Lixing Zhou

Room-temperature saturated ferroelectric polarization in BiFeO3 ceramics synthesized by rapid liquid phase sintering

Single-phased ferroelectromagnet BiFeO3 ceramics with high resistivity were synthesized by a rapid liquid phase sintering technique. Saturated ferroelectric hysteresis loops were observed at room temperature in the ceramics sintered at 880u200a°C for 450 s. The spontaneous polarization, remnant polarization, and the coercive field are 8.9 μC/cm2, 4.0 μC/cm2, and 39 kV/cm, respectively, under an applied field of 100 kV/cm. It is proposed that the formation of Fe2+ and an oxygen deficiency leading to the higher leakage can be greatly suppressed by the very high heating rate, short sintering period, and liquid phase sintering technique. The latter was also found effective in increasing the density of the ceramics. The sintering technique developed in this work is expected to be useful in synthesizing other ceramics from multivalent or volatile starting materials.

Down-regulation of HDAC3 inhibits growth of cholangiocarcinoma by inducing apoptosis

Class I histone deacetylases (HDACs) inhibit expression of tumor suppressor genes by removing acetyl groups from histone lysine residues, thereby increasing cancer cell survival and proliferation. We evaluated the expression of class I HDACs in cholangiocarcinoma (CCA). HDAC3 expression was specifically increased in CCA tissues and correlated with reduced patient survival. HDAC3 overexpression inhibited apoptosis and promoted CCA cell proliferation. Conversely, HDAC3 knockdown or pharmacological inhibition decreased CCA cell growth and increased caspase-dependent apoptosis. Inhibition of class I HDACs blocked HDAC3-catalyzed deacetylation and increased expression of downstream pro-apoptotic targets in vitro and in vivo. These results demonstrate for the first time that down-regulation of HDAC3 induces apoptosis in human CCA cells, indicating that inhibiting HDAC3 may be an effective therapeutic strategy for treating CCA .Class I histone deacetylases (HDACs) inhibit expression of tumor suppressor genes by removing acetyl groups from histone lysine residues, thereby increasing cancer cell survival and proliferation. We evaluated the expression of class I HDACs in cholangiocarcinoma (CCA). HDAC3 expression was specifically increased in CCA tissues and correlated with reduced patient survival. HDAC3 overexpression inhibited apoptosis and promoted CCA cell proliferation. Conversely, HDAC3 knockdown or pharmacological inhibition decreased CCA cell growth and increased caspase-dependent apoptosis. Inhibition of class I HDACs blocked HDAC3-catalyzed deacetylation and increased expression of downstream pro-apoptotic targets in vitro and in vivo. These results demonstrate for the first time that down-regulation of HDAC3 induces apoptosis in human CCA cells, indicating that inhibiting HDAC3 may be an effective therapeutic strategy for treating CCA.

Bifidobacterium longum affects the methylation level of forkhead box P3 promoter in 2, 4, 6-trinitrobenzenesulphonic acid induced colitis in rats

Bifidobacterium longum (B.xa0Longum) is a common probiotic colonized in the human gut and against the development of chronic inflammation including inflammatory bowel disease (IBD). But the underlying mechanism remains unknown. The aim of this study was to evaluate the affection of B.xa0longum on the methylation levels of forkhead box P3 (Foxp3) promoter. 2, 4, 6-trinitrobenzenesulphonic acid (TNBS)-induced colitis rat models were treated with B.xa0longum or medium, respectively. The genomic DNA of spleen peripheral blood mononuclear cells (PBMC) cells was extracted. After bisulphite treatment and pyrosequencing, the methylation levels of each CpG sites in the promoter of forkhead box protein P3 (Foxp3) were analyzed. B.xa0Longum treatment changes the methylation level in Foxp3 promoter in TNBS-treated colitis rats, and significantly demethylates several CpG sites in Foxp3 promoter. The demethylation of Foxp3 promoter might be involved in the effectiveness of B.xa0Longum treatment for IBD. Further research remains necessary to investigate the role of B.xa0Longum in Foxp3 demethylation. Using B.xa0Longum or its metabolic products is an option for further investigations on potential treatments for IBD.

