1-Pyrroline-5-carboxylate inhibit T cell glycolysis in prostate cancer microenvironment by SHP1/PKM2/LDHB axis.

BACKGROUND: Our previous studies demonstrated that 1-Pyrroline-5-carboxylate (P5C) released by prostate cancer cells inhibits T cell proliferation and function by increasing SHP1 expression. We designed this study to further explore the influence of P5C on T cell metabolism, and produced an antibody for targeting P5C to restore the functions of T cells. METHOD: We co-immunoprecipated SHP1 from T cells and analyzed the proteins that were bound to it using liquid chromatography mass spectrometry (LC/MS-MS). The influence of P5C on T cells metabolism was also detected by LC/MS-MS. Seahorse XF96 analyzer was further used to identify the effect of P5C on T cells glycolysis. We subsequently designed and produced an antibody for targeting P5C by monoclonal technique and verified its effectiveness to restore the function of T cells in vitro and in vivo. RESULT: PKM2 and LDHB bind SHP1 in T cells, and P5C could increase the levels of p-PKM2 while having no effect on the levels of PKM2 and LDHB. We further found that P5C influences T cell energy metabolism and carbohydrate metabolism. P5C also inhibits the activity of PKM2 and decreases the content of intracellular lactic acid while increasing the activity of LDH. Using seahorse XF96 analyzer, we confirmed that P5C remarkably inhibits glycolysis in T cells. We produced an antibody for targeting P5C by monoclonal technique and verified that the antibody could oppose the influence of P5C to restore the process of glycolysis and function in T cells. Meanwhile, the antibody also inhibits the growth of prostate tumors in an animal model. CONCLUSION: Our study revealed that P5C inhibits the process of glycolysis in T cells by targeting SHP1/PKM2/LDHB complexes. Moreover, it is important that the antibody for targeting P5C could restore the function of T cells and inhibit the growth of prostate tumors.

Suppresses of LIM kinase 2 promotes radiosensitivity in radioresistant non-small cell lung cancer cells.

Radiation resistance has always been one of the main obstacles to tumor radiotherapy. Therefore, understanding the mechanisms underlying radiotherapy resistance is a focus of research. In this study, we induced two radiation-resistant cell lines to mimic the radiation resistance of NSCLC and investigated the mechanisms of radiotherapy resistance. Cell radiosensitivity was analyzed by single-cell gel electrophoresis, colony formation and tumor sphere formation assays. A wound healing assay was used to analyze cell migration. Western blotting and siRNA were used to identify the potential mechanism. In animal model experiments, xenograft tumors were used to verify the difference between radiotherapy-resistant and nonresistant NSCLC models after radiotherapy. Our results showed that NSCLC radiation-resistant cells exhibited more radioresistance and migratory abilities under low-dose irradiation. The expression of LIMK2 and p-CFL1 were upregulated in NSCLC radiation-resistant cells. Knockdown of LIMK2 significantly enhanced the radiosensitivity of NSCLC-resistant cells. In vivo, low-dose radiotherapy suppressed tumor growth, induced apoptosis and upregulated the expression of LIMK2 in xenograft tumors. However, radiotherapy had little effect on the NSCLC radiation resistance model. In conclusion, NSCLC radiation-resistant cells exhibit more radioresistance and migratory ability under low-dose irradiation. Strikingly, knockdown of LIMK2 enhanced the radiosensitivity of NSCLC-resistant cells.

Pan-cancer analysis identified OAS1 as a potential prognostic biomarker for multiple tumor types.

