Knockdown of ribosome RNA processing protein 15 suppresses migration of hepatocellular carcinoma through inhibiting PATZ1-associated LAMC2/FAK pathway.

BACKGROUND: Ribosomal RNA processing protein 15 (RRP15) has been found to regulate the progression of hepatocellular carcinoma (HCC). Nevertheless, the extent to which it contributes to the spread of HCC cells remains uncertain. Thus, the objective of this research was to assess the biological function of RRP15 in the migration of HCC. METHODS: The expression of RRP15 in HCC tissue microarray (TMA), tumor tissues and cell lines were determined. In vitro, the effects of RRP15 knockdown on the migration, invasion and adhesion ability of HCC cells were assessed by wound healing assay, transwell and adhesion assay, respectively. The effect of RRP15 knockdown on HCC migration was also evaluated in vivo in a mouse model. RESULTS: Bioinformatics analysis showed that high expression of RRP15 was significantly associated with low survival rate of HCC. The expression level of RRP15 was strikingly upregulated in HCC tissues and cell lines compared with the corresponding controls, and TMA data also indicated that RRP15 was a pivotal prognostic factor for HCC. RRP15 knockdown in HCC cells reduced epithelial-to-mesenchymal transition (EMT) and inhibited migration in vitro and in vivo, independent of P53 expression. Mechanistically, blockade of RRP15 reduced the protein level of the transcription factor POZ/BTB and AT hook containing zinc finger 1 (PATZ1), resulting in decreased expression of the downstream genes encoding laminin 5 subunits, LAMC2 and LAMB3, eventually suppressing the integrin ß4 (ITGB4)/focal adhesion kinase (FAK)/nuclear factor κB kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway. CONCLUSIONS: RRP15 promotes HCC migration by activating the LAMC2/ITGB4/FAK pathway, providing a new target for future HCC treatment.

Chemokine receptor CCR1 regulates macrophage activation through mTORC1 signaling in nonalcoholic steatohepatitis.

BACKGROUND AND AIMS: Chemokine (CC motif) receptor 1 (CCR1) promotes liver fibrosis in mice. However, its effects on nonalcoholic steatohepatitis (NASH) remain unclear. Therefore, the present study aimed to investigate the role of CCR1 in the progression of NASH. METHODS: Human serum and liver tissues were obtained from patients with NASH and controls. Systemic (Ccr1-/-) and liver macrophage-knockout Ccr1 (Ccr1LKD) mice were fed a high-cholesterol and high-fat (CL) diet for 12 weeks or a methionine/choline-deficient (MCD) diet for 4 weeks. BX471 was used to pharmacologically inhibit CCR1 in CL-fed mice. RESULTS: CCR1 was significantly upregulated in liver samples from patients with NASH and in animal models of dietary-induced NASH. In the livers of mice fed a CL diet for 12 weeks, the CCR1 protein colocalized with F4/80+ macrophages rather than with hepatic stellate cells. Compared to their wild-type littermates, Ccr1-/- mice fed with the CL or MCD diet showed inhibition of NASH-associated hepatic steatosis, inflammation, and fibrosis. Mechanistically, Ccr1 deficiency suppressed macrophage infiltration and activation by attenuating the mechanistic target of rapamycin complex 1 (mTORC1) signaling. Similar results were observed in Ccr1LKD mice administered the CL diet. Moreover, CCR1 inhibition by BX471 effectively suppressed NASH progression in CL-fed mice. CONCLUSIONS: Ccr1 deficiency mitigated macrophage activity by inhibiting mTORC1 signaling, thereby preventing the development of NASH. Notably, the CCR1 inhibitor BX471 protected against NASH. These findings would help in developing novel strategies for the treatment of NASH.

Melatonin alleviates diet-induced steatohepatitis by targeting multiple cell types in the liver to suppress inflammation and fibrosis.

The pathogenesis of nonalcoholic steatohepatitis (NASH), a severe stage of nonalcoholic fatty liver disease, is complex and implicates multiple cell interactions. However, therapies for NASH that target multiple cell interactions are still lacking. Melatonin (MEL) alleviates NASH with mechanisms not yet fully understood. Thus, we herein investigate the effects of MEL on key cell types involved in NASH, including hepatocytes, macrophages, and stellate cells. In a mouse NASH model with feeding of a methionine and choline-deficient (MCD) diet, MEL administration suppressed lipid accumulation and peroxidation, improved insulin sensitivity, and attenuated inflammation and fibrogenesis in the liver. Specifically, MEL reduced proinflammatory cytokine expression and inflammatory signal activation and attenuated CD11C+CD206- M1-like macrophage polarization in the liver of NASH mice. The reduction of proinflammatory response by MEL was also observed in the lipopolysaccharide-stimulated Raw264.7 cells. Additionally, MEL increased liver fatty acid ß-oxidation, leading to reduced lipid accumulation, and restored the oleate-loaded primary hepatocytes. Finally, MEL attenuated hepatic stellate cell (HSC) activation and fibrogenesis in the liver of MCD-fed mice and in LX-2 human HSCs. In conclusion, MEL acts on multiple cell types in the liver to mitigate NASH-associated phenotypes, supporting MEL or its analog as potential treatment for NASH.

