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Hemp powder and PVDF blended approach were used to modify PVDF membrane, then the blend interlayer film microstructure and thermal properties, mechanical properties as well as peel strength between CFRP and other properties were tested, and the influence of hemp flour content on the blend membrane performance was studied. Experimental results show that with the increase of the mass fraction of hemp powder, blend membrane surface finish lower, more irregular cross-section structure, density and thickness increase, the blend film becomes brittle, while mechanical properties dropped significantly; with the increase of the mass fraction of hemp powder, the inter-layer blend membranes with CFRP / wood composites, interlaminar strength firstly increases and then decreases, when the mass fraction of hemp powder is 6%, the maximum interlaminar strength value is 0.36 N/mm. [ABSTRACT FROM AUTHOR]

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]

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]

• Rutin mitigates hepatic fibrogenesis via TLR4-P2X7r signaling. • Rutin decreases fibrosis markers in activated HSCs via suppressing TLR4. • Rutin protects primary hepatocytes via blocking TLR4-P2X7r. Rutin is a flavonol glycoside widely existing in plants, used as food antioxidant and nutritional enhancer. Rutin has vitamin P-like effect and anti-inflammatory effect. This study aims to investigate the effects and potential mechanisms of rutin against hepatic fibrosis in vivo and in vitro. The present study found that rutin significantly decreased fibrosis markers, and TLR4, IRAK4, P2X7r/NLRP3 signaling pathway in activated HSCs, as well as functioning as TLR4 inhibitor. In primary hepatocytes, rutin also inhibited TLR4-IRAK-P2X7r signaling pathway underlying TGF-β stimulation. In TAA-induced mice, rutin could attenuate the histopathological changes, fibrosis markers, and inflammatory factor. Rutin also suppressed TLRs, IL-1 receptor associated kinase, P2X7r, and NLRP3 expressions. Activation of TLRs/P2X7r signaling is required for HSCs activation, contributing to hepatic fibrosis in mice. Rutin exhibited a protective effect against hepatic fibrosis at least partly through suppressing TLR4 and P2X7r signaling. [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]

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]

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]

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: 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]

[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]

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]

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] • 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]

• 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]

[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]

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]

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]

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]

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 24 h and P2x7R selective antagonist A438079 (10 μM) was supplemented to LX-2 cells 1 h before LPS or CM stimulation. In addition LX-2 cells were primed with LPS for 4 h and subsequently stimulated for 30 min with 3 mM of adenosine 5′-triphosphate (ATP). A438079 was supplemented to LX-2 cells 10 min prior to ATP. Directly treated with LPS on LX-2 cells, mRNA expressions of interleukin (IL)-1β, 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-1β mRNA expression. LPS combined with ATP dramatically increased protein synthesis and cleavage of IL-1β 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 30 min 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-1β 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. [ABSTRACT FROM AUTHOR]

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-β 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-β-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 (5 g/kg body weight) via gavage. TQ (20 or 40 mg/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-β-induced the activation of HSCs and ethanol-induced liver injury. [ABSTRACT FROM AUTHOR]

In this article we developed a geometrical wetting condition for diffuse-interface simulation of ternary fluid flows with moving contact lines. The wettability of the substrate in the presence of ternary fluid flows is represented by multiple contact angles, corresponding to the different material properties between the respective fluid and the substrate. Displacement of ternary fluid flows on the substrate leads to the occurrence of moving contact point, at which three moving contact lines meet. We proposed a weighted contact angle model, to replace the jump in contact angle at the contact point by a relatively smooth transition of contact angle over a region of ‘diffuse contact point’ of finite size. Based on this model, we extended the geometrical formulation of wetting condition for two-phase flows with moving contact lines to ternary flows with moving contact lines. Combining this wetting condition, a Navier–Stokes solver and a ternary-fluid model, we simulated two-dimensional spreading of a compound droplet on a substrate, and validated the numerical results of the drop shape at equilibrium by comparing against the analytical solution. We also checked the convergence rate of the simulation by investigating the axisymmetric drop spreading in a capillary tube. Finally, we applied the model to a variety of applications of practical importance, including impact of a circular cylinder into a pool of two layers of different fluids and sliding of a three-dimensional compound droplet in shear flows. [ABSTRACT FROM AUTHOR]

