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Two-dimensional spintronics has become a hot topic in recent years due to its advantages and potential in manipulating electron spins. In this paper, the electronic structures and magnetic properties of the Janus NbSSe monolayer are calculated using first-principles and Monte Carlo methods. Our study shows that the ground state of the material is a ferromagnetic metal. Under carrier doping, it undergoes a second-order phase transition from metal to half-metal, achieving 100% spin polarization, and enhancing or weakening ferromagnetic coupling. The value of the magnetocrystalline anisotropy energy is 570.96 μeV, and doping with an appropriate concentration of holes can transform the easy magnetization axis from in-plane to out-of-plane. Since the out-of-plane mirror symmetry is broken, we study the charge changes in the layer under the action of an external electric field. Due to the combined action of the external electric field and the built-in electric field, the layer exhibits a unique charge transfer mode. It is predicted that the Curie temperature of the material is about 156 K. When doped with 4.01 × 1013 cm−2 (0.04 holes per atom) concentration holes, the Curie temperature can reach about 350 K, indicating that the Curie temperature of the material can be reasonably controlled by regulating the carrier concentration. The coercive force calculated from the hysteresis loop is 0.01 T, and its hysteresis loss is low, showing its response to the external magnetic field. All of the above results indicate the application potential of this material in spin-electronic devices. [ABSTRACT FROM AUTHOR]

High-performance and stable spintronic devices have garnered considerable attention in recent years. Based on first-principle and Monte Carlo calculations, we demonstrate that under reasonable carrier doping, H-VSe2 exhibits 100% spin polarization, a magnetic anisotropy energy of 581 μeV, a tunable easy-axis, and a Curie temperature of 330 K. Moreover, Dzyaloshinskii–Moriya interactions in H-VSe2 and magnetic hysteresis loops are determined theoretically for the first time, which provides more precise and comprehensive descriptions of its magnetic properties under finite temperatures and external magnetic field. This work suggests that H-VSe2 is a powerful candidate for spintronic devices, and it provides solid theoretical support for future experiments. [ABSTRACT FROM AUTHOR]

Investigating high-performance and stable spintronics devices has been a research hotspot in recent years. In this paper, we employed first-principles methods and Monte Carlo (MC) simulations to explore the structure, electronic, and magnetic properties of monolayer NbSe2, as well as its behavior under carrier concentration modulation. The research on the electronic structure reveals that by introducing an appropriate amount of holes, the material can undergo a transition from metal to a half-metal state, achieving 100% high spin polarization. Investigation of magnetic crystalline anisotropy shows that the magnetic crystal anisotropy energy of 1210 μeV in out-of-plane is beneficial to maintain ferromagnetic order at high temperatures. In addition, doping with suitable carriers can effectively enhance or strengthen the ferromagnetic coupling in NbSe2 so that the magnetization easy axis is shifted. This reveals the potential application prospects of NbSe2 in electronically controlled spintronic devices. Analysis of the Fermi surface shows that both holes and electron doping increase the Fermi velocity of the material. The effect of hole doping is particularly significant, indicating its potential application in Fermi velocity engineering. Under the theoretical framework of the extended two-dimensional Ising model, based on MC simulation, the Curie temperature (TC) of NbSe2 is predicted to be 162 K. The effects of carrier concentration and the magnetic field on the magnetic and thermal properties of monolayer NbSe2 are simulated. The results show that appropriately increasing the hole doping concentration and magnetic field is conducive to obtaining ferromagnetic half-metallic materials with TC higher than room temperature, which provides theoretical support for experimental preparation. [ABSTRACT FROM AUTHOR]

Objective: This study aims to evaluate the risk stratification among elderly Nasopharyngeal carcinoma (NPC) patients (≥60 years old) and select the beneficiaries from concurrent chemotherapy (CCRT) combined with induction chemotherapy (IC). Materials and Methods: A total of 909 elderly non‐metastatic NPC patients treated with cisplatin‐based CCRT or IC + CCRT between January 2007 and December 2016 were included. Prognostic nomograms were generated according to clinical characteristics and serum biomarkers. The survival outcomes of patients treated with CCRT versus IC + CCRT were compared in three well‐matched risk groups (high, medium, and low risk) after PSM analysis. Benefit of IC in people older or younger than 70 years and effect of different IC regimens and cycles on prognosis were analyzed. Results: Nomograms of overall survival (OS) (C‐index: 0.64, 95% CI, 0.61–0.89) and disease special survival (DSS) (C‐index: 0.65, 95% CI, 0.62–0.71) showed good prognostic accuracy. The nomogram for DSS included variables of age, gender, ACE, EBV DNA, N stage, and T stage. OS included variables of age, smoking history, ACE, ALB, EBV DNA, N stage, and T stage. The corresponding 5‐year OS rates of high, medium and low risk groups were 87.4%, 82.2%, and 60.9%, respectively (p < 0.001), while the 5‐year DSS rates were 92.2%, 84.3%, and 69.0%, respectively (p < 0.001). In the high risk group, IC + CCRT led to significantly higher 5‐year OS and DSS rate compared with CCRT (5‐year OS rate, 73.5% versus 51.8%, p = 0.006; 5‐year DSS rate, 81.4% versus 61.3%, p = 0.002). While in the medium and low risk groups, OS and DSS were not significantly different (OS: p = 0.259, 0.186; DSS: p = 0.29, 0.094). Subgroup analysis showed in the high risk group, only people younger than 70 years old could benefit from IC. TPF and IC cycles of three could lead to the best survival results. Conclusion: Compared with CCRT, OS, and DSS among high risk elderly patients were significantly improved by the addition of IC in patients younger than 70 years old. TPF and three IC cycles were recommended. [ABSTRACT FROM AUTHOR]

Purpose: Using real-world evidence, this study aimed to identify elderly nasopharyngeal carcinoma (NPC) patients who would benefit from chemotherapy.Methods and Materials: 1714 elderly NPC patients between April 2007 and December 2017 were identified. Recursive partitioning analysis (RPA) was used to generate risk-stratified outcomes. Prognostic factors were performed for individual comparisons of different risk groups to assess chemotherapy benefits.Results: The median follow-up was 59.3 (0.39-170.09) months. Epstein Barr virus (EBV) DNA and T stage were included in the RPA-generated risk stratification, categorizing patients into a good-prognosis group (EBV DNA ≤ 4000 copies/mL & T1-2), and a poor-prognosis group (EBV DNA ≤ 4000 copies/mL & T3-4 and EBV DNA > 4000 copies/mL & any T). Overall survival (OS) was significantly higher in the good-prognosis group compared with the training set (HR = 0.309, 95% CI 0.184-0.517; P < 0.001), and validated in the testing set (HR = 0.276, 95% CI 0.113-0.670; P = 0.002). In the poor-prognosis group, a significantly improved OS for chemoradiotherapy (CRT) compared with RT alone was observed (HR = 0.70, 95% CI 0.55-0.88; P = 0.003). Patients who received induction chemotherapy (IC) + concurrent chemoradiotherapy (CCRT) and CCRT had a significantly improved OS compared with RT alone (IC + CCRT vs. RT alone: P = 0.002; CCRT vs. RT alone: P = 0.008) but not in the IC + RT group (P = 0.306). The 5-year OS for CRT versus RT-alone with ACE-27 scores of 0, 1 and 2 were 76.0% versus 70.0% (P = 0.014), 80.5% versus 68.2% (P = 0.150) and 58.5% versus 62.2% (P = 0.490), respectively; for those aged 60-64, 65-70 and ≥ 70 years old they were 80.9% versus 75.9% (P = 0.068), 73.3% versus 63.4% (P = 0.270) and 64.8% versus 67.1% (P = 0.820), respectively.Conclusions: For elderly NPC patients a simple screening cutoff for chemotherapy beneficiaries might be EBV DNA < 4000 copies/ml & T3-4 and EBV DNA ≥ 4000 copies/ml & any T, but not for those > 70 years old and with an ACE-27 score > 1. IC + CCRT and CCRT were effective forms of chemotherapy. [ABSTRACT FROM AUTHOR]