Background: 2',5'-oligoadenylate synthetase 1 (OAS1), has been reported as a tumor driver gene in breast carcinoma and pancreatic carcinoma. However, the role of OAS1 in most tumors has not been reported. Methods: The original data of 35 tumor types were down load from the TCGA (The Cancer Genome Atlas) database and Human Protein Atlas (HPA) database. TIMER2, Kmplot, UALCAN, and TISIDB tools were used to investigate the expression and function of OAS1, and the role of OAS1 in prognosis, diagnostic value, and immune characteristics of pan-cancer. LUAD and PRAD cell lines, A549, H1975, PC-3 and C4-2 were utilized to perform cell function tests. Results: OAS1 expression was up-regulated in 12 tumor types and down-regulated in 2 tumor types. High OAS1 expression was correlated with poor prognosis in 6 tumor types, while high OAS1 expression was correlated with good prognosis in 2 tumor types. OAS1 was correlated with molecular subtypes in 8 tumor types and immune subtypes in 12 tumor types. OAS1 was positively associated with the expression of numerous immune checkpoint genes and tumor mutational burden (TMB). OAS1 had potential diagnostic value in 15 tumor types. Silence of OAS1 significantly inhibited the cell proliferation ability, and promoted G2/M cell cycle arrest of LUAD and PRAD cells. Meanwhile, silence of OAS1 enhanced cisplatin-induced apoptosis of LUAD and PRAD cells, but weakened cell migration. Conclusion: This pan-cancer study suggests that OAS1can be used as a molecular biomarker for prognosis in pan-cancer and may play an important role in tumor immune response.

GRAP2 is a prognostic biomarker and correlated with immune infiltration in lung adenocarcinoma.

BACKGROUND: GRAP2 is an adaptor protein involved in leukocyte signal activation; however, the prognostic value of GRAP2 and its correlation with immune infiltration in lung adenocarcinoma (LUAD) are unclear. METHODS: Original data were downloaded from the TCGA database and Gene Expression Omnibus (GEO) database. GRAP2 expression was analyzed with the TCGA and TIMER databases. We evaluated the influence of GRAP2 on clinical prognosis using the Kaplan-Meier plotter, GEO, and GEPIA database. The TIMER and TISIDB databases were used to investigate correlations between GRAP2 expression and cancer immune characteristics. Finally, we confirmed the expression of GRAP2 in LUAD by immunohistochemistry staining. RESULTS: The transcription levels of GRAP2 were significantly lower in several human cancer types, including LUAD, than in adjacent normal tissues. Immunohistochemistry staining confirmed that LUAD tumor tissues had lower GRAP2 protein expression levels than adjacent normal tissues. GRAP2 downregulation was associated with poorer overall survival, pathologic stage, T stage, N stage, and primary therapy outcome in LUAD. Mechanistically, we found a hub gene set that included a total of 91 genes coexpressed with GRAP2, which were closely related to the immune response in LUAD. The expression levels of GRAP2 were positively correlated with the infiltration levels of multiple immune cells and the cumulative survival time of a few immune cells. GRAP2 expression was found to be positively correlated with that of multiple immune markers, chemokines, chemokine receptors, and MHC molecules in LUAD. CONCLUSIONS: GRAP2 can be used as a biomarker for assessing prognosis and immune infiltration levels in LUAD.

Efficient and Durable Flame-Retardant Coatings on Wood Fabricated by Chitosan, Graphene Oxide, and Ammonium Polyphosphate Ternary Complexes via a Layer-by-Layer Self-Assembly Approach.

An efficient and durable flame-retardant coating was constructed on wood via a layer-by-layer (LBL) self-assembly approach by using a chitosan (CS), graphene oxide (GO), and ammonium polyphosphate (APP) ternary flame-retardant system. Both scanning electron microscopy (SEM) characterization and Fourier transform infrared spectroscopy (FT-IR) analysis indicated that CS-GO and APP polyelectrolytes were successfully deposited on wood, and the deposition amount was increased with the numbers of the LBLs. Thermogravimetric analysis revealed that the CS-GO-APP coating could decrease the initial and maximum thermal decomposition temperature of the coated wood while increase the char residue significantly, which may be attributed to the earlier degradation of CS and APP and effective heat barrier of the incorporated GO, thus increasing the thermal stability of the modified wood. The limited oxygen index (LOI) and cone calorimeter analysis results of the pristine and coated wood indicated that the fire resistance was significantly improved after CS-GO-APP modification; when 15 BLs were deposited on the wood, the LOI was increased from pristine 22 to 42, while the heat release rate and total heat release decreased from pristine 105.50 kW/m2 and 62.43 MJ/m2 to 57.51 kW/m2 and 34.31 MJ/m2, respectively. What is more, the 24 h immersion experiments and abrasion tests proved the excellent durability of the deposited coating. Furthermore, the SEM images of the char residues after flaming test proved that the CS-GO-APP assembly coating could promote the char layer formation on the wood surface and block the heat and flame spread, thus protecting the wood from fire attacking.

