[Mechanism of Shenling Baizhu Powder on treatment of alcoholic liver disease by regulating TLR4/NLRP3 pathway].

This study aims to investigate the regulatory effects of Shenling Baizhu Powder(SBP) on cellular autophagy in alcoholic liver disease(ALD) and its intervention effect through the TLR4/NLRP3 pathway. A rat model of chronic ALD was established by gavage of spirits. An ALD cell model was established by stimulating BRL3A cells with alcohol. High-performance liquid chromatography(HPLC) was utilized for the compositional analysis of SBP. Liver tissue from ALD rats underwent hematoxylin-eosin(HE) and oil red O staining for pathological evaluation. Enzyme-linked immunosorbent assay(ELISA) was applied to quantify lipopolysaccharides(LPS), tumor necrosis factor-alpha(TNF-α), interleukin-1 beta(IL-1ß), and interleukin-18(IL-18) levels. Quantitative reverse transcription polymerase chain reaction(qRT-PCR) was conducted to evaluate the mRNA expression of myeloid differentiation factor 88(MyD88) and Toll-like receptor 4(TLR4). The effect of different drugs on BRL3A cell proliferation activity was assessed through CCK-8 analysis. Western blot analysis was performed to examine the protein expression of NOD-like receptor pyrin domain-containing 3(NLRP3), nuclear factor-kappa B P65(NF-κB P65), phosphorylated nuclear factor-kappa B P65(p-P65), caspase-1, P62, Beclin1, and microtubule-associated protein 1 light chain 3(LC3Ⅱ). The results showed that SBP effectively ameliorated hepatic lipid accumulation, reduced liver function, mitigated hepatic tissue inflammation, and reduced levels of LPS, TNF-α, IL-1ß, and IL-18. Moreover, SBP exhibited the capacity to modulate hepatic autophagy induced by prolonged alcohol intake through the TLR4/NLRP3 signaling pathway. This modulation resulted in decreased expression of LC3Ⅱ and Beclin1, an elevation in P62 expression, and the promotion of autolysosome formation. These research findings imply that SBP can substantially enhance liver function and mitigate lipid irregularities in the context of chronic ALD. It achieves this by regulating excessive autophagic responses caused by prolonged spirit consumption, primarily through the inhibition of the TLR4/NLRP3 pathway.

Proteome profiling of early gestational plasma reveals novel biomarkers of congenital heart disease.

Prenatal diagnosis of congenital heart disease (CHD) relies primarily on fetal echocardiography conducted at mid-gestational age-the sensitivity of which varies among centers and practitioners. An objective method for early diagnosis is needed. Here, we conducted a case-control study recruiting 103 pregnant women with healthy offspring and 104 cases with CHD offspring, including VSD (42/104), ASD (20/104), and other CHD phenotypes. Plasma was collected during the first trimester and proteomic analysis was performed. Principal component analysis revealed considerable differences between the controls and the CHDs. Among the significantly altered proteins, 25 upregulated proteins in CHDs were enriched in amino acid metabolism, extracellular matrix receptor, and actin skeleton regulation, whereas 49 downregulated proteins were enriched in carbohydrate metabolism, cardiac muscle contraction, and cardiomyopathy. The machine learning model reached an area under the curve of 0.964 and was highly accurate in recognizing CHDs. This study provides a highly valuable proteomics resource to better recognize the cause of CHD and has developed a reliable objective method for the early recognition of CHD, facilitating early intervention and better prognosis.

Effects of particle size on the structure, cooking quality and anthocyanin diffusion of purple sweet potato noodles.

The effects of different particle sizes of purple sweet potato flour (PSPF) on the structure and quality of noodles and the diffusion kinetics of anthocyanins during cooking were studied. As the particle size of the PSPF decreased (from 269 to 66 µm), the adverse effects of the addition of PSPF on the quality of noodles were reduced. The smaller particle size of PSPF was beneficial for the secondary structure orderliness and the tighter microstructure of PSP noodles. The diffusion of anthocyanins in noodles to the soup during cooking could be fitted well with Fick's second law, and diffusion coefficients were in the range of 8.3248-14.0893 × 10-9 m2/s. The noodles with 15% 66 µm PSPF showed the best cooking properties, the highest sensory score, the highest anthocyanin retention ability and a compact and orderly microstructure. Thus, they could be considered as noodles rich in anthocyanins for commercial application.

