BP Network Model Based on SCLBOA for House Price Forecasting.

Butterfly optimization algorithm (BOA) is a new swarm intelligence algorithm mimicking the behaviors of butterflies. However, there is still much room for improvement. In order to enhance the convergence speed and accuracy of the BOA, we present an improved algorithm SCLBOA based on SIBOA, which incorporates a logical mapping and a Lévy flight mechanism. The logical chaotic map is used for population initialization, and then the Lévy flight mechanism is integrated into the SCLBOA algorithm. To evaluate the performance of the SCLBOA, we conducted many experiments on standard test functions. The simulation results suggest that the SCLBOA is capable of high-precision optimization, fast convergence, and effective global optimization, all of which show that our method outperforms other methods in solving mathematical optimization problems. Finally, the BP network is optimized according to the SCLBOA (SCLBOA-BP) to further verify the availability of the algorithm. Simulation experiments prove the practicability of this method by building a Boston housing price prediction model for training.

A Three-Stage Dynamic Assessment Framework for Industrial Control System Security Based on a Method of W-HMM.

Industrial control systems (ICS) are applied in many fields. Due to the development of cloud computing, artificial intelligence, and big data analysis inducing more cyberattacks, ICS always suffers from the risks. If the risks occur during system operations, corporate capital is endangered. It is crucial to assess the security of ICS dynamically. This paper proposes a dynamic assessment framework for industrial control system security (DAF-ICSS) based on machine learning and takes an industrial robot system as an example. The framework conducts security assessment from qualitative and quantitative perspectives, combining three assessment phases: static identification, dynamic monitoring, and security assessment. During the evaluation, we propose a weighted Hidden Markov Model (W-HMM) to dynamically establish the system's security model with the algorithm of Baum-Welch. To verify the effectiveness of DAF-ICSS, we have compared it with two assessment methods to assess industrial robot security. The comparison result shows that the proposed DAF-ICSS can provide a more accurate assessment. The assessment reflects the system's security state in a timely and intuitive manner. In addition, it can be used to analyze the security impact caused by the unknown types of ICS attacks since it infers the security state based on the explicit state of the system.

Involvement of TLR4 signaling regulated-COX2/PGE2 axis in liver fibrosis induced by Schistosoma japonicum infection.

BACKGROUND: Hepatic stellate cell (HSC) activation plays a pivotal role in hepatic inflammation and liver fibrosis. TLR4 pathway activation has been reported to be involved in mice liver fibrosis induced by hepatitis virus infection, alcohol abuse, biliary ligation, carbon tetrachloride 4 treatment, and Schistosoma japonicum (Sj) infection. The effect and mechanisms of the cyclooxygenase 2 (COX2)/prostanoid E2 (PGE2) axis on liver fibrosis induced by Sj are still unclear. METHODS: Mice liver fibrosis were induced by cutaneous infection of Sj cercariae. COX-2 inhibitor, NS398 were injected from week 5 to week 7, while TLR4 inhibitor TAK242 were injected from week 4 to week 8 post Sj infection. Human HSCs line, LX-2 cells were cultured and exposed to LPS or synthetic PGE2, or pretreated by TAK242, TLR4-siRNA or NS398. Liver tissue and serum or in vitro cultured cell lysaste were collected at indicated time courses for exploring the relationship between TLR4 and COX2-PGE2 axis through qPCR, western blot, immunohistochemical assay, ect. One-way analysis of variance among multiple groups followed by Uncorrected Fisher's LSD-t test or paired comparisons through t test were performed to tell the statistical differences. RESULTS: This study investigated the link between the COX2/PGE2 axis and TLR4 signaling in the induction of liver fibrogenesis in mice during Sj infection and in vitro culture of HSC strain-LX-2. The COX2/PGE2 axis was positively associated with Sj-induced liver fibrosis. TLR4 pathway activation stimulated the COX2/PGE2 axis in Sj-infected mice and in lipopolysaccharide (LPS)-exposed cultured HSCs. Synthetic PGE2 activated cultured HSCs through upregulation of alpha smooth muscle actin (α-SMA) expression. In LPS-triggered HSCs, NS398, a COX2 inhibitor, led to suppression of PGE2 synthesis and reduced expression of α-SMA and type I collagen (COL I). CONCLUSIONS: These results indicate firstly the positive association of the COX2/PGE2 axis with liver fibrosis induced by Sj infection. TLR4 signaling may at least partially control the COX2/PGE2 axis in Sj-infected mice liver and in vitro cultured HSCs. The COX2/PGE2-EP2/EP4 axis might be a good drug target against liver fibrosis induced by Sj infection.