The present study was conducted to investigate the protective effect of betulin, a triterpene from the bark of Betula platyphylla Suk, against ethanol-induced alcoholic liver injury and its possible underlying mechanisms. In vitro , human hepatic stellate cell line, LX-2 cells were treated with betulin (6.25, 12.5 and 25 μM) prior to ethanol (50 mM) for 24 h. Cell viability was analyzed by methyl thiazolyl tetrazolium assay, protein expressions were assessed by Western blot. In vivo , we induced alcoholic liver injury in male C57BL/6 mice, placing them on Lieber-DeCarli ethanol-containing diets for 10 days and then administering a single dose of ethanol (5 g/kg body weight) via gavage. Betulin (20 and 50 mg/kg) were given by gavage every day. In vitro results showed that betulin effectively decreased LX-2 cell viability, attenuated collagen-I, α-smooth muscle actin (α-SMA) levels, activated liver kinase B-1 (LKB1) and adenosine monophosphate-activated protein kinase (AMPK) phosphorylation. Betulin suppressed the expression of sterol regulatory element-binding protein-1 (SREBP-1), and genetic deletion of AMPK blocked the effect of betulin on SREBP-1 in ethanol treated LX-2 cells. In vivo , betulin attenuated the increases in serum aminotransferase and triglyceride levels in the mice fed with chronic-binge ethanol, while significantly inhibited SREBP-1 expression and activated LKB1-AMPK phosphorylation. Additionally, betulin enhanced the sirtuin 1 (SIRT1) expression mediated by ethanol. Taken together, betulin alleviates alcoholic liver injury possibly through blocking the regulation of SREBP-1 on fatty acid synthesis and activating SIRT1-LKB1-AMPK signaling pathway. [ABSTRACT FROM AUTHOR]

Acanthoic acid (AA) is a pimaradiene diterpene isolated from the root bark of Acanthopanax koreanum Nakai (Araliaceae) with a wide range of pharmacological activities, including anti-cancer, anti-inflammatory, anti-diabetes, liver protection, gastrointestinal protection, and cardiovascular protection. In addition, AA promotes its pharmacological effects by targeting liver X receptors (LXRs), nuclear factor-kappa B (NF-κB), Toll-Like Receptor 4 (TLR4) and IL-1 receptor-associated kinase (IRAK) signaling pathways, or AMP-activated protein kinase (AMPK) signaling pathway, etc. Also, some studies focus on the structural modification of AA to improve its pharmacological activities. The review summarizes the pharmacological activities, molecular mechanism, and the structural modification of AA, which might supply information for the development of AA in the future. [Display omitted] • Acanthoic Acid is active ingredient from Acanthopanax koreanum Nakai (Araliaceae). • A Review on the pharmacology, molecular mechanism, and structural modification of AA. • Provide experimental and theoretical basis for the research of AA and its derivatives. • Benefit for the development of new drugs based on Acanthoic acid. [ABSTRACT FROM AUTHOR]