Gestational palmitic acid suppresses embryonic GATA-binding protein 4 signaling and causes congenital heart disease.

Dysregulated maternal fatty acid metabolism increases the risk of congenital heart disease (CHD) in offspring with an unknown mechanism, and the effect of folic acid fortification in preventing CHD is controversial. Using gas chromatography coupled to either a flame ionization detector or mass spectrometer (GC-FID/MS) analysis, we find that the palmitic acid (PA) concentration increases significantly in serum samples of pregnant women bearing children with CHD. Feeding pregnant mice with PA increased CHD risk in offspring and cannot be rescued by folic acid supplementation. We further find that PA promotes methionyl-tRNA synthetase (MARS) expression and protein lysine homocysteinylation (K-Hcy) of GATA4 and results in GATA4 inhibition and abnormal heart development. Targeting K-Hcy modification by either genetic ablation of Mars or using N-acetyl-L-cysteine (NAC) decreases CHD onset in high-PA-diet-fed mice. In summary, our work links maternal malnutrition and MARS/K-Hcy with the onset of CHD and provides a potential strategy in preventing CHD by targeting K-Hcy other than folic acid supplementation.

An IGF1-expressing endometrial stromal cell population is associated with human decidualization.

BACKGROUND: Decidualization refers to the process of transformation of endometrial stromal fibroblast cells into specialized decidual stromal cells that provide a nutritive and immunoprivileged matrix essential for blastocyst implantation and placental development. Deficiencies in decidualization are associated with a variety of pregnancy disorders, including female infertility, recurrent implantation failure (RIF), and miscarriages. Despite the increasing number of genes reportedly associated with endometrial receptivity and decidualization, the cellular and molecular mechanisms triggering and underlying decidualization remain largely unknown. Here, we analyze single-cell transcriptional profiles of endometrial cells during the window of implantation and decidual cells of early pregnancy, to gains insights on the process of decidualization. RESULTS: We observed a unique IGF1+ stromal cell that may initiate decidualization by single-cell RNA sequencing. We found the IL1B+ stromal cells promote gland degeneration and decidua hemostasis. We defined a subset of NK cells for accelerating decidualization and extravillous trophoblast (EVT) invasion by AREG-IGF1 and AREG-CSF1 regulatory axe. Further analysis indicates that EVT promote decidualization possibly by multiply pathways. Additionally, a systematic repository of cell-cell communication for decidualization was developed. An aberrant ratio conversion of IGF1+ stromal cells to IGF1R+ stromal cells is observed in unexplained RIF patients. CONCLUSIONS: Overall, a unique subpopulation of IGF1+ stromal cell is involved in initiating decidualization. Our observations provide deeper insights into the molecular and cellular characterizations of decidualization, and a platform for further development of evaluation of decidualization degree and treatment for decidualization disorder-related diseases.

Influence of the pendant groups on electrochemical water oxidation catalyzed by cobalt(II) triazolylpyridine complexes.