Purpose. To quantify the long-term evaluation of optic chiasma (OC) and/or optic nerve(s) (ONs) and to develop predictive models for radiation-induced optic neuropathy (RION) in nasopharyngeal carcinoma after intensity-modulated radiotherapy (IMRT). Methods and Materials. A total of 3,662 patients' OC/ONs with full visual acuity and dosimetry data between 2010 and 2015 were identified. Critical dosimetry predictors of RION were chosen by machine learning and penalized regression for survival. A nomogram containing dosimetry and clinical variables was generated for predicting RION-free survival. Results. The median follow-up was 71.79 (2.63–120.9) months. Sixty-six eyes in 51 patients (1.39%) developed RION. Two patients were visual field deficient, and 49 patients had visual acuity of less than 0.1 (20/200). The median latency time was 36 (3–90) months. The 3-, 5-, and 8-year cumulative incidence of RION was 0.78%, 1.19%, and 1.97%, respectively. Dmax was the most critical dosimetry variable for RION (AUC: 0.9434, the optimal cutoff: 64.48 Gy). Patients with a Dmax ≥64.48 Gy had a significantly higher risk of RION (HR = 102.25; 95%CI, 24.86–420.59; P < 0.001). Age (>44 years) (HR = 2.234, 95% CI = 1.233–4.051, p = 0.008), advanced T stage (T3 vs. T1-2: HR = 7.516, 95% CI = 1.725–32.767, p = 0.007 ; T4 vs. T1-2: HR = 37.189, 95% CI = 8.796–157.266, P < 0.001), and tumor infiltration/compression of the OC/ONs (HR = 4.572, 95% CI = 1.316–15.874, p = 0.017) were significant clinical risk factors of RION. A nomogram comprising age, T stage, tumor infiltration/compression of the OC/ON, and Dmax significantly outperformed the model, with only Dmax predicting RION (C-index: 0.916 vs. 0.880, P < 0.001 in the training set; 0.899 vs. 0.874, P = 0.038 in the test set). The nomogram-defined high-risk group had a worse 8-year RION-free survival. Conclusions. In the IMRT era, Dmax <60 Gy is safe and represents an acceptable dose constraint for most NPC patients receiving IMRT. A reasonable trade-off for selected patients with unsatisfactory tumor coverage due to proximity to the optic apparatus would be Dmax <65 Gy. Caution should be exercised when treating elderly and advanced T-stage patients or those with tumor infiltration/compression of the OC/ON. Our nomogram shows strong efficacy in predicting RION. [ABSTRACT FROM AUTHOR]

Purpose: To explore the peripheral blood cells (neutrophil/monocyte/lymphocyte/platelet) to apolipoprotein AI or high‐density lipoprotein‐cholesterol ratio (NAR, MAR, LAR, PAR, NHR, MHR, LHR, and PHR) as independent prognostic indicators for stage III nasopharyngeal carcinoma (NPC). Patients and methods: Between 2009 and 2014, 562 patients diagnosed with stage III NPC who were treated with a concomitant chemotherapy and intensity‐modulated radiotherapy with cumulative cisplatin dose ≥200 mg/m2 were included in this retrospective study. Routine blood and biochemical variables and baseline clinical characteristics (T and N stage, age, sex, and induction chemotherapy) were collected. After inserting 19 hematological parameters into a set, we applied the least absolute shrinkage and selection operator (LASSO) algorithm and restricted cubic splines regression to select valuable parameters for predicting 5‐year overall survival (OS). Subsequently, univariate and multivariate survival analyses were used to assess independent indicators of 5‐year OS, distant metastasis survival, regional recurrence‐free survival (RRFS), and disease‐free survival. Results: NAR, MAR, serum lactated dehydrogenase (LDH), and Epstein‐Barr virus (EBV)‐DNA were selected using LASSO regression, and the optimal cut‐off values for NAR, MAR, EBV‐DNA, and, LDH were 4.39, 0.3, 1590 copies/mL, and 218.4 IU/L, respectively. In multivariate survival analysis, higher NAR was associated with both poor 5‐year OS and RRFS (hazard ratio [HR], 1.88; 95% confidence interval [CI], 1.09‐3.25, P =.024; HR, 3.13; 95% CI, 1.42‐6.91, P =.005, respectively). Conclusion: NAR could be an attractive indicator for evaluating the 5‐year OS in patients with stage III NPC, which is closely related to inflammation and circulating lipid metabolism. Level of Evidence: 4 [ABSTRACT FROM AUTHOR]

Recently, the authors proposed the hybrid Local Domain-Free Discretization and Immersed Boundary Method (LDFD-IBM) (Wu et al. 2012), which can be used to solve the flow problem within complex domain with truly 2nd order accuracy (Wu 2017). As a non-conforming mesh method, LDFD-IBM can be extended to handle the moving boundary problems. In this paper, the strategy of LDFD-IBM for incompressible flows problems with moving boundary is presented. The numerical tests are carried out to validate the method, including the simulation of flows past single/multiple moving objects. [ABSTRACT FROM AUTHOR]

The primary objective of the treatment of malignant ascites in advanced stages is to alleviate symptoms using procedures such as diuresis, paracentesis of subretinal fluid and vena cava anastomosis. The effectiveness of systemic or intraperitoneal chemotherapy treatment is limited, and more efficacious therapies are required. The authors of the present study demonstrated that an antimicrobial peptide, cecropinXJ, isolated from the larvae of Bombyx mori, selectively inhibits the proliferation of gastric cancer cells. However, the effects of antibacterial peptides on gastric ascites tumor remains unclear. In the present study, the therapeutic effects of cecropinXJ were investigated in mice bearing malignant ascites. Compared with bovine serum albumin treatment, cecropinXJ and doxorubicin (Dox) significantly inhibited the formation and growth of malignant ascites, and prolonged the survival time of ascites tumor‑bearing mice. In addition, cecropinXJ treatment normalized the hematological and biochemical phenotypes, induced tumor cell apoptosis in ascites and improved the survival of mice bearing malignant ascites when compared with Dox treatment. These results suggested that cecropinXJ might be a promising therapeutic candidate for the treatment of gastric cancer‑associated ascites. [ABSTRACT FROM AUTHOR]

Diphenyliodonium cations were firstly introduced into halobismuthate system to synthesize two new hybrids, i. e. (DPI) 4 (Bi 2 I 10 ) ( 1 ) and (DPI) 4 (Bi 2 Br 10 )·H 2 O ( 2 ) (DPI = diphenyliodonium). Two hybrids are isostructures containing (Bi 2 X 10 ) 4- halobismuthate dimmers and diphenyliodonium cations. Hypervalent I(III)⋯X interactions and C H⋯X (X I, Br) hydrogen bonds stabilize the structures and contribute to the structural extending from 0-D clusters to 2-D layer/1-D chain. The broader absorption spectra and lower energy gap of 1 were led by strong I⋯I interactions. Two compounds display thermochromism behaviors, whose mechanisms were verified by theoretical calculations. [ABSTRACT FROM AUTHOR]

In current study, we aimed to reveal the potential antifibrotic effects of oligomeric proanthocyanidin (OPC) from grape seeds on lipopolysaccharide (LPS)-activated, HSC-T6, a rat hepatic stellate cell line. HSC-T6 cells were treated with OPC 1 h prior to LPS, and then incubated for indicated time. OPC inhibited cells viability of HSC-T6 cells and decrease protein expression of collagen I, α-smooth muscle actin (α-SMA), tissue inhibitors of metalloproteinases I (TIMP-1) on LPS-induced HSC-T6 cells. OPC also significantly inhibited phosphorylation of LPS-stimulated phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK). Furthermore, OPC pretreatment blocked LPS-triggered nuclear factor-kappa B (NF-κB) translocation from cytosol to nuclear. OPC, as well as specific inhibitors of NF-κB, PI3K and JNK could effectively inhibited α-SMA and collagen I expression. In conclusion, we demonstrated that the anti-fibrotic mechanism of OPC might be involved the inhibition of HSC activation and transdifferentiation by suppressing NF-κB activation through JNK/ERK MAPK and PI3K/Akt phosphorylation. Thus, OPC possesses the potential inhibitory property of HSC activation through NF-κB modulation involving MAPK-PI3K/AKT pathways. [ABSTRACT FROM AUTHOR]

The study evaluated the potential protective effect and underlying mechanism of Cucurbitacin E (CuE) in both thioacetamide-induced hepatic fibrosis and activated HSCs. CuE inhibited the proliferation of activated HSC/T-6 cells in a concentration- and time-dependent manner; triggered the activation of caspase-3, cleaved PARP, altered ratio of bcl-2-to-bax, and affected cytochrome C protein in a time- and concentration-dependent manner. CuE arrested activated HSCs at the G2/M phase. Furthermore, CuE reduced levels of p-Erk/MAPK and also inhibited the protein and mRNA expressions of α-SMA, TIMP-1 and collagen I in activated HSC-T6 cells. CuE inhibited PI3 K and Akt phosphorylation, and reduced the levels of p-mTOR and p-P70S6 K and increased the expression of p-AMPK, which is similar with AICAR and metformin. C57BL/6 mice were intraperitoneally injected with thioacetamide (TAA) for five continuous weeks (100 or 200 mg/kg, three times per week) along with daily administration of CuE (5 or 10 mg/kg/d) and curcumin (Cur, 20 mg/kg). CuE treatments significantly reduced serum ALT/AST levels, α-SMA, TIMP-1, and collagen I protein expressions. HE, Masson trichrome, Sirius red and immunohistochemical staining also suggested that CuE could ameliorate hepatic fibrosis. Our findings suggest that CuE induces apoptosis of activated HSC and ameliorates TAA-induced hepatic fibrosis through activation of AMPK and blocking mTOR-dependent signaling pathway. [ABSTRACT FROM AUTHOR]

Adult mammals possess limited ability to regenerate their lost tissues or organs. The epoch-making strategy of inducing pluripotency in somatic cells incorporates multiple applications in regenerative medicine. However, concerns about the clinical translation of induced pluripotent stem (iPS) cells still exist because of the occurrence of aberrancies, even in genome integration-free methods. As cellular reprogramming is multi-gene-oriented, versatile, bioactive small molecules could concomitantly modulate the transcriptional machinery and aid the generation of clinical grade iPS cells. The availability of optimal cell sources has additional influence on the clinical translation of iPS cells. Herein we provide a critical overview of methods and cell sources available for iPS cell production. We think the review will be a useful resource for researchers who aim to develop small molecules for speeding up the journey of iPS cells from the laboratory to the clinic. [Copyright &y& Elsevier]