Fabrication of Durable Hydrophobic/Superhydrophobic Wood Using an Alkyl Ketene Dimer by a Simple and Feasible Method.

To improve the hydrophobicity of precious hardwood, a facile sanding pretreatment and alkyl ketene dimer (AKD) modification were performed. After the AKD modification, the wood was highly hydrophobic, and the contact angle was 143°. The increased hydrophobicity could be attributed to the ester bond formed between the wood hydroxyl groups and AKD, which was confirmed by attenuated total reflectance-Fourier transform infrared spectroscopy. Sanding pretreatment could further greatly increase the wood hydrophobicity and render it superhydrophobic, not only in a cross-section but also in the tangential and radial sections. The changed wood surface roughness could be responsible for the increased hydrophobicity, which was confirmed by characterization with a scanning electron microscope (SEM) and a three-dimensional optical microscope. Apart from the improved hydrophobicity, the AKD-modified wood exhibited excellent water, acid, and toluene resistance. After a 12 h immersion, the contact angle did not change significantly, and the acid immersion contributed to an improvement in the hydrophobicity of the wood. Furthermore, the resultant AKD-modified wood exhibited an excellent self-cleaning effect.

Dry Sliding Tribological Behaviors of Electrodeposited Ni-GO/SiC Composite Coating on the 2218 Aluminum Alloy.

Electrodeposition has attracted tremendous interest in functional coatings due to its advantages of high efficiency, inexpensiveness and ease of implementation. In this work, nickel graphene oxide (Ni-GO), nickel silicon carbide (Ni-SiC) and nickel graphene oxide/silicon carbide (Ni-GO/SiC) composite coatings were electrodeposited on the 2218 aluminum alloy (2218AlA) substrate. The microstructure, microhardness, bonding strength and tribological behaviors of the composite coatings were carried out. According to the results obtained, the composite coatings were dense and compact, with no visible defects and microcracks, and well bonded to 2218AlA substrate. The microhardness of composite coatings was significantly increased compared to that of the 2218AlA substrate. The microhardness of Ni-SiC composite coating was the highest, reaching 3.14 times that of the 2218AlA substrate. The friction response time, friction coefficient and wear rate of the composite coatings were obviously lower. For the Ni-GO composite coating, the average friction coefficient is the smallest at 45.35% of the 2218AlA substrate, while the wear rate is the smallest at 46.97% of the 2218AlA substrate. However, the comprehensive tribological performances of the Ni-GO/SiC composite coating were superior. The abrasive and adhesive wear were the main wear mechanisms of composite coatings, but the degree of damage was different.

GPI Is a Prognostic Biomarker and Correlates With Immune Infiltrates in Lung Adenocarcinoma.

