Tetramethylpyrazine inhibits neutrophil extracellular traps formation and alleviates hepatic ischemia/reperfusion injury in rat liver transplantation.

Hepatic ischemia/reperfusion injury (IRI) is an adverse effect for liver transplantation which is characterized by immune response mediated inflammation. Recent studies report that neutrophil extracellular traps (NETs) are implicated in hepatic IRI. The aim of this study was to explore the mechanism of action of tetramethylpyrazine (TMP), the main chemical composition of Ligusticum chuanxiong in treatment of ischemic related diseases. Data showed that hepatic IRI increases the leak of alanine aminotransferase (ALT) and aspartate transaminase (AST), and stimulates formation of NETs. Extracellular DNA/NETs assay, hematoxylin-eosin (HE) staining, immunofluorescence assay, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) and Western blot assay, showed that TMP significantly reduces formation of NETs and alleviates hepatic IRI. Moreover, TMP and Diphenyleneiodonium (DPI) suppressed ROS production in neutrophils. In addition, analysis showed that activation of NADPH oxidase plays a role in formation of NETs triggered by hepatic IRI. Notably, TMP inhibited formation of NETs though inhibition of NADPH oxidase. Additionally, Combination treatment using TMP and DPI was more effective compared with monotherapy of either of the two drugs. These findings show that combination therapy using TMP and DPI is a promising method for treatment hepatic IRI.

miR-505-5p alleviates acute rejection of liver transplantation by inhibiting Myd88 and inducing M2 polarizationof Kupffer cells.

The occurrence of acute rejection after liver transplantation seriously impairs the prognosis of patients. miRNA is involved in many physiological and pathological processes of the body, but the mechanism of miRNA action in liver transplantation is not completely clear. In this study, we discuss the role of miR-505-5p in acute rejection after liver transplantation and its putative regulating mechanism. We construct an allogeneic rat liver transplantation model, observe the morphological and pathological changes in liver tissue, detect the expression levels of Myd88, miR-505-5p, IL-10 and TNF-α, and confirm that Myd88 is one of the direct targets of miR-505. The effects of miR-505-5p on the Myd88/TRAF6/NF-κB and MAPK pathways are detected both in vitro and in vivo, and the standard markers of Kupffer cell M1/M2 polarization are also detected. The results of qRT-PCR experiments show that miR-505-5p has a downward trend in rats with acute rejection. Western blot analysis reveals that over-expression of miR-505-5p induces the reduction of NF-κB and MAPK pathways both in vitro and in vivo. The role of miR-505-5p in alleviating acute rejection after transplantation may be accomplished by inducing M2-type polarization of Kupffer cells. In conclusion, we find that miR-505-5p alleviates acute rejection of liver transplantation by inducing M2 polarization of macrophages via the Myd88/TRAF6 axis, which suggests a potential strategy based on miRNAs in the follow-up treatment of liver transplantation.

Efficient saccharification of Lycium barbarum leaf biomass by using enzyme cocktails produced by a novel fungus Aspergillus costaricensis LS18.

The utilization of agro-industrial residues is an interesting issue contributing to sustainable development and environmental protection. Lycium barbarum leaves (LBL) are agro-industrial residues of the L. barabrum berry cultivation and seriously underutilized, leading to resource waste and environmental pollution. In this study, we prepared cost-effective enzyme cocktails with high xylanase activity from a novel soil-derived fungal strain Aspergillus costaricensis LS18. The xylanase activity of these on-site produced enzyme cocktails was 3.49 ± 0.55 U/mL. Through the hydrolysis using the enzyme cocktails with 6% substrate loading at 45 °C for 12 h, 86.57 ± 1.81% of total reducing sugars (RS) from LBL was released. The concentration of RS in the hydrolysates reached 8.17 ± 0.33 mg/mL. In this study, LBL were added values by two mutually independent bioprocess ways. On the one hand, LBL were used as the only nutrients in the medium for the on-site production of enzyme cocktails by fermentation. On the other hand, through hydrolysis using this enzyme cocktail, LBL biomass was efficiently hydrolyzed and fermentable monosugars were gained. This study could benefit to the exploitation of LBL resources and provide the references for utilization of other agro-industrial residues.

Salidroside alleviates hepatic ischemia-reperfusion injury during liver transplant in rat through regulating TLR-4/NF-κB/NLRP3 inflammatory pathway.