Faecalibacterium prausnitzii Produces Butyrate to Maintain Th17/Treg Balance and to Ameliorate Colorectal Colitis by Inhibiting Histone Deacetylase 1

BackgroundnInflammatory bowel disease (IBD)-associated dysbiosis is characterized by a loss of Faecalibacterium prausnitzii, whose supernatant exerts an anti-inflammatory effect. However, the anti-inflammatory substances in F. prausnitzii supernatant and the mechanism in ameliorating colitis in IBD have not yet been fully investigated.nnnMethodsnExperimental colitis models were induced and evaluated by clinical examination and histopathology. Levels of cytokines and ratio of T cells were detected by enzyme-linked immunosorbent assay and flow cytometry analysis, respectively. F. prausnitzii supernatant was separated by macroporous resins. After extraction, the substances in supernatant were identified by gas chromatography-mass spectrometer. T-cell differentiation assay was conducted in vitro. Changes in signaling pathways were examined by immunoblot, immunohistochemistry, and immunofluorescent staining.nnnResultsnWe found that the supernatant of F. prausnitzii could regulate T helper 17 cell (Th17)/regulatory T cell (Treg) differentiation. Then, we identified butyrate produced by F. prausnitzii that played the anti-inflammatory effects by inhibiting interleukin (IL)-6/signal transducer and the activator of transcription 3 (STAT3)/IL-17 pathway and promoting forkhead box protein P3 (Foxp3). Finally, we demonstrated that the target of butyrate was histone deacetylase 1 (HDAC1).nnnConclusionsnIt is butyrate, instead of other substances produced by F. prausnitzii, that maintains Th17/Treg balance and exerts significant anti-inflammatory effects in colorectal colitis rodents, by inhibiting HDAC1 to promote Foxp3 and block the IL-6/STAT3/IL-17 downstream pathway. F. prausnitzii could be an option for further investigation for IBD treatment. Targeting the butyrate-HDAC1-T-cell axis offers an effective novel approach in the treatment of inflammatory disease.

Metformin facilitates BG45‑induced apoptosis via an anti‑Warburg effect in cholangiocarcinoma cells

Cholangiocarcinoma (CCA) is a highly lethal malignancy with an often late diagnosis and consequent poor prognosis. Chemotherapy is the only therapeutic strategy for most patients. Compared to normal cells, tumor cells preferentially metabolize glucose to lactate, even in aerobic conditions. Such metabolic alterations not only support the growth and invasion of tumor cells, but also promote their chemoresistance. The purpose of our study was to explore the role of metformin in regulating the metabolism of CCA, as well as to investigate whether metformin could act as a chemosensitizer of the HDAC3 inhibitor BG45, and therefore have potential for the treatment of CCA. Through bioinformatic analysis, we found that aberrant metabolism contributed to the proliferation of CCA cells. Seahorse XF96 Extracellular Flux Analyzer analysis and lactate production analysis showed that metformin could act as a suppressor of the Warburg effect in CCA cells. Western blotting showed that metformin decreased the expression of LDHA, which plays a key role in the Warburg effect. However, suppression of the Warburg effect was not sufficient to induce CCA cellular apoptosis. According to our previous research, which showed that an HDAC3 inhibitor (MI192) was involved in CCA apoptosis, we observed that metformin combined with BG45 (a novel specific HDAC3 inhibitor) effectively induced the apoptosis of CCA cells inxa0vitro. Furthermore, inxa0vivo experiments revealed that the combined treatment with metformin and BG45 markedly reduced CCA growth in a CCA xenograft model. Our data revealed that reversing the Warburg effect with metformin sensitizes cells to the antitumor effects of HDAC3 inhibitors. This provides a rationale for using the combination of metformin and BG45 as a new therapeutic strategy in the treatment of CCA.

SIRT2 Promotes the Migration and Invasion of Gastric Cancer through RAS/ERK/JNK/MMP-9 Pathway by Increasing PEPCK1-Related Metabolism

Metastasis is the most important feature of gastric cancer (GC) and the most widely recognized reason for GC-related deaths. Unfortunately, the underlying mechanism behind this metastasis remains unknown. Mounting evidence suggests the dynamic regulatory role of sirtuin2 (SIRT2), a histone deacetylase (HDAC), in cell migration and invasion. The present study aims to evaluate the biological function of SIRT2 in GC and identify the target of SIRT2 as well as evaluate its therapeutic efficacy. We found that SIRT2 was upregulated in GC tissues compared to adjacent normal tissues, and this was correlated with reduced patient survival. Although CCK8 and colony-formation assays showed that SIRT2 overexpression marginally promoted proliferation in GC cell lines, SIRT2 knockdown or treatment with SirReal2 decreased the migration and invasion of GC cells. We demonstrated both in vitro and in vivo that SirReal2 could inhibit the deacetylation activity of SIRT2 and its downstream target PEPCK1, which is related to mitochondrial metabolism and RAS/ERK/JNK/MMP-9 pathway. Taken together, these results demonstrate for the first time that SirReal2 selectively targets SIRT2 and decreases migration as well as invasion in human GC cells. SirReal2 therefore shows promise as a new drug candidate for GC therapy.