Sphingosine 1-phosphate/microRNA-1249-5p/MCP-1 axis is involved in macrophage-associated inflammation in fatty liver injury in mice.

Monocyte chemotactic protein-1 (MCP-1) is one of the most representative inflammatory cytokines, and has been proved to be markedly increased in injured liver and sphingosine 1-phosphate (S1P)-treated macrophages. However, microRNAs (miRNAs) targeting MCP-1 and the role of miRNA/MCP-1 axis in S1P-mediated liver inflammation remain largely unknown. Here, we demonstrate that MCP-1 expression is increased in the liver and isolated liver macrophages of MCDHF mice. Moreover, there is a positive correlation between the hepatic levels of S1P and MCP-1. We then predict miRNAs targeting MCP-1 by bioinformatics analysis and select miRNA-1249-5p (miR-1249-5p) from the intersection of TargetScan database and downregulated miRNAs in the injured liver. S1P significantly upregulates the expression of MCP-1 and decreases miR-1249-5p expression in macrophages. MiR-1249-5p directly targets 3'-UTR of MCP-1 and negatively regulates its expression in S1P-treated macrophages. Administration of miR-1249-5p agomir decreases hepatic MCP-1 levels and attenuates liver inflammation in MCDHF mice. Protein-protein interaction network by STRING displays that S1P system is closely associated with MCP-1/CCR2 axis in the network of inflammation. In conclusion, we characterize the vital role of miR-1249-5p in negatively regulating MCP-1 expression in vitro and in vivo, which may open new perspectives for pharmacological treatment of liver disease.

Cannabinoid Receptor 1/miR-30b-5p Axis Governs Macrophage NLRP3 Expression and Inflammasome Activation in Liver Inflammatory Disease.

Nod-like receptor (NLR) family pyrin domain containing 3 (NLRP3) has been regarded as an important initiator or promoter in multiple inflammatory diseases. However, the relationship between cannabinoid receptor 1 (CB1) and macrophage NLRP3 inflammasome and the corresponding molecular mechanism in liver inflammation remain unclear. Mouse liver injury models were induced by carbon tetrachloride (CCl4) or methionine-choline-deficient and high fat (MCDHF) diet. Human liver tissues were obtained from patients with different chronic liver diseases. CB1 expression was increased in liver tissue and macrophages of CCl4- and MCDHF-treated mice, positively correlated with NLRP3. CB1 agonist ACEA (Arachiodonyl-2'-Chloroethylamide) promoted NLRP3 expression and NLRP3 inflammasome activation in macrophages. CB1 blockade with its antagonist AM281 reduced NLRP3 expression, inflammasome activation, and liver inflammation in CCl4- and MCDHF-treated mice. MicroRNA-30b-5p (miR-30b-5p), screened by the intersection of bioinformatics databases and downregulated miRNAs in injured liver, negatively correlated with NLRP3 in mouse and human liver. miR-30b-5p was involved in CB1-mediated activation of NLRP3 inflammasome in macrophages by directly targeting NLRP3. Importantly, administration of miR-30b-5p agomir targeted NLRP3 and attenuated liver inflammation in the injured liver. Altogether, CB1/miR-30b-5p axis modulates NLRP3 expression and NLPR3 inflammasome activation in macrophages during liver inflammation, which provides a potential target for liver disease.