Salidroside has anti-inflammatory, antioxidant and hepatoprotective properties. However, its effect on hepatic ischemia-reperfusion injury (IRI), an unavoidable side effect associated with liver transplantation, remains undefined. Here, we aimed to determine whether salidroside alleviates hepatic IRI and elucidate its potential mechanisms. We used both in vivo and in vitro assays to assess the effect and mechanisms of salidroside on hepatic IRI. Hepatic IRI rat models were pretreated with salidroside (5, 10 or 20 mg/kg/day) for 7 days following liver transplantation while hypoxia/reoxygenation (H/R) model of RAW 264.7 macrophages were pretreated with salidroside (1, 10 or 50 µM). The effect of salidroside on hepatic IRI was assessed using hematoxylin-eosin staining, terminal deoxynucleotidyl transferase dUTP nick-end labeling staining, qRT-PCR, immunosorbent assay and western blotting. Our in vivo assays showed that salidroside significantly reduced pathological liver damage, serum aminotransferase levels and serum levels of IL-1, IL-18 and TNF-α. Besides, salidroside reduced the expression of TLR-4/NF-κB/NLRP3 inflammatory pathway associated proteins (TLR-4, MyD88, p-IKKα, p-IKKß, p-IKK, p-IκBα, p-P65, NLRP3, ASC, Cleaved caspase-1, IL-1ß, IL-18, TNF-α and IL-6) in rats after liver transplantation. On the other hand, data from the in vitro analysis demonstrated that salidroside blocks expression of TLR-4/NF-κB/NLRP3 inflammatory pathway related proteins in the RAW264.7 cells treated with H/R. The salidroside-specific anti-inflammatory effects were partially inhibited by the TLR-4 agonist lipopolysaccharide. Taken together, our study showed that salidroside inhibits hepatic IRI following liver transplantation by modulating the TLR-4/NF-κB/NLRP3 inflammatory pathway.

Traditional uses, phytochemistry, pharmacology and current uses of underutilized Xanthoceras sorbifolium bunge: A review.

ETHNOPHARMACOLOGICAL RELEVANCE: The Plant Xanthoceras sorbifolium Bunge (X. sorbifolia) has a long history of medicinal use as a traditional Chinese herbal medicine to deal with sterilizing, killing sperm, stabilizing capillary, hemostasis, lowering cholesterol, rheumatism, and pediatric enuresis. Additionally, X. sorbifolia is an oil crop for the production of edible oil due to the health-promotion effect. In recent years, X. sorbifolia has attracted worldwide attention as an important economic crop with low investment and high-income potential. AIM OF THE REVIEW: This review aims to provide a comprehensive appraisal of X. sorbifolia, including the traditional uses, nutrients, phytochemical data, biological activities, and current applications. The natural compounds of X. sorbifolia and potential utilization in pharmacology are highlighted. The aim of this review is to inspire the research enthusiasm to X. sorbifolia and promote the comprehensive utilization of X. sorbifolia. MATERIALS AND METHODS: The research information of X. sorbifolia was collected via Elsevier, American Chemical Society (ACS), PubMed, Web of Science, China National Knowledge Infrastructure (CNKI), Baidu scholar, and Google scholar. Additionally, some information was collected from Ph.D. and Master's dissertations, as well as local books. RESULTS: The identification of approximately 195 major phytochemical compounds from different parts of X. sorbifolia is presented in this review, including triterpenoids, flavonoids, phenolic acids, coumarins, lignans, meroterpenoids, monoterpene, alkaloids, and sterol. Among them, triterpenoids, flavonoids, and phenolic acids are the major compounds. Extracts from X. sorbifolia exhibited a wide range of biological activities, such as antioxidant, antibacterial, anti-tumor, anti-neuroinflammatory, anti-adipogenesis, anti-obesity, anti-HIV, gastroprotective, immunoregulatory, and anti-inflammatory activities. CONCLUSIONS: Modern pharmacological studies have been well supported and clarified the traditional medicinal uses of X. sorbifolia, which brought a promising prospect for the pharmaceutical value of this plant. However, the related mechanisms between the structure and pharmacological effects were seldom reported. Also, at present, effective and in-depth research on X. sorbifolia is still relatively lacking. Moreover, there is little research on toxicological experiments. Further clinical trials should also be performed to accelerate the drug research and development.

Thrombomodulin-mediated Inhibition of Neutrophil Extracellular Trap Formation Alleviates Hepatic Ischemia-reperfusion Injury by Blocking TLR4 in Rats Subjected to Liver Transplantation.

BACKGROUND: Hepatic ischemia-reperfusion injury (IRI) is an unavoidable outcome of liver transplantation, during which neutrophil extracellular traps (NETs) may play a critical role in the IRI-induced immune response to inflammation. The purpose of this study was to identify the function of recombinant human thrombomodulin (rTM) in the remission of hepatic IRI after liver transplantation and elucidate the specific mechanism. METHODS: NET formation (NETosis) was detected in the serum of liver transplantation patients and rats following liver transplantation. Hematoxylin-eosin staining, terminal deoxynucleotidyl transferase 2´-deoxyuridine, 5´-triphosphate nick-end labeling staining, immunohistochemistry, and immunofluorescence were used to assess the effect of rTM on NETosis in vitro and in vivo. RESULTS: We found that rTM markedly inhibited neutrophil formation in NETs, reduced apoptosis in hepatocytes, alleviated rat hepatic IRI, and improved liver function. In vitro, rTM inhibited neutrophil formation in NETs, and lipopolysaccharide (a Toll-like receptor 4 agonist) reversed the inhibitory effect of rTM on NETosisN. rTM blocked a Toll-like receptor 4 and the downstream extracellular signal-regulated kinase/c-Jun NH2 terminal kinase and nicotinamide adenine dinucleotide phosphate (NADPH)/reactive oxygen species/peptidylarginine deiminase 4 signaling pathways to protect against hepatic IRI and inhibit NETosis. In addition, we demonstrated that combined treatment with rTM and an NADPH oxidative inhibitor had a better effect than either treatment alone. CONCLUSIONS: NETs are a potential therapeutic target in hepatic IRI, and rTM could be used to prevent IR-induced hepatic injury. In addition, cotargeting NETosis-related signaling pathways might be a novel therapeutic strategy for hepatic IRI treatment.