The development of low-cost catalysts for the water oxidation reaction (WOR) is important for solving the bottleneck issues in water splitting and benefits the widespread utilization of renewable energy sources. Herein, four cobalt(II) triazolylpyridine complexes, namely [Co(DTE)2(H2O)2](ClO4)2·CH3COCH3 (1), [Co(DTE)2Cl2]·2CH3OH (2) (DTE = (1-(2-acetoxymethyl)-4-(2-pyridyl)1,2,3-triazole), [Co(DTEL)2(CH3OH)2](ClO4)2 (3), and [Co(DTEL)2Cl2]·H2O (4) (DTEL = (1-(2-hydroxy)-4-(2-pyridyl)1,2,3-triazole), were synthesized and characterized. The crystal structures of 1-3 were determined by X-ray single crystal diffraction analysis. The electrocatalytic water oxidation by 1-4 was studied in 0.1 M NaOAc-HOAc solutions. Complexes 1-4 were single-site molecular catalysts for the WOR under near-neutral conditions. The overpotentials for the WOR were 440 mV and 480 mV. The faradaic efficiencies were 77-92%. The rate constants kcat were 0.21-0.96 s-1. The catalytic activities were affected by the pendant groups of DTE and DTEL. Complexes with DTE (1 and 2) showed better activities than those with DTEL (3 and 4). Moreover, complexes 1-4 adsorbed on indium-doped tin oxide (ITO) and glassy carbon electrode surfaces were active for the WOR. A mechanism was proposed for the WOR catalyzed by 1-4.

A Practical Risk-Based Model for Early Warning of Seafarer Errors Using Integrated Bayesian Network and SPAR-H.

Unsafe crew acts (UCAs) related to human errors are the main contributors to maritime accidents. The prediction of unsafe crew acts will provide an early warning for maritime accidents, which is significant to shipping companies. However, there exist gaps between the prediction models developed by researchers and those adopted by practitioners in human risk analysis (HRA) of the maritime industry. In addition, most research regarding human factors of maritime safety has concentrated on hazard identification or accident analysis, but not on early warning of UCAs. This paper proposes a Bayesian network (BN) version of the Standardized Plant Analysis Risk-Human Reliability Analysis (SPAR-H) method to predict the probability of seafarers' unsafe acts. After the identification of performance-shaping factors (PSFs) that influence seafarers' unsafe acts during navigation, the developed prediction model, which integrates the practicability of SPAR-H and the forward and backward inference functions of BN, is adopted to evaluate the probabilistic risk of unsafe acts and PSFs. The model can also be used when the available information is insufficient. Case studies demonstrate the practicability of the model in quantitatively predicting unsafe crew acts. The method allows evaluating whether a seafarer is capable of fulfilling their responsibility and providing an early warning for decision-makers, thereby avoiding human errors and sequentially preventing maritime accidents. The method can also be considered as a starting point for applying the efforts of HRA researchers to the real world for practitioners.

Diagnosis of Ectopic Intrathyroidal Parathyroid Adenoma with Nodular Goiter by 18F Fluorocholine: A Case Report.

The occurrence of ectopic intrathyroidal parathyroid adenoma (EPTA) is very rare, which causes some difficulties in diagnosis and complicates treatment. In addition, the occurrence of EPTA with nodular goiter (NG) is rare, which makes diagnosis difficult and requires the assistance of clinical evidence, imaging data, and cytological examination results. Therefore, we present a patient with a final diagnosis of ETPA with NG.

Programmed Cell Death Ligand 1-Transfected Mouse Bone Marrow Mesenchymal Stem Cells as Targeted Therapy for Rheumatoid Arthritis.

Programmed cell death 1 ligand (PD-L1) and its receptor (PD-1) are key molecules for immunoregulation and immunotherapy. PD-L1 binding PD-1 is an effective way to regulate T or B cell immunity in autoimmune diseases such as rheumatoid arthritis (RA). In our study, we overexpressed PD-L1 by constructing a recombinant of PD-L1-lentiviral vector, which was subsequently used to transfect mouse bone marrow mesenchymal stem cells (MBMMSCs) and significantly suppressed the development of collagen-induced arthritis (CIA) in DBA/1j mice. In addition, PD-L1-transfected MBMMSCs (PD-L1-MBMMSCs) ameliorated joint damage, reduced proinflammatory cytokine expression, and inhibited T and B cell activation. Furthermore, PD-L1-MBMMSCs decreased the number of dendritic cells and increased the numbers of regulatory T cells and regulatory B cells in joints of CIA mice. In conclusion, our results provided a potential therapeutic strategy for RA treatment with PD-L1-MBMMSC-targeted therapy.

Aberrant expression of five miRNAs in papillary thyroid carcinomas.