Abstract: The purpose of the study was to investigate the anti-fibrotic effect and the potential mechanisms of action of betulinic acid (BA) against hepatic fibrosis in vivo and in vitro. BA is an active compound isolated from the bark of the birch tree Betula spp. (Betulaceae). Liver fibrosis was induced by intraperitoneal injections of thioacetamide (TAA, 200mg/kg) twice weekly for 6weeks in Wistar rats. The administration of BA (20 or 50mg/kg) was started following TAA injections and was continued for 6 or 8weeks to evaluate both the preventive and the protective effects. BA demonstrated great efficacy in preventing and curing hepatic fibrosis via attenuating the TAA-mediated increases in liver tissue hydroxyproline and α-smooth muscle actin (α-SMA). In vitro, BA effectively decreased the HSC-T6 cell viability induced by TNF-α and showed low toxicity in normal human chang liver cells. Moreover, BA significantly attenuated the expression of α-SMA and tissue inhibitor of metalloproteinase-1 (TIMP-1) and increased the levels of matrix metalloprotease (MMP)-13. BA also inhibited the expression of Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88) and the activation of nuclear factor-κB (NF-κB) in a time-dependent manner. This study provides evidence that BA exerts a significant anti-fibrosis effect by modulating the TLR4/MyD88/NF-κB signaling pathway. [Copyright &y& Elsevier]

Abstract: 25-OCH3-PPD is a dammarane-type triterpene sapogenin isolated from the roots, leaves and seeds of Panax notoginseng, which has shown anti-tumor effects in several human cancer lines. In this study, we evaluated the effects of 25-OCH3-PPD on apoptosis of activated t-HSC/Cl-6 cells induced by tumor necrosis factor-α (TNF-α). The inhibitory effects of eleven compounds isolated from Panax ginseng and P. notoginseng were detected in activated t-HSC/Cl-6 cells. 25-OCH3-PPD produced a significant inhibitory effect on activated t-HSC/Cl-6 cells. However, 25-OCH3-PPD showed almost no effect on the cell viability of Chang liver cells, a type of normal human hepatic cell line. Therefore, we aimed to determine the anti-fibrotic potential of 25-OCH3-PPD and to characterize the signal transduction pathways involved in activated HSCs. 25-OCH3-PPD decreased the fibrosis markers, including α-smooth muscle actin (α-SMA), transforming growth factor β-1 (TGF-β1) and tissue inhibitors of metalloproteinases-1 (TIMP-1). 25-OCH3-PPD elevated the level of cellular GSH in activated HSCs, which demonstrated that 25-OCH3-PPD might inhibit HSC activation by its antioxidant capacity. Further analyses revealed that 25-OCH3-PPD increased the levels of cleaved caspase-3, decreased the ratio of Bcl-2/Bax and the expression of survivin via c-FLIP-mediated NF-κB activation and shed light on the regulation of apoptosis. Therefore, 25-OCH3-PPD may prove to be an excellent candidate agent for the therapy of hepatic fibrosis. [Copyright &y& Elsevier]

Abstract: The hepatoprotective effects and molecular mechanisms of baicalein on acute liver failure induced by d-galactosamine (d-GalN)/lipopolysaccharides (LPS) were investigated in vivo. Mice were administered with different doses of baicalein (50, 100 or 150mg/kg, p.o.) 1h before injection of d-GalN (700mg/kg)/LPS (10μg/kg) and then sacrificed 6h after treatment with d-GalN/LPS. Pretreatment with baicalein prevented d-GalN/LPS-induced liver damage by preventing associated increases of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and by reducing serum tumor necrosis factor α (TNF-α), nitric oxide (NO) or inducible nitric oxide synthase (iNOS) expressions. The molecular mechanisms involved in baicalein-induced inhibition of d-GalN/LPS-caused apoptosis were associated with the protection of mitochondria, increasing the Bcl-2/Bax ratio, blocking the release of cytochrome c, and suppressing the phosphorylation of IκBα, ERK and JNK. Moreover, baicalein activated c-FLIPL, XIAP and cIAP2 proteins, potentially blocking the recruitment of NF-κB signaling molecules. The results support the investigation of baicalein as a therapeutic candidate for acute liver apoptosis or injury and indicate that baicalein might inhibit liver apoptosis by mediating one or more of these pathways. [Copyright &y& Elsevier]

Ethnopharmacological relevance: This study examined the protective effects of total saponins from Ornithogalum saundersiae (Liliaceae) on d-galactosamine (d-GalN) and lipopolysaccharide (LPS) – induced fulminant hepatic failure. Materials and methods: Total saponins of Ornithogalum saundersiae (Liliaceae) (OC) were prepared with ethyl alcohol extract from bulbs of the plant. Mice were given an intraperitoneal injection of d-GalN (700mg/kg)/LPS (10μg/kg). OC (100mg/kg, 200mg/kg and 300mg/kg) was administered orally for 3 days continuously, and at the last day at 1h before the d-GalN/LPS injection. Mice were sacrificed at 8h after the d-GalN/LPS injection. The liver injury was assessed biochemically, investigating aspartate aminotransferase (AST), alanine aminotransferase (ALT), malondialdehyde (MDA), glutathione (GSH) activities, and the expressions of caspase-3 and hypoxia inducible factor-1α (HIF-1α) as well. Tumor necrosis factor (TNF-α) content was measured after d-GalN/LPS induced 1h by ELISA assay. The survival rates after application of OC in 24h also were observed. Results: d-GalN/LPS increased the serum aminotransferase levels and lipid peroxidation, while decreased the reduced glutathione level. The pretreatment with OC attenuated these changes in a dose-dependent manner. Elevation of TNF-α level and activation of caspase-3, HIF-1α were observed in the d-GalN/LPS group, which was attenuated by OC. The survival rate of the OC groups was significantly higher than that of the d-GalN/LPS group. Conclusions: Protection afforded by OC against d-GalN/LPS-induced fulminant hepatic failure is the result of reduced oxidative stress, inhibited expression of caspase-3, HIF-1α, and anti-apoptotic activity. [Copyright &y& Elsevier]

Abstract: This study investigated the hepatoprotective effects of gentiopicroside on d-galactosamine (d-GalN) and lipopolysaccharide (LPS)-induced fulminant hepatic failure. Mice were administrated orally with gentiopicroside (40 or 80mg/kg body weight) at 12h and 1h before d-GalN (700mg/kg)/LPS (10μg/kg) injection. Gentiopicroside markedly reduced the increases in serum aminotransferase activities and lipid peroxidation. The glutathione content decreased in d-GalN/LPS alone group, and this decrease was attenuated by gentiopicroside. Increases in serum tumor necrosis factor-α (TNF-α), which were observed in d-GalN/LPS alone group, were significantly reduced by gentiopicroside. Importantly, gentiopicroside attenuated d-GalN/LPS-induced apoptosis of hepatocytes, as estimated by the caspase-3 cleavage, poly(ADP-ribose) polymerase (PARP) cleavage, and DNA fragmentation. d-GalN/LPS-induced caspase-8 and -9 activation was significantly suppressed by gentiopicroside. Moreover, increased cytosolic cytochrome c protein was reduced by gentiopicroside. Also, the increased ratio of Bax and Bcl-2 protein was significantly attenuated by gentiopicroside. After 6h of d-GalN/LPS injection, phosphorylated c-jun N-terminal kinase (JNK) and extracellular signal regulated kinase (ERK) was significantly increased, whereas phosphorylation JNK and ERK were attenuated by gentiopicroside. Our results suggest that gentiopicroside offers remarkable hepatoprotection against damage induced by d-GalN/LPS related with its anti-apoptotic activities. [ABSTRACT FROM AUTHOR]

Agriophyllum squarrosum (L.) Moq. is a traditional Mongol medicine generally used to treat diabetes. To investigate the protective effects and potential mechanisms of Agriophyllum oligosaccharides (AOS) on liver injury in type 2 diabetic db/db mice. The db/db mice were divided into the model group (Model), metformin group (MET), high-dose AOS group (HAOS), and low-dose AOS group (LAOS). Nondiabetic littermate control db/m mice were used as the normal control group (Control). Mice in AOS groups were treated with AOS (380 or 750 mg/kg) daily, for 8 weeks. At 8 weeks, blood samples were collected to detect lipid and enzyme parameters concerning hepatic function, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), total protein (TP), albumin (ALB), globulin (GLB), triglyceride (TG), total cholesterol (TC), and high-density lipoprotein cholesterol (HDL-C). Random blood glucose (RBG) test, oral glucose tolerance test (OGTT), and oral maltose tolerance test (OMTT) were also conducted. Microscopy was used to observe morphological changes in the liver of AOS-treated groups. Real-time PCR was used to detect the mRNA expression, including insulin receptor substrate 2 (IRS-2), phosphatidylinositol 3 kinase (PI3K), protein kinase B (AKT), peroxisome proliferator-activated receptor (PPAR)-γ, insulin receptor (INS-R), and Glut4. Furthermore, western blotting was performed to identify proteins, including phosphorylation of IRS-2 (p-IRS-2), PI3K, p-AKT, PPAR-γ, INS-R, and Glut4. Hepatic protein expression of p-IRS-2, PI3K, p-AKT, PPAR-γ, INS-R, and Glut4 was observed using immunohistochemical staining. AOS treatment significantly decreased RBG, OGTT, and OMTT in mice, as well as serum ALT and AST activities. AOS groups demonstrated significantly higher expressions of p-IRS-2, PI3K, PPAR-γ, p-AKT, INS-R, and Glut4 protein and IRS-2, PI3K, AKT, PPAR-γ, INS-R, and Glut4 mRNA in the liver tissue of db/db mice; the degeneration and necrosis of hepatocytes and formation of collagen fibres markedly reduced, improving the structural disorder in the liver. The results suggest that AOS could protect the liver in type 2 diabetes, in part by activating insulin in the INS-R/IRS2/PI3K/AKT/Glut4/PPAR-γ signal pathway, facilitating hepatocyte proliferation, and further reducing the blood glucose levels. Image 1 • AOS presented therapeutic effect of diabetic hepatopathy in mice. • AOS reduced blood glucose and alleviated diabetic liver injury. • AOS exhibited antidiabetic and hepatoprotective effects via regulating INS-R/IRS2/PI3K/AKT/Glut4/PPAR-γ pathway. [ABSTRACT FROM AUTHOR]

