Effect of RGS5 deficiency on body weight at initial of feeding and body weight, mean food intake, fat and liver weight after 24 weeks of feeding (n = 8–10).

<p>Data are means ± SEM.</p>##<p><i>p</i><0.01 vs. WT mice fed an NC;</p><p>*<i>p</i><0.05 and</p><p>**<i>p</i><0.01 vs. WT mice fed an HF.</p

Metabolic and inflammatory variables in circulation at initial of feeding (n = 8).

<p>Data are means ± SEM.</p>##<p><i>p</i><0.01 vs. WT mice fed an NC;</p><p>**<i>p</i><0.01 vs. WT mice fed an HF.</p

RGS5 deficiency exacerbated fat accumulation in liver.

<p><b>A</b> Histology of liver with hematoxylin-eosin. <b>B</b> Histology of liver with oil red O. <b>C</b> Expression levels of mRNA related to fatty acid metabolism in the liver of WT (a dotted line at value 1) and KO (black) mice fed an HF for 24 weeks (n = 6). Values represent means ± SEM. *<i>p</i><0.05 and **<i>p</i><0.01 compared with WT mice.</p

RGS5 deficiency promoted inflammation and JNK, NF-κB signaling in the adipose tissue, liver and skeletal muscle of mice fed an HF for 24 weeks.

<p><b>A</b> Expression levels of mRNA related to inflammation in the visceral adipose tissue of WT (a dotted line at value 1) and KO (black) mice (n = 6). <b>B</b> Expression levels of mRNA related to inflammation in the liver of WT (a dotted line at value 1) and KO (black) mice(n = 6). <b>C</b> Expression levels of mRNA related to inflammation in the gastrocnemius muscle of WT (a dotted line at value 1) and KO (black) mice (n = 6). <b>D</b> Phosphorylation levels of proteins related to inflammatory signaling in the visceral adipose tissue, liver and gastrocnemius muscle of KO and WT mice (n = 6). <b>E</b> Quantitative measurements of p-JNK, p-IκBα and p-NF-κBp65 protein relative to their total protein between WT mice (a dotted line at value 1) and KO mice (black). Values represent means ± SEM. *<i>p</i><0.05 and **<i>p</i><0.01 compared with WT mice.</p

Effect of RGS5 deficiency on body weight, fat mass and adipocyte size.

<p><b>A</b> Representative photograph of WT and KO mice fed an NC and HF for 24 weeks. <b>B</b> Growth curves of WT (black) and KO (blank) mice fed an NC (triangle) and an HF (rhombus) (n = 8–11). <b>C</b> Histology of visceral adipose tissue with hematoxylin-eosin. <b>D</b> Mean adipocyte size of the visceral adipose tissue in WT (black) and KO (blank) mice fed an NC and an HF for 24 weeks (n = 5). <b>E</b> Expression levels of mRNA related to adipogenesis in the visceral fat of WT (a dotted line at value 1) and KO (black) mice fed an HF for 24 weeks (n = 6). Values represent means ± SEM. #<i>p</i><0.05 and ##<i>p</i><0.01 compared with WT mice fed an NC; *<i>p</i><0.05 and **<i>p</i><0.01 compared with WT mice fed an HF.</p

RGS5 deletion resulted in decreased peripheral insulin sensitivity and suppressed the Akt/GSK3β signaling pathway in mice fed an HF for 24 weeks.

<p><b>A,B,C</b> Blood glucose levels during GTT were determined at the indicated time points after i.p. injection with a bolus of glucose in WT and KO mice fed an NC (A) and HF (B) and corresponding AUC (C) (n = 6–8). <b>D,E,F</b> Blood glucose levels during ITT were determined at the indicated time points after i.p. injection with a bolus of insulin in WT and KO mice fed an NC (D) and HF (E) and corresponding AUC (F) (n = 6–8). <b>G</b> Phosphorylation levels of proteins related to insulin signaling in the visceral adipose tissue, liver and gastrocnemius muscle of WT and KO mice (n = 6). <b>H</b> Quantitative measurements of p-Akt and p-GSK3β protein relative to their total protein between WT mice (a dotted line at value 1) and KO mice (black). Values represent means ± SEM. #<i>p</i><0.05 and ##<i>p</i><0.01 compared with WT mice fed an NC; *<i>p</i><0.05 and **<i>p</i><0.01 compared with WT mice fed an HF.</p

RGS5 deficiency exacerbated hyperinsulinemia.