BACKGROUND: The miRNAs play critical roles in the progression of various tumors. Our study aimed to screen and identify miRNAs to investigate their diagnostic and prognostic value for papillary thyroid carcinoma (PTC). METHODS: miRNAs were evaluated in PTC (n = 30) tissues, A-PTC (n = 30), benign nodules (n = 35) and A-benign nodules (n = 35). The expression levels of five miRNAs were quantified using real-time, quantitative PCR. ROC analysis was used to evaluate the miRNA diagnostic value. RESULTS: The expression of miR-1296-5p, miR-1301-3p, and miR-532-5p was significantly downregulated (p = 0.0001, p = 0.0006, p = 0.0024, respectively), while miR-551b-3p and miR-455-3p were significantly upregulated in PTC tissues compared to A-PTC tissues (p = 0.0005, p = 0.0046, respectively). Interestingly, the expression of miR-1296-5p was downregulated, while miR-551b-3p and miR-455-3p were upregulated in the A-PTC group compared to the A-benign group. Moreover, the miR-1296-5p expression level was associated with tumor size, the number of foci and the TNM stage; the miR-455-3p expression level was correlated with patient age, tumor size, and TNM stage; and the miR-532-5p expression level was correlated with patient age, lymph node metastasis and TNM stage correspondingly. ROC analysis revealed that the AUCs for miR-1301-3p, miR-1296-5p, miR-455-3p, miR-532-5p, and miR-551b-3p were 0.773, 0.790, 0.783, 0.744, and 0.650, respectively. CONCLUSIONS: Our results indicated that miR-1296-5p, miR-1301-3p, miR-532-5p, miR-551b-3p, and miR-455-3p are aberrantly expressed in papillary thyroid carcinomas and correlated with clinicopathological features. ROC curve analysis indicated that these five miRNAs have a potential diagnostic value. Consequently, we speculate that the five altered miRNAs may serve as potential diagnostic and prognostic biomarkers for PTC.

Low chorionic villous succinate accumulation associates with recurrent spontaneous abortion risk.

Dysregulated extravillous trophoblast invasion and proliferation are known to increase the risk of recurrent spontaneous abortion (RSA); however, the underlying mechanism remains unclear. Herein, in our retrospective observational case-control study we show that villous samples from RSA patients, compared to healthy controls, display reduced succinate dehydrogenase complex iron sulfur subunit (SDHB) DNA methylation, elevated SDHB expression, and reduced succinate levels, indicating that low succinate levels correlate with RSA. Moreover, we find high succinate levels in early pregnant women are correlated with successful embryo implantation. SDHB promoter methylation recruited MBD1 and excluded c-Fos, inactivating SDHB expression and causing intracellular succinate accumulation which mimicked hypoxia in extravillous trophoblasts cell lines JEG3 and HTR8 via the PHD2-VHL-HIF-1α pathway; however, low succinate levels reversed this effect and increased the risk of abortion in mouse model. This study reveals that abnormal metabolite levels inhibit extravillous trophoblast function and highlights an approach for RSA intervention.

Psychosocial risk factors associated with esophageal cancer in Chinese cohort: A systematic review and meta-analysis.

ABSTRACT: Previous studies were controversial about the role of psychosocial factors in the pathogenesis of esophageal cancer (EC). This study aimed to systematically evaluate the effect size of psychosocial risk factors for EC in Chinese cohort.A literature search was conducted in both English and Chinese databases, and odds ratios (OR) with the corresponding 95% confidence intervals (CI) were pooled using a random-effects model.28 studies were identified with a total of 6951 EC cases and 7469 controls. The meta-analysis indicated a higher risk of EC among the individuals with psychological trauma (OR: 2.36, 95% CI: 1.71-3.26), Type A behavior (OR: 1.40, 95% CI: 1.17-1.67), depression (OR: 4.00, 95% CI: 2.44-6.55), melancholy (OR: 2.06, 95% CI: 1.32-3.20), always in sulks (OR: 2.49, 95% CI: 1.21-5.12), and irritable personality (OR: 2.13, 95% CI: 1.58-2.89). A lower EC risk was found in the individuals with good interpersonal relationship (OR: 0.35, 95% CI: 0.17-0.70) and outgoing personality (OR: 0.39, 95% CI: 0.19-0.78).This meta-analysis suggested a potential association between psychosocial factors and EC risk. For the individuals with psychosocial risk factors, physicians should pay more attention to EC screening.

