Solitary intraosseous neurofibroma in the mandible mimicking a cystic lesion: A case report and review of literature.

BACKGROUND: Neurofibromas are benign tumors of a neurogenic origin. If these tumors occur without any other signs of neurofibromatosis, they are classified as isolated neurofibromas. Neurofibromas in the oral cavity mostly occur within soft tissues, indicating that solitary intraosseous neurofibromas in the mandible are rare. Due to the absence of specific clinical manifestations, early diagnosis and treatment of these tumors are difficult to achieve. CASE SUMMARY: A 37-year-old female patient visited our hospital due to numbness and swelling of the gums in the right lower molar area that had persisted for half a month. The patient's overall condition and intraoral examination revealed no significant abnormalities. She was initially diagnosed with a cystic lesion in the right mandible. However, after a more thorough examination, the final pathological diagnosis was confirmed to be neurofibroma. Complete tumor resection and partial removal of the right inferior alveolar nerve were performed. As of writing this report, there have been no signs of tumor recurrence for nine months following the surgery. CONCLUSION: This case report discusses the key features that are useful for differentiating solitary intraosseous neurofibromas from other cystic lesions.

Preparation of Molybdenum Disulfide with Different Nanostructures and Its Adsorption Performance for Copper (â ¡) Ion in Water.

The environmental problems in the world are attracting increasing amounts of attention, and heavy metal pollution in the water has become one of the focuses of the ecological environment. Molybdenum disulfide (MoS2) has excellent adsorption performance because of its extremely high specific surface area and unique active site structure, which has attracted an increasing amount of attention in the field of heavy metal disposal in various types of water. In this paper, two sorts of MoS2 nanoparticles, spherical and lamellar, were synthesized by different chemical methods. Their morphology and structure were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), and a Raman spectrometer. The adsorption properties of two sorts of MoS2 nanoparticles for copper (Ⅱ) ions in water were investigated by changing the pH value, adsorption time, initial concentration of solution, adsorption temperature, etc. Finally, the adsorption mechanism was analyzed by kinetic, isothermal, and thermodynamic models. The results show that two microstructures of MoS2 nanoparticles can be used as efficient adsorption materials for removing heavy metal ions from water, although there are differences in adsorption capacity between them, which expands the theoretical basis of heavy metal adsorption in a water environment.

Ferroptosis and metabolic syndrome and complications: association, mechanism, and translational applications.

Metabolic syndrome is a medical condition characterized by several metabolic disorders in the body. Long-term metabolic disorders raise the risk of cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM). Therefore, it is essential to actively explore the aetiology of metabolic syndrome (MetS) and its comorbidities to provide effective treatment options. Ferroptosis is a new form of cell death that is characterized by iron overload, lipid peroxide accumulation, and decreased glutathione peroxidase 4(GPX4) activity, and it involves the pathological processes of a variety of diseases. Lipid deposition caused by lipid diseases and iron overload is significant in metabolic syndrome, providing the theoretical conditions for developing ferroptosis. Recent studies have found that the major molecules of ferroptosis are linked to common metabolic syndrome consequences, such as T2DM and atherosclerosis. In this review, we first discussed the mechanics of ferroptosis, the regulatory function of inducers and inhibitors of ferroptosis, and the significance of iron loading in MetS. Next, we summarized the role of ferroptosis in the pathogenesis of MetS, such as obesity, type 2 diabetes, and atherosclerosis. Finally, we discussed relevant ferroptosis-targeted therapies and raised some crucial issues of concern to provide directions for future Mets-related treatments and research.

In-situ construction of 3D hetero-structured sulfur-doped nanoflower-like FeNi LDH decorated with NiCo Prussian blue analogue cubes as efficient electrocatalysts for boosting oxygen evolution reaction.