• Blockade of P2x7R with its selective inhibitor, A438079, reverses thioacetamide-induced liver damage and fibrosis via inhibiting P2x7R-NLRP3 inflammasome activation • Ectopic overexpression of P2x7R lowered the threshold of extracellular matrix (ECM) deposition in HSCs • Macrophages stimulated by LPS/ATP aggravated ECM deposition in HSCs through activating P2x7R • IL-1β secreted by LPS/ATP activated macrophages amplifies the fibrosis signal from macrophages HSCs (hepatic stellate cells) contribute to the excessive extracellular matrix (ECM) deposition, inflammatory pathways and crucial cell-cell interactions in hepatic disease leading to fibrosis. P2x7R is considered a potential orchestrater in liver fibrosis. For this reason, this work explored the role of P2x7R in liver fibrosis and the mechanism by which P2x7R in macrophages promotes fibrogenesis. In a model of liver fibrosis induced by administration of thioacetamide (TAA), inhibition of P2x7R with its selective inhibitor A438079 reversed TAA-induced liver damage and fibrosis. The mechanism was linked to inhibition of P2x7R-NLRP3 inflammasome activation and thereby infiltration of macrophages and neutrophils into the liver. This result indicated that the P2x7R-TLR4-NLRP3 axis is involved in the process of TGF-β-mediated ECM deposition in HSCs. Ectopic overexpression of P2x7R lowered the threshold of extracellular matrix (ECM) deposition and maintained HSCs in an activated state. The culture medium of THP-1 macrophages stimulated by LPS/ATP aggravated ECM deposition in HSCs by activating P2x7R. Additionally, IL-1β secreted by LPS / ATP activated macrophages amplified fibrosis. These data indicate that P2x7R plays a key regulative role in the activation and maintenance of HSCs promoted by macrophages. Thus, pharmacological inhibition of P2x7R could be a potential therapeutic mechanism to treat human liver fibrosis. [ABSTRACT FROM AUTHOR]

Background and Purpose: Regulating macrophage-hepatocyte crosstalk through P2X7 receptors has led to new pharmacological strategies to reverse alcoholic hepatosteatosis. We investigated how tetrahydroxystilbene glucoside (2354glu), isolated from Polygonum multiflorum, modulates macrophage-hepatocyte crosstalk during alcoholic hepatosteatosis.Experimental Approach: A model of alcoholic hepatosteatosis was established by giving ethanol intragastrically to C57BL/6 mice. HepG2 cells were incubated in conditioned medium from LPS+ATP-activated THP-1 human macrophages with silenced or overexpressed P2X7 receptors. THP-1 macrophages or mouse peritoneal macrophages were pretreated with 2354glu for 1 hr prior to LPS+ATP stimulation. Western blots, RT-PCR and immunohistochemical analysis were used, along with over-expression and silencing of P2X7 receptors.Key Results: Knockdown or overexpression of P2X7 receptors in THP-1 macrophages affected release of mature IL-1β and, subsequently, modulated lipid metabolism in HepG2 cells via the LKB-AMPK pathway. 2354glu ameliorated alcoholic hepatosteatosis in mice by regulating LKB1-AMPK-SREBP1 pathway and its target genes. Suppression of P2X7 receptor activation by 2354glu inhibited IL-1β release and reduced macrophage and neutrophil infiltration. In macrophages stimulated with LPS+ATP, expression of P2X7 receptors, caspase-1 and NF-κB, release of IL-1β, calcium influx and PI uptake were reduced by 2354glu. SIRT1-LKB1-AMPK-SREBP1 axis-mediated lipid accumulation in HepG2 cells was reduced when they were cultured with conditioned media from LPS+ATP-activated THP-1 macrophages pretreated with 2354glu.Conclusion and Implications: Modulation of P2X7 receptors in macrophages regulated lipid accumulation in hepatocytes during alcoholic hepatosteatosis. 2354glu might be a promising candidate that targets P2X7 receptors in macrophages interacting with hepatocytes during alcoholic hepatosteatosis. [ABSTRACT FROM AUTHOR]

Recent studies on biphenyl-containing compounds, a type of PD-1/PD-L1 blocker which binds to PD-L1 and induces dimerisation, have focussed on its immune function. Herein, 10 novel biphenyl derivatives were designed and synthesised. The results of the CCK-8 showed that compounds have different anti-tumour activities for tumour cells in the absence of T cells. Particularly, 12j–4 can significantly induce the apoptosis of MDA-MB-231 cells (IC50 = 2.68 ± 0.27 μM). In further studies, 12j–4 has been shown to prevent the phosphorylation of AKT by binding to cytoplasmic PD-L1, which induces apoptosis in MDA-MB-231 cells through non-immune pathways. The inhibition of AKT phosphorylation restores the activity of GSK-3β, ultimately resulting in the degradation of PD-L1. Besides, in vivo study indicated that 12j–4 repressed tumour growth in nude mice. As these biphenyls exert their anti-tumour effects mainly through non-immune pathways, they are worthy of further study as PD-L1 inhibitors. 10 novel biphenyl derivatives were designed and synthesised. 12j–4 can cause the apoptosis of MDA-MB-231 cells with an IC50 value of 2.68 ± 0.27 μM in the absence of immune cells. 12j–4 prevents the phosphorylation of AKT by binding to cytoplasmic PD-L1 to induce apoptosis through non-immune pathways. [ABSTRACT FROM AUTHOR]

Background and Purpose: Regulating P2X7 receptor-mediated activation of NLRP3 inflammasomes could be a therapeutic strategy to treat alcoholic hepatosteatosis. We investigated whether this process was modulated by gentiopicroside, the main active secoiridoid glycoside from Gentiana manshurica Kitagawa.Experimental Approach: In vivo models of acute and chronic alcoholic hepatosteatosis were established by intragastrically administered ethanol or using chronic plus binge ethanol feeding of Lieber-DeCarli liquid diet to male C57BL/6 mice. In vitro, HepG2 cells were treated with ethanol. RAW 264.7 macrophages and murine bone marrow-derived macrophages (BMDMs) were stimulated with LPS and ATP.Key Results: In both the acute and chronic alcohol-induced mouse hepatosteatosis models, gentiopicroside decreased serum aminotransferases and triglyceride accumulation. Up-regulated SREBP1, down-regulated PPARα and phosphorylated acetyl-CoA carboxylase caused by acute and chronic alcohol feeding were modulated by gentiopicroside, through the elevation of LKB1 and AMPK. Suppression of P2X7 receptor-NLRP3 activation by gentiopicroside inhibited IL-1β production. In ethanol-exposed HepG2 cells, gentiopicroside reduced lipogenesis and promoted lipid oxidation via activation of P2X7 receptor-NLRP3 inflammasomes. Genetic or pharmacological blockade of P2X7 receptors enhanced AMPK activity and reduced SREBP1 expression in ethanol-treated HepG2 cells. Gentiopicroside down-regulated P2X7 receptor-mediated inflammatory responses in LPS/ATP-stimulated RAW 264.7 macrophages and BMDMs. IL-1β from macrophages accelerated lipid accumulation in hepatocytes. Depleting macrophages by clodronate liposomes ameliorated alcoholic hepatosteatosis, and it was further alleviated by gentiopicroside.Conclusions and Implications: Activation of LKB1/AMPK signalling by gentiopicroside was mediated by the P2X7 receptor-NLRP3 inflammasome, suggesting the therapeutic value of blocking P2X7 receptors in the treatment of alcoholic hepatosteatosis. [ABSTRACT FROM AUTHOR]

One novel organic-inorganic hybrid compound based on α-H4(SiW12O40) using 1,10-phenanthroline-5,6-dione (Dione) as neutral organic ligand, namely, [Cu(Dione)2(H2O)]2(SiW12O40), has been synthesized under hydrothermal condition. The organic-inorganic hybrid material, [Cu(Dione)2(H2O)]2(SiW12O40) crystallizes in the orthorhombic space group Pbca with the unit-cell parameters a = 15.5453(10) Å, b = 21.3948(15)Å, c = 22.0731(15)Å, α = 90.00°, β = 90.00° and γ = 90.00°. Single-crystal X-ray diffraction analyses reveal that this compound is zero-dimensional structure. In this compound, intermolecular O-H***O hydrogen bonds play important roles which link the architecture to form 2D supramolecular structure. The compound was characterized by infrared spectrum, thermogravimetric analysis, X-ray photoelectron spectroscopy and photoluminescent spectrum. [ABSTRACT FROM AUTHOR]