Frequency noise reduction of delay-coupled quantum cascade lasers.

This work theoretically investigates the frequency noise and spectral linewidth characteristics of mutually delay-coupled quantum cascade lasers, which are operated in the stable locking regime. We demonstrate that the mutual injection significantly reduces the frequency noise at proper coupling phases. However, the relative intensity noise is insensitive to the mutual injection. Influences of the pump current, the linewidth broadening factor, the coupling phase, and the delay time on the frequency noise are discussed as well. In addition, it is found that the appearance of multiple compound laser modes can deteriorate the frequency noise performance of the lasers.

miR-1301-3p suppresses tumor growth by downregulating PCNA in thyroid papillary cancer.

OBJECTIVE: Thyroid carcinoma is the most common endocrine tumor, and thyroid papillary carcinoma is the most common form. Although thyroid papillary carcinoma presents a good prognosis, some patients still exhibit recurrence or distant metastasis. miR-1301-3p has been found involved in the occurrence and development of some special tumors. Our study aims to investigate the miR-1301-3p expression in thyroid papillary carcinoma, to explore its biological function, and to provide a potential marker for diagnosis and treatment of thyroid papillary carcinoma. MATERIALS AND METHODS: The tissue samples from 70 patients with PTC (n = 35) and benign tumors (n = 35) were collected respectively. miR-1301-3p expression were detected by qPCR. Diagnostic value of miR-1301-3p was analyzed by ROC curve. CCK-8 assays and flow cytometry were performed to detect the effect of miR-1301-3p on TPC-1 function. PCNA expression of protein was detected by WB. RESULTS: Compared with the normal group, the expression of miR-1301-3p was obviously decreased in both benign group and PTC group. With the higher T and N grades, the lower expression of miR-1301-3p. ROC curve analysis showed that the diagnostic values of miR-1301-3p for benign tumor and PTC were 0.766 and 0.881, respectively. Vitro experiments showed that miR-1301-3p was decreased in TPC-1 cells, then, upregulated miR-1301-3p blocked the TPC-1 cell cycle in G1/S phase, and inhibited the proliferation. PCNA expression was significantly increased in TPC-1 cells and significantly decreased after upregulation of miR-1301-3p. CONCLUSION: The present study showed that the expression of miR-1301-3p in PTC was significantly decreased, which was related to T and N grade. Upregulation of miR-1301-3p could inhibit cell proliferation and cell migration. miR-1301-3p may serve as a potential biomarker for the early diagnosis and treatment of PTC.

The Wnt antagonist and secreted frizzled-related protein 5: implications on lipid metabolism, inflammation, and type 2 diabetes mellitus.

Various reports have suggested that secreted frizzled-related protein (SFRP) 5 (SFRP5) plays a regulatory role in the processes of cellular proliferation and differentiation, by means of inactivating the Wnt/ß-catenin signaling pathway. Recently, SFRP5 has been identified as an anti-inflammatory adipokine, which may be induced during preadipocyte proliferation, differentiation, and maturation. This review aims to identify the recent progress in the research and development of SFRP5 that can play a role in influencing lipid metabolism, inflammation, and type 2 diabetes mellitus (T2DM). Recent evidence has indicated that SFRP5 is capable of stimulating adipocyte differentiation via inhibition of the Wnt/ß-catenin signaling pathway. In addition, SFRP5 binding with wingless-type murine mammary tumor virus integration site family, member 5A (Wnt5a), inhibits the activation of c-Jun N-terminal kinase (JNK) downstream of the Wnt signaling pathway. An antagonistic relationship has been found between the reductions in inflammatory cytokine production and serine phosphorylation of insulin receptor substrate-1 (IRS-1) in regard to inhibition of insulin signaling network. By this mechanism, SFRP5 exerts its influence on metabolic function. Based on our review of the current available literature, we support the notion that SFRP5 can be used as a therapeutic target in the treatment of T2DM.