At present, it is urgent for us to develop non-noble metal-based catalysts with abundant reserves and high efficiency towards oxygen evolution reaction (OER) in water electrolysis devices. Herein, cubic NiCo-Prussian blue analogue (PBA)/ flower-like FeNi layered double hydroxide (LDH) heterostructure was facilely in-situ formed on porous nickel foam (NF) via hydrothermal strategy coupled by subsequent sulfurizing treatment (named as S-FeNi LDH@PBA/NF), showing largely facilitated electron transfer over homogeneous counterpart. Also, we investigated the effects of different Fe/Ni feeding ratios on their catalytic properties in some detail. The as-prepared S-FeNi LDH@PBA/NF demonstrated the superior OER activity (e.g. only 243 mV of overpotential required for 50 mA cm-2) and stability. Accordingly, using the catalyst as anode, the home-assembled S-FeNi LDH@PBA/NF//Pt/C/NF electrolyzer exhibited small Tafel slope (83.1 mV dec-1) and ultra-stability, showing the potential feasibility in practical water electrolysis. This strategy provides a hopeful model to enhance the OER performance by effectively constructing advanced catalyst with promising heterostructure and optimal electronic structure.

One-step pyrolysis synthesis of nitrogen, manganese-codoped porous carbon encapsulated cobalt-iron nanoparticles with superior catalytic activity for oxygen reduction reaction.

Replacing precious metal catalysts with low-price and abundant catalysts is one of urgent goals for green and sustainable energy development. It is imperative yet challenging to search low-cost, high-efficiency, and long-durability electrocatalysts for oxygen reduction reaction (ORR) in energy conversion devices. Herein, three-dimensional low-cost Co3Fe7 nanoparticles/nitrogen, manganese-codoped porous carbon (Co3Fe7/N, Mn-PC) was synthesized with the mixture of dicyandiamide, cobalt (II) tetramethoxyphenylporphyrin (Co(II)TMOPP), hemin, and manganese acetate by one-step pyrolysis and then acid etching. The resultant Co3Fe7/N, Mn-PC exhibited excellent durability and prominent ORR activity with more positive onset potential (Eonset, 0.98 V) and half-wave potential (E1/2, 0.87 V) in 0.1 M KOH electrolyte, coupled with strong methanol resistance. The pyrolysis temperature and optimal balance of graphite with pyridine-nitrogen are of significance for the ORR performance. The prepared Co3Fe7/N, Mn-PC displayed excellent ORR performance over commercial Pt/C in the identical environment. It was ascribed to the uniform 3D architecture, Mn- and N-doping effects by finely adjusting the electronic structures, coupled with the synergistic catalytic effects of multi-compositions and multi-active sites. This work provides some constructive guidelines for preparation of low-cost and high-efficiency ORR electrocatalysts.

Mn, N, P-tridoped bamboo-like carbon nanotubes decorated with ultrafine Co2P/FeCo nanoparticles as bifunctional oxygen electrocatalyst for long-term rechargeable Zn-air battery.

Rational synthesis of cost-effectiveness, ultra-stable and high-efficiency bifunctional oxygen catalysts are pivotal for Zn-air batteries. Herein, fine Co2P/FeCo nanoparticles (NPs) anchored on Mn, N, P-codoped bamboo-like carbon nanotubes (Co2P/FeCo/MnNP-BCNTs) are constructed in the coexistence of melamine, poly(4-vinylpyridine) and adenosine-5'-diphosphate disodium salt (ADP) by convenient pyrolysis and follow-up acid treatment. The as-prepared catalyst exhibits the higher onset potential (Eonset = 0.97 V vs. RHE) and half-wave potential (E1/2 = 0.88 V vs. RHE) for oxygen reduction reaction (ORR), coupled with excellent oxygen evolution reaction (OER) with the lower overpotential of 324 mV at 10 mA cm-2. Notably, the home-made Zn-air battery delivers the greater peak power density of 220 mW cm-2, together with the outstanding cycling stability. The excellent performances of Co2P/FeCo/MnNP-BCNTs catalyst are mainly attributed to the highly conductive carbon nanotubes and the synergistic effects between carbon nanotubes and Co2P/FeCo NPs. This work offers a novel strategy to explore advanced bifunctional oxygen catalysts for high-efficiency metal-air batteries.

