[Retracted] Inhibition of RKIP aggravates thioacetamide­induced acute liver failure in mice.

[This retracts the article DOI: 10.3892/etm.2018.6542.].

Impact of Monascus purpureus fermentation on antioxidant activity, free amino acid profiles and flavor properties of kelp (Saccharina japonica).

This study evaluated the efficacy of Monascus purpureus fermentation on Saccharina japonica (SJ). Healthy substances and antioxidant activity of fermented SJ (FSJ) were determined. Results showed that fermentation caused the release of phenolic compounds and flavonoids, which resulted in the enhancement of antioxidant activity. Essential amino acids and γ-aminobutyric acid also greatly accumulated in FSJ. Sensory evaluation and gas chromatography-ion mobility spectrometry (GC-IMS) were used to evaluate flavor properties of FSJ. A lexicon consisted of 24 descriptors was established for SJ and FSJ, of which 14 descriptors were regarded as odor attributes. A total of 46 volatile compounds were identified by GC-IMS and showed positive correlation with odor attributes. Fifteen volatile compounds were screened as key compounds, tricarboxylic acid cycle, embden-meyerhof-parnas and amino acid catabolism were main formation metabolisms of them. Advanced properties of FSJ indicated that fermentation is a promising approach for the production of SJ food.

Synergistic Approach toward Erbium-Passivated Triple-Anion Organic-Free Perovskite Solar Cells with Excellent Performance for Agrivoltaics Application.

All-inorganic perovskite solar cells (IPSCs) have gained massive attention due to their less instability against common degradation factors (light, heat, and moisture) than their organic-inorganic hybrid counterparts. Inorganic perovskites bear a general formula of CsPbX3 (X = Cl, I, Br). The mixed halide CsPbIBr2 perovskite possesses an intermediate band gap of 2.03 eV with enhanced stability, which is still available for photovoltaic applications and the research focus of this work. We present a synergistic approach of pre-heated solution dropping with inorganic additive inclusion to deposit the organic-free triple anion CsPbIBr2 PSC. Erbium (Er)-passivated triple-anion CsI(PbBr2)0.97(ErCl3)0.03 IPSCs with inorganic carrier selective layers (CTLs), that is, organic-free, are fabricated with enhanced carrier diffusion length and crystalline grain size while lessening the grain boundaries near perovskite active layer (PAL)-bulk/carrier selective interfaces. As a result, the trap-state densities within the perovskite bulk were suppressed with stabilized CTL/PAL interfaces for smooth and enhanced carrier transportation. Therefore, for the first time, we contradict the common belief of VOC loss due to halide segregation, as a nice VOC of about 1.34 V is achieved for an organic-free IPSC through enriching initial radiative efficiency, even when halide segregation is present. The optimized organic-free IPSC yielded a power conversion efficiency of 11.61% and a stabilized power output of 10.72%, which provides the potential opportunity to integrate into agrivoltaics (AgV) projects.

First-principles study on the strain-mediated g-C3N4/blue phosphorene heterostructures for promising photocatalytic performance.

Well-designed two-dimensional heterogeneous photocatalysts have attracted significant attention due to the enhancement in visible-light absorption and effective charge separation. In this paper, the electronic and optical properties of g-C3N4/BlueP (blue phosphorene) heterojunction under varying strains were investigated systematically by first-principles calculations. The results showed that the type transformation of g-C3N4/BlueP heterojunction can be achieved by suitable biaxial strain. The CBM was found to be composed of g-C3N4as electron acceptor, while the VBM was contributed by BlueP as electron donor which solved the problem of high electron-hole recombination of type-I heterostructures. The band gap and band edge alignment under -6% to -8% compressive biaxial strain could satisfy the REDOX (reduction-oxidation) potential of photolysis water. A wide optical response range and good absorbance were also observed for the heterostructure under strain, which improved the solar utilization rate compared with individual g-C3N4and BlueP.

Methyl helicterilate ameliorates alcohol-induced hepatic fibrosis by modulating TGF-ß1/Smads pathway and mitochondria-dependent pathway.