BACKGROUND: Glucose-6-phosphate isomerase (GPI) plays an important role in glycolysis and gluconeogenesis. However, the role of GPI in lung adenocarcinoma (LUAD) remains unclear. METHODS: All original data were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and integrated via R 3.2.2. GPI expression was explored with TCGA, GEO, and Oncomine databases. Immunohistochemistry staining was used to analyze GPI expression in clinical specimens. The correlations between GPI and cancer immune characteristics were analyzed via the TIMER and TISIDB databases. GPI-specific siRNAs were used to verify the role of GPI expression on cell proliferation and cell cycle distribution. RESULTS: In general, GPI is predominantly overexpressed and has reference value in the diagnosis and prognostic estimation of LUAD. Upregulated GPI was associated with poorer overall survival, clinical stage, N stage, and primary therapy outcome in LUAD. Mechanistically, we identified a hub gene that included a total of 56 GPI-related genes, which were tightly associated with the cell cycle pathway in LUAD patients. Knockdown of GPI induced cell proliferation inhibition and cell cycle arrest. GPI expression was positively correlated with infiltrating levels of Th2 cells and regulatory T cells (Tregs); in contrast, GPI expression was negatively correlated with infiltrating levels of CD8+ T cells, central memory T cells, dendritic cells, macrophages, mast cells, and eosinophils. GPI was negatively correlated with the expression of immunostimulators, such as CD40L, IL6R, and TMEM173, in LUAD. CONCLUSION: GPI may play an important role in the cell cycle and can be used as a prognostic biomarker for determining the prognosis and immune infiltration in LUAD.

Hardness Prediction of Grind-Hardening Layer Based on Integrated Approach of Finite Element and Cellular Automata.

As an emerging composite processing technology, the grind-hardening process implements efficient removal on workpiece materials and surface strengthening by the effective utilization of grinding heat. The strengthening effect of grind-hardening on a workpiece surface is principally achieved by a hardened layer, which is chiefly composed of martensite. As a primary parameter to evaluate the strengthening effect, the hardness of the hardened layer mostly depends on the surface microstructure of the workpiece. On this basis, this paper integrated the finite element (FE) and cellular automata (CA) approach to explore the distribution and variation of the grinding temperature of the workpiece surface in a grind-hardening process. Moreover, the simulation of the transformation process of "initial microstructure-austenite-martensite" for the workpiece helps determine the martensite fraction and then predict the hardness of the hardened layer with different grinding parameters. Finally, the effectiveness of the hardness prediction is confirmed by the grind-hardening experiment. Both the theoretical analysis and experiment results show that the variation in the grinding temperature will cause the formation to a certain depth of a hardened layer on the workpiece surface in the grind-hardening process. Actually, the martensite fraction determines the hardness of the hardened layer. As the grinding depth and feeding speed increase, the martensite fraction grows, which results in an increase in its hardness value.

Carbon Monoxide Inhibits T Cell Proliferation by Suppressing Reactive Oxygen Species Signaling.

Aims: Carbon monoxide (CO) confers antiproliferative effects on T cells; however, how these effects are produced remains unclear. Reactive oxygen species (ROS) have recently emerged as important modulators of T cell proliferation. In this study, we aimed to determine whether the inhibitory effects of CO on T cell proliferation are dependent on the inhibition of ROS signaling. Results: Pretreatment with CO-releasing molecule-2 (CORM-2) had potent inhibitory effects on mouse T cell proliferation stimulated by anti-CD3/CD28 antibodies. Interestingly, CORM-2 pretreatment markedly suppressed intracellular ROS generation as well as the activity of NADPH oxidase and mitochondrial complexes I-IV in T cells after stimulation. The inhibitory effects of CORM-2 on both ROS production and T cell proliferation were comparable with those produced by the use of antioxidant N-acetylcysteine or a combined administration of mitochondrial complex I-IV inhibitors. Moreover, increasing intracellular ROS via hydrogen peroxide supplementation largely reversed the inhibitory effect of CORM-2 on the proliferation of T cells. The inhibitory effects of CORM-2 on both cell proliferation and intracellular ROS production were also shown in a T cell proliferation model involving stimulation by allogeneic dendritic cells or phorbol 12-myristate 13-actetate/ionomycin, as well as in spontaneous cell proliferation models in EL-4 and RAW264.7 cells. In addition, CORM-2 treatment significantly inhibited T cell activation in vivo and attenuated concanavalin A-induced autoimmune hepatitis. Innovation: CO inhibits T cell proliferation via suppression of intracellular ROS production. Conclusion: The study could supply a general mechanism to explain the inhibitory effects of CO on T cell activation and proliferation, favoring its future application in T cell-mediated diseases.