Both HuR and miR-29s regulate expression of CB1 involved in infiltration of bone marrow monocyte/macrophage in chronic liver injury.

Bone marrow-derived monocytes/macrophages (BMMs) play a vital role in liver inflammation and fibrogenesis. Cannabinoid receptor 1 (CB1) mediates the recruitment of BMMs into the injured liver. In this study, we revealed the molecular mechanisms under CB1-mediated BMM infiltration. Carbon tetrachloride (CCl4 ) was employed to induce mouse liver injury. In vivo, human antigen R (HuR) was upregulated in macrophages of injured liver. HuR messenger RNA (mRNA) expression was positively correlated with CB1 and F4/80 mRNA expression. Furthermore, we detected the binding between HuR and CB1 mRNA in CCl4 -treated livers. In vitro, HuR modulated arachidonyl-2'-chloroethylamide (ACEA, CB1 agonist)-induced BMM migration by regulating CB1 expression. HuR promoted CB1 expression via binding to CB1 mRNA. ACEA promoted the association between HuR and CB1 mRNA via inducing HuR nucleoplasmic transport. In the cytoplasm, HuR competed with the miR-29 family to improve CB1 expression and BMM migration. In conclusion, our results prove that HuR regulates CB1 expression and influences ACEA-induced BMM migration by competing with miR-29 family.

Sphingosine 1-Phosphate Receptor Blockade Affects Pro-Inflammatory Bone Marrow-Derived Macrophages and Relieves Mouse Fatty Liver Injury.

Fatty liver injury is characterized by liver fat accumulation and results in serious health problems worldwide. There is no effective treatment that reverses fatty liver injury besides etiological therapy. Inflammation is an important macrophage-involving pathological process of liver injury. Here, we investigated the role of sphingosine 1-phosphate receptors (S1PRs) in fatty liver injury and explored whether S1PR2/3 blockade could cure fatty liver injury. A methionine-choline-deficient and a high-fat (MCDHF) diet was used to induce fatty liver injury, and the number of macrophages was evaluated by flow cytometry. Gene expressions were detected using RT-qPCR and cytometric bead array. In MCDHF-diet-fed mice, pro-inflammatory factor expressions were upregulated by fatty liver injury. The S1P level and S1PR2/3 expressions were significantly elevated. Moreover, increased S1P level and S1PR2/3 mRNA expressions were positively correlated with pro-inflammatory factor expressions in the liver. Furthermore, the number of pro-inflammatory macrophages (iMφ) increased in injured liver, and they were mainly bone-marrow-derived macrophages. In vivo, S1PR2/3 blockade decreased the amount of iMφ and inflammation and attenuated liver injury and fibrosis, although liver fat accumulation was unchanged. These data strongly suggest that anti-inflammatory treatment by blocking the S1P/S1PR2/3 axis attenuates fatty liver injury, which might serve as a potential target for fatty liver injury.

Single-Cell Transcriptomes Reveal Characteristic Features of Mouse Hepatocytes with Liver Cholestatic Injury.

Hepatocytes are the main parenchymal cells of the liver and play important roles in liver homeostasis and disease process. The heterogeneity of normal hepatocytes has been reported, but there is little knowledge about hepatocyte subtype and distinctive functions during liver cholestatic injury. Bile duct ligation (BDL)-induced mouse liver injury model was employed, and single-cell RNA sequencing was performed. Western blot and qPCR were used to study gene expression. Immunofluoresence was employed to detect the expressions of marker genes in hepatocytes. We detected a specific hepatocyte cluster (BDL-6) expressing extracellular matrix genes, indicating these hepatocytes might undergo epithelia-mesenchymal transition. Hepatocytes of BDL-6 also performed tissue repair functions (such as angiogenesis) during cholestatic injury. We also found that four clusters of cholestatic hepatocytes (BDL-2, BDL-3, BDL-4, and BDL-5) were involved in inflammatory process in different ways. To be specific, BDL-2/3/5 were inflammation-regulated hepatocytes, while BDL-4 played a role in cell chemotaxis. Among these four clusters, BDL-5 was special. because the hepatocytes of BDL-5 were proliferating hepatocytes. Our analysis provided more knowledge of hepatocyte distinctive functions in injured liver and gave rise to future treatment aiming at hepatocytes.