Influenza virus and coronavirus epidemics or pandemics have occurred in succession worldwide throughout the early 21st century. These epidemics or pandemics pose a major threat to human health. Here, we outline a critical role of the host cell protease TMPRSS2 in influenza virus and coronavirus infections and highlight an antiviral therapeutic strategy targeting TMPRSS2. [ABSTRACT FROM AUTHOR]

[Display omitted] • TLR ligands promoted NET formation. • ATP accelerated NETosis and the decoration of IL-1β on dsRNA-induced NETs. • IL-36R was activated and magnified IL-36 signal in psoriatic lesions. • NET formation during psoriatic pathogenesis was strengthened by IL-36R activation. NETosis happens when neutrophils are activated and neutrophil extracellular traps (NETs) are formed synchronously, which is a hallmark of psoriasis. However, the specific trigger that drives NET formation and the distinct contents and interaction with interleukin-36 receptor (IL-36R) of NETs remain to be further elucidated. This work identified NET formation driven by toll-like receptor (TLR) 3 ligand (especially polyinosinic-polycytidylic acid (Poly(I:C)) were enhanced by purinergic receptor P2X ligand-gated ion channel 7 receptor (P2X7R) ligands (especially adenosine 5′-triphosphate (ATP)). NET formation was accompanied by the secretion of inflammatory cytokines and characterized by IL-1β decoration. NET formation blockade decreased expressions of inflammatory cytokines and chemokines, which consequently improved inflammatory responses. Additionally, imiquimod (IMQ)-induced psoriasiform symptoms including neutrophilic infiltration tended to be time-sensitive. Mouse primary keratinocytes and mice deficient in Il1rl2 , which encodes IL-36R, mitigated inflammatory responses and NET formation, thereby delaying the pathophysiology of psoriasis. Together, the findings provided the therapeutic potential for IL-36 targeting NET inhibitors in psoriasis treatment. [ABSTRACT FROM AUTHOR]

We investigated the anti -fibrotic mechanism of tetrandrine, a bisbenzylisoquinoline alkaloid from the Chinese herb, Stephania tetrandra , on the immortalized HSC-T6 rat hepatic stellate cell line. Tetrandrine (0.39–50 μM) dose- and time-dependently inhibited HSC-T6 cell viability within 24 h and exhibited almost no cytotoxicity at concentrations lower than 6.25 μM in the presence of tumor necrosis factor-α (TNF-α). At a much high concentration (50 μM), tetrandrine caused fatal cytotoxity in both HSCs and hepatocytes. TNF-α time-dependently increased α-smooth muscle actin (α-SMA) expression, while a lower concentration of tetrandrine (6.25 μM) prior to TNF-α treatment reduced the expression of α-SMA and TNFR-1-associated death domain (TRADD). TNF-α treatment induced TGF-β-activated kinase-1 (TAK1) and c -Jun N -terminal kinase (JNK) phosphorylation, which were attenuated by tetrandrine. Furthermore, TNF-α treatment activated nuclear factor-κB (NF-κB) nuclear translocation and IκB-α degradation. Tetrandrine treatment prior to TNF-α reduced nuclear phosphorylated and total NF-κB p65, while the cytosolic IκB-α and NF-κB p65 levels significantly increased. In addition, treatment with only tetrandrine induced the cleavage of caspase-3 and PARP within a range of higher concentrations. Tetrandrine-induced apoptosis was confirmed by the TUNEL assay and flow-cytometric analysis. Treatment with only tetrandrine markedly reduced α-SMA expression, except for at lower concentrations of tetrandrine. A higher concentration of tetrandrine (25 μM) induced a significant increase in JNK and extracellular signal-regulated kinase (ERK) phosphorylation, NF-κB nuclear translocation and IκB-α degradation. In conclusion, the anti -fibrogenic effects of tetrandrine on HSCs involved a dosage-dependent signaling pathway, based on the tetrandrine concentration, by regulating TAK1, JNK and NF-κB. The present data provides strong evidence for the anti -fibrotic dosage-dependent signaling pathway of tetrandrine. [ABSTRACT FROM AUTHOR]

Background and Purpose: Interleukin‐36 is induced by proinflammatory cytokines and promotes inflammatory responses, creating an IL‐36‐based inflammation loop. Although hepatocytes, produce IL‐36 responses to drug‐induced liver injury, little is known about the mechanistic role of IL‐36 signalling during the progression of alcoholic steatohepatitis (ASH). Regarding IL‐36/IL‐36R and P2X7R coregulating the inflammatory response, we elucidated that modulation of IL‐36R‐P2X7R‐TLR axis affected hepatocyte steatosis as well as the IL‐36‐based inflammatory feedback loop that accompanies the onset of ASH. Experimental Approach: C57BL/6J mice were subjected to either chronic‐plus‐binge ethanol feeding or acute gavage with multiple doses of ethanol to establish ASH, followed by pharmacological inhibition or genetic silencing of IL‐36R and P2X7R. AML12 cells or mouse primary hepatocytes were stimulated with alcohol, LPS plus ATP or Poly(I:C) plus ATP, followed by silencing of IL‐36γ, IL‐36R or P2X7R. Key Results: P2X7R and IL‐36R deficiency blocked the inflammatory loop, specifically initiated by IL‐36 cytokines, in hepatocytes of mice suffering from ASH. Pharmacological inhibition to P2X7R or IL‐36R alleviated lipid accumulation and inflammatory response in ASH. IL‐36R was indispensable for P2X7R modulated NLRP3 inflammasome activation in ASH, and IL‐36 led to a vicious cycle of P2X7R‐driven inflammation in alcohol‐treated hepatocytes. TLR ligands promoted IL‐36γ production in hepatocytes, based on synergism with P2X7R. Conclusions and Implications: Blockade of IL‐36 based inflammatory feedback loop, via IL‐36R‐P2X7R‐TLRs‐modulated NLRP3 inflammasome activation, circumvented steatosis and inflammation that accompanies the onset of ASH, suggesting that targeting IL‐36 can serve as a novel therapeutic approach to combat ASH. [ABSTRACT FROM AUTHOR]

Gout is a chronic disease caused by monosodium urate (MSU) crystal deposition in the joints and surrounding tissues. We examined the effects of Taxifolin, a natural flavonoid mainly existing in vegetables and fruits, on MSU-induced gout. Pretreatment with Taxifolin significantly reduced IL-1β, Caspase-1 and HMGB1 levels, upregulation of autophagy-related protein, LC3, as well as improved phagocytosis of macrophages. This study indicated that Taxifolin-attenuated inflammatory response in MSU-induced acute gout model by decreasing pro-inflammatory cytokine production and promoting the autophagy and phagocytic capacity of macrophages. Dietary supplementation with Taxifolin induces the autophagy and attenuated inflammatory response, which in consequence modulates acute gout. A preventive strategy combining dietary interventions with Taxifolin may offer a potential therapeutic alternative to pharmacological treatment to reduce inflammatory response to gout. [ABSTRACT FROM AUTHOR]

Abstract: The current study was conducted to investigate the anti-fibrotic effect and its possible underlying mechanisms of thymoquinone (TQ) against hepatic fibrosis in vivo. TQ is the major active compound derived from the medicinal Nigella sativa. Liver fibrosis was induced in male Kunming mice by intraperitoneal injections of thioacetamide (TAA, 200mg/kg). Mice were treated concurrently with TAA alone or TAA plus TQ (20mg/kg or 40mg/kg) given daily by oral gavage. Our data demonstrated that TQ treatment obviously reversed liver tissue damage compared with TAA alone group, characterized by less inflammatory infiltration and accumulation of extracellular matrix (ECM) proteins. TQ significantly attenuated TAA-induced liver fibrosis, accompanied by reduced protein and mRNA expression of α-smooth muscle actin (α-SMA), collagen-І and tissue inhibitor of metalloproteinase-1 (TIMP-1). TQ downregulated the expression of toll-like receptor 4 (TLR4) and remarkably decreased proinflammatory cytokine levels as well. TQ also significantly inhibited phosphatidylinositol 3-kinase (PI3K) phosphorylation. Furthermore, TQ enhanced the phosphorylation adenosine monophosphate-activated protein kinase (AMPK) and liver kinase B (LKB)-1. In conclusion, TQ may reduce ECM accumulation, and it may be at least regulated by phosphorylation of AMPK signaling pathways, suggesting that TQ may be a potential candidate for the therapy of hepatic fibrosis. [Copyright &y& Elsevier]