Preparation and characterization of high-strength and water resistant lignocelluloses based composites bonded by branched polyethylenimine (PEI).

High-strength and water resistant lignocelluloses based composites (LC) were fabricated using branched polyethylenimine (PEI) as the main bonding agent combined with glutaraldehyde cross-linking reaction and grinding pre-treatment. Physical and mechanical properties of different composites prepared were measured and investigated. It is evident that PEI was efficient in endowing LC with high strength and excellent water resistance. The obtained physical and mechanical properties of LC were complied with the requirement of the Chinese national standard for medium-density fiberboard (MDF). Most notably, the glutaraldehyde cross-linking and grinding pre-treatment could further improve these properties. When 5% PEI and 2.5% glutaraldehyde were incorporated, together with 2-hour grinding treatment, the LC prepared exhibited the optimum modulus of rupture (MOR) 58.1 MPa, modulus of elasticity (MOE) 5077 MPa, internal bonding strength (IB) 2.14 MPa, and thickness swell (TS) 30.2%. The excellent properties obtained could be attributed to the cross-linking effect and Schiff's base addition reaction among lignocelluloses, PEI and glutaraldehyde, which were confirmed by the Fourier transform infrared spectroscopy (FT-IR) and X-ray photoelectron spectroscopy (XPS) analysis. The high-strength LC prepared in this study is expected to be used as load-bearing material in structural application.

Latency-associated nuclear antigen inhibits lytic replication of Kaposi's sarcoma-associated herpesvirus by regulating let-7a/RBPJ signaling.

Latency-associated nuclear antigen (LANA) is the key factor in the establishment and maintenance of latency of Kaposi's sarcoma-associated herpesvirus (KSHV). A cellular protein, recombination signal binding protein for immunoglobulin kappa J region (RBPJ), is essential for the lytic reactivation of KSHV. However, whether RBPJ expression is regulated by KSHV is not clear. Here, we show that LANA upregulates let-7a and its primary transcripts in parallel with its reduction of RBPJ expression. An increase in notch intracellular domain (NICD) and the downregulation of NF-κB and LIN28B contribute to the upregulation of let-7a by LANA. Let-7a represses RBPJ expression by directly binding the 3' untranslated region of RBPJ. Let-7a overexpression or RBPJ knockdown led to a dose- and time-dependent inhibition of lytic reactivation of KSHV. Collectively, these findings support a model wherein LANA inhibits the lytic replication of KSHV by regulating let-7a/RBPJ signaling.

1-Pyrroline-5-carboxylate released by prostate Cancer cell inhibit T cell proliferation and function by targeting SHP1/cytochrome c oxidoreductase/ROS Axis.

BACKGROUND: Tumor cell mediated immune-suppression remains a question of interest in tumor biology. In this study, we focused on the metabolites that are released by prostate cancer cells (PCC), which could potentially attenuate T cell immunity. METHODS: Prostate cancer cells (PCC) media (PCM) was used to treat T cells, and its impact on T cell signaling was evaluated. The molecular mechanism was further verified in vivo using mouse models. The clinical significance was determined using IHC in human clinical specimens. Liquid chromatography mass spectroscopy (LC/MS-MS) was used to identify the metabolites that are released by PCC, which trigger T cells inactivation. RESULTS: PCM inhibits T cells proliferation and impairs their ability to produce inflammatory cytokines. PCM decreases ATP production and increases ROS production in T cells by inhibiting complex III of the electron transport chain. We further show that SHP1 as the key molecule that is upregulated in T cells in response to PCM, inhibition of which reverses the phenotype induced by PCM. Using metabolomics analysis, we identified 1-pyrroline-5-carboxylate (P5C) as a vital molecule that is released by PCC. P5C is responsible for suppressing T cells signaling by increasing ROS and SHP1, and decreasing cytokines and ATP production. We confirmed these findings in vivo, which revealed changed proline dehydrogenase (PRODH) expression in tumor tissues, which in turn influences tumor growth and T cell infiltration. CONCLUSIONS: Our study uncovered a key immunosuppressive axis, which is triggered by PRODH upregulation in PCa tissues, P5C secretion in media and subsequent SHP1-mediated impairment of T cell signaling and infiltration in PCa.

