-terminal segment as bait identified MUPP1, a protein that contains 13 PDZ domains and has been localized to the post-synaptic compartment, as a candidate partner protein for Tech.

Nuclear translocation of the SRF co-activator MAL in cortical neurons: role of RhoA signalling.

Although it is well established that RhoA signaling pathways play key roles in regulating neuronal morphology, their involvement in other aspects of neuronal function has received little attention. Recent studies have elucidated a novel intracellular signaling pathway used by RhoA to elicit activation of serum response factor (SRF)-mediated transcription. In this pathway, activation of RhoA triggers nuclear translocation of the SRF co-activator, megakaryocytic acute leukemia (MAL).

Tech: a RhoA GEF selectively expressed in hippocampal and cortical neurons.

Recent studies implicating the Rho family of small G proteins in the regulation of neuronal morphology have focused attention on identifying key components of Rho signaling pathways in neurons. To this end, we have conducted studies aimed at defining the localization and function of Tech, a Rho guanine nucleotide exchange factor (GEF) family member that is highly enriched in brain. We have found that Tech is selectively expressed in cortical and hippocampal neurons with prominent Tech immunostaining apparent in the cell bodies and dendrites of these cells.

Routing of membrane proteins to large dense core vesicles in PC12 cells.

Routing of membrane proteins to large dense core vesicles in neuroendocrine cells can depend on information in both the lumenal and cytoplasmic domains. This study in PC12 cells focuses on the routing, cleavage, and secretion of an integral membrane protein, peptidylglycine alpha-amidating monooxygenase (PAM), examining both endogenous and virally derived membrane PAM. The role of the lumenal catalytic domains in membrane PAM trafficking was examined by replacement with an epitope tag.