Exclusive enteral nutrition protects against inflammatory bowel disease by inhibiting NF‑κB activation through regulation of the p38/MSK1 pathway

Although enteral nutrition therapy for inflammatory bowel disease has been confirmed to be an effective treatment method, the exact mechanism responsible for the effects of enteral nutrition remains unclear. The aim of the present study was to investigate the protective effect of exclusive enteral nutrition (EEN) against colitis, and to elucidate the potential mechanisms by inhibiting p65 activation via regulating the p38/mitogen- and stress-activated protein kinase-1 (MSK1) pathway. Experiments were performed by establishing dextran sulfate sodium (DSS)-mice colitis and picrylsulfonic acid solution (TNBS)-induced rat colitis, and the results demonstrated that EEN treatment attenuated body weight loss, colon length shortening and colonic pathological damage caused by colitis. EEN also inhibited inflammatory cells infiltration and decreased myeloperoxidase and inducible nitric oxide synthase activities. Furthermore, EEN significantly reduced the production of pro-inflammatory mediators in serum and the colon. Mechanically, EEN suppressed activation of p65 by inhibiting the p38/MSK1 pathway. In conclusion, the present study demonstrated that EEN attenuated DSS- and TNBS-induced colitis by inhibiting p65 activation via regulating the p38/MSK1 pathway, thus suggesting that EEN is effective in the treatment of colitis.

Berberine promotes glucose uptake and inhibits gluconeogenesis by inhibiting deacetylase SIRT3

ObjectiveMany studies have confirmed the glucose-lowering effect of berberine in type 2 diabetes patients. Although the mechanism of action of berberine involves the improvement of insulin sensitivity, its hypoglycemic mechanism remains elusive. Here we show a new mechanism by which berberine antagonizes glucagon signaling and find that SIRT3 is involved in the hypoglycemic effect of berberine.MethodsGene knockout and overexpression were used to assess the inhibitory effect of berberine on SIRT3. Downstream signaling pathways and the hypoglycemic effect of SIRT3 were evaluated by immunoblotting and metabolic monitoring.ResultsWe found that berberine led to mitochondrial dysfunction and AMP accumulation by inhibiting deacetylase SIRT3. We confirmed that AMP accumulation activated the AMPK signaling pathway and further promoted glucose uptake. Simultaneously, AMP accumulation reduced cyclic AMP (cAMP) levels and abrogated the phosphorylation of critical protein targets of protein kinase A (PKA). Furthermore, we found that phosphoenolpyruvate carboxykinase 1 (PEPCK1) is a key gluconeogenesis enzyme that can be stabilized by glucagon. Berberine caused significant PEPCK1 ubiquitination and degradation by antagonizing glucagon and was accompanied by high levels of PEPCK1 acetylation. Interestingly, berberine-induced glucagon inhibition is independent of AMPK activation. The in vivo data from sirt3 knockout mice were further confirmed by the in vitro experiments.ConclusionsBerberine promotes glucose uptake and inhibits gluconeogenesis by inhibiting SIRT3, and regulating mitochondria-related pathways may provide a novel approach to the development of antidiabetic drugs.

Interfacial coupling and negative spin Hall magnetoresistance in Pt/NiO/YIG

Inserting an antiferromagnetic layer of NiO between Pt and Y3Fe5O12 (YIG) changes the positive sign of the spin Hall magnetoresistance (SMR) in Pt/YIG to a negative sign at low temperature. Here, we use polarized neutron reflectometry to explore the coupling between NiO and YIG to understand the mechanism of the negative SMR. A weak uncompensated magnetic moment is observed in the NiO and the direction of this moment is perpendicular to YIG. Therefore, we infer that the spin axis of NiO is perpendicular to YIG. This result directly supports the explanation that the negative SMR results from the pure spin current reflected back by the NiO layer and the spin-flop coupling between NiO and YIG.Inserting an antiferromagnetic layer of NiO between Pt and Y3Fe5O12 (YIG) changes the positive sign of the spin Hall magnetoresistance (SMR) in Pt/YIG to a negative sign at low temperature. Here, we use polarized neutron reflectometry to explore the coupling between NiO and YIG to understand the mechanism of the negative SMR. A weak uncompensated magnetic moment is observed in the NiO and the direction of this moment is perpendicular to YIG. Therefore, we infer that the spin axis of NiO is perpendicular to YIG. This result directly supports the explanation that the negative SMR results from the pure spin current reflected back by the NiO layer and the spin-flop coupling between NiO and YIG.