CO suppresses prostate cancer cell growth by directly targeting LKB1/AMPK/mTOR pathway in vitro and in vivo.

BACKGROUND: CO is a freely diffusible gas that acts as a physiological mediator of many biological and cellular processes, which has been shown to possess anticancer effect in many kinds of cancers. However, the effect of CO on prostate cancer has not been demonstrated. Therefore, we analyzed the antitumor activities and related mechanisms of CO on prostate cancer in vitro and in vivo. METHODS: Cell viability of LNCaP and PC-3 cells after CORM-2 treatment was measured by CCK-8 assay, whereas the ATP production were detected by ATP detection assay. The early apoptosis induced by CO was evaluated by flow cytometry, and the expression level of apoptosis-related molecules (Caspases 3, 8, 9 and cleaved-Caspases 3, 8, 9) was detected using Western blot. Matrigel in vitro invasion assay was used to evaluate the effect of CO on cell invasion. We then evaluated the impact of CO on the expression of several key regulators involved in the LKB1 signaling pathway. At last, xenograft tumor in nude mice was used to further investigate the antitumor effect of CO in vivo. RESULTS: Our results showed that CO could significantly inhibit proliferation and invasion, and induce apoptosis in human prostate cancer cell lines. The expression of LKB1 could be up-regulated after CO treatment, and CO also could increase p-AMPK levels and decrease p-mTOR. Furthermore, LKB1 knockdown could weaken the effect of CO on prostate cancer cells. In vivo, CO treatment significantly suppressed tumor growth and induced apoptosis in xenografts tumor in nude mice. CONCLUSIONS: CO possesses striking anticancer effect in human prostate cancer cells in vitro and in vivo, which is largely mediated by LKB1-AMPK-mTOR axis.

Fabrication of Bi19S27I3 nanorod cluster films for enhanced photodetection performance.

Thin-film photodetectors built from one-dimensional nanostructures have attracted extensive attention due to their significance in basic scientific research and potential technological applications. It is still desirable to develop new materials with a wide response range for application in photodetectors. In this work, a Bi19S27I3 nanorod cluster film has been successfully fabricated on various rigid substrates by a facile solvothermal method. The component nanorods exhibit an oriented growth along the [001] direction. The UV-Vis-NIR absorption spectrum shows a continuous strong absorption spanning the whole visible light to near-infrared region and presents a direct band gap of 0.83 eV for the prepared Bi19S27I3 nanorod clusters. The spectral photoresponse of the Bi19S27I3-based photodetector device demonstrates a broad photoresponse ranging from ultraviolet to near infrared. The photocurrent results reveal that the photodetector exhibits a more sensitive response towards near-infrared light than visible light. Furthermore, the photodetector based on the Bi19S27I3 nanorod cluster film shows significantly enhanced photodetection performance compared to Bi19S27I3 nanorod powder. The photocurrent and on-off ratio of the prepared nanorod cluster film are respectively up to 400 times and several times higher than those of the powder sample. The on-off ratios are about 265 and 66 under NIR illumination and 48 and 11 under visible light for the film and powder samples, respectively. These results suggest a great potential application of the prepared Bi19S27I3 nanorod cluster film in optoelectronic devices.

Lignocellulose-Chitosan-Multiwalled Carbon Nanotube Composites with Improved Mechanical Strength, Dimensional Stability and Fire Retardancy.

