Background and Purpose: Increasing evidence suggests systemic inflammationcaused skeletal muscle atrophy as a major clinical feature of cachexia. Triptolide obtained from Tripterygium wilfordii Hook F possesses potent anti-inflammatory and immunosuppressive effects. The present study aims to evaluate the protective effects and molecular mechanisms of triptolide on inflammation-induced skeletal muscle atrophy. Experimental Approach: The effects of triptolide on skeletal muscle atrophy were investigated in LPS-treated C2C12 myotubes and C57BL/6 mice. Protein expressions and mRNA levels were analysed by western blot and qPCR, respectively. Skeletal muscle mass, volume and strength were measured by histological analysis, micro-CT and grip strength, respectively. Locomotor activity was measured using the open field test. KEY RESULTS: Triptolide (10-100 fM) up-regulated protein synthesis signals (IGF-1/p-IGF-1R/IRS-1/p-Akt/p-mTOR) and down-regulated protein degradation signal atrogin-1 in C2C12 myotubes. In LPS (100 ngÁml À1 )-treated C2C12 myotubes, triptolide up-regulated MyHC, IGF-1, p-IGF-1R, IRS-1 and p-Akt. Triptolide also down-regulated ubiquitin-proteasome molecules (n-FoxO3a/atrogin-1/MuRF1), proteasome activity, autophagy-lysosomal molecules (LC3-II/LC3-I and Bnip3) and inflammatory mediators (NF-κB, Cox-2, NLRP3, IL-1β and TNF-α). However, AG1024, an IGF-1R inhibitor, suppressed triptolide-mediated effects on MyHC, myotube diameter, MuRF1 and p62 in LPS-treated C2C12 myotubes. In LPS (1 mgÁkg À1 , i.p.)-challenged mice, triptolide (5 and 20 μgÁkg À1 Áday À1 , i.p.) decreased plasma TNF-α levels and it increased skeletal muscle volume, cross-sectional area of myofibers, weights of the gastrocnemius and tibialis anterior muscles, forelimb grip strength and locomotion.Conclusions and Implications: These findings reveal that triptolide prevented LPS-induced inflammation and skeletal muscle atrophy and have implications for the discovery of novel agents for preventing muscle wasting.
The objective of this study was to investigate whether quantum dot 705 (QD705) disrupts the cellular antioxidant systems leading to hepatotoxicity in mice. Mice were intravenously injected with QD705 and then sacrificed at week 12 or 16. Homeostasis of antioxidant-related metals, antioxidant activities, induction of oxidative stress, and toxicity in the liver were investigated. Although no histopathological change was observed, a time- and dose-dependent increase in metallothionein expression and reduction in liver function was noticed. Increased copper, zinc, and selenium levels and enhancements of the trace metal-corresponding transporters were noted at week 12. At week 16, a decline of selenium from its elevated level at week 12 was observed, which was accompanied by changes in glutathione peroxidase activity as well as in redox status. A significant reduction in superoxide dismutase activity was observed at 16 weeks. Furthermore, a corresponding elevation of heme oxygenase-1 expression, 8-oxo-7,8-dihydro-2'-deoxyguanosine, interleukin-6 and tumor necrosis factor-alpha suggested the presence of oxidative stress, oxidative DNA damage and inflammation.
QD705 is a cadmium/selenium/tellurium (Cd/Se/Te)-based quantum dot with good potential for biomedical applications. Although the biological fate of QD705 is established, its chemical fate in the biological system is still unknown. Since the chemical nature of Cd in QD705 (either stays as bounded Cd or becomes free Cd) is closely related to the toxicity of this nanocrystal, information on its chemical fate is critically needed. In this study we investigated the chemical fate of QD705 in the kidneys of mice. We used the molar ratio of Cd and Te (increased Cd/Te ratio signifies increased Cd release from QD705) and the induction of tissue metallothionein (MT) as markers for elevated free Cd in tissues. Our study indicated that 100% of QD705 (measured as Cd) was still retained in the body 16 weeks after exposure, with significant time redistribution to the kidneys. Furthermore, there were an elevation in both the molar Cd/Te ratio and MT-1 expression in the kidneys, suggesting that free Cd was released from QD705. Thus QD705 is not as stable or biologically inert as many may have once believed. Our study demonstrated that free Cd indeed can be released from QD705 in the kidneys and increases the risk of renal toxicity.
Although zinc oxide nanoparticles (ZnONPs) have been applied in nanotechnology, their kinetics and tissue distribution in vivo are unknown. Here we compared the kinetics and tissue distribution of 10 nm (65)ZnONPs, 71 nm (65)ZnONPs and (65)Zn(NO(3))(2) in mice after intravenous injection. The areas under the curves and the half-lives in the second compartment of (65)Zn(NO(3))(2) were greater than those of (65)ZnONPs; the kinetic parameters were similar for both (65)ZnONPs. However, the tissue distributions for the three forms were different. ZnONPs preferentially accumulated in the liver and spleen at 24 h. At day 28, (65)Zn concentration was highest in bone and the proportion of recovered (65)Zn radioactivity was highest in the carcass; these had the same ranking, 10 nm (65)ZnONPs > 71 nm (65)ZnONPs> (65)Zn(NO(3))(2). Although more than 80% of the 10 nm (65)ZnONPs had been excreted by day 28, greater amounts of the 10 nm (65)ZnONPs than the 71 nm (65)ZnONPs or (65)Zn(NO(3))(2) had accumulated in other organs (brain, lung, heart and kidneys). Zn ions seem to have a longer half-life in the plasma, but ZnONPs show greater tissue accumulation. Although the size of the ZnONPs had no obvious effect on the kinetics, nevertheless the smaller ZnONPs tended to accumulate preferentially in some organs.
Cadmium (Cd) is a component in quantum dot 705 (QD705). Whether QD705 behaves similar to Cd in vivo is of great concern. We compared the distributional kinetics of cadmium chloride (CdCl(2)) and QD705 in mice after intravenous injection. QD705 showed a longer plasma and body retention than CdCl(2) and could be detected in the brain during early exposure. While both the liver and spleen demonstrated a constant Cd concentration for 28 days after QD705 injection, it is likely that this represents intact QD705 stored in mononuclear phagocytes. The kidneys showed a time-dependent accumulation of Cd in the QD705-exposed animals. By day 28, Cd in the kidneys from QD705 was 3-fold that of CdCl(2). QD705 and CdCl(2) have very different kinetics in distribution and metabolism. The long body retention of QD705 in the kidneys may mean that QD705 has even more renal toxicity than CdCl(2).
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