The steroid hormone 20-hydroxyecdysone counteracts insulin signaling via insulin receptor dephosphorylation.

The insulin receptor (INSR) binds insulin to promote body growth and maintain normal blood glucose levels. While it is known that steroid hormones such as estrogen and 20-hydroxyecdysone counteract insulin function, the molecular mechanisms responsible for this attenuation remain unclear. In the present study, using the agricultural pest lepidopteran Helicoverpa armigera as a model, we proposed that the steroid hormone 20-hydroxyecdysone (20E) induces dephosphorylation of INSR to counteract insulin function. We observed high expression and phosphorylation of INSR during larval feeding stages that decreased during metamorphosis. Insulin upregulated INSR expression and phosphorylation, whereas 20E repressed INSR expression and induced INSR dephosphorylation in vivo. Protein tyrosine phosphatase 1B (PTP1B, encoded by Ptpn1) dephosphorylated INSR in vivo. PTEN (phosphatase and tensin homolog deleted on chromosome 10) was critical for 20E-induced INSR dephosphorylation by maintaining the transcription factor Forkhead box O (FoxO) in the nucleus, where FoxO promoted Ptpn1 expression and repressed Insr expression. Knockdown of Ptpn1 using RNA interference maintained INSR phosphorylation, increased 20E production, and accelerated pupation. RNA interference of Insr in larvae repressed larval growth, decreased 20E production, delayed pupation, and accumulated hemolymph glucose levels. Taken together, these results suggest that a high 20E titer counteracts the insulin pathway by dephosphorylating INSR to stop larval growth and accumulate glucose in the hemolymph.

Different prognostic association of systolic blood pressure at different time points with postdischarge events in patients hospitalized for decompensated heart failure.

BACKGROUND: The association of systolic blood pressure (SBP) with mortality in heart failure (HF) patients is paradoxical, and the time points of baseline SBP are also different across prior studies. We hypothesized that the levels of SBP at admission and at discharge had different associations with postdischarge events. METHODS: The study population included patients hospitalized for decompensated HF in the Heart Failure Center of Fuwai Hospital from January 1, 2009 to December 31, 2014. The primary outcome was a composite of cardiovascular (CV) death and heart transplantation. Multivariate Cox proportional-hazards and restricted cubic spline analyses were used to assess the relationships between SBP at different time points and outcomes. RESULTS: In total, 2005 patients were included with a median follow-up of 48.4 months. The median age was 59 years, and 69.9% were male. Multivariate Cox analyses showed that compared with SBP < 105 mmHg, higher SBP at admission was associated with better long-term primary outcome (105-119 mmHg, HR = 0.764, P = 0.005; 120-134 mmHg, HR = 0.658, P < 0.001; ≥ 135 mmHg, HR = 0.657, P = 0.001). Patients whose discharge SBP was higher than 135 mmHg had a similar primary outcome as those with SBP < 105 mmHg (HR = 0.969, P = 0.867), and the results remained unchanged even after adjusting for admission SBP (HR = 1.235, P = 0.291). The results of restricted cubic spline analysis indicated similar associations. CONCLUSIONS: Lower but not higher SBP at admission is associated with more CV deaths/heart transplantations (a reverse J-shaped curve). In contrast, there is a U-shaped association between discharge SBP and CV mortality/heart transplantation.

Genome-wide profiling of Epstein-Barr virus integration by targeted sequencing in Epstein-Barr virus associated malignancies.

Rationale: Epstein-Barr virus (EBV) is associated with multiple malignancies with expression of viral oncogenic proteins and chronic inflammation as major mechanisms contributing to tumor development. A less well-studied mechanism is the integration of EBV into the human genome possibly at sites which may disrupt gene expression or genome stability. Methods: We sequenced tumor DNA to profile the EBV sequences by hybridization-based enrichment. Bioinformatic analysis was used to detect the breakpoints of EBV integrations in the genome of cancer cells. Results: We identified 197 breakpoints in nasopharyngeal carcinomas and other EBV-associated malignancies. EBV integrations were enriched at vulnerable regions of the human genome and were close to tumor suppressor and inflammation-related genes. We found that EBV integrations into the introns could decrease the expression of the inflammation-related genes, TNFAIP3, PARK2, and CDK15, in NPC tumors. In the EBV genome, the breakpoints were frequently at oriP or terminal repeats. These breakpoints were surrounded by microhomology sequences, consistent with a mechanism for integration involving viral genome replication and microhomology-mediated recombination. Conclusion: Our finding provides insight into the potential of EBV integration as an additional mechanism mediating tumorigenesis in EBV associated malignancies.

