Inhibition of acid-sensing ion channel 1a in hepatic stellate cells attenuates PDGF-induced activation of HSCs through MAPK pathway.

Acid-sensing ion channels (ASICs), a group of Na(+)-selective and Ca(2+)-permeant ligand-gated cation channels, can be transiently activated by extracellular acid. Among seven subunits of ASICs, acid-sensing ion channel 1a (ASIC1a), which is responsible for Ca(2+) transportation, is elevated in response to inflammation, tumor, and ischemic injury in central nervous system and non-neuronal tissues. In this study, we demonstrated for the first time the presence of ASIC1a in rat liver and hepatic stellate cells (HSCs). Furthermore, the expression of ASIC1a was increased in primary HSCs and liver tissues of CCl4-treated rats, suggesting that ASIC1a may play certain role in liver fibrosis. Interestingly, we identified that the level of ASIC1a was significantly elevated in response to platelet-derived growth factor (PDGF) induction in a time- and dose-dependent manner. It was also established that Ca(2+)-transporting ASIC1a was involved in acid-induced injury of different cell types. Moreover, inhibition or silencing of ASIC1a was able to inhibit PDGF-induced pro-fibrogenic effects of activated rat HSCs, including cell activation, de novo synthesis of extracellular matrix components through mitogen-activated protein kinase signaling pathway. Collectively, our studies identified that ASIC1a was expressed in rat liver and HSCs and provided a strong evidence for the involvement of the ASIC1a in the progression of hepatic fibrosis.

Inhibition of ASICs reduces rat hepatic stellate cells activity and liver fibrosis: an in vitro and in vivo study.

Hepatic fibrosis is a chronic inflammation-associated disease, which is involved in the infiltration of inflammatory cells and releasing of proinflammatory cytokines. In the pathological process, protons are released by damaged cells and acidosis is considered to play a critical role in cell injury. Although the underlying mechanism (s) remain ill-defined, ASICs (acid-sensing ion channels) are assumed to be involved in this process. The diuretic, amiloride, is neuroprotective in models of cerebral ischemia, a property attributable to the inhibition of central ASICs by the drug. However, the effect of inhibition of ASICs by amiloride in the liver fibrotic process remains unclear. We found that amiloride (25, 50, or 100 µM) could restrain acid-induced HSCs at pH6 in vitro. In vivo experiments showed that amiloride could significantly alleviate liver injury, decreasing levels of profibrogenic cytokines, collagen deposition, and reducing pathological tissue damage. In summary, amiloride inhibits hepatic fibrosis in vivo and in vitro, which is probably associated with the downregulation of ASICs.

Role of interleukin-22 in liver diseases.

INTRODUCTION: Interleukin (IL)-22, originally referred to as IL-TIF for IL-10-related T cell-derived inducible factor, is a member of the IL-10-like cytokine family. IL-22 is highly expressed by Th17 cells and is tightly linked to chronic inflammation, including inflammatory bowel disease and local intestinal inflammation among others. MATERIALS AND METHODS: A PubMed and Web of Science databases search was performed for studies providing evidences on the role of IL-22 in liver diseases. CONCLUSION: IL-22 plays an important role in ameliorating liver injury in many rodent models by targeting hepatocytes that express high levels of IL-22 receptor 1 and IL-10 receptor 2. This review concisely summarizes the role of IL-22 in the development progression of liver disease of different etiologies. It is focused mainly on the IL-22 intracellular signaling and its influence on liver diseases.

Antidepressant-like effect of resveratrol: involvement of antioxidant effect and peripheral regulation on HPA axis.

This study focused on exploring the antidepressant potential of resveratrol (RES) and its possible mechanisms of action. Cell injury was induced by corticosterone (CORT) and detected through cell viability and contents of lactate dehydrogenase (LDH) and malonaldehyde (MDA). A rat model of depression was established through 3weeks of consecutive chronic unpredictable mild stress (CUMS), and both the depression-like behaviors and the activity of the hypothalamic-pituitary-adrenal (HPA) axis were tested. Apart from the inhibitory effect on MDA production in vitro and in vivo, the results showed that RES (10(-10)mol/L to 10(-5)mol/L) could significantly increase the cell viability and decrease the LDH activity and that RES (15mg/kg) treatment could alleviate the depression-like behavior of CUMS rats, as indicated by increased sucrose preference and decreased immobility in forced swimming test and tail suspension test. Rats that received RES treatment displayed a reduction of serum CORT, suggesting that RES affected the hyperactivity of the HPA axis in CUMS rats. However, RES did not affect the expression of corticotropin-releasing hormone (CRH) mRNA in the hypothalamus of CUMS rats. In summary, our results demonstrated that in addition to its widely known antioxidant properties, RES also has antidepressant-like effects, and suggested that the underlying mechanism might involve its peripheral effect on the regulation of the HPA axis.

Anti-tumor effect of 4-Amino-2-Trifluoromethyl-Phenyl Retinate on human breast cancer MCF-7 cells via up-regulation of retinoid receptor-induced gene-1.

4-Amino-2-Trifluoromethyl-Phenyl Retinate (ATPR) is one of the retinoid derivatives designed and synthesized in our team. In this paper, we explored the potential anti-tumor effects of ATPR in breast cancer. Here we found that ATPR showed remarkable anti-proliferative effects in a dose- and time-dependent manner, caused cell cycle arrest in the G0/G1 phase and significantly increased the expression of retinoid receptor-induced gene-1 (RRIG1). ATPR decreased the expression of phosphorylation-ERK (p-ERK) and increased the expression of estrogen receptor ß (ERß) and phosphorylation-p38 (p-p38). Following RRIG1 knockdown by RNAi interference, we found that the changes of ERß, p-ERK and p-p38 induced by ATPR were both depressed. Our data suggest that ATPR could inhibit the proliferation and induce differentiation of MCF-7 cells via mediating the expression of RRIG1.

Elimination of matrix effect and simultaneous determination of multi-components in complex systems by matrix coefficient non-linearity multivariate calibration based on single point response signals.

In order to deal with the matrix effect in the simultaneous determination of multi-components in a complex system, we have developed a novel method named matrix coefficient multivariate calibration method (MCMCM) for simultaneously determining n analytes in complex systems. The calibration models of n analytes, which are based on the experimental data of known samples, are first transformed into n linear equations, and then the equations are solved to obtain matrix calibration coefficients of the analytes in congeneric samples. In this way, the concentrations of n analytes in the unknown sample could be obtained easily and simultaneously by solving another n-variate linear equations with the help of the matrix calibration coefficients obtained-above. The method proposed in this work has been tested by voltammetry and atomic absorption spectrometry (AAS) with satisfactory results. On determining the elements such as Cu, Pb, Cd, Ni, Zn, Fe, Mn, Co, Ca, Mg, etc. in synthetic samples, the relative standard deviations (RSDs) of the results were 0.91 - 4.5%, and the recoveries were 95.8 - 105%. For actual samples, the RSDs and the recoveries were 1.5 - 6.9 and 92.0 - 110%, respectively.