<p><b>A</b> The level of fasting blood glucose in WT (black) and KO (blank) mice fed an NC (triangle) and HF (rhombus) from 0 to 24 weeks (n = 8–11). <b>B,C</b> The level of plasma insulin in WT (black) and KO (blank) mice fed an NC(triangle) and HF (rhombus) from 0 to 24 weeks (B) and corresponding AUC (C) (n = 8). Values represent means ± SEM. #<i>p</i><0.05 and ##<i>p</i><0.01 compared with WT mice fed an NC; *<i>p</i><0.05 and **<i>p</i><0.01 compared with WT mice fed an HF.</p

Amplification of arsenic genotoxicity by TiO₂ nanoparticles in mammalian cells: new insights from physicochemical interactions and mitochondria

<p>Titanium dioxide nanoparticles (TiO₂ NPs) have shown great adsorption capacity for arsenic (As); however, the potential impact of TiO₂ NPs on the behavior and toxic responses of As remains largely unexplored. In the present study, we focused on the physicochemical interaction between TiO₂ NPs and As(III) to clarify the underlying mechanisms involved in their synergistic genotoxic effect on mammalian cells. Our data showed that As(III) mainly interacted with TiO₂ NPs by competitively occupying the sites of hydroxyl groups on the surface of TiO₂ NP aggregates, resulting in more aggregation of TiO₂ NPs. Although TiO₂ NPs at concentrations used here had no cytotoxic or genotoxic effects on cells, they efficiently increased the genotoxicity of As(III) in human-hamster hybrid (A_L) cells. The synergistic genotoxicity of TiO₂ NPs and As(III) was partially inhibited by various endocytosis pathway inhibitors while it was completely blocked by an As(III)-specific chelator. Using a mitochondrial membrane potential fluorescence probe, a reactive oxygen species (ROS) probe together with mitochondrial DNA-depleted ρ⁰ A_L cells, we discovered that mitochondria were essential for mediating the synergistic DNA-damaging effects of TiO₂ NPs and As(III). These data provide novel mechanistic proof that TiO₂ NPs enhanced the genotoxicity of As(III) via physicochemical interactions, which were mediated by mitochondria-dependent ROS.</p

Graphene Oxide Attenuates the Cytotoxicity and Mutagenicity of PCB 52 via Activation of Genuine Autophagy

Graphene oxide (GO), owing to its large surface area and abundance of oxygen-containing functional groups, is emerging as a potential adsorbent for polychlorinated biphenyls (PCBs), which accumulate over time and are harmful to both natural ecosystems and human health. However, the effect of GO against PCB-induced toxicity remains largely unexplored. The present study aimed to investigate the protective effect of GO against PCB 52 induced cytotoxic and genotoxic response in mammalian cells at various exposure conditions and clarify the protective role of autophagy. Pretreatment with GO dramatically decreased PCB 52 induced cytotoxicity and <i>CD59</i> gene mutation in human–hamster hybrid (A_L) cells. The toxic response in cells either pretreated with PCB 52 and then treated with GO or concurrently treated with GO and PCB 52 did not differ significantly from the toxic response in the cells treated with PCB 52 alone. Using autophagy inhibitors (3-methyladenine and wortmannin) and inducers (trehalose and rapamycin), we found that genuine autophagy induced by GO was involved in decreasing PCB 52 induced toxicity. These findings suggested that GO has an antagonistic effect against the toxicity of PCB 52 mainly by triggering a genuine autophagic process, which might provide new insights into the potential application of GO in PCB disposal and environmental and health risk assessment

Hypermethylation status and clinical outcome in patients with juvenile myelomonocytic leukemia (JMML).

<p>(A) Kaplan–Meier curves represent the probability of transplantation-free survival (TFS) in the 92 patients with JMML. TFS was defined as the probability of being alive and transplantation free. Both death and transplantation were considered events. The probability of 5-year TFS in the aberrant methylation score (AMS) 0 cohort (solid line) was significantly higher than that in the AMS 1–2 (long dashed line) and AMS 3–4 cohorts (dashed line), p < 0.001. (B) Kaplan–Meier curves represent the probability of overall survival (OS) in the 92 patients with JMML. Death was considered an event. The probability of OS in both the AMS 0 (solid line) and 1–2 cohorts (long dashed line) was significantly higher than that in the AMS 3–4 cohort (dashed line), p < 0.001.</p