Atomically thin van der Waals tunnel field-effect transistors and its potential for applications.

Power dissipation is a crucial problem as the packing density of transistors increases in modern integrated circuits. Tunnel field-effect transistors (TFETs), which have high energy filtering provided by band-to-band tunneling (BTBT), have been proposed as an alternative electronics architecture to decrease the energy loss in bias operation and to achieve steep switching at room temperature. Very recently, the BTBT behavior has been demonstrated in van der Waals heterostructures by using unintentionally doped semiconductors. The reason of the BTBT formation is attributed to a significant band bending near the heterointerface, resulting in carrier accumulations. In this work, to investigate charge transport in type-III transistors, we adopted the same band-bending concept to fabricate van der Waals BP/MoS2 heterostructures. Through analyzing the temperature dependence of their electrical properties, we carefully ruled out the contribution of metal-semiconductor contact resistances and improved our understanding of carrier injection in 2D type-III transistors. The BP/MoS2 heterostructures showed both negative differential resistance and 1/f 2 current fluctuations, strongly demonstrating the BTBT operation. Finally, we also designed a TFET based on this heterostructure with an ionic liquid gate, and this TFET demonstrated an subthreshold slope can successfully surmount the thermal limit of 60 mV/decade. This work improves our understanding of charge transport in such layered heterostructures and helps to improve the energy efficiency of next-generation nanoscale electronics.

[Evaluation of continuous curvilinear buccal-cervical incision in combined radical resection of buccal cancer].

PURPOSE: To evaluate the clinical effect of continuous curvilinear buccal-cervical incision in combined radical resection of buccal cancer. METHODS: From January 2015 to December 2018, a total of 87 patients with buccal cancer were collected, of whom 42 underwent continuous curvilinear buccal-cervical incision (experimental group) and 45 underwent conventional cervical T shaped incision combined with a buccal incision (control group). Exposure of surgical filed in two groups was evaluated. The length of incision, duration of radical resection, and the incidence of postoperative complications were compared between two groups. The patients were followed-up for 7-43 months. Modified vancouver scar scale (VSS) and University of Washington Quality of Life (UW-QOL) were used to evaluate the postoperative scar and quality of life in both groups. Statistical analysis was performed on the data using SPSS 22.0 software package. RESULTS: The length of the incision in the experimental group was (36.40±5.08) cm, which was shorter than that of the control group (39.93±5.22) cm. Duration of combined radical resection in the experimental group was shorter than that of the control group. The incidence of neck complications in the experimental group was lower than that of the control group. The postoperative scar assessment and quality of life of the experimental group were better than that of the control group. The difference was statistically significant (P<0.05). There was no significant difference between the two groups in terms of the exposure of the surgical field, postoperative recurrence and metastasis rate. CONCLUSIONS: Continuous curvilinear buccal-cervical incision has good exposure of the surgical field and shorter duration of radical resection, which ensures en bloc resection of tumor and cervical lymph nodes. It limits the formation of skin cicatrix, reduces the occurrence of postoperative complications and results in a good aesthetic and functional effect, therefore it is a recommended incision for clinical practice.

[Concentrations and pollution assessment of mercury in farmland soil of Xinqiao Mining Area of Tongling, Anhui, China.] / é“œé™µæ–°æ¡¥çŸ¿åŒºå‘¨è¾¹å†œç”°åœŸå£¤æ±žå«é‡åˆ†å¸ƒç‰¹å¾åŠå ¶æ±¡æŸ“è¯„ä»·.

