Mercury exists naturally and as a man-made contaminant. The release of processed mercury can lead to a progressive increase in the amount of atmospheric mercury, which enters the atmospheric-soil-water distribution cycles where it can remain in circulation for years. Mercury poisoning is the result of exposure to mercury or mercury compounds resulting in various toxic effects depend on its chemical form and route of exposure. The major route of human exposure to methylmercury (MeHg) is largely through eating contaminated fish, seafood, and wildlife which have been exposed to mercury through ingestion of contaminated lower organisms. MeHg toxicity is associated with nervous system damage in adults and impaired neurological development in infants and children. Ingested mercury may undergo bioaccumulation leading to progressive increases in body burdens. This review addresses the systemic pathophysiology of individual organ systems associated with mercury poisoning. Mercury has profound cellular, cardiovascular, hematological, pulmonary, renal, immunological, neurological, endocrine, reproductive, and embryonic toxicological effects.

BackgroundAged 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 FindingsCompared to 6- and 27-month rats, the phosphorylation of Akt (Ser473 and Thr308) was higher in soleus muscles of very aged rats (33-months). Paradoxically, these increases in Akt phosphorylation were associated with diminished mammalian target of rapamycin (mTOR) phosphorylation, along with decreased levels of insulin receptor beta (IR-β), phosphoinositide 3-kinase (PI3K), phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and phosphorylation of phosphoinositide-dependent kinase-1 (PDK1) (Ser241). In vitro Akt kinase measurements and ex vivo muscle incubation experiments demonstrated age-related impairments of Akt kinase activity, which were associated with increases in Akt S-nitrosylation and inducible nitric oxide synthase (iNOS). Impairments in Akt function occurred parallel to increases in myocyte apoptosis and decreases in myocyte size and the expression of myosin and actin. These age-related disorders were attenuated by treating aged (27-month) animals with acetaminophen (30 mg/kg body weight/day) for 6-months.ConclusionsThese data demonstrate that Akt dysfunction and increased S-nitrosylation of Akt may contribute to age-associated disorders in skeletal muscle and that acetaminophen may be efficacious for the treatment of age-related muscle dysfunction.

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Sepsis is a life threatening disease that is associated with high mortality. Existing treatments have failed to improve survivability in septic patients. The purpose of this present study is to evaluate whether cerium oxide nanoparticles (CeO2NPs) can prevent lipopolysaccharide (LPS) induced severe sepsis mortality by preventing hepatic dysfunction in male Sprague Dawley rats. Administration of a single dose (0.5 mg/kg) of CeO2NPs intravenously to septic rats significantly improved survival rates and functioned to restore body temperature, respiratory rate and blood pressure towards baseline. Treatment-induced increases in animal survivability were associated with decreased hepatic damage along with reductions in serum cytokines/chemokines, and diminished inflammatory related signaling. Kupffer cells and macrophage cells exposed to CeO2NPs exhibited decreases in LPS-induced cytokine release (TNF-α, IL-1β, IL-6, HMGB1) which were associated with diminished cellular ROS, reduced levels of nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2), and decreased nuclear factor-kappa light chain enhancer of activated B cells (NF-kB) transcriptional activity. The findings of this study indicate that CeO2NPs may be useful as a therapeutic agent for sepsis.

Background: Cerium oxide (CeO 2 ) nanoparticles have been posited to have both beneficial and toxic effects on biological systems. Herein, we examine if a single intratracheal instillation of CeO 2 nanoparticles is associated with systemic toxicity in male Sprague-Dawley rats. Methods and results:Compared with control animals, CeO 2 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 CeO 2 nanoparticles also exhibited reductions in liver weight (P , 0.05) and dose-dependent hydropic degeneration, hepatocyte enlargement, sinusoidal dilatation, and accumulation of granular material. No histopathological alterations were observed in the kidney, spleen, and heart. Analysis of serum biomarkers suggested an elevation of acute phase reactants and markers of hepatocyte injury in the rats exposed to CeO 2 nanoparticles. Conclusion: Taken together, these data suggest that intratracheal instillation of CeO 2 nanoparticles can result in liver damage.

To examine the effect of extreme old age on muscle plasticity, 6- (adult) and 36-mo-old (old) male Fischer 344 x Brown Norway hybrid rats underwent bilateral surgical ablation of the gastrocnemius muscle to functionally overload (OV) the fast-twitch plantaris muscle for 8 wk. Plantaris muscle wet weight, muscle cross-sectional area (CSA), and average fiber CSA decreased by 44, 42, and 40%, respectively, in old compared with adult rats, and peak isometric tetanic tension decreased by 83%. Compared with muscles in age-matched controls, plantaris muscle mass increased by 53% and type I, IIA, and IIX/IIB CSA increased by 91, 76, and 103%, respectively, in adult-OV rats, but neither wet mass nor fiber CSA increased in old-OV rats. OV decreased type I, IIA, and IIX/IIB mean fiber CSA by 31, 35, and 30%, respectively, in old-OV rats. Collectively, our data indicate that in extreme old age the plantaris muscle undergoes significant loss of mass, fiber CSA, and contractile function, as well as its capacity to undergo hypertrophy in response to a chronic increase in mechanical load.

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.

Cancer cachexia is a muscle wasting condition that occurs in response to a malignant growth in the body. The mechanisms regulating cardiac muscle mass with cachexia are not well understood. Using the ApcMin/+ mouse model of colorectal cancer, we investigated how cachexia affects the regulation of 5′-adenosine monophosphate-activated protein kinase (AMPK), protein kinase B (Akt) and mammalian target of rapamycin (mTOR) signaling in the heart. Compared to age-matched C57BL/6 (BL6) mice, ApcMin/+ body mass and heart mass were lower at 12 (11±5 and 8±3%, respectively) and 20 weeks (26±3 and 6±4%, respectively) of age (P<0.05). Diminished heart mass in the 20-week-old ApcMin/+ mice coincided with a decreased rate of myofibrillar protein synthesis and increased AMPKα phosphorylation. Cachexia decreased mTOR phosphorylation and the phosphorylation of the mTOR substrates, S6 ribosomal protein and 4EBP1 independent of Akt activation. These changes in mTOR-related protein signaling were accompanied by modest increases in the amount of Beclin1 but not protein ubiquitination or cardiomyocyte apoptosis. Taken together, these data suggest that loss of cardiac mass during cachexia progression in the ApcMin/+ mouse is associated with an Akt-independent suppression of anabolic signaling and evidence of increased autophagy.