Diphenyleneiodonium ameliorates acute liver rejection during transplantation by inhibiting neutrophil extracellular traps formation in vivo.

Neutrophil extracellular traps (NETs) play critical roles in hepatic ischemic reperfusion injury (IRI) induced immune responses to inflammation. Diphenyleneiodonium (DPI) is an NADPH oxidative inhibitor that has been implicated in the regulation of NETs formation. However, the effects of NETs and their underlying mechanisms during DPI treatment of acute rejection (AR) after liver transplantation have not been elucidated. This study tested the hypothesis that blocking NETs formation by DPI treatment could be a potential therapeutic target against AR after liver transplantation. NETs were found to be excessively formed within the livers and serum of transplantation models, which could be an independent risk factor for AR. DPI was shown to alleviate hepatic injury and maintain liver functions by inhibiting NETs formation through the nicotinamide adenine dinucleotide phosphate (NADPH)/ROS/peptidylarginine deiminase 4 (PAD4) signaling pathway. NETs are highly involved in AR after liver transplantation. By inhibiting NETs formation, DPI suppresses activation of the NADPH/ROS/PAD4 signaling pathway which acts against AR after liver transplantation. Therefore, DPI is a potential candidate for the therapeutic management of AR after liver transplantation. Combination treatment containing both DPI and tacrolimus revealed a better antidamage efficacy than adjusting either treatment alone, suggesting that the joint therapy might be a promising solution in AR after liver transplantation.

FBXW5 aggravates hepatic ischemia/reperfusion injury via promoting phosphorylation of ASK1 in a TRAF6-dependent manner.

Liver ischemia/reperfusion injury (IRI) is an inevitable pathological process exacerbating the occurrence of rejection in liver transplantation. At present, there is still a lack of sufficient cognition for the mechanism as well as effective clinical strategies. F-box/WD repeat-containing protein 5 (FBXW5), a key modulator of stress signalling, was recently reported to participate in hepatic immunity. However, the role of FBXW5 in liver IRI is still unclear. In the present study, we found expression of FBXW5 was increased in liver IRI both in vivo and in vitro. Inhibition of FBXW5 significantly alleviated both mitogen-activated protein kinase (MAPK) and inhibitor of nuclear factor kappa-B kinase (IKK) pathways, thus resulting in cytokine release, hepatic pathological injury and apoptosis. Over-expression of FBXW5 achieved an opposite effect. Investigations on the mechanism showed that FBXW5 intensified hepatic inflammation by promoting phosphorylation of ASK1, while blockade of TRAF6 could abolish this process. Moreover, reinforce of mTOR amplified the anti-inflammatory efficacy derived from inhibition of FBXW5, indicating the function of FBXW5/ASK1/TRAF6 axis in hepatic IRI might be relatively independent of mTOR-guided M2 polarization of Kupffer cell. Taken together, FBXW5 could be a key accelerator in liver IRI by enhancing activation of ASK1 in a TRAF6-dependent manner. The joint intervention towards both FBXW5 and mTOR might be a promising strategy to protect liver from IRI.

Saccharogenic refining of Ginkgo biloba leaf residues using a cost-effective enzyme cocktail prepared by the fungal strain A32 isolated from ancient ginkgo biloba tree.

To reduce environmental pollution and waste of biomass from Ginkgo biloba leaf residues (GBLRs), we developed a cost-effective enzyme system to hydrolyze GBLRs into available reducing sugars (RS). Biomass characteristics of GBLRs were investigated, which indicated that the acid hydrolyzed fraction was 49.43% of the dry weight of GBLRs. The fraction could be effectively converted into RS by an enzyme cocktail with high polygalacturonase activity without traditionally intricate pretreatment. The strain A32 isolated from the ancient ginkgo soil was used for the production of the enzyme cocktail, and a response surface methodology was used to optimize the enzymatic production. The enzyme cocktail released 87.2% of RS from GBLRs at 35 â„ƒ for 72 h with 1% (m/v) of loading, and the RS concentration arrived 8.95 ± 0.39 mg/ml with 9% of GBLRs loading. The cost-effective system of self-prepared enzyme cocktail is promising for facilitating GBLRs' bio-based industry.