To investigate the effects of mining activities on mercury (Hg) enrichment in farmland soil, soil samples were collected from four villages (Xinjian Village, Yehu Village, Xinhu Village and Hucheng Village) in the vicinity of Xinqiao Mining Area, Tongling. Hg concentration was measured by atomic fluorescence spectrophotometer. The geo-accumulation index was used to evaluate the Hg pollution level of the soils. The results showed that average concentration of total Hg in farmland soil was (0.137±0.078) mg·kg-1, which exceeded the background value of soil Hg in Tongling area. The average concentration of Hg in four villages followed the order of Xinjian Village (0.221 mg·kg-1)>Xinhu Village (0.118 mg·kg-1)>Yehu Village(0.115 mg·kg-1)>Hucheng Village (0.096 mg·kg-1). Moreover, the average Hg concentration of different forms in Xinjian Village followed the order of residue (0.036 mg·kg-1) > alkali soluble (0.031 mg·kg-1) > hydrogen peroxide soluble (0.022 mg·kg-1)> acid soluble (0.020 mg·kg-1)> water soluble (0.012 mg·kg-1). The distance from the mining area was the main factor affecting the distribution of soil Hg concentration in farmlands. The contaminated Xinqiao River, to some degree, had exa-cerbated soil Hg pollution. Soil organic matter affected the accumulation and transformation of total Hg and hydrogen peroxide Hg in the farmlands. The order of the geo-accumulation index followed as Xinjian Village(1.559) >Xinhu Village(0.654) >Yehu Village(0.616) >Hucheng Village(0.356). The pollution level of farmland soil in Xinjian Village belonged to middle level of Hg pollution,which deserved more attention.

Ginsenoside 25-OCH3-PPD Promotes Activity of LXRs To Ameliorate P2X7R-Mediated NLRP3 Inflammasome in the Development of Hepatic Fibrosis.

Ginseng is widely used in energy drinks, dietary supplements, and herbal medicines, and its pharmacological actions are related with energy metabolism. As an important modulating energy metabolism pathway, liver X receptors (LXRs) can promote the resolving of hepatic fibrosis and inflammation. The present study aims to evaluate the regulation of 25-OCH3-PPD, a ginsenoside isolated from Panax ginseng, against hepatic fibrosis and inflammation in thioacetamide (TAA)-stimulated mice by activating the LXRs pathway. 25-OCH3-PPD decreases serum ALT/AST levels and improves the histological pathology of liver in TAA-induced mice; attenuates transcripts of pro-fibrogenic markers associated with hepatic stellate cell activation; attenuates the levels of pro-Inflammatory cytokines and blocks apoptosis happened in liver; inhibits NLRP3 inflammasome by affecting P2X7R activation; and regulates PI3K/Akt and LKB1/AMPK-SIRT1. 25-OCH3-PPD also facilitates LX25Rs and FXR activities decreased by TAA stimulation. 25-OCH3-PPD also decreases α-SMA via regulation of LXRs and P2X7R-NLRP3 in vitro. Our data suggest the possibility that 25-OCH3-PPD promotes activity of LXRs to ameliorate P2X7R-mediated NLRP3 inflammasome in the development of hepatic fibrosis.

Acanthoic acid suppresses lipin1/2 via TLR4 and IRAK4 signalling pathways in EtOH- and lipopolysaccharide-induced hepatic lipogenesis.