This study aimed to investigate the effect and underlying mechanism of Methyl helicterilate from Helicteres angustifolia (MHHA) on alcohol-induced hepatic fibrosis. The results showed that MHHA treatment markedly alleviated alcohol-induced liver injury and notably reduced collagen deposition in liver tissue. It significantly enhanced the activity of alcohol dehydrogenase and aldehyde dehydrogenase. Moreover, MHHA treatment markedly decreased the content of inflammatory cytokines, alleviated collagen accumulation, and inhibited the expression of TGF-ß1 and Smad2/3 in liver tissue. The experiments in cells showed that MHHA significantly inhibited HSC activation by blocking TGF-ß1/Smads signaling pathway. Additionally, it notably induced HSC apoptosis by modulating the mitochondria-dependent pathway. The present study demonstrates that MHHA treatment significantly ameliorates alcoholic hepatic fibrosis and the underlying mechanism may be ascribed to the inhibition of the TGF-ß1/Smads pathway and regulation of the mitochondria-mediated apoptotic pathway.

Methyl helicterate inhibits hepatic stellate cell activation through downregulating the ERK1/2 signaling pathway.

The present study was to investigate the inhibitory effect of methyl helicterate (MH) on hepatic stellate cells (HSC-T6), primarily elucidating the underlying mechanism of MH against liver fibrosis. HSC-T6 cells were activated by platelet-derived growth factor (PDGF) stimulation, and then the effects of MH on cell viability, cytomembrane integrity, colony, migration, apoptosis, and cell cycle were detected. Moreover, the regulative mechanism of MH on HSCs was investigated by detecting the activation of the extracellular signal-regulated kinase (ERK1/2) signaling pathway. The results showed that MH significantly inhibited HSC-T6 cell viability and proliferation in a concentration-dependent manner. It notably promoted the release of lactate dehydrogenase, destroying cell membrane integrity. MH also markedly inhibited HSC-T6 cell clonogenicity and migration. Moreover, MH treatment significantly induced cell apoptosis and arrested cell cycle at the G2 phase. The further study showed that MH inhibited the expression of ERK1, ERK2, c-fos, c-myc, and Ets-1, blocking the ERK1/2 pathway. In conclusion, this study demonstrates that MH significantly inhibits HSC activation and promotes cell apoptosis via downregulation of the ERK1/2 signaling pathway.

Methyl helicterte ameliorates liver fibrosis by regulating miR-21-mediated ERK and TGF-ß1/Smads pathways.

Methyl helicterate (MH) has been reported to have protective effects against CCl4-induced hepatic injury and fibrosis in rats, but its protective mechanism, especially on hepatic stallete cells (HSCs), remains unclear. Recently, our pilot experiment showed that MH could inhibit miR-21 expression in HSC-T6 cells, suggesting that miR-21 may be one of the targets of MH to intervene liver fibrosis. To verify the hypothesis, the present study would focus on the regulatory effect of MH on the miR-21-mediated ERK and TGF-ß1/Smads pathways. Briefly, rats were intraperitoneally injected with 0.5 ml porcine serum (PS) twice a week for 24 weeks to induce liver fibrosis, and meanwhile, the rats were treated with MH from weeks 16 to 24. In vitro experiment, miR-21 expression in HSC-T6 cells was up- or down-regulated using lentiviral transfection assay. Collagen accumulation, inflammatory cytokines, cell apoptosis, miR-21 expression, and activation of the ERK and TGF-ß1/smad2/3 pathways were then assessed. The results showed that MH treatment markedly alleviated PS-induced liver injury, as evidenced by the attenuation of histopathological changes and the decrease in serum alanine and aspartate aminotransferases activity. MH significantly decreased the content of inflammatory cytokines and recruited the anti-oxidative defense system. Moreover, MH treatment significantly decreased miR-21 expression and inhibited the activation of the ERK and TGF-ß1/smad2/3 pathways in liver tissues. In vitro experiments showed that MH strongly inhibited HSC-T6 cell activation and reduced collagen accumulation. Interestingly, miR-21 overexpression significantly promoted HSC-T6 cell proliferation, reduced HSC apoptosis, and increased collagenation, while these abnormal changes induced by miR-21overexpression were significantly reversed by MH treatment. Furthermore, miR-21 overexpression notably activated the ERK and TGF-ß1/Smads pathways via repressing SPRY2 and Smad7 expression respectively, however, these effects were largely abolished by MH treatment. In conclusion, our study demonstrates that MH significantly alleviates PS-induced liver injury and fibrosis by inhibiting miR-21-mediated ERK and TGF-ß1/Smads pathways.

Methyl Helicterate Inhibits Hepatic Stellate Cell Activation Through Modulation of Apoptosis and Autophagy.