In this study, a series of novel naphthalimide-benzotriazole conjugates (1a – 3c) based on 1, 8-naphthalimide as a core skeleton, aiming at G-quadruplexes, were designed and synthesized, and their anti-cancer activity and mechanism were studied. Using the CCK-8 assay, FRET melting, EMSA, CD, and molecular docking, intracellular assays, western blotting, immunofluorescence, and flow cytometry. By the CCK-8 assay, it was found that the compound, 2-(3-(piperazin-1-yl)propyl)-6-(1H-benzo [d][1,2,3]triazol-1-yl)-1 H -benzo[ de ]isoquinoline-1,3(2 H)-dione (3a), has better activity against A549 cells. Through extracellular assays, including FRET melting, EMSA, CD, and molecular docking, results showed that 3a selectively interacted with BCL2 G-quadruplex(es). Further studies by intracellular assays, including western blotting, immunofluorescence, flow cytometry, etc., verified that 3a mediated the death of A549 cells by two pathways: inhibition of the expression of the BCL2 gene, causing tumor cell apoptosis, and promotion of genetic instability, causing autophagy. This study suggests that the type of compounds, in particular, 3a , may be a potential molecule to explore for BCL2 G-quadruplex-targeted drugs against lung cancer. Our findings demonstrate that compound 3a as a BCL2 G-quadruplex ligand induces DNA damage, autophagy, and apoptosis in A549 cells. This study provides us with a type of lead compound as an anti-tumor drug. [Display omitted] • 9 novel naphthalimide-benzotriazole conjugates were synthesized. • 3a showed the strongest inhibitory activity against A549 cells. • 3a stabilized Bcl-2 G-quadruplexes and induced apoptosis and autophagic cell death. [ABSTRACT FROM AUTHOR]

Targeting hepatic stellate cells (HSCs) can improve the therapeutic efficacy of medicines used to treat hepatic fibrosis. The present work aimed to study the feasibility of homing devices with vitamin A(V A) chemically attached for delivering betulin(Bt)specifically to HSCs. The manufacture and characterisation of V A modified poly (ethylene glycol) -poly (lactide-co-glycolide) block copolymer micelles loaded with Bt (Bt/ V A PPMs) and their potential therapeutic benefits in vitro and in vivo are described in this paper. Bt/V A PPMs were made in a nearly spherical core-shell configuration with diameters under 200nm. In vitro release study showed that Bt/V A PPMs exhibited steady and continuous release for over 168 hours. Bt/V A PPMs had good biocompatibility at the cellular level, according to the safety evaluation, and elicited no inflammatory response in mice. More importantly, as uptake behavior studied in cells and bioimaging experiments in vivo , Bt/V A PPMs exhibited an instinctive liver- targeting capability to focus on activated HSCs. Efficacy tests revealed that administering Bt/V A PPMs effectively inhibits collagen I expression in LX-2 cells in vitro , and this effect was also seen in a mouse model of liver fibrosis. Overall, results demonstrated that Bt/V A PPMs is a promising drug delivery system that possesses specific HSCs targeting ability for treating hepatic fibrosis. [Display omitted] [ABSTRACT FROM AUTHOR]

Using an appropriate method to filter the atmospheric CO 2 mole fractions is not only essential to understand the long-term trend in regional areas but also to study the sources/sinks in the vicinity of the observatory, especially for regional stations where the observed records are frequently influenced by local sources/sinks. In this study, four data selection approaches are used to filter the observed atmospheric CO 2 records from 2009 to 2013 at the Longfengshan (LFS) World Meteorological Organization/Global Atmosphere Watch (WMO/GAW) regional station located in northeastern China. The methods include the methane tracer method (CT), black carbon tracer method (BC), robust extraction of the baseline signal (REBS), and meteorological method (MET). All four methods can accurately capture CO 2 seasonal cycles. However, the CT and REBS induce errors on seasonal value estimations, typically in summer. The BC and MET are better to separate the CO 2 mole fractions into regional or local events, but the BC slightly underestimates the regional CO 2 values during the winter–spring period. In general, the MET is the most reasonable to identify the influence of local sources/sinks and is suitable to be applied at other regional stations. By using the MET, the annual growth rate of regional CO 2 at LFS is calculated to be 3.0 ± 0.8 ppm yr −1 (1−σ) from 2009 to 2013. [ABSTRACT FROM AUTHOR]