Gadolinium Chloride Restores the Function of the Gap Junctional Intercellular Communication between Hepatocytes in a Liver Injury.

BACKGROUND: Gadolinium chloride (GdCl3) has been reported to attenuate liver injury caused by a variety of toxicants. Gap junctional intercellular communication (GJIC) is thought to be essential in controlling liver homeostasis and pathology. Here we evaluate the effects of GdCl3 on functional GJIC and connexin expression in mouse models and primary hepatocytes. METHODS: Mice were administered GdCl3 intraperitoneally the day before a carbon tetrachloride (CCl4) injection or bile duct ligation (BDL) operation. Primary hepatocytes were treated with CCl4 or lipopolysaccharides (LPS), with or without GdCl3. A scrape loading/dye transfer assay was performed to assess the GJIC function. The expression of connexins was examined by real-time reverse transcription polymerase chain reaction (RT-PCR), western blot and immunofluorescent staining. RESULTS: CCl4 treatment or the BDL operation led to the dysfunction of GJIC and a down-regulation of Cx32 and Cx26 in injured liver. GdCl3 administration restored GJIC function between hepatocytes by facilitating the transfer of fluorescent dye from one cell into adjacent cells via GJIC, and markedly prevented the decrease of Cx32 and Cx26 in injured liver. In primary hepatocytes, CCl4 or LPS treatment induced an obvious decline of Cx32 and Cx26, whereas GdCl3 pretreatment prevented the down-regulation of connexins. In vivo GdCl3 protected hepatocytes and attenuated the liver inflammation and fibrosis in liver injury mouse models. CONCLUSION: GdCl3 administration protects functional GJIC between hepatocytes, and prevents the decrease of connexin proteins at mRNA and protein levels during liver injury, leading to the alleviation of chronic liver injury.

Sphingosine 1-Phosphate (S1P)/S1P Receptor2/3 Axis Promotes Inflammatory M1 Polarization of Bone Marrow-Derived Monocyte/Macrophage via G(α)i/o/PI3K/JNK Pathway.

BACKGROUND/AIMS: Macrophages, the most plastic cells in the haematopoietic system, are found in all tissues and show great functional heterogeneity. Sphingosine 1-phosphate (S1P)/ S1P receptors (S1PRs) system is widely involved in the process of inflammatory disease, whereas little evidence concerning its role in functional macrophage polarization is available. Thus, the present study was designed to evaluate the effects of S1P/S1PRs on functional polarization of macrophage in mouse bone marrow (BM)-derived monocyte/macrophages (BMMs). METHODS: For the detection of M1 macrophage markers, such as CD86, tumor necrosis factor (TNF)-α, monocyte chemotactic protein (MCP)-1/ chemokine (C-C motif) ligand (CCL) 2, nitric oxide synthase (NOS) 2, and macrophage inflammatory protein (MIP)-1ß, RT-qPCR and cytometric bead array (CBA) were performed in cultured primary BMMs after the treatment with selective S1PR2/3 antagonists or specific S1PRs siRNA. Western blotting and immunofluorescence were used for the detection of phosphorylation of JNK1/2. RESULTS: BMMs expressed S1PR1-3 and interestingly, S1PR2/3, but not S1PR1, mediates S1P-induced M1 macrophage polarization of BMMs as their siRNA or antagonists reduced M1 genes' expression. We found that PTX (inhibitor of G(α)i/o), LY294002 (inhibitor of PI3K) or SP600125 (inhibitor of JNK1/2) prevented up-regulation of M1 genes expression mediated by S1P/S1PR2/3 signal, and S1P-induced JNK phosphorylation was inhibited by antagonists of S1PR2/3, PTX or LY294002. CONCLUSION: Collectively, our results demonstrate that S1P/S1PR2/3 plays a key role in regulating M1 type polarization of BMMs and acts by activating G(α)i/o/PI3K/JNK signaling pathway, with potential implications for new approaches to inflammatory liver disease therapy.