BACKGROUND/AIMS: Activated hepatic stellate cells (HSCs) are the major source of extracellular matrix (ECM). Therefore inhibiting HSC activation is considered as an effective strategy to inhibit the process of liver fibrosis. This study aimed to investigate the underlying mechanism of methyl helicterate (MH) isolated from Helicteres angustifolia on the activation of HSCs. METHODS: HSC-T6 cells were treated with various concentration of MH and autophagy was inhibited by 3-Methyl adenine (3-MA) or RNA interference. Cell viability was observed by MTT assay and cell colony assay. Cell cycle and apoptosis were analyzed using flow cytometry. Autophagic vacuoles were observed by transmission electron microscopy and monodansyl cadaverine (MDC) staining. Moreover, autophagy-related genes and proteins were detected using real-time PCR and Western blot assays, respectively. RESULTS: MH significantly inhibited HSC activation, as evidenced by the inhibition of cell viability, colony formation and the expression of α-SMA and collagen I. MH caused cell cycle arrest in G2/M phase. Moreover, MH significantly induced apoptosis through regulating the mitochondria-dependent pathway and the activity of caspases. MH treatment significantly increased lysosomes and autophagosomes, and enhanced the formation of autophagic vacuoles and autophagic flux. Interestingly, inhibiting autophagy by 3-MA or RNA interference abolished the ability of MH in inhibiting HSC activation. On the other hand, induction of autophagy promoted MH-induced HSC apoptosis. Further study showed that MH-induced HSC apoptosis and autophagy was mediated by the JNK and PI3K/Akt/mTOR pathways. CONCLUSION: Our results demonstrate that MH-induced HSC apoptosis and autophagy may be one of the important mechanisms for its anti-fibrosis effect.

Inhibition of RKIP aggravates thioacetamide-induced acute liver failure in mice.

Accumulating evidence has indicated that Raf kinase inhibitor protein (RKIP) is involved in several intracellular signaling pathways; its abnormal expression is associated with tumor progression and metastasis in several human neoplasms. However, the role of RKIP in acute liver injury has remained elusive. In the present study, acute liver failure was induced by thioacetamide in mice, and locostatin was used to interfere with RKIP expression. It was found that RKIP expression was significantly inhibited by locostatin. Down-regulation of RKIP expression resulted in severe liver injury and extensive release of alanine aminotransferase and aspartate aminotransferase. In addition, reduced RKIP expression significantly enhanced the levels of reactive oxygen species and the content of pro-inflammatory factors such as tumor necrosis factor-α as well as interleukin-6 and -1ß, and decreased the levels of nuclear factor E2-related factor-2 and heme oxygenase-1. Furthermore, down-regulation of RKIP promoted the activation of the nuclear factor-κB and extracellular signal-regulated kinase signaling pathways. In conclusion, the present study indicates an inverse correlation between RKIP level and the degree of hepatic injury, that is, a decrease in RKIP expression may exacerbate acute liver failure.

Who, What and Where (WWW) Problems in Scientific Communities.

The results of the National Higher Education Entrance Examination (Gaokao, in Chinese) have a life-long effect on most Chinese by labeling them clever or not. Some of the following rules of the Gaokao enhance the damage, for example, the rule of Who, What and Where. In general, Who you are and What you have done are of secondary importance, but Where you graduated from, especially the college of first-record is the most important, but discriminatory criterion in the recruitment courses of most of scientific communities and social organizations in China.

Trolline Ameliorates Liver Fibrosis by Inhibiting the NF-κB Pathway, Promoting HSC Apoptosis and Suppressing Autophagy.