OBJECTIVES: In alcoholic liver disease, alcohol and lipopolysaccharide (LPS) are major stimulation factors of hepatic lipogenesis. Our objective was to determine the protective mechanism of acanthoic acid (AA) in EtOH- and LPS-induced hepatic lipogenesis. METHODS: HSC-T6 cells were treated with ethanol (200 mm) plus LPS (1 µg/ml) for 1 h, followed by AA (10 or 20 µm) for another 6 h. C57BL/6 mice were pretreated with of AA (20 and 40 mg/kg) or equal volume of saline and then exposed to three doses of ethanol (5 g/kg body weight) within 24 h. The mice were sacrificed at 6 h after the last ethanol dosing. KEY FINDINGS: Acanthoic acid significantly decreased the expressions of α-SMA, collagen-I, SREBP-1, and lipin1/2 induced, also decreased fat droplets caused by EtOH/LPS. AA treatment decreased the protein expressions of TLR4, CD14, IRAK4, TRAF3, p-TAK1 and NF-κB increased by EtOH/LPS on HSC cells. Results in vivo were consistent with results in vitro. CONCLUSIONS: Our data demonstrated that AA might modulate hepatic fibrosis and lipid deposition in HSC-T6 cell stimulated with ethanol combined with LPS by decreasing lipin1/2 via TLR4 and IRAK4 signalling pathways, and AA might be considered as a potential therapeutic candidate for alcoholic liver disease.

Nasopharyngeal carcinoma risk prediction via salivary detection of host and Epstein-Barr virus genetic variants.

Genetic susceptibility and Epstein-Barr virus (EBV) infection are important etiological factors in nasopharyngeal carcinoma (NPC). In this study, in southern China, where NPC is endemic, a single nucleotide polymorphism (SNP) in the EBV-encoded RPMS1 gene (locus 155391: G > A [G155391A]) and seven host SNPs (rs1412829, rs28421666, rs2860580, rs2894207, rs31489, rs6774494, and rs9510787) were confirmed to be significantly associated with NPC risk in 50 NPC cases versus 54 hospital-based controls with throat washing specimens and 1925 NPC cases versus 1947 hospital-based controls with buffy coat samples, respectively. We established a strategy to detect the NPC-associated EBV and host SNPs using saliva samples in a single test that is convenient, noninvasive, and cost-effective and displays good compliance. The potential utility of this strategy was tested by applying a risk prediction model integrating these EBV and host genetic variants to a population-based case-control study comprising 1026 incident NPC cases and 1148 controls. Receiver operating characteristic (ROC) curve analysis revealed an area under the curve of the NPC risk prediction model of 0.74 (95% CI: 0.71-0.76). Net reclassification improvement (NRI) analysis showed that inclusion of the EBV SNP significantly improved the discrimination ability of the model (NRI = 0.30, P < 0.001), suggesting the promising value of EBV characteristics for identifying high-risk NPC individuals in endemic areas. Taken together, we developed a promising NPC risk prediction model via noninvasive saliva sampling. This approach might serve as a convenient and effective method for screening the population with high-risk of NPC.

Acanthoic acid protectsagainst ethanol-induced liver injury: Possible role of AMPK activation and IRAK4 inhibition.

The aim of this study was to investigate the effects of acanthoic acid (AA) on the regulation of inflammatory response, lipid accumulation, and fibrosis via AMPK- IRAK4 signaling against chronic alcohol consumption in mice. Ethanol-induced liver injury was induced in male mice by Lieber-DeCarli diet for 28d. And mice in AA groups were gavaged with AA (20 or 40mg/kg) for 28d. AA treatment significantly decreased serum AST and TG, hepatic TG levels, serum ethanol and LPS levels compared with chronic ethanol administration. AA ameliorated histological changes, lipid droplets, hepatic fibrosis, and inflammation induced by ethanol. AA significantly increased the expressions of p-LKB1, p-AMPK, and SIRT1 caused by chronic ethanol administration, and attenuated the increasing protein expressions of IRAK1 and IRAK4.siRNA against AMPKα1 blocked AMPKα1 and increased IRAK4 protein expressions, compared with control-siRNA-transfected group, while AA treatment significantly decreased IRAK4 expressions compared with AMPKα1-siRNA-transfected group. AMPK-siRNA also blocked the decreased effect of AA on inflammatory factors. AA decreased over-expression of IRAK4 and inflammation under ethanol plus LPS challenge. AA recruited LKB1-AMPK phosphorylation and activated SIRT1 to regulate alcoholic liver injury, especially, inhibited IRAK1/4 signaling pathway to regulate lipid metabolism, hepatic fibrosis and inflammation caused by alcohol consumption.

Acanthoic Acid Can Partially Prevent Alcohol Exposure-Induced Liver Lipid Deposition and Inflammation.