Cannabinoid Receptor 1 Participates in Liver Inflammation by Promoting M1 Macrophage Polarization via RhoA/NF-κB p65 and ERK1/2 Pathways, Respectively, in Mouse Liver Fibrogenesis.

Macrophage M1/M2 polarization mediates tissue damage and inflammatory responses. Cannabinoid receptor (CB) 1 participated in liver fibrogenesis by affecting bone marrow (BM)-derived monocytes/macrophages (BMMs) activation. However, the knowledge of whether CB1 is involved in the polarization of BMMs remains limited. Here, we found M1 gene signatures (including CD86, MIP-1ß, tumor necrosis factor, IL-6, and inducible nitric oxide synthase) and the amount of M1 macrophages (CD86+ cells, gated by F4/80) were significantly elevated in carbon tetrachloride (CCl4)-induced mouse injured livers, while that of M2 type macrophages had little change by RT-qPCR and fluorescence-activated cell sorting (FACS). Our preceding study confirmed CB1 was involved in CCl4-induced liver fibrogenesis. Our results noted CB1 expression showed positive correlation with CD86. Blockade of CB1 by its antagonist or siRNA in vivo downregulated the mRNA and protein levels of M1 markers using RT-qPCR, western blot, and Cytometric Bead Array (CBA) assays, and reduced the proportion of M1 macrophages. Moreover, chimera mouse models, which received BM transplants from EGFP-transgenic mice or clodronate liposome injection mouse models, in which Kupffer cells were depleted, were performed to clarify the role of CB1 on the polarization of Kupffer cells and BMMs. We found that CB1 was especially involved in BMM polarization toward M1 phenotype but have no effect on that of Kupffer cells. The reason might due to the lower CB1 expression in Kupffer cells than that of BMMs. In vitro, we discovered CB1 was involved in the polarization of BMMs toward M1. Furthermore, CB1-induced M1 polarization was apparently impaired by PTX [G(α)i/o protein inhibitor], Y27632 (ROCK inhibitor), and PD98059 [extracellular signal-regulated kinase (ERK) inhibitor], while SB203580 (p38 inhibitor) and compound C (AMPK inhibitor) had no such effect. ACEA (CB1 agonist) activated G(α)i/o coupled CB1, then enlarged GTP-bound Rho and phosphor-ERK1/2, independently. NF-κB p65 nuclear translocation is also a marker of M1 phenotype macrophages. We found that CB1 switched on NF-κB p65 nuclear translocation only depending on G(α)i/o/RhoA signaling pathway. CONCLUSION: CB1 plays a crucial role in regulating M1 polarization of BMMs in liver injury, depending on two independent signaling pathways: G(α)i/o/RhoA/NF-κB p65 and G(α)i/o/ERK1/2 pathways.

miR-27b-3p, miR-181a-1-3p, and miR-326-5p are involved in the inhibition of macrophage activation in chronic liver injury.