Swertiamarin ameliorates diet-induced obesity by promoting adipose tissue browning and oxidative metabolism in preexisting obese mice.

Obesity is a risk factor for many metabolic diseases. Efficient therapeutic strategies are urgently needed. Swertiamarin (STM) prevents obesity and the associated insulin resistance and inflammation. However, the therapeutic effects of STM on preexisting obesity remain unclear. Therefore, in this study we aim to investigate the effects of STM on energy expenditure and fat browning in mice with preexisting obesity. C57BL/6J mice are fed with a high-fat diet (HFD) for 8 weeks to induce obesity and then gavaged (or not) with STM for 10 weeks. The whole-body energy metabolism of mice is examined by indirect calorimetry. The results show that after 10 weeks of treatment, STM markedly prevents HFD-induced weight gain, chronic inflammation, insulin resistance, and hepatic steatosis. STM promotes oxygen consumption and energy expenditure. The level of uncoupling protein 1 is enhanced in the brown and white adipose tissues of STM-treated mice. STM increases the phosphorylation of AMP-activated protein kinase and the expressions of genes involved in fat oxidation, reducing fat deposition in skeletal muscles. Meanwhile, STM does not affect the intestinal microbiotic composition. Overall, STM supplementation may serve as a potential therapy for obesity.

Using Scalable Graphene via Press-and-Peel: A Robust and Storable Tape.

The independent expertise required by the preparation and application of graphene has brought a challenge to the more fluent development of graphene devices. We combine the advantages of chemical vapor deposition and micromechanical exfoliation methods of synthesizing graphene to develop a "graphene tape" for the fast utilization of graphene, which is robust, storable, and user-friendly. Prepared by pretransferring graphene to the surface of a polymer carrier film with weak interfacial adhesion, this graphene tape enables the acquisition, patterning, and layer-by-layer epitaxy of scalable graphene on a target substrate through simple cutting, pressing, and peeling off. Multiple characterizations demonstrate its comparable quality with as-synthesized graphene even after stored for over 30 days, overcoming the time and space limitations of acquiring a graphene sample. We believe that this graphene tape can bridge the current gap between graphene synthesis and applications and promote industrial progress of graphene-based devices in the post-Moore era.

Evaporation Kinetics of Sessile Water Droplets on a Smooth Stainless Steel Surface at Elevated Temperatures and Pressures.

The evaporation of water droplets on a solid surface at elevated temperatures under a pressurized condition has not yet been well understood, although this phenomenon is of both theoretical and practical significance. In this work, water droplet evaporation on smooth stainless steel surfaces in nitrogen gas atmosphere at elevated pressures and temperatures (up to 2 MPa and 202.4 °C, respectively) was investigated experimentally. It was observed that the increase in pressure diminishes the proportion of the constant contact radius stage over the entire evaporation time, whereas an opposite trend was found when raising the temperature, due to the change in the surface pinning ability with pressure (and temperature). The results also suggested that the evaporation mode transition is mainly affected by temperature rather than pressure. In addition, the evaporation rate was calculated under various degrees of subcooling, revealing that the evaporation rate increases almost linearly with pressure when keeping the degree of subcooling constant. However, when fixing the test temperature, a nonlinear decrease of the evaporation rate with pressure was observed. A power law growth of the evaporation rate with temperature was also found at a constant pressure. Last, it was uncovered by a theoretical analysis that the saturated vapor concentration is the dominant factor dictating the evaporation rate.

Understanding the Temperature Dependence of Contact Angles of Water on a Smooth Hydrophobic Surface under Pressurized Conditions: An Experimental Study.

It is of both practical and scientific significance to understand the temperature dependence of contact angles of water on various surfaces. However, the variation trend of water wettability on a smooth hydrophobic surface with increasing temperature remains unclear. In this work, in situ characterization of the contact angle of water on Teflon (polytetrafluoroethylene) surfaces and the interfacial tension of water over a temperature spectrum from ∼25 to 160 °C under pressurized conditions (2, 3, and 5 MPa) in a nitrogen atmosphere was conducted by employing the sessile drop and pendant drop methods, respectively. A nearly invariant trend of the contact angle was observed over the entire temperature and pressure range. As expected, however, it was shown that the water-N2 interfacial tension almost linearly declines with increasing temperature and that pressure has a negative effect on the interfacial tension. Based on the theory of surface thermodynamics, the effects of temperature on the contact angles were analyzed in combination with the gas adsorption effect. Estimations on the solid-gas interfacial tension, surface entropy, and the heat of immersion were made to gain more insights into the temperature dependence of the water contact angle on a smooth hydrophobic surface.