Aims: The present study aims to detect the effect of acanthoic acid (AA) on alcohol exposure-induced liver lipid deposition and inflammation, and to explore the mechanisms. Methods: C57BL/6 mice were pretreated with single dose of AA (20 and 40 mg/kg) by oral gavage or equal volume of saline, and then exposed to three doses of ethanol (5 g/kg body weight, 25%, w/v) by gavage within 24 h. The mice were sacrificed at 6 h after the last ethanol dosing. Serum and hepatic indexes were detected by western blot, RT-PCR, and histopathological assay. AML-12 cells were pretreated with AA (5, 10, 20 µM), or AICAR (500 µM), GW3965 (1 µM), SRT1720 (6 µM), Nicotinamide (20 mM) for 2 h, respectively, and then following treated with EtOH (200 mM) and lipopolysaccharide (LPS) (10 ng/ml) for additional 48 h. Cell protein and mRNA were collected for western blot and RT-PCR. Cytokines interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) release were detected by ELISA assay. Results: It was found that AA significantly decreased acute ethanol-induced increasing of the serum ALT/AST, LDH, ALP levels, and hepatic and serum triglyceride levels, and reduced fat droplets accumulation in mice liver. AA significantly suppressed the levels of sterol regulatory element binding protein 1 (SREBP-1), cytochrome P4502E1 (CYP2E1), IL-1ß, and caspase-1 induced by ethanol. Furthermore, a significant decline of sirtuin 1 (Sirt1) and liver X receptors (LXRs) levels was observed in EtOH group, compared with normal group mice. And AA pretreatment increased the Sirt1 and LXRs levels, and also ameliorated phosphorylation of liver kinase B-1 (LKB-1), adenosine monophosphate-activated protein kinase (AMPK), acetyl CoA carboxylase (ACC) proteins, compared with EtOH group. However, the levels of peroxisome proliferator activated receptor -α or -γ (PPAR-α or PPAR-γ) induced by acute ethanol were reversed by AA. In EtOH/LPS cultivated AML-12 cells, AA decreased IL-1ß and TNF-α levels, lipid droplets, and SREBP-1 and CYP2E1 expressions, compared with EtOH/LPS treatment. AA also significantly increased protein expressions of Sirt1, p-LKB1, p-ACC, PPARα, and decreased protein expression of PPARγ, compared with EtOH/LPS treatment. Conclusion: Acanthoic acid can partially prevent alcohol exposure-induced liver lipid deposition and inflammation via regulation of LKB1/Sirt1/AMPK/ACC and LXRs pathways.

Potentiation of hepatic stellate cell activation by extracellular ATP is dependent on P2X7R-mediated NLRP3 inflammasome activation.

Purinergic receptor P2x7 (P2x7R) is a key modulator of liver inflammation and fibrosis. The present study aimed to investigate the role of P2x7R in hepatic stellate cells activation. Lipopolysaccharide (LPS) or the conditioned medium (CM) from LPS-stimulated RAW 264.7 mouse macrophages was supplemented to human hepatic stellate cells, LX-2 for 24h and P2x7R selective antagonist A438079 (10µM) was supplemented to LX-2 cells 1h before LPS or CM stimulation. In addition LX-2 cells were primed with LPS for 4h and subsequently stimulated for 30min with 3mM of adenosine 5'-triphosphate (ATP). A438079 was supplemented to LX-2 cells 10min prior to ATP. Directly treated with LPS on LX-2 cells, mRNA expressions of interleukin (IL)-1ß, IL-18 and IL-6 were increased, as well as mRNA expressions of P2x7R, caspase-1, apoptosis-associated speck-like protein containing CARD (ASC) and NOD-like receptor family, pyrin domain containing 3 (NLRP3) mRNA. LPS also increased α-smooth muscle actin (α-SMA) and type I collagen mRNA expressions, as well as collagen deposition. Interestingly treatment of LX-2 cells with LPS-activated CM exhibited the greater increase of above factors than those in LX-2 cells directly treated with LPS. Pretreatment of A438079 on LX-2 cells stimulated by LPS or LPS-activated CM both suppressed IL-1ß mRNA expression. LPS combined with ATP dramatically increased protein synthesis and cleavage of IL-1ß and its mRNA level than those in HSC treated with LPS or ATP alone. Additionally LX-2 cells primed with LPS and subsequently stimulated for 30min with ATP greatly increased mRNA and protein expression of caspase-1, NLRP3 and P2x7R, as well as liver fibrosis markers, α-SMA and type I collagen. These events were remarkably suppressed by A438079 pretreatment. siRNA against P2x7R reduced protein expression of NLRP3 and α-SMA, and suppressed deposition and secretion of type I collagen. The involvement of P2X7R-mediated NLRP3 inflammasome activation in IL-1ß production of HSC might contribute to ECM deposition and suggests that blockade of the P2x7R-NLRP3 inflammasome axis represents a potential therapeutic target to liver fibrosis.