Irisin Alleviates Advanced Glycation End Products-Induced Inflammation and Endothelial Dysfunction via Inhibiting ROS-NLRP3 Inflammasome Signaling.

The activation of NLR family pyrin domain containing 3 (NLRP3) inflammasome have been implicated in the initiation or progression of atherosclerosis. Recent research showed that irisin, a newly discovered adipomiokine, alleviates endothelial dysfunction in type 2 diabetes partially via reducing oxidative/nitrative stresses, suggesting that irisin may be a promising candidate for the treatment of vascular complications of diabetes. However, the association between irisin and NLRP3 inflammasome in the pathogenesis of atherosclerosis remains unclear. In the present study, we cultured human umbilical vein endothelial cells (HUVECs) in advanced glycation end products (AGEs) medium; exogenous irisin (0.01, 0.1, 1 µg/ml) were used as an intervention reagent. siRNA and adenoviral vector were constructed to realize silencing and over-expression of NLRP3 gene. Our data showed that irisin significantly reversed AGEs-induced oxidative stress and NLRP3 inflammasome signaling activation (p < 0.05), and increased the endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) production in a dose-dependent manner (p < 0.05). siRNA-mediated knockdown NLRP3 facilitated the irisin-mediated anti-inflammatory and antiatherogenic effects (p < 0.05). However, these irisin-mediated effects were reversed by over-expression NLRP3 (p < 0.05). Taken together, our results reveal that irisin alleviates AGEs-induced inflammation and endothelial dysfunction via inhibiting ROS-NLRP3 inflammasome signaling, suggest a likely mechanism for irisin-induced therapeutic effect in vascular complications of diabetes.

Identification of a novel gene pairs signature in the prognosis of gastric cancer.

Current prognostic signatures need to be improved in identifying high-risk patients of gastric cancer (GC). Thus, we aimed to develop a reliable prognostic signature that could assess the prognosis risk in GC patients. Two microarray datasets of GSE662254 (n = 300, training set) and GSE15459 (n = 192, test set) were included into analysis. Prognostic genes were screened to construct prognosis-related gene pairs (PRGPs). Then, a penalized Cox proportional hazards regression model identified seven PRGPs, which constructed a prognostic signature and divided patients into high- and low-risk groups according to the signature score. High-risk patients showed a poorer prognosis than low-risk patients in both the training set (hazard ratios [HR]: 6.086, 95% confidence interval [CI]: 4.341-8.533) and test set (1.773 [1.107-2.840]). The PRGPs signature also achieved a higher predictive accuracy (concordance index [C-index]: 0.872, 95% CI: 0.846-0.897) than two existing molecular signatures (0.706 [0.667-0.744] for a 11-gene signature and 0.684 [0.642-0.726] for a 24-lncRNA signature) and TNM stage (0.764 [0.715-0.814]). In conclusion, our study identified a novel gene pairs signature in the prognosis of GC.

Irisin protects against neuronal injury induced by oxygen-glucose deprivation in part depends on the inhibition of ROS-NLRP3 inflammatory signaling pathway.