A novel composite composed of lignocellulose (LC), glutaraldehyde crosslinked chitosan (GC) and multiwalled carbon nanotube (MWCNT) was fabricated by the hot-pressing process. The effect of the additional GC and MWCNT on the mechanical strength, dimensional stability and fire retardancy of lignocellulose composites was investigated. The results showed that LC/GC/MWCNT composite exhibited the maximum modulus of rupture (MOR) of 35.3 MPa, modulus of elasticity (MOE) of 2789.1 MPa and internal bonding (IB) strength of 1.2 MPa. Meanwhile, the LC/GC/MWCNT composite displayed improved dimensional stability with a thickness swelling (TS) value of 22.4%. Besides, the LC/GC/MWCNT composite exhibited improved fire retardancy with a limiting oxygen index of 29.0%. The peak heat release rate, the total heat release, the total smoke production and the maximum smoke production ratio of LC/GC/MWCNT composite decreased by 15.9%, 10.7%, 45.5% and 20.7% compared with those of LC composite, respectively. Therefore, the LC/GC/MWCNT composite may be a promising candidate for green wood based composites.

Down-regulation of nuclear HMGB1 reduces ischemia-induced HMGB1 translocation and release and protects against liver ischemia-reperfusion injury.

Hepatocyte-specific HMGB1 deletion has been found to worsen the injury and inflammation in liver ischemia-reperfusion injury (IRI), highlighting a role for intracellular HMGB1 in cellular protection. Down-regulation of nuclear HMGB1 by small interfering RNA (siRNA) might not only decrease its injurious extracellular role by reducing its release but also serve to maintain its beneficial intracellular role, thus protecting against IRI. We established a non-lethal liver IRI model in mice via segmental hepatic warm ischemia for 1 h and reperfusion for 6 h. HMGB1-siRNA achieved a reduction of ~60-70% in the nuclear HMGB1 expression in the liver at 48 h post-treatment. Knockdown of nuclear HMGB1 expression dramatically reduced both the degree of nuclear-cytoplasmic translocation of HMGB1 during hepatic ischemia and of HMGB1 release after hepatic reperfusion, resulting in significant preservation of liver function and a marked reduction in pathological damage. Also, HMGB1-siRNA pretreatment markedly inhibited the increases in hepatic expression of TLR4, TLR2, RAGE, TNF-α, IL-1ß, IL-6, MCP-1, iNOS, and COX-2 seen in control mice after hepatic reperfusion. We demonstrated for the first time that down-regulation of nuclear HMGB1 reduces ischemia-induced HMGB1 release and protects against liver IRI, which is helpful for better understanding the role of HMGB1 in organ IRI.

Schistosoma japonicum serine protease inhibitor increases endothelial barrier function.

Schistosomiasis remains the second most prevalent zoonotic disease after malaria in veterinary medicine. The egg lodgement in target host tissue plays important roles in pathogenesis of this disease, but the process prior to egg-laying is still elusive. Surely, investigation of how this parasite invades and moves inside corresponding host will probably improve our understanding of homeostasis and maintenance of animal health, further, of related pathogenesis and thus potential intervention against schistosomiasis. TNT-coupled transcription/translation-expressed Sj serpin was employed for the protease inhibition assay. Transendothelial resistance (TER), its charge selectivity and size selectivity, were measured by the ussing chamber technique in serpin-transfected or recombinant serpin-treated HUVEC monolayer. The expressions of junction proteins were assayed using real-time PCR, Western blot and immunostaining. Sj serpin blocks the protease activity of elastase in a time-dependent manner; and Sj serpin can increase TER ofendothelial monolayer by decreasing its paracellular size selectivity, but not by interfere with the charge selectivity. Altered expression of tight junction protein claudin-2 was not observed at either RNA or protein levels; however, we found a marked increase in the expression of occludin, ZO-1,VE-cadherin and beta-catenin. Sj serpin can increase the transendothelial barrier function by decreasing the transendothelial permeability, implying serpin as a potential target to limit the invasion of schistosome into animal blood vessel.