Salidroside Regulates Inflammatory Response in Raw 264.7 Macrophages via TLR4/TAK1 and Ameliorates Inflammation in Alcohol Binge Drinking-Induced Liver Injury.

The current study was designed to investigate the anti-inflammatory effect of salidroside (SDS) and the underlying mechanism by using lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages in vitro and a mouse model of binge drinking-induced liver injury in vivo. SDS downregulated protein expression of toll-like receptor 4 (TLR4) and CD14. SDS inhibited LPS-triggered phosphorylation of LPS-activated kinase 1 (TAK1), p38, c-Jun terminal kinase (JNK), and extracellular signal-regulated kinase (ERK). Degradation of IκB-α and nuclear translocation of nuclear factor (NF)-κB were effectively blocked by SDS. SDS concentration-dependently suppressed LPS mediated inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein levels, as well as their downstream products, NO. SDS significantly inhibited protein secretion and mRNA expression of of interleukin (IL)-1ß and tumor necrosis factor (TNF)-α. Additionally C57BL/6 mice were orally administrated SDS for continuous 5 days, followed by three gavages of ethanol every 30 min. Alcohol binge drinking caused the increasing of hepatic lipid accumulation and serum transaminases levels. SDS pretreatment significantly alleviated liver inflammatory changes and serum transaminases levels. Further investigation indicated that SDS markedly decreased protein level of IL-1ß in serum. Taken together, these data implied that SDS inhibits liver inflammation both in vitro and in vivo, and may be a promising candidate for the treatment of inflammatory liver injury.

Upregulation of SIRT1-AMPK by thymoquinone in hepatic stellate cells ameliorates liver injury.

Thymoquinone (TQ) is a biologically active compound isolated from the seeds of Nigella sativa L. (Ranuculaceae). This study investigated the hepato-protective effect of TQ on liver injury through AMP-activated protein kinase (AMPK) signaling in hepatic stellate cells (HSCs). In vitro, TGF-ß time-dependently attenuated liver kinase B-1 (LKB1) and AMPK phosphorylation, which were blocked by pretreatment with TQ and AICAR (an activator of AMPK). TQ significantly inhibited collagen-Ι, α-SMA, TIMP-1 and enhanced MMP-13 expression, contributing to prevent TGF-ß-induced human HSCs activation. Moreover, TQ induced peroxisome proliferator activated receptor-γ (PPAR-γ) expression, which was inhibited by genetic deletion of AMPK. In vivo, C57BL/6 mice were fed with ethanol diet for 10 days, then administering a single dose of ethanol (5g/kg body weight) via gavage. TQ (20 or 40mg/kg) were given by gavage every day. TQ attenuated the increases in serum aminotransferase and hepatic triglyceride in mice fed with ethanol, while significantly activated LKB1 and AMPK phosphorylation. In addition, TQ enhanced the sirtuin 1 (SIRT1) expression. In conclusion, we demonstrate that AMPK pathway is a key therapeutic target for controlling liver injury and TQ confers hepato-protection against TGF-ß-induced the activation of HSCs and ethanol-induced liver injury.