Recent studies found that irisin, a newly discovered skeletal muscle-derived myokine during exercise, is also synthesized in various tissues of different species and protects against neuronal injury in cerebral ischemia. The NOD-like receptor pyrin 3 (NLRP3) inflammasome play an important role in detecting cellular damage and mediating inflammatory responses to aseptic tissue injury during ischemic stroke. However, it is unclear whether irisin is involved in the regulation of NLRP3 inflammasome activation during ischemic stroke. In the present study, PC12 neuronal cells were exposed to oxygen-glucose deprivation (OGD), exogenous irisin (12.5, 25, 50nmol/L) or NLRP3 inhibitor glyburide (50, 100, 200µmol/L) were used as an intervention reagent, NLRP3 was over-expressed or suppressed by transfection with a NLRP3 expressing vector or NLRP3-specifc siRNA, respectively. Our data showed that both irisin and its precursor protein fibronectin type III domain containing 5 (FNDC5) expression were significantly down-regulated (p<0.05); but oxidative stress and ROS-NLRP3 inflammasome signaling were activated by OGD (p<0.05); treatment with irisin or inhibition of NLRP3 reversed OGD-induced oxidative stress and inflammation (p<0.05). However, these irisin-mediated effects were blunted by over-expression NLRP3 (p<0.05). Taken together, our results firstly revealed that irisin mitigated OGD-induced neuronal injury in part via inhibiting ROS-NLRP3 inflammatory signaling pathway, suggesting a likely mechanism for irisin-induced therapeutic effect in ischemic stroke.

Blockade of high-mobility group box 1 attenuates intestinal mucosal barrier dysfunction in experimental acute pancreatitis.

The release of inflammatory cytokines, that plays a dominant role in local pancreatic inflammation and systemic complications in severe acute pancreatitis (SAP). High-mobility group box 1 (HMGB1) is implicated in the mechanism of organ dysfunction and bacterial translocation in SAP. This current study aims to investigate possible role of HMGB1 in the intestinal mucosal barrier dysfunction of SAP, and the effect of anti-HMGB1 antibody treatment in intestinal mucosal injury in SAP. Our data revealed that the HMGB1 expression was significantly increased in AP mice induced by caerulein and LPS, and the inhibition of HMGB1 played a protective role in intestinal mucosal barrier dysfunction, reduced the serum level of other proinflammatory cytokines include IL-1ß, IL-6, TNF-α. Next we investigated the downstream receptors involving in HMGB1 signaling. We found that the expressions of toll-like receptor (TLR) 4 and TLR9 were elevated in ileum of AP mice, the administration of HMGB1 neutralizing antibody significantly reduced the TLR4 and TLR9 expression. It was concluded that HMGB1 contributed the mechanism to the intestinal mucosal barrier dysfunction during AP. Blockade of HMGB1 by administration of HMGB1 neutralizing antibody may be a beneficial therapeutic strategy in improving intestinal mucosal barrier dysfunction in SAP.

Ischemic Preconditioning-Induced SOCS-1 Protects Rat Intestinal Ischemia Reperfusion Injury via Degradation of TRAF6.

BACKGROUND: The inflammatory immune response plays an important role in mesenteric ischemia and ischemia-reperfusion injury. Toll-like receptor 4 (TLR4) is a critical receptor in transduction of the inflammatory response and plays an important role in intestinal homeostasis. Tumor necrosis factor receptor-associated factor 6 (TRAF6), known as a key adaptor protein downstream of TLR4, is involved in the inflammatory response by activating multiple apoptotic signaling pathways. However, mechanisms of the suppressor of cytokine signaling-1 (SOCS-1) in regulating cell inflammation and apoptosis are still obscure. OBJECTIVES: To investigate the TLR4-TRAF6 signaling pathway in intestinal ischemia and reperfusion injury, as well as SOCS-1 expression after ischemic preconditioning in the rat intestine. METHODS: The small bowel ischemia, ischemia-reperfusion, and preconditioning models were induced using ligation of the superior mesenteric artery in male Sprague-Dawley rats; then, the mRNA and protein levels of TLR4, TRAF6, and SOCS-1 were analyzed using real-time PCR, Western blot, and immunohistochemistry, respectively. RESULTS: The expression of TLR4 and TRAF6 was gradually increased with increasing intestinal ischemia duration, but increased substantially after ischemia-reperfusion injury. After ischemic preconditioning, TLR4 and TRAF6 expressions decreased; however, expression of SOCS-1 and the TLR4-TRAF6 pathway inhibitor was increased. CONCLUSION: These data show that ischemic preconditioning may induce the activation of SOCS-1 to inhibit the TLR4-TRAF6 signaling pathway, thereby playing a protective role in ischemia-reperfusion injury.