Intestinal epithelial cells (IECs) contribute to regulation of gut injury after intestinal ischemia/reperfusion (II/R). Exosomes are well documented to deliver bioactive molecules to recipient cells for the purpose of modulating cell function. However, the role of IEC-derived exosomes in gut damage after II/R and the underlying mechanisms remain unclear. Here, we investigated the effects of exosomal miR-23a-3p on gut damage using primary IECs that underwent oxygen-glucose deprivation (OGD) as well as II/R rats. We observed that exosomes released by IECs attenuated damage in IECs that underwent OGD in vitro (P < 0.05) as well as the degree of gut injury after an II/R assault in vivo (P < 0.05). Injection of miR-23a-3p knockdown exosomes aggravated the II/R injury, whereas PF-6260933, a small-molecule inhibitor of MAP4K4, partly reversed the injury. Underlying mechanistic studies revealed that exosomal miR-23a-3p attenuated gut damage by regulating its downstream target, MAP4K4. [Display omitted] • Intestinal epithelial cell (IEC)-derived exosomes reduce the damage of IECs. • IEC-derived exosomes decrease the intestinal ischemia-reperfusion (II/R) injury. • Exosomal miR-23a-3p secreted by IECs alleviates the II/R injury. • Exosomal miR-23a-3p reduces the II/R injury by regulating MAP4K4. [ABSTRACT FROM AUTHOR]

A new complex, [Cu 2 (1,10-phenanthroline-5,6-dione) 3 (PMo 12 O 40)] 2 ·3H 2 O (1), was prepared via solvothermal method. A one-dimensional structure was formed by the bonding of ligand and metal. Then, a two-dimensional layered structure was constructed by hydrogen bonding. The structures were characterized using X-ray powder diffraction, Fourier transform infrared spectroscopy, differential thermal analysis and thermogravimetric analysis, X-ray photoelectron spectroscopy, and ultraviolet–visible diffuse reflectance spectroscopy. The degradation of metronidazole under UV light was studied under varying ionic strength and solution pH conditions. Compared with original conditions, the addition of sodium chloride significantly increased the degradation rate of metronidazole to 80.2%. Complex 1 can be easily prepared, and it has a stable one-dimensional structure that form a two-dimensional layered structures by hydrogen bonding. The complex exhibited high efficiency for metronidazole degradation. They can be reused and separated easily. [Display omitted] • The solid complex 1 can be easily prepared and have stable 1D/2D crystal structure. • Complex 1 shows higher purity, better thermal stability and suitable forbidden bandwidth. • Having high photodegradation efficiency for metronidazole, especially NaCl is added. [ABSTRACT FROM AUTHOR]

Abstract: Thymoquinone (TQ) is the major active compound derived from the medicinal Nigella sativa. In the present study, we investigated the anti-fibrotic mechanism of TQ in lipopolysaccharide (LPS)-activated rat hepatic stellate cells line, T-HSC/Cl-6. T-HSC/Cl-6 cells were treated with TQ (3.125, 6.25 and 12.5μM) prior to LPS (1μg/ml). Our data demonstrated that TQ effectively decreased activated T-HSC/Cl-6 cell viability. TQ significantly attenuated the expression of CD14 and Toll-like receptor 4 (TLR4). TQ also significantly inhibited phosphatidylinositol 3-kinase (PI3K) and serine/threonine kinase-protein kinase B (Akt) phosphorylation. The expression of α-SMA and collagen-I were significantly decreased by TQ. Furthermore, TQ decreased X linked inhibitor of apoptosis (XIAP) and cellular FLIP (c-FLIPL) expression, which are related with the regulation of apoptosis. Furthermore, TQ significantly increased the survival against LPS challenge in d-galactosamine (d-GlaN)-sensitized mice, and decreased the levels of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), which were in line with in vitro results. Our data demonstrated that TQ attenuates liver fibrosis partially via blocking TLR4 expression and PI3K phosphorylation on the activated HSCs. Therefore, TQ may be a potential candidate for the therapy of hepatic fibrosis. [Copyright &y& Elsevier]

Abstract: Inhibition of Rho kinase (ROCK) has been shown to improve diabetic-related disorders. In this study, the cardio-protective effects and potential mechanisms of fasudil, a selective ROCK inhibitor, on diabetic cardiomyopathy were investigated in a streptozotocin (STZ)-induced diabetic rat model. Eight weeks after diabetes was induced by a single tail vein injection of 60mg/kg STZ, rats were administered long-term fasudil or captopril as a control over a four-week period. Similar to the effect of captopril, fasudil treatment significantly protected against STZ-induced hemodynamic, histopathologic changes and decreased serum lactate dehydrogenase and creatine phosphokinase. Moreover, fasudil significantly down-regulated ROCK I mRNA expression and ROCK activity, reduced cardiac collagen deposition, and decreased the incidence of apoptosis and ratio of Bax/Bcl-2 protein expression. Additionally, fasudil potently elevated superoxide dismutase activity and suppressed the extent of lipid peroxidation in sera and hearts of diabetic rats. Our findings indicated that long-term treatment with fasudil could improve cardiac dysfunction, attenuate myocardial injury and prevent pathological changes in a rat model of diabetic cardiomyopathy. These effects could be attributed to regulation of antioxidative activities, suppression of myocardial hypertrophy, apoptosis, fibrosis and subsequent cardiac remodeling. These results may help to expand the clinical application of fasudil for diabetic cardiomyopathy. [Copyright &y& Elsevier]

A new cation-induced hybrid iodoargentate, [(PIP-H2)4·(Ag4I12)·H2O]n (1) (PIP = piperazine) has been obtained by the routine synthetic reaction in DMF solution and structurally determined. 1 crystallizes in monoclinic system, space group P21/n with unit cell parameters: a = 12.718(3), b = 9.3861(19), c = 20.098(4)Å, β = 90.33(3)°, V = 2399.1(8)Å3, Z = 4, C8H24Ag2I6N4O, Mr = 1169.45, Dc = 3.238 g/cm3, F(000) = 2080, μ(MoKα) = 9.356mm-1, the final R1 = 0.0681 and wR = 0.1757 for 5255 observed reflections with I > 2σ(I). In 1, 0-D [Ag4I12]8- clusters were constructed from four vertex-sharing AgI4 tetrahedra and further linked by hydrogen bonds to give a 2-D layer. Luminescence can be detected in the title compound. Quantum chemistry calculation with DFT method was carried out to reveal its electronic structure. [ABSTRACT FROM AUTHOR]

Objectives The hepatoprotective activity and molecular mechanism of betulinic acid (BA) was investigated on acute liver failure induced by d-galactosamine (D-GalN)/lipopolysaccharide (LPS) in vivo. Methods Mice were administered with different doses of BA (20 mg/kg or 50 mg/kg, i.p.) 1 h before injection of D-GalN (700 mg/kg)/LPS (10 µg/kg) and sacrificed 6 h after treatment with D-GalN/LPS. Key findings Pretreatment with BA significantly prevented the increases of serum aspartate aminotransferase and alanine aminotransferase, while it increased the content of glutathione and catalase, and reduced malondialdehyde. BA showed obvious anti-oxidant effects and prevented D-GalN/LPS-induced apoptosis, as indicated by DNA ladder. BA treatment resulted in regulation of the mitogen-activated protein kinase. We found that BA mediated production of c-jun NH2-terminal protein kinase and extracellular signal-regulated kinase induced by D-GalN/LPS, promoted the expression of B-cell CLL/lymphoma 2 (Bcl-2) and restored mitochondrial outer membrane permeabilization. Conclusions The results suggested that BA prevented D-GalN/LPS-induced acute liver failure by upregulation of Bcl-2 and antioxidation and mediation of cytokines causing apoptotic cell death and lessened liver damage. [ABSTRACT FROM AUTHOR]

[Display omitted] • Parthenolide ameliorated IMQ-induced psoriasis-like skin inflammation response by inhibiting NETs release targeting IL-36. • Parthenolide suppressed IL-36γ production in psoriatic keratinocytes Cells. • The Par cream was prepared to explore therapeutic effect of the different delivery routes. • Par ameliorated psoriatic inflammation both through delivery route of intragastrical and transdermal administration. Psoriasis is an inflammatory skin disease that occurs repeatedly over time. The natural product of sesquiterpene lactones, Parthenolide (Par), is isolated from Tanacetum parthenium L. (feverfew) which has significant effects on anti-inflammatory. The therapeutic effect of the medication itself is crucial, but different routes of administration of the same drug can also produce different effects. The aim of our research sought to investigate the ameliorating effects of Par in psoriasis-like skin inflammation and its related mechanism of action. In the IMQ-induced model, intragastric administration of Par reduced the Psoriasis Area and Severity Index (PASI) score, improved skin erythema, scaling, and other symptoms. And Par decreased the expression of Ki67, keratin14, keratin16 and keratin17, and increased the expression of keratin1. Par could reduce IL-36 protein expressions, meanwhile the expression of Il1b , Cxcl1 and Cxcl2 mRNA were also decreased. Par regulated the expression levels of F4/80, MPO and NE. However, skin transdermal administration of Par was more effective. Similarly, Par attenuated IL-36γ, IL-1β and caspase-1 activated by Poly(I:C) in in vitro and ex vivo. In addition, Par also reduced NE, PR3, and Cathepsin G levels in explant skin tissues. Par ameliorated psoriasis-like skin inflammation in both in vivo and in vitro , especially after treatment with transdermal drug delivery, possibly by inhibiting neutrophil extracellular traps and thus by interfering IL-36 signaling pathway. It indicated that Par provides a new research strategy for the treatment of psoriasis-like skin inflammation and is expected to be a promising drug. [ABSTRACT FROM AUTHOR]

