Downregulation of PI3K-γ in a mouse model of sepsis-induced myocardial dysfunction.

A key component during sepsis is the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway, of which the PI3K-γ isoform is a major regulator in many inflammatory responses. However, the role of PI3K-γ in the development of sepsis-induced myocardial dysfunction (SIMD) is unknown. In this study, we established a model of SIMD induced by lipopolysaccharide (LPS), subsequently used the selective inhibitor LY294002 and AS605240 to block the effect of PI3K and PI3K-γ, respectively. Cardiac function was evaluated by echocardiography, hearts were obtained for histological and protein expression examinations. ELISA was used to measure the serum levels of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), cardiac troponin I (cTnI) and heart-type fatty acid binding protein (H-FABP). LPS-treated mice showed an increase to cardiac inflammation, myocardial damage and production of TNF-α, IL-6, NF-κB, cTnI and H-FABP. Administration of AS605240 to LPS-treated mice reduced some patho-physiological characteristics of SIMD and reduced TNF-α, IL-6, cTnI and H-FABP production. However, administration of LY294002 did not improve those same conditions. The results showed that PI3K-γ is likely a crucial element in SIMD by regulating the PI3K/Akt pathway, and become a new marker of myocardial injury. Inhibition of PI3K-γ might be a potential therapeutic target in SIMD.

Interleukin-27 is elevated in sepsis-induced myocardial dysfunction and mediates inflammation.

INTRODUCTION: Interleukin (IL)-27 is an important cytokine involved in many human inflammatory diseases. In this study, we investigated its role in the pathogenesis of sepsis-induced myocardial dysfunction (SIMD). METHODS: Twenty patients with SIMD and 24healthy donors were prospectively enrolled. Expression of IL-27 was detected in serum from SIMD patients by ELISA. Cardiac dysfunction was induced by administration of Escherichia coli lipopolysaccharide (LPS) to C57BL/6 (wild type) or IL-27R-/- mice. IL-27 mRNA in the myocardium was measured by RT-PCR. Cytokine levels in serum were determined by ELISA. RESULTS: Expression of IL-27 in the serum was markedly increased in patients with SIMD compared with that in controls. Serum IL-27 levels and cardiac IL-27 mRNA expression were significantly increased after LPS injection compared with control specimens. Compared with wild-type mice, IL-27R-/- mice had higher expression of brain natriuretic peptide, cardiac troponin I, IL-6, IL-12, tumor necrosis factor-α and transforming growth factor-ß. CONCLUSIONS: IL-27 is an important protective mediator of SIMD.

Curcumin Promotes the Expression of IL-35 by Regulating Regulatory T Cell Differentiation and Restrains Uncontrolled Inflammation and Lung Injury in Mice.

Interleukin (IL)-35, which has an anti-inflammatory role in acute respiratory distress syndrome (ARDS)/acute lung injury (ALI), is relatively promising as a drug target. Studies have shown that curcumin may play a therapeutic role in ALI and enhance the suppressive function of regulatory T cells (Tregs). To illustrate the effect of curcumin on the regulation of Treg cell differentiation and expression of IL-35, we built a cecal ligation and puncture (CLP)-induced acute lung injury mouse mode with curcumin pretreatment. The expression of IL-35 in serum, severity of lung injury, IL-17A in lung tissue, survival rate, Treg-related cytokines levels in serum, nuclear factor-kappa B (NF-κB)'s nuclear translocation in lung tissue, and splenic CD4+CD25+FOXP3+ Tregs were assessed. Furthermore, the proportion of Tregs, STAT5, and IL-35 expression during naïve CD4+ T cell differentiation in vitro was measured. Compared with the CLP group, the increased IL-35 expression in CLP with the curcumin pretreatment (CLP + Cur) group was consistent with the decreased severity of lung injury, IL-17A protein levels in lung tissue, and Treg-related cytokines levels. Pretreatment with curcumin, the survival rate climbed to 50%, while the mortality rate was 100% in the CLP group. In addition, splenic CD4+CD25+FOXP3+ Treg cells increased in the CLP + Cur group. In vitro, CD4+CD25+FOXP3+ Treg cells from naïve CD4+ T cells, STAT5 proportion, and IL-35 expression increased after curcumin treatment. These findings showed that curcumin might regulate IL-35 by activating the differentiation of Treg cells to control the inflammation in acute lung injury.

Curcumin regulates the differentiation of naïve CD4+T cells and activates IL-10 immune modulation against acute lung injury in mice.