Macrophages are central players in inflammation, which leads to liver injury. It has been reported that continuous macrophage activation initiates this process. Our previous data show that the anti-inflammatory factor, 15-deoxy-Δ12, 14-prostaglandin J2 (15d-PGJ2), inhibits bone marrow (BM)-derived macrophage (BMM) migration and inflammatory cytokine production. However, the underlying mechanism of 15d-PGJ2 inhibited BMM activation is still unclear. Here, we evaluate the role of 15d-PGJ2/PPARγ axis in BMM activation. 15d-PGJ2 reduced activated BMM population in injured livers. Inflammatory cytokine expressions (MIP-1ß, TNF-α, NOS2) were depressed by 15d-PGJ2 in macrophages isolated from treated livers. In vitro, 15d-PGJ2 inhibited BMM activation via PPARγ. Moreover, miR-27b-3p, miR-181a-1-3p, and miR-326-5p target MIP-1ß, TNF-α, and NOS2 mRNA, respectively. The miRNA expressions were decreased in damaged livers, macrophages isolated from injured livers, and activated BMMs, which were renewed by 15d-PGJ2/PPARγ axis. In activated BMMs, the miRNA inhibitors attenuated inhibitory effect of PPARγ agonist (troglitazone or ciglitazone), while replenishing the lack of miRNAs induced by PPARγ deficiency using miRNA mimics caused a decline of inflammatory cytokines. In conclusion, these data suggest that 15d-PGJ2/PPARγ axis regulates BMM activation via promoting miR-27b-3p, miR-181a-1-3p, and miR-326-5p expressions. KEY MESSAGES: 15d-PGJ2 inhibits BMM activation via PPARγ activation. 15d-PGJ2/PPARγ axis promotes expression of miR-27b-3p, miR-181a-1-3p, and miR-326-5p. miR-27b-3p, miR-181a-1-3p, and miR-326-5p have an inhibitory effect on BMM activation via 15d-PGJ2/PPARγ axis.

Positive Feedback Regulation between Transglutaminase 2 and Toll-Like Receptor 4 Signaling in Hepatic Stellate Cells Correlates with Liver Fibrosis Post Schistosoma japonicum Infection.

Liver fibrosis induced by Schistosoma japonicum (Sj) infection is characterized by the accumulation of extracellular matrix (ECM). The activated and differentiated hepatic stellate cells (HSCs) are the predominant ECM-producing cell type in the liver. Toll-like receptor (TLR) 4 pathway activation plays a key role in mice liver fibrosis models induced by alcohol, biliary ligation, and carbon tetrachloride 4. In this work, we found that TLR4 pathway activation correlated with the severity of liver fibrosis post Sj infection. The TLR4 receptor inhibitor TAK242 reduced the extent of liver fibrosis. The increased expression of TLR4, α-smooth muscle actin (α-SMA), and cytoglobin was observed in the HSCs of mouse liver after Sj infection. In response to stimulation with either lipopolysaccharide or Sj's soluble egg antigen (SEA), high levels of TLR4 and α-SMA were induced in HSCs and were inhibited by TAK242 treatment. In previous work, we had reported that a high level of transglutaminase 2 (TGM2) is crucial for liver fibrosis post Sj infection. Herein, we found that TLR4 signaling also controlled Tgm2 expression. Inhibition of TGM2 activity by cystamine (CTM) in Sj-infected mice or in HSCs induced with all-trans-retinoic acid (ATRA) stimulation led to a lowered activation of TLR4 signaling and a reduced α-SMA expression. These results were confirmed by downregulating the Tgm2 gene by specific siRNA. These observations implied the presence of a positive feedback regulation between TGM2 and TLR4 signaling in HSCs that correlated with liver fibrosis post Sj infection. This novel connection between TGM2 and TLR4 pathway activation in liver fibrosis induced by Sj infection enhances our understanding of liver diseases.

Tissue Transglutaminase-Regulated Transformed Growth Factor-ß1 in the Parasite Links Schistosoma japonicum Infection with Liver Fibrosis.