• The commercially available graphene without any pre-treatment was selected as modifier and the graphene modified asphalt with different dosages were prepared. • With the aid ofAFM & FTIR, the modification mechanism indicates that graphene served as asphaltene is only physical blended without chemical reactions occurring. And graphene act as the micellar nucleus is dispersed uniformly in asphalt. • Diffusion theory is introduced to explain the influence of graphene on the "bee structures". • Nano-scaled materials with unique characteristics are also drawing attention to modified asphalt, which can give the asphalt pavement excellent performance. In this work, commercially available graphene without any pre-treatment selected as modifier, graphene-modified asphalt with different dosages was prepared. The physical properties, anti-ageing characters, and rheological properties were analyzed. With the aid of microscopic characterization, atomic force microscopy (AFM) and Fourier transform infrared spectroscopy (FTIR), modification mechanism was studied. The research results indicate that incorporating nano-scaled graphene in asphalt can bring effective improvement on the anti-ageing property, high-temperature stability, and temperature sensitivity. Graphene served as asphaltene with high surface energy are dispersed uniformly, and act as the micellar nucleus in asphalt. The increased viscosity and the graphene sheets can impede and prevent the diffusion of oxygen into the asphalt. The FTIR absorption peak at 1030 cm−1 for the S O stretching vibration reveals anti-ageing properties of graphene-modified asphalt. Diffusion theory is introduced to explain the influence of graphene on the "bee structures". The AFM results also contribute to a better understanding of the modification and anti-ageing mechanism of the graphene-modified asphalt. [ABSTRACT FROM AUTHOR]

As the largest genus of Gentianaceae family, the Gentiana genus harbors over 400 species, widely distributed in the alpine areas of temperate regions worldwide. Plants from Gentiana genus are traditionally used to treat a wide variety of diseases including easing pain dispelling rheumatism, and treating liver jaundice, chronic pharyngitis and arthritis in China since ancient times. In this review, a systematic and constructive overview of the traditional uses, phytochemistry, molecular mechanisms, toxicology and pharmacological activities of the researched species of genus Gentiana is provided. The used information in this review is based on various databases (PubMed, Science Direct, Wiley online library, Wanfang Data, Web of Science) through a search using the keyword " Gentiana " in the period of 1981–2019. Besides, other ethnopharmacological information was acquired from Chinese herbal classic books and Chinese pharmacopoeia 2015 edition. The plants from Gentiana genus have a long tradition of various medicinal uses in Europe and Asia. Phytochemical studies showed that the main bioactive components isolated from this genus includes iridoids xanthones and flavonoids. These compounds and extracts isolated from this genus show a wide range of protective activities including hepatic protection, gastrointestinal protection, cardiovascular protection, immunomodulation, joint protection, pulmonary protection, bone protection and reproductive protection. Molecular mechanism studies also indicated several potential therapeutic targets in the treatment of certain diseases by plants from this genus. Besides, natural products from this plant show no significant animal toxicity, cytotoxicity or genotoxicity. This review summarized the traditional medicinal uses, phytochemistry, pharmacology, toxicology and molecular mechanism of genus Gentiana , providing references and research tendency for plant-based drug development and further clinical studies. Image 1 [ABSTRACT FROM AUTHOR]

Gout, the most prevalent inflammatory arthritis worldwide, released interleukin-1β (IL-1β) and Cathepsin B inflammatory mediators that constitute the hallmark of the disease. Herein we aimed to investigate whether procyanidin B2 (PCB2), a natural dietary compound, can suppress MSU crystals-stimulated gouty inflammation. Treated with lipopolysaccharide (LPS) plus MSU, both mouse peritoneal macrophages (MPM) and mouse bone marrow-derived macrophages (BMDM) released a large amount of mature IL-1β compared to those treated with MSU or LPS alone, while IL-1β release was blocked by TLR4 and its downstream effector inhibitors. In two mouse models of gout, oral administration of PCB2 suppressed MSU crystals-induced increasing expression of IL-1β, Cathepsin B and NLRP3 in the air pouch skin and paws, accompanied with the downregulation prostaglandin E2 (PGE2) in pouch exudates. Inflammatory immune cell infiltration including macrophages and neutrophils were significantly blocked by PCB2 in air pouch skin and paws of mice gout groups. PCB2 also suppressed the release of IL-1β and Cathepsin B induced by MSU plus LPS in MPM. Our results suggest that the inhibitory effects of PCB2 on NLRP3 inflammasome may alleviate inflammatory response in gout, and this might be a promising anti-inflammatory mechanism of PCB2 against the inflammation in gout. [ABSTRACT FROM AUTHOR]

Proteolytic cleavage of influenza A virus (IAV) hemagglutinin by host proteases is crucial for virus infectivity and spread. The transmembrane serine protease TMPRSS2 was previously identified as the essential protease that can cleave hemagglutinin of many subtypes of influenza virus and spike protein of coronavirus. Herein, we found that a guanine rich tract, capable of forming intramolecular G-quadruplex in the presence of potassium ions, in the promoter region of human TMPRSS2 gene was quite important for gene transcriptional activity, hence affecting its function. Furthermore, 7 new synthesized benzoselenoxanthene analogues were found to enable stabilizing such G-quadruplex. More importantly, compounds can down-regulate TMPRSS2 gene expression, especially endogenous TMPRSS2 protein levels, and consequently suppress influenza A virus propagation in vitro. Our results provide a new strategy for anti-influenza A virus infection by small molecules targeting the TMPRSS2 gene G-quadruplex and thus inhibiting TMPRSS2 expression, which is valuable for developing small molecule drugs against influenza A virus and also may be a potential candidate as anti- SARS-CoV-2 (Severe Acute Respiratory Syndrome CoV 2) lead molecules. [ABSTRACT FROM AUTHOR]

Background: Increased use of thin-section computed tomography (CT) scans has revealed that small lung nodules, termed ground-glass nodules, are frequent in primary breast cancer patients and are associated with pre-invasive or invasive pulmonary adenocarcinomas. However, little is known of the incidence and fate of ground-glass nodules. Purpose: To elucidate the incidence and natural course of CT-detected pulmonary ground-glass nodules in Chinese women with breast cancer. Material and Methods: We retrospectively reviewed data from female breast cancer patients who underwent lung CT scans and who were followed for ≥3 months after the initial scan to identify the incidence of ground-glass nodules and any changes in them during the follow-up period. Results: Between January 2008 and April 2018, 693 out of 4682 breast cancer patients (14.8%) had persistent lung ground-glass nodules as detected by CT scan. The median age was 52 years (interquartile range [IQR] = 45–62 years). Median nodule size was 4.9 mm in diameter on initial CT scan. Frequency of growth was 7.5% (52/693 patients). Median volume doubling time was 1092 days (IQR = 719–1808 days) for 39 growing in size nodules. Initial nodule size, nodule type, and follow-up period were independent predictors of nodule growth. Conclusion: Most pulmonary ground-glass nodules in breast cancer patients were stable during long-term follow-up; most growing nodules had an indolent clinical course, suggesting that nodules should be monitored until growth is detected. This information is clinically relevant for accurate diagnosis of cancer stage and for appropriate treatment plans for patients with lung ground-glass nodules. [ABSTRACT FROM AUTHOR]

[Display omitted] • Ligustilide improved lipid accumulation and inflammation in alcoholic steatosis based on RXFP1. • Ligustilide inhibited the RXFP1-NLRP3 axis to reduce the release of inflammatory factors. • Ligustilide reduced the infiltration of immune cells via inhibiting the formation of NETs. Ligustilide (Lig) is the main active ingredient of Umbelliferae Angelicae Sinensis Radix (Chinese Angelica) and Chuanxiong Rhizoma (Sichuan lovase rhizome). Lig possesses various pharmacological properties and could treat obesity by regulating energy metabolism. However, the impact and regulatory mechanism of Lig on alcoholic hepatic steatosis remains unclear. This study aimed to explore the therapeutic effect of Lig on alcoholic hepatic steatosis and its related pharmacological mechanism. With chronic and binge ethanol feeding, liver tissue damage and lipid accumulation in mice suffering alcoholic hepatic steatosis were significantly improved after Lig treatment. Lig effectively regulated the expression levels of lipid metabolism-related proteins in alcoholic hepatic steatosis. In addition, Lig reduced RXFP1 expression, inhibited the activation of NLRP3 inflammasome, and blocked NET formation. Lig reduced the infiltration of immune cells to the liver and the further prevented the occurrence of alcohol-stimulated inflammatory response in liver. Lig significantly regulated lipid accumulation in alcohol exposed AML12 cells via modulating PPARα and SREBP1. In MPMs, Lig decreased the expression of RXFP1, inhibited the activation of NLRP3 in macrophages stimulated by LPS/ATP, and slowed down the occurrence of inflammatory response. Lig sustained lipid metabolism homeostasis in alcoholic hepatic steatosis, through inhibiting the activation of NLRP3 inflammasomes and the formation of NETs, especially targeting RXFP1 in macrophages. [ABSTRACT FROM AUTHOR]