OBJECTIVES: Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is one type of respiratory failure characterized by rapid onset of widespread inflammation in the lungs. Curcumin has been reported to be an anti-inflammatory factor through enhancing the function of regulatory T cells (Tregs). This study aimed to explore the effect of curcumin on the differentiation of Tregs and the role of curcumin in ALI/ARDS. METHODS: A cecal ligation and puncture (CLP)-induced acute lung injury mouse model was used to explore the effect of curcumin in ALI/ARDS. The severity of lung injury was evaluated. Immunohistochemistry of IL-17A and MPO in lung tissue was examined. Treg-related cytokine levels in serum and bronchoalveolar lavage fluid (BALF) were tested. The expression of nuclear factor-kappa B (NF-κB) in lung tissue was detected. Macrophages in lung tissue were detected by immunofluorescence. Splenic CD4+CD25+FOXP3+ Tregs were quantified, and the differentiation of Tregs from naïve CD4 + T cell and STAT5 was evaluated. The expression of IL-10 during naïve CD4 + T cell differentiation in vitro was tested. RESULTS: Curcumin alleviated lung injury in the induced CLP mouse model and suppressed inflammation. IL-17A, MPO-producing neutrophils, and NF-κB p65 expression in lungs of CLP mice decreased significantly after pretreatment with curcumin. We found curcumin could regulate M1/M2 macrophage levels in lungs of CLP mice. This may have been through regulating the differentiation of Tregs and the production of Treg-derived IL-10. Treg-derived IL-10 is the main factor that could affect macrophage polarization. We found curcumin could increase Treg proportions in vivo and up-regulate IL-10 expression in serum and BALF of CLP mice. In our in vitro experiments, we found curcumin could promote Treg differentiation and increase the production of IL-10. CONCLUSIONS: Curcumin can reduce the degree of severity of ALI and uncontrolled inflammation through promoting the differentiation of naïve CD4 + T cells to CD4+ CD25+ FOXP3+ Tregs. Curcumin promotes the conversion of macrophages from M1 to M2. The differentiation of Tregs induced by curcumin may be one source of IL-10 immune modulation.

Experiment research of cisplatin implants inhibiting transplantation tumor growth and regulating the expression of KLK7 and E-cad of tumor-bearing mice with gastric cancer.

OBJECTIVE: To study the influence of cisplatin implants on transplantation tumor growth and the expression of tissue kallikrein-7 (KLK7) and E-cadherin (E-cad) in tumor-bearing mice with gastric cancer. METHODS: BALB/c nude mice were collected as experimental animal and were randomly divided into model control group (Group A), tail intravenous injection of cisplatin group (Group B), intratumor injection of cisplatin group (Group C) and cisplatin implants treatment group (Group D). After the drugs intervening, the weight and volume of transplantation tumors were measured on Day 20, Day 30 and Day 40 and serum and KLK7 and E-cad contents in transplanted tumor tissue were examined. RESULTS: On Day 20, Day 30 and Day 40 after treatment, the weight and volume of transplantation tumors of tumor-bearing mice in four groups were different (Group A > Group B > Group C > Group D). The contents of KLK-7 and E-cad in tumor tissue and serum of tumor-bearing mice in four groups were different (Group A > Group B > Group C > Group D in KLK-7) and (Group A < Group B < Group C < Group D in E-cad). The weight and volume, and KLK7 and E-cad contents of transplantation tumors in four groups were significant difference (P < 0.05). CONCLUSION: Cisplatin implants can inhibit the growth of transplanted tumor tissue and down-regulated KLK7 expression and up-regulated E-cad expression of tumor-bearing mice with gastric cancer.

Clinical significance of dynamic detection for serum levels of MCP-1, TNF-α and IL-8 in patients with acute pancreatitis.

OBJECTIVE: To observe dynamic changes of levels of monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-α (TNF-α) and interleukin-8 (IL-8) in patients with acute pancreatitis and to investigate its evaluation value on the severity of acute pancreatitis. METHODS: A total of 109 patients with acute pancreatitis admitted were divided into mild acute pancreatitis group (MAP group, 42 cases), moderately severe acute pancreatitis (MSAP group, 35 cases) and severe acute pancreatitis (SAP group, 32 cases). ELISA was used to detect the serum levels of MCP-1, TNF-α and IL-8 of patients at day 1, day 4 and day 7 of admission to hospital. RESULTS: The serum levels of MCP-1, TNF-α and IL-8 from MAP group, MSAP group and SAP group at day 1 of admission to hospital all significantly increased. There was a significant difference between MAP group and control group, MSAP group and MAP group, SAP group and MSAP group (P < 0.05). The serum concentrations of IL-8 from MASP group and SAP group obviously increased at day 1, and there was significant difference between MASP group and MAP group, SAP group and MSAP group (P < 0.05), while the difference between MAP group and control group was not obvious (P > 0.05); The serum concentrations of MCP-1, TNF-α and IL-8 from MAP group all reached the highest level at day 4, which were significantly higher than the detection levels at day 1. In MSAP group and SAP group, the serum concentrations of MCP-1, TNF-α and IL-8 were the highest at day 1, which were significantly higher than the detection levels at day 4 and 7. At each detecting timing, the serum concentrations of MCP-1, TNF-α and IL-8 from MSAP group and SAP group were all higher than those of MAP group and MSAP group, respectively. CONCLUSIONS: The dynamic changes of serum levels of MCP-1, TNF-α and IL-8 in patients with acute pancreatitis have their rules, and the change rule of MAP group was different with that of MSAP and SAP group, which showed the reference value for the diagnosis and illness severity evaluation of acute pancreatitis.

