Imprinted CDKN1C is a tumor suppressor in rhabdoid tumor and activated by restoration of SMARCB1 and histone deacetylase inhibitors

SMARCB1 is deleted in rhabdoid tumor, an aggressive paediatric malignancy affecting the kidney and CNS. We hypothesized that the oncogenic pathway in rhabdoid tumors involved epigenetic silencing of key cell cycle regulators as a consequence of altered chromatin-remodelling, attributable to loss of SMARCB1, and that this hypothesis if proven could provide a biological rationale for testing epigenetic therapies in this disease. We used an inducible expression system to show that the imprinted cell cycle inhibitor CDKN1C is a downstream target for SMARCB1 and is transcriptionally activated by increased histone H3 and H4 acetylation at the promoter. We also show that CDKN1C expression induces cell cycle arrest, CDKN1C knockdown with siRNA is associated with increased proliferation, and is able to compete against the anti-proliferative effect of restored SMARCB1 expression. The histone deacetylase inhibitor (HDACi), Romidepsin, specifically restored CDKN1C expression in rhabdoid tumor cells through promoter histone H3 and H4 acetylation, recapitulating the effect of SMARCB1 on CDKNIC allelic expression, and induced cell cycle arrest in G401 and STM91-01 rhabdoid tumor cell lines. CDKN1C expression was also shown to be generally absent in clinical specimens of rhabdoid tumor, however CDKN1A and CDKN1B expression persisted. Our observations suggest that maintenance of CDKN1C expression plays a critical role in preventing rhabdoid tumor growth. Significantly, we report for the first time, parallels between the molecular pathways of SMARCB1 restoration and Romidepsin treatment, and demonstrate a biological basis for the further exploration of histone deacetylase inhibitors as relevant therapeutic reagents in the treatment of rhabdoid tumor.

Effect of training on activation of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase pathways in rat soleus muscle

1. The effect of a chronic programme of either low- or moderate-to-high-intensity treadmill running on the activation of the extracellular-signal regulated protein kinase (ERK1/2) and the p38 mitogen-activated protein kinase (MAPK) pathways was determined in rat muscle. 2. Sprague-Dawley rats were assigned to one of three groups: (i) sedentary (NT; n = 8); (ii) low-intensity training (8 m/min; LIT; n = 16); and (iii) moderate-to-high-intensity training (28 m/min; HIT;n = 16). The training regimens were planned so that animals covered the same distance and had similar glycogen utilization for both LIT and HIT exercise sessions. 3. A single bout of LIT or HIT following 8 weeks of training led to a twofold increase in the phosphorylation of ERK1/2 (P = 0.048) and a two- to threefold increase in p38 MAPK (P = 0.005). Extracellular signal-regulated kinase 1/2 phosphorylation in muscle sampled 48 h after the last exercise bout was similar to sedentary values, while p38 MAPK phosphorylation was 70-80% lower than sedentary. One bout of LIT or HIT increased total ERK1/2 and p38 MAPK expression, with the magnitude of this increase being independent of prior exercise intensity or duration. Extracellular signal-regulated kinase 1/2 expression was increased three- to fourfold in muscle sampled 48 h after the last exercise bout irrespective of the prior training programme (P = 0.027), but p38 MAPK expression was approximately 90% lower than sedentary values. 4. In conclusion, exercise-training of different intensities/durations results in selective postexercise activation of intracellular signalling pathways, which may be one mechanism regulating specific adaptations induced by diverse training programmes.

Graphene quantum dots induce apoptosis, autophagy, and inflammatory response via p38 mitogen-activated protein kinase and nuclear factor-κB mediated signaling pathways in activated THP-1 macrophages.