Transforming growth factor (TGF-ß1) is among the strongest factors of liver fibrogenesis, but its association with Schistosoma-caused liver fibrosis is controversial. Tissue transglutaminase (tTG) is the principal enzyme controlling TGF-ß1 maturation and contributes to Sj-infected liver fibrosis. Here we aim to explore the consistency between tTG and TGF-ß1 and TGF-ß1 source and its correlation with liver fibrosis after Sj-infection. TGF-ß1 was upregulated at weeks 6 and 8 upon liver fibrosis induction. During tTG inhibition, TGF-ß1 level decreased in sera and liver of infected mice. TGF-ß1 showed positive staining in liver containing Sj adult worms and eggs. TGF-ß1 was also detected in Sj adult worm sections, soluble egg antigen and Sj adult worm antigen, and adult worms' culture medium. The TGF-ß1 mature peptide cDNA sequence and its extended sequence were amplified through RT-PCR and RACE-PCR using adult worms as template, and sequence is analyzed and loaded to NCBI GenBank (number GQ338152.1). TGF-ß1 transcript in Sj eggs was higher than in adult worms. In Sj-infected liver, transcriptional level of TGF-ß1 from Sj, but not mouse liver, correlated with liver fibrosis extent. This study provides evidence that tTG regulates TGF-ß1 and illustrates the importance of targeting tTG in treating Sj infection-induced fibrosis.

Effect of mild hypothermia on the expression of toll-like receptor 2 in lung tissues with experimental acute lung injury.

OBJECTIVE AND DESIGN: Our study aimed to determine the effect of mild hypothermia (MHT) on the expression of toll-like receptor 2 (TLR2) in lung tissue with acute lung injury. The animals were randomly divided into control, model and mild hypothermia groups. METHODS: A total of 40 rats was used in the study. Acute lung injury was induced by lipopolysaccharide and MHT was maintained at 32.5∼33.0 °C using body surface ice-bag placement combined with animal thermostat system. The ratio of PaO2/FiO2 was recorded. The mRNA and protein expressions of TLR2 were measured by real-time polymerase chain reaction and western blotting respectively. Moreover, enzyme linked immunosorbent assay were used for the quantification of TNF-α. RESULTS: The ratio of PaO2/FiO2 was increased by MHT. TLR2 and TNF-α were increased in the rat lung 1h and 8h in the rats with acute lung injury while they were significantly decreased by MHT. Histological examination revealed that MHT alleviated the degree of inflammation. CONCLUSION: Our study suggested that MHT might improve the lung function by inhibiting the inflammation via down-regulating the expressions of TLR2 in the acute injury lung tissues.

Involvement of IL-13 and tissue transglutaminase in liver granuloma and fibrosis after schistosoma japonicum infection.

Schistosomiasis, one of the most devastating parasitic diseases, is caused by Schistosoma japonicum (Sj) infection resulting in serious liver fibrosis. Interleukin- (IL-) 13, which is produced by TH2 cells, is a critical profibrotic cytokine found in various organs, including the liver. Tissue transglutaminase (tTG), a group of multifunctional enzymes, serves a central function in the pathogenesis of chronic liver diseases. However, the relationship between IL-13, tTG, and liver fibrosis during Schistosoma infection has not been established. This study investigated the involvement of IL-13 and tTG in liver fibrogenesis during Sj infection in mice. Five weeks after Sj infection, granuloma and fibrosis development in the liver coincided with an increase in IL-13 and tTG in the liver and the upregulation of serum IL-13 in infected mice. Administration of cystamine, an inhibitor of tTG, abrogated the increase in both tTG and IL-13 in infected mice and ameliorated liver fibrogenesis and granuloma development. This result establishes a novel link among IL-13, tTG, and liver granuloma and fibrosis under Sj infection. Based on their important functions in liver fibrosis induced by Sj infection, IL-13 and tTG could be promising potential drug targets against schistosomiasis.

[Expression of Toll-like receptors 2 and 6 in mice liver during Schistosoma japonicum infection].

