Inhibition of miR-431-5p attenuated liver apoptosis through KLF15/p53 signal pathway in S100 induced autoimmune hepatitis mice.

AIMS: The purpose of this study was to investigate the effects of miR-431-5p on hepatocyte apoptosis in AIH. MATERIALS AND METHODS: We used intraperitoneal injection of S100 to establish AIH mouse model and injected AAV into tail vein on day 14 of modeling to regulate miR-431-5p expression. The expression of ALT, AST, IgG and apoptosis-related proteins Bax, Bcl-2 and cleaved caspase 3 were measured in each group. Cellular experiments were performed using miR-431-5p mimics or inhibitors to transfect LPS-stimulated AML12 cells, and apoptosis was verified using Western blot and Hoechst 33342/PI Double Staining. The target of miR-431-5p, KLF15, was screened using databases and verified by the luciferase reporter assay. The relationship between KLF15 and p53 was verified by si-KLF15 and PFTß (a p53-specific inhibitor). KEY FINDINGS: Here, we observed that the increase in the level of miR-431-5p was accompanied by a decrease in the expression of Krüppel-like zinc finger transcription factor 15 (KLF15). In addition, the deletion of miR-431-5p significantly reduced hepatocyte apoptosis in AIH mice induced by liver S100 and apoptosis of AML12 cells induced by LPS stimulation, accompanied by decreased expression of Bax and cleaved caspase-3 as well as increased expression of Bcl-2. Moreover, KLF15 was the direct and functional target of miR-431-5p. Furthermore, miR-431-5p negatively regulated the expression of KLF15, and KLF15 deletion partially abolished the inhibitory effect of miR-431-5p deletion on apoptosis by activating p53 signaling. SIGNIFICANCE: In summary, miR-431-5p may be a potential therapeutic target for AIH.

Celecoxib attenuates depressive-like behavior associated with immunological liver injury in C57BL/6 mice through TNF-α and NF-κb dependent mechanisms.

AIM: Depression associating patients with chronic liver diseases is a major treatment goal. This study aimed to evaluate the potential hepatoprotective and antidepressant effects of celecoxib in a model of experimental autoimmune hepatitis (EAH) and depressive-like behavior in C57BL/6 mice. MAIN METHODS: EAH was induced by immunization with S-100 liver antigen emulsified in complete Freund's adjuvant (CFA). Mice were randomly allocated to 5 groups; control phosphate buffered saline group; control CFA group; EAH group, and 2 groups of EAH plus celecoxib (7.5 or 15mg/kg/d respectively). Mice were assessed behaviorally by novelty-suppressed test, tail suspension test, locomotor assessment and forced swimming tests. Serum liver enzymes and hepatic hydroxyproline content were biochemically analyzed. Histopathological analysis for liver and brain sections and immunohistochemical studies for hepatic and hippocampal tumor necrosis factor (TNF-α), nuclear factor Kappa-B (NF-κB) and caspase-3 were performed. KEY FINDINGS: EAH group exhibited significant depressive-like changes, increase in liver enzymes and hepatic hydroxyproline content. Signs of autoimmune hepatitis and structural changes in hippocampus were confirmed by histopathological studies. Immunohistochemical examination revealed overexpression of hepatic and hippocampal TNF-α, NF-κB and caspase-3 positive cells. Celecoxib (7.5mg/kg/d) significantly ameliorated hepatic biochemical changes, hepatic and hippocampal histopathological and immunohistochemical changes induced in EAH group. Celecoxib (15mg/kg/d) significantly ameliorated the behavioral changes, histopathological and immunohistochemical changes in hippocampus, with non-significant change in hepatic biochemical profile, histopathological and immunohistochemical changes induced in EAH group. SIGNIFICANCE: The celecoxib (7.5mg/kg/d) through its anti-inflammatory effect may represent a new therapeutic approach to treat autoimmune hepatitis associated with depressive symptoms.

Cerebrospinal fluid S100B correlates with brain atrophy in Alzheimer's disease.

S100B is a predominantly astrocytic protein with dose-dependent cytotoxic and neurotrophic properties encoded on chromosome 21q22.3. Concentrations of S100B were measured in the cerebrospinal fluid (CSF) of 31 patients with Alzheimer's disease (AD), 36 patients with frontotemporal lobe dementia (FTLD) and 49 patients with other non-inflammatory neurological diseases. Additional CSF S100B concentrations were correlated with normalised brain volume measurements in AD and FTLD. CSF S100B was significantly higher in AD (Mean+/-standard deviation=0.4+/-0.2 ng/ml) and FTLD (0.42+/-0.19 ng/ml) patients when compared with control subjects (0.25+/-0.08, P<0.001). In patients with AD, S100B correlated negatively with normalised brain volume (R(S)=-0.53, P<0.001). No such correlation was found for FTLD patients. This study supports the concept that S100B is of pathological relevance for degeneration of the central nervous system in AD.

Chicks injected with antisera to either S-100 alpha or S-100 beta protein develop amnesia for a passive avoidance task.

The cellular expression of S-100 beta protein is upregulated in Alzheimer's disease and in Down's syndrome, and this protein has been implicated in memory-related processes in laboratory animals. However, the possibility that the alpha subunit of S-100 is also involved in memory has not yet been examined. In the present study, day-old black Australorp white Leghorn cockerel chicks (Gallus domesticus) received injections of monoclonal antisera to S-100 alpha (1:50) or S-100 beta (1:500) into each hemisphere immediately after training on a one-trial passive avoidance task. The chicks displayed significantly lower retention levels than control birds that had been injected with antisera to carbonic anhydrase, or with saline (p < .01). S-100 alpha antisera had an amnestic effect when injected between 0 and 20 min after training, with memory deficits occurring from 30 min post-learning, at the point of transition between the A and the B phases of the Gibbs-Ng intermediate memory stage. By contrast, the S-100 beta antisera needed to be injected either 5 min before or immediately after training and produced amnesia 10 min earlier, at the start of the A phase of the intermediate memory stage. We conclude that the two subunits of the S-100 protein are required at different points in the sequence of events leading to the consolidation of passive avoidance memory.