BACKGROUND/AIMS: Previous studies have shown that trolline possesses various forms of pharmacological activity, including antibacterial and antiviral potency. The present paper addressed the putative hepatoprotective effects of trolline. METHODS: Rats received 2 ml/kg CCl4 (mixed 1: 1 in peanut oil) intragastrically twice a week for 8 weeks to induce hepatic fibrosis. The animals were then treated with trolline for additional 4 weeks. Liver pathology and collagen accumulation were observed by hematoxylin-eosin and Masson's trichrome staining, respectively. Serum transaminase activity and collagen-related indicator level were determined by commercially available kits. NF-κB pathway activation was also examined. Moreover, the effects of trolline on hepatic stellate cell (HSC-T6) apoptosis, mitochondrial membrane potential (MMP), and autophagy were assessed. RESULTS: Trolline significantly alleviated CCl4-induced liver injury and notably reduced the accumulation of collagen in liver tissues. Trolline treatment also markedly decreased inflammatory cytokines levels by inhibiting the NF-κB pathway. Trolline strongly inhibited HSC-T6 activation and notably induced cell apoptosis by modulating the Bax/Bcl-2 ratio, caspase activity, and MMP. Moreover, trolline significantly inhibited HSC-T6 autophagy, as evidenced by the decrease in the formation of autophagic vacuoles and the number of autophagosomes, by regulating the expression levles of LC3, Beclin-1, P62, Atg 5 and 7. CONCLUSION: Our study demonstrates that trolline ameliorates liver fibrosis, possibly by inhibiting the NF-κB pathway, promoting HSCs apoptosis and suppressing autophagy.

[Knockdown of Raf kinase inhibitor protein promotes the proliferation of LX-2 human hepatic stellate cells].

Objective To investigate the role of Raf kinase inhibitor protein (RKIP) in the proliferation of LX-2 human hepatic stellate cells. Methods The recombinant plasmid siRNA-RKIP was transfected into LX-2 cells. Five days later, the stably transfected cells were screened and cultured. MTT assay was used to detect cell proliferation after RKIP was silenced. Cell apoptosis and cell cycle distribution were evaluated by flow cytometry. The expressions of α-smooth muscle actin (α-SMA) and collagen type 1 (Col1) mRNA were detected by quantitative real-time PCR. The expressions of RKIP, α-SMA, Col1 and extracellular signal-regulated kinases/mitogen-activated protein kinase (ERK/MAPK) signaling pathway related proteins were assessed by Western blot analysis. Results Compared with the control group, knockdown of RKIP significantly induced LX-2 cell proliferation, reduced cell apoptosis, raise cell number in G2, and increased the proteins and mRNA expressions of Col1 and α-SMA. Moreover, low-expression of RKIP significantly enhanced the phosphorylation of ERK/MAPK. Conclusion Knockdown of RKIP promotes LX-2 cell proliferation; its mechanism is related to the activation of ERK/MAPK signaling pathway.

Didymin ameliorates hepatic injury through inhibition of MAPK and NF-κB pathways by up-regulating RKIP expression.

A flavone was isolated from Origanum vulgare and identified as didymin (O. vulgare didymin, OVD). The protective effect and mechanism of OVD on acute liver injury was then assessed in vivo and in vitro. Our results showed that OVD significantly alleviated CCl4-induced liver injury in mice and markedly decreased serum ALT and AST activities. OVD treatment significantly reduced CYP2E1 activity, lipid peroxidation level, ROS generation, NO production and pro-inflammatory cytokines (such as TNF-α, IL-6 and IL-1ß) in liver tissues and RAW 264.7 cells, but enhanced the hepatic antioxidative enzymes activities. Further study showed that OVD significantly inhibited the NF-κB and MAPK pathways. Interestingly, OVD notably enhanced Raf kinase inhibitor protein (RKIP) expression, and the effects of OVD on histological changes, oxidative stress and inflammation was largely abolished by the RKIP specific inhibitor locostatin. Our findings indicate that OVD can ameliorate CCl4-induced liver injury, which may be ascribed to its radical scavenging action, antioxidant activity, and modulation of MAPK and NF-κB signaling pathways.

Didymin induces apoptosis through mitochondrial dysfunction and up-regulation of RKIP in human hepatoma cells.

In the present study, a flavonoid was isolated from Origanum vulgare and identified as didymin. The effect and mechanism of O. vulgare didymin (OVD) on human HepG2 liver carcinoma cell was then assessed. Our results showed that OVD strongly inhibited the viability, clonogenicity and migration of HepG2 cells. OVD significantly induced apoptosis and induced cell cycle arrest at G2/M phase by regulating cyclin B1, cyclin D1 and CDK4. The anti-proliferative and pro-apoptotic effects were associated with changes in the Bcl-2/Bax ratio and induction of caspase-mediated apoptosis. Moreover, OVD attenuated the mitochondrial membrane potential, accompanied by the release of cytochrome c. In addition, OVD inhibited the ERK/MAPK and PI3K/Akt pathways by increasing the level of Raf kinase inhibitor protein (RKIP). Our study indicates that OVD induces apoptosis against of HepG2 cells through mitochondrial dysfunction and inactivation of the ERK/MAPK and PI3K/Akt pathways by up-regulating RKIP.