OBJECTIVE: To investigate the expression of hepatic Toll-like receptor 1 (TLR1), TLR2 and TLR6 on mice with Schistosoma japonicum infection. METHODS: Fifty BALB/c mice were infected with 20 +/- 3 S. japonicum cercariae through abdominal skin. At 6 weeks post-infection, the mice (n = 10) in treatment group were administered intragastrically with praziquantel [250 microg/(g x d)] for 3 d. The livers of mice (n = 10) were collected at pre-infection and 5, 6, 8 and 12 weeks post-infection, and then the mRNA expression levels of hepatic TLR1, TLR2, TLR6 gene were detected with reverse transfer PCR. Hepatic TLR2, TLR6 protein levels were detected by immunohistochemical staining. RESULTS: The mRNA levels of TLR1, TLR2, and TLR6 on 5, 6, 8 and 12 weeks post infection were significantly higher than that of uninfected mice. After praziquantel treatment, the mRNA level of TLR2 and TLR6 in murine liver of treatment group was lower than that of infection group, but the level of TLR1 mRNA had no obvious change. Furthermore, immunohistochemistry results revealed that the expression of TLR2 and TLR6 proteins in murine liver was up-regulated at 5, 6, 8 and 12 weeks post-infection. After praziquantel treatment, the percentage of TLR2 positive area in liver of infected mice without and with praziquantel treatment were (44.2 +/- 4.3)%, (8.8 +/- 3.1)%, respectively, and TLR2 protein level was considerably down-regulated (P < 0.01). The percentage of TLR6 positive area in liver of infected mice without and with praziquantel treatment was (48.4 +/- 5.4)%, (37.4 +/- 3.5)%, respectively, and TLR6 level decreased slightly (P < 0.05). CONCLUSION: The expression level of TRL2 and TLR6 in murine liver increases after Schistosoma japonicum infection. While compared with TLR2, the role of TLR6 in this progress is a weaker one.

[Effects of hypothermia on the concentration of surfactant protein A during endotoxin induced acute lung injury in rats].

OBJECTIVE: To investigate the effect of hypothermia (HT) on the concentration of surfactant protein A (SP-A) during lipopolysaccharide (LPS) induced acute lung injury (ALI) in rats. METHODS: Forty male Wistar rats were randomly divided into three groups. The ALI model was reproduced by LPS intratracheal instillation; only saline was instilled intratracheally for control group. Rats in both model group and control group were sacrificed respectively at 1 hour and 8 hours (each n=8). In HT group the body temperature was lowered to 32.5-33.0 centigrade 1 hour after LPS instillation, and 8 rats were sacrificed at 8 hours. The arterial blood gas was determined in all the groups before and 1 hour and 8 hours after instillation of saline or LPS, and the oxygenation index (PaO(2)/FiO(2)) was calculated. The concentration of SP-A in bronchoalveolar lavage fluid (BALF) was determined by enzyme linked immunosorbent assay. The morphological changes in lung tissue of rats were observed under light microscope. RESULTS: At 1 hour after intratracheal instillation of LPS, the PaO(2)/FiO(2) of each group reached the diagnostic criterion of ALI. Compared with control 1 hour group, the SP-A (µg/L) in BALF of model 1 hour group was decreased (53.27±1.95 vs. 74.81±6.55, P<0.01); the SP-A in model 8 hour group and HT 8 hour group (4.35±2.76 and 51.36±2.33) was both obviously decreased compared with control 8 hour group (70.81±5.01, both P<0.01). Compared with model 8 hour group, the SP-A of HT 8 hour group was obviously increased (P<0.01). Results of light microscopic examination, it was revealed that the alveolar structure of control 1 hour group and control 8 hour group was almost normal. Inflammatory response in lung tissues in model 8 hour group was found to be most serious; compared with model 8 hour group, inflammatory response in lung tissues in model 1 hour group and HT 8 hour group was reduced in certain degree. CONCLUSION: A certain extent of HT may reduce lung injury of early endotoxin induced ALI rats by delaying lowering of alveolar SP-A levels.