[Display omitted] • J-1063 suppressed ECM deposition in HSCs, preventing the progress of HSCs transdifferentiation. • J-1063 exerted its anti-hepatic fibrosis activity by inhibiting the activation of TGF-β/Smad signaling pathway. • J-1063 prevented fibrotic inflammation by inhibiting the activation of NLRP3 inflammasome. • J-1063 inhibited the infiltration of macrophages and neutrophils in TAA-induced liver fibrosis. In the present study, we completed the synthesis of a pyrazole derivative J-1063 and evaluated the kinase inhibitory activity of J-1063 activin receptor-like kinase 5 (ALK5) and p38α mitogen-activated protein (MAP) in the enzymatic assay. We evaluated anti-fibrotic effects of J-1063 on TGF-β-induced hepatic stellate cells activation and TAA induced mice liver fibrosis. J-1063 showed much prior anti-fibrotic effects than those with LY2157299. Our data revealed that J-1063 exerted anti-fibrotic activity by inhibiting TGF-βR1 (ALK5), which is likely related to the inhibition of TGF-β--Smad signaling and NLRP3 inflammasome activation. The results suggest that J-1063 might be potential candidates for further anti-liver fibrosis drug development. [ABSTRACT FROM AUTHOR]

Abstract: Ethanol consumption leads to many kinds of liver injury and suppresses innate immunity, but the molecular mechanisms have not been fully delineated. The present study was conducted to determine whether betulinic acid (BA) or betulin (BT) would ameliorate acute ethanol-induced fatty liver in mice, and to characterize whether Toll like receptor 4 (TLR4) and signal transducer and activator of transcription 3 (STAT3) were involved in ethanol-stimulated hepatic stellate cells (HSCs). EtOH (5mg/kg) and BA or BT (20 or 50mg/kg) were applied in vivo, while EtOH (50mM) and BA or BT (12.5 or 25μM) were applied in vitro. Administration of BA or BT significantly prevented the increases of serum ALT and AST caused by ethanol, as well as serum TG. Supplement of BA or BT prevented ethanol-induced acidophilic necrosis, increased hepatocyte nuclei and stromal inflammation infiltration as indicated by liver histopathological studies. Administration of BA or BT significantly decreased CYP2E1 activities and expression of SREBP-1caused by ethanol, however, lower dosage of BA or BT showed slight effects on CYP2E1 activity or expression of SREBP-1c. BA or BT administration significantly decreased the expression of TLR4, and increased the phosphorylation of STAT3. In vitro, BA or BT treatment reduced the expressions of α-SMA and collagen-I in ethanol-stimulated HSCs via regulation of TLR4 and STAT3, coincided with in vivo. All of these findings demonstrated that BA or BT might ameliorate acute ethanol-induced fatty liver via TLR4 and STAT3 in vivo and in vitro, promising agents for ethanol-induced fatty liver therapies. [Copyright &y& Elsevier]

Abstract: Cryptotanshinone (CTN), one of the major constituents of tanshinones, was investigated for anti-inflammatory activity in the murine macrophage cell line RAW 264.7. CTN inhibited the production of nitric oxide (NO) production, as well as expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) in lipopolysaccharide (LPS)-stimulated macrophages. Since CTN was considered as inhibiting LPS-triggered phosphorylation of mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-κB activation, we consequently evaluated the expression of toll-like receptor 4 (TLR4) and CD14, as well as phosphorylation of TGF-β-activated kinase 1 (TAK1). CTN reduced the expression of CD14 and TLR4, and suppressed LPS-induced phosphorylation of TAK1. Furthermore, CTN significantly increased the survival rate against LPS challenge in D-galactosamine-sensitized mice, which was in line with in vitro results. These results suggested that CD14/TLR4 and TAK1 might be the potential molecular targets for addressing the protective effects of CTN on LPS-induced inflammatory effects in macrophages. [Copyright &y& Elsevier]

Abstract: A hybrid iodoargentate [(APHEN-H)2(Ag4I6)] n (1) (APHEN=5-amino-1,10-phenanthroline) has been obtained by the routine synthetic reaction and structurally determined. In 1, a chain was defined by edge-sharing of Ag4I6 units, and its quasi-three-dimensional hybrid structure was constructed from π–π interactions and CI hydrogen bonds. Experimental band gap of about 2.30eV indicates its semiconductor nature. Strong luminescence can be detected in the title compound, which has been assigned by theoretical calculation with DFT method. [Copyright &y& Elsevier]