Background: Lung cancer is the leading cause of cancer mortality among women in China, and incidence and mortality continue to rise despite the fact that smoking prevalence is very low among Chinese women. Aim: This study investigated tobacco smoking and trends in histological subtypes of female lung cancer in a central cancer hospital in China. Methods: Demographic, smoking history and histological information on female lung cancer patients diagnosed or treated from 2000 to 2012 was collected from the Cancer Hospital, Chinese Academy of Medical Science (CHCAMS). The classification of histological subtypes and clinical stages were conducted using the ICD‐O‐3 and Eighth AJCC Cancer Staging Manuals. Time‐trends of histological subtypes were analyzed based on annual percentage change (APC). Results: Overall, 5870 female cases of lung cancer were included in the analysis. The number of female lung cancer patients increased from 509 (2000–2002) to 1744 (2011–2012). The most common histological type of lung cancer was adenocarcinoma (ADC) (72.93%), followed by small cell lung cancer (SCLC) (11.06%), squamous cell carcinoma (SCC) (8.38%) and other (7.63%). Among smokers, the proportion of SCC decreased from 40.5% to 23.7% (P = 0.005), while ADC increased from 35.7% to 50.7% (P = 0.009). In non‐smokers, ADC increased from 63.1% to 80.6% (P = 0.006) and SCC decreased from 13.6% to 4.5% (P = 0.016). Among SCC cases, smokers made up a larger proportion of early stage (I/II: 47.1%) compared with late stages (III, 34.3%; IV, 18.6%). Conclusion: The number of female lung cancer patients has increased in CHCAMS. In both smoking and non‐smoking cases, the proportion of adenocarcinoma increased. Squamous cell carcinomas were more likely to be diagnosed in early stages among smokers. [ABSTRACT FROM AUTHOR]

Thymoquinone (TQ) is a main aromatic component of Nigella sativa L. seeds or Agastache rugosa (Fisch. & C.A.Mey.) Kuntze. The protective mechanism of TQ against acute liver injury induced by acetaminophen (APAP), however, remains unclear. We aimed to investigated the hepato-protective mechanism of TQ on the development of APAP-induced acute liver injury. Male kunming mice were pretreated with TQ or N-acetylcysteine (NAC) before a single APAP injection. Human Chang liver cells were incubated with TQ, SP600125 or AICAR in presence of APAP for 24 h. TQ pretreatment reduced levels of serum aminotransferases and increased hepatic glutathione and glutathione peroxidase activities via inhibiting CYP2E1 expression. TQ inhibited JNK, ERK and P38 phosphorylation induced by APAP. Meanwhile, TQ inhibited PI3K/mTOR signaling activation and activated AMPK phosphorylation. Moreover, TQ prevented APAP-induced hepatocytes apoptosis regulated by Bcl-2 and Bax. Furthermore, TQ inhibited STAT3 phosphorylation on APAP-induced acute liver injury. In addition, TQ significantly inhibited P2X7R protein expression and IL-1 β release. APAP-enhanced JNK phosphorylation and APAP-suppressed AMPK phosphorylation were also observed in Chang liver cells, and these changes were recovered by pretreatment with TQ, SP600125 and AICAR. Our findings suggest that TQ may actively prevent APAP-induced acute liver injury, and the effect may be mediated by JNK and AMPK signaling pathways. [ABSTRACT FROM AUTHOR]

[Display omitted] • J-1048, a pyrazole derivative, has significant inhibitory activity upon to ALK5 with high selectivity. • J-1048 inhibited TGF-β/Smad signal transduction pathway during liver fibrosis. • J-1048 blocked P2X7R-NLRP3 inflammasome activation in progression of liver fibrosis. • J-1048 has a particular inhibitory effect on the recruitment of inflammatory cells. Liver fibrosis is a worldwide challenge of health issue. Developing effective new drugs for treating liver fibrosis is of great importance. In recent years, chemically synthesized drugs have significant advantages in treating liver fibrosis. Small molecule pyrazole derivatives as activin receptor-like kinase 5 (ALK5) inhibitors have also shown anti-fibrotic and tumor growth inhibitory effects. To develop the candidate with anti-fibrotic effect, we synthesized a novel pyrazole derivative, J-1048. The inhibitory effect of J-1048 on ALK5 and p38α mitogen-activated protein (MAP) kinase activity was assessed by enzymatic assays. We established an in vivo liver fibrosis model by injecting thioacetamide (TAA) into mice and in vitro model of TGF-β stimulated hepatic stellated cells to explore the inhibition mechanisms and therapeutic potential of J-1048 as an ALK5 inhibitor in liver fibrosis. Our data showed that J-1048 inhibited TAA-induced liver fibrosis in mice by explicitly blocking the TGF-β/Smad signaling pathway. Additionally, J-1048 inhibited the production of inflammatory cytokine Interleukin-1β (IL-1β) by inhibiting the purinergic ligand-gated ion channel 7 receptor (P2X7r) -Nucleotide-binding domain-(NOD-)like receptor protein 3 (NLRP3) axis, thereby alleviating liver fibrosis. Our findings demonstrated that a novel small molecule ALK5 inhibitor, J-1048, exhibited strong potential as a clinical therapeutic candidate for liver fibrosis. [ABSTRACT FROM AUTHOR]

Abstract Dictamnine (DTM) is a natural alkaloid isolated from the root of Dictamnus dasycarpus Turcz and has been shown to exhibit multiple biological functions, including anti-inflammatory, antifungal, anti-angiogenic and anticancer activity. However, the mechanisms by which dictamnine inhibits tumor growth are not fully understood. In this study, we investigated the effectiveness of dictamnine as a treatment for cancer and to identify the underlying mechanisms of its anticancer activity. Here, dictamnine showed the potent inhibitory activity against HIF-1α and Slug activation induced by hypoxia in various human cancer cell lines. This compound markedly decreased the hypoxia-induced accumulation of HIF-1α and Slug protein in a dose-dependent manner. Further analysis revealed that dictamnine inhibited HIF-1α protein synthesis, without affecting its degradation. Our results demonstrated that dictamnine reduced HIF-1α protein synthesis by downregulating the mTOR/p70S6K/eIF4E and MAPK pathways, and reduced the expression of Slug by inhibiting the GSK-3β/Slug signaling pathway. Moreover, epithelial-mesenchymal transition (EMT) was inhibited in dictamnine-treated tumors by downregulation of HIF-1α and Slug, as reflected by the upregulation of E-cadherin and Occludin, and the downregulation of N-cadherin and Vimentin. Phenomenological experiments showed that dictamnine reduced migration and invasion, inhibited HCT116 cell proliferation and promoted HCT116 cell apoptosis by downregulating HIF-1α and Slug. In vivo studies further confirmed that dictamnine treatment caused significant inhibition of tumor growth in a xenograft tumor model. These findings suggest that dictamnine is a potent cancer inhibitor, providing a rationale for anticancer pathway-targeted therapy. Highlights • Dictamnine decreased the hypoxia-induced HIF-1α and Slug protein. • Dictamnine downregulating the mTOR/p70S6K/eIF4E, MAPK, and GSK-3β/Slug pathways. • Dictamnine inhibited EMT markers by downregulating HIF-1α and Slug. • Dictamnine inhibited migration, invasion, proliferation and promoted apoptosis. • Dictamnine may be a potential therapeutic agent for inhibiting cancer progression. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Leucodin inhibited LPS/ATP-induced IL-1β cleavage in macrophage through P2x7R-NLRP3 axis. • Leucodin inhibited lipid deposition in ethanol-exposed steatotic hepatocytes. • Leucodin might be a promising therapeutic potential targeting inflammation and lipid metabolism in ALD. Abstract The current study was aimed to reveal that leucodin, a sesquiterpene lactone from Artemisia capillaris could inhibit the inflammatory response in macrophages and the lipid accumulation in hepatocytes via P2x7R-NLRP3 inflammasome activation. Several types of macrophages including mouse peritoneal macrophages, mouse bone marrow-derived macrophages and human macrophages THP-1 cells were pretreated with different concentrations of leucodin for 1 h and then stimulated with LPS and ATP. LPS plus ATP initiated IL-1β cleavage and release in mouse peritoneal macrophages and peaked at 4 h. Leucodin did not show significant toxicity within 200 μM and effectively inhibited pro-IL-1β cleavage and release of mature-IL-1β in macrophages. Also, P2x7R antagonist and caspase-1 inhibitor also decreased IL-1β release and cleavage. Additionally, leucodin suppressed P2x7R, TLR4 and NLRP3 expression in LPS/ATP-stimulated macrophages. HepG2 cells were pretreated with different concentrations of leucodin for 1 h and then exposed to ethanol for 24 h. Leucodin suppressed lipid accumulation and enhanced phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) in HepG2 cells exposed to ethanol. In addition, leucodin inhibited the expression of sterol regulatory element binding protein-1 (SREBP1) and ACC in ethanol-treated HepG2 cells. Leucodin possessed the capacity for inhibiting inflammatory response in macrophages and suppressing lipid accumulation in hepatocytes, suggesting a promising therapeutic potential targeting inflammation and lipid metabolism in alcoholic liver disease. [ABSTRACT FROM AUTHOR]

Abstract: 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 m m) plus LPS (1 μg/ml) for 1 h, followed by AA (10 or 20 μ m) 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. [ABSTRACT FROM AUTHOR]

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 28 d. And mice in AA groups were gavaged with AA (20 or 40 mg/kg) for 28 d. 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. [ABSTRACT FROM AUTHOR]