The biomedical application of graphene quantum dots (GQDs) is a new emerging area. However, their safety data are still in scarcity to date. Particularly, the effect of GQDs on the immune system remains unknown. This study aimed to elucidate the interaction of GQDs with macrophages and the underlying mechanisms. Our results showed that GQDs slightly affected the cell viability and membrane integrity of macrophages, whereas GQDs significantly increased reactive oxygen species (ROS) generation and apoptotic and autophagic cell death with an increase in the expression level of Bax, Bad, caspase 3, caspase 9, beclin 1, and LC3-I/II and a decrease in that of Bcl-2. Furthermore, low concentrations of GQDs significantly increased the expression of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-8, whereas high concentrations of GQDs elicited opposite effects on the cytokines production. SB202190, a selective inhibitor of p38 mitogen-activated protein kinase (MAPK), abolished the cytokine-inducing effect of GQDs in macrophages. Moreover, GQDs significantly increased the phosphorylation of p38 MAPK and p65, and promoted the nuclear translocation of nuclear factor-κB (NF-κB). Taken together, these results show that GQDs induce ROS generation, apoptosis, autophagy, and inflammatory response via p38MAPK and NF-κB mediated signaling pathways in THP-1 activated macrophages.

Insights into the transport of alkali metal ions doped into a plastic crystal electrolyte

The application of organic ionic plastic crystals (OIPCs) as a new class of solid electrolyte for energy storage devices such as lithium batteries and, more recently, sodium batteries is attracting increasing attention. Key to this is achieving sufficient target ion transport through the material. This requires fundamental understanding of the structure and dynamics of OIPCs that have been doped with the necessary lithium or sodium salts. Here we report, for the first time, the atomic level structure and transport of both lithium and sodium ions in the plastic crystalline phases of an OIPC diethyl(methyl)(isobutyl)phosphonium hexafluorophosphate. These molecular dynamics simulations reveal two types of coordination geometries of the alkali metal ion first solvation shells, which cooperate closely with the metal ion hopping motion. The significantly different ion migration rates between two metal ion doped systems could also be related to the differences in solvation structures.

Adsorption kinetics and optimum conditions for Cr(VI) removal by activated carbon prepared from luffa sponge

Activated carbon (AC) prepared from luffa sponge was firstly used as an adsorbent to remove Cr(VI) from aqueous solution. The Cr(VI) adsorption behaviors of AC under different conditions, including initial Cr(VI) concentration, quantity of AC, solution pH, and temperature were investigated. The optimal conditions for adsorption of Cr(VI) by AC were pH = 1, initial Cr(VI) concentration = 80 mg/L, T = 303 K, and AC content = 1.6 g/L. The adsorption kinetics could be described by the pseudo-second-order model. Fourier transform infrared spectroscopy was used to investigate the sorption mechanism. Some functional groups such as C–O and O–H were formed on the carbon surface, which could then react with Cr(VI). The surface structure of AC before and after adsorption was analyzed by scanning electronic microscopy. Adsorbed ions choked some of the pores in AC after adsorption. The Brunauer–Emmett–Teller surface area and average pore size of the AC were 834.13 m2/g and 5.17 nm, respectively. The maximum adsorption of Cr(VI) by AC was 149.06 mg/g, which makes AC prepared from luffa sponge promising for removing Cr(VI) from wastewater.

Isotherm, kinetic, and thermodynamic equations for cefalexin removal from liquids using activated carbon synthesized from loofah sponge

Activated carbon (AC) developed from loofah sponge with phosphoric acid activation was applied to absorb cefalexin (CEX) in aqueous solution. AC was characterized by N2 adsorption–desorption isotherms and Fourier transform infrared spectroscopy (FTIR). Factors influencing the adsorption process were investigated. The equilibrium adsorption isotherms and kinetics of CEX were also studied. The results showed that AC prepared from loofah sponge had rough surface and abundant pores. The determination results of specific surface area (810.12 m²/g) and average pore size (5.28 nm) suggested the high adsorption capability. At low concentration, the AC could adsorb about 95% of CEX. The adsorption effect was independent of the temperature and pH. The maximum adsorption amount of CEX was about 55.11 mg/g at 308 K. The equilibrium data agreed well with Freundlich isotherm equation (R² = 0.9957) at 308 K, which indicated multilayer adsorption. FTIR analysis suggested the existence of phosphorus-containing functional groups, C–O bond, and C=C bond on the surface of AC of which the peak intensity of AC after adsorption was slightly lower after adsorption, indicating that the AC surface groups interacted with or were covered by the CEX species.