Didymin Alleviates Hepatic Fibrosis Through Inhibiting ERK and PI3K/Akt Pathways via Regulation of Raf Kinase Inhibitor Protein.

BACKGROUND: Didymin has been reported to have anti-cancer potential. However, the effect of didymin on liver fibrosis remains illdefined. METHODS: Hepatic fibrosis was induced by CCl4 in rats. The effects of didymin on liver pathology and collagen accumulation were observed by hematoxylin-eosin and Masson's trichrome staining, respectively. Serum transaminases activities and collagen-related indicators levels were determined by commercially available kits. Moreover, the effects of didymin on hepatic stellate cell apoptosis and cell cycle were analyzed by flow cytometry. Mitochondrial membrane potential was detected by using rhodamine-123 dye. The expression of Raf kinase inhibitor protein (RKIP) and the phosphorylation of the ERK/MAPK and PI3K/Akt pathways were assessed by Western blot. RESULTS: Didymin significantly ameliorated chronic liver injury and collagen deposition. It strongly inhibited hepatic stellate cells proliferation, induced apoptosis and caused cell cycle arrest in G2/M phase. Moreover, didymin notably attenuated mitochondrial membrane potential, accompanied by release of cytochrome C. Didymin significantly inhibited the ERK/MAPK and PI3K/Akt pathways. The effects of didymin on the collagen accumulation in rats and on the biological behaviors of hepatic stellate cells were largely abolished by the specific RKIP inhibitor locostatin. CONCLUSION: Didymin alleviates hepatic fibrosis by inhibiting ERK/MAPK and PI3K/Akt pathways via regulation of RKIP expression.

Raf Kinase Inhibitory Protein Down-Expression Exacerbates Hepatic Fibrosis In Vivo and In Vitro.

BACKGROUND/AIMS: Raf kinase inhibitory protein (RKIP) is closely associated with numerous tumors and participates in their development through regulating the growth, apoptosis, invasion and metastasis of tumor cells. However, the role of RKIP in chronic liver injury and particularly in liver fibrosis is still unclear. METHODS: In the present study, hepatic fibrosis was induced by porcine serum (PS) in rats and primary hepatic stellate cells (HSCs) were isolated from rat livers. Moreover, locostatin was used to interfere with RKIP expression. RESULTS: RKIP expression was significantly inhibited by locostatin in both liver tissues of rats and primary HSCs. Down-regulating RKIP expression resulted in serious liver injury, extensive accumulation of collagen, and significant increase in the levels of ALT, AST and TNF-α during liver fibrosis in rats. Moreover, down-regulating RKIP significantly promoted HSCs proliferation and colony formation in vitro. Reduced RKIP significantly increased the production of collagen and the level of α-SMA as well as the expression of MMP-1 and MMP-2 in both liver tissues and primary HSCs. Furthermore, down-regulating RKIP promoted the activation of the ERK and TLR4 signaling pathways. CONCLUSION: Our findings clearly indicate an inverse correlation between RKIP level and the degree of the liver injury and fibrosis. The decrease in RKIP expression may exacerbate chronic liver injury and liver fibrosis.

Calculation of exchange integrals and Curie temperature for La-substituted barium hexaferrites.

As the macro behavior of the strength of exchange interaction, state of the art of Curie temperature Tc, which is directly proportional to the exchange integrals, makes sense to the high-frequency and high-reliability microwave devices. Challenge remains as finding a quantitative way to reveal the relationship between the Curie temperature and the exchange integrals for doped barium hexaferrites. Here in this report, for La-substituted barium hexaferrites, the electronic structure has been determined by the density functional theory (DFT) and generalized gradient approximation (GGA). By means of the comparison between the ground and relative state, thirteen exchange integrals have been calculated as a function of the effective value Ueff. Furthermore, based on the Heisenberg model, the molecular field approximation (MFA) and random phase approximation (RPA), which provide an upper and lower bound of the Curie temperature Tc, have been adopted to deduce the Curie temperature Tc. In addition, the Curie temperature Tc derived from the MFA are coincided well with the experimental data. Finally, the strength of superexchange interaction mainly depends on 2b-4f1, 4f2-12k, 2a-4f1, and 4f1-12k interactions.