Exogenous cytochrome c inhibits the expression of transforming growth factor-ß1 in a mouse model of sepsis-induced myocardial dysfunction via the SMAD1/5/8 signaling pathway.

The current study investigated the role of exogenous cytochrome c in sepsis-induced myocardial dysfunction (SIMD) using a mouse model and aimed to elucidate its effect on transforming growth factor-ß1 (TGF-ß1) expression during this process. A total of 75 male Kunming mice were randomly divided into the following five group: Normal (N, n=15); sham-operation (SHAM, n=15); sepsis (CLP, n=15); normal saline (NS, n=15); and cytochrome c (Cytc, n=15). Animals were sacrificed at 0, 6 or 12 h and the samples were analyzed using transmission electron microscopy, histopathological examination, reverse transcription-quantitative polymerase chain reaction, ELISA, protein analysis by western blotting. The SIMD model was developed and a significant downregulation of TGF-ß1 gene expression, in addition to a reduction in the plasma and protein levels of TGF-ß1 as well as the protein levels of TGF-ß1-activated SMAD 1/5/8 were observed in the CLP group. The data from the current study indicate that using exogenous cytochrome c as a therapeutic strategy for SIMD is feasible, and may function via the downregulation of TGF-ß1 expression through the SMAD 1/5/8 signaling pathway.

The effect of curcumin on sepsis-induced acute lung injury in a rat model through the inhibition of the TGF-ß1/SMAD3 pathway.

Curcumin has the potential to treat inflammatory diseases. This study investigated its effect on sepsis-induced acute lung injury (ALI) in a rat model. 125 healthy rats were randomly divided into five groups, including normal group, sham-operated group, sepsis group, dimethyl sulfoxide group, and curcumin-treated group (25 rats in each subgroup). Sepsis-induced acute lung injury was affected by cecal ligation and puncture surgery. At 0, 6, 12, 24, and 48 h after treatment, the lungs were harvested for histological and protein expression examinations. 24h after the initial treatment, real-time PCR and Western blot analysis showed that the expression of TGF-ß1 and SMAD3-dependent signaling pathway was significantly decreased in the curcumin-treated group than other control groups (P<0.05). Therefore, curcumin played a protective role in sepsis-induced ALI, possibly through the inhibition of the expression of TGF-ß1/SMAD3 pathway which may provide a new strategy for the treatment of sepsis-induced ALI.

[Application of small remote sensing satellite constellations for environmental hazards in wetland landscape mapping: taking Liaohe Delta, Liaoning Province of Northeast China as a case].

To timely and accurately acquire the spatial distribution pattern of wetlands is of significance for the dynamic monitoring, conservation, and sustainable utilization of wetlands. The small remote sensing satellite constellations A/B stars (HJ-1A/1B stars) for environmental hazards were launched by China for monitoring terrestrial resources, which could provide a new data source of remote sensing image acquisition for retrieving wetland types. Taking Liaohe Delta as a case, this paper compared the accuracy of wetland classification map and the area of each wetland type retrieved from CCD data (HJ CCD data) and TM5 data, and validated and explored the applicability and the applied potential of HJ CCD data in wetland resources dynamic monitoring. The results showed that HJ CCD data could completely replace Landsat TM5 data in feature extraction and remote sensing classification. In real-time monitoring, due to its 2 days of data acquisition cycle, HJ CCD data had the priority to Landsat TM5 data (16 days of data acquisition cycle).

Notch-induced Asb2 expression promotes protein ubiquitination by forming non-canonical E3 ligase complexes.

Notch signaling controls multiple developmental processes, thus demanding versatile functions. We have previously shown that this may be partly achieved by accelerating ubiquitin-mediated degradation of important regulators of differentiation. However, the underlying mechanism was unknown. We now find that Notch signaling transcriptionally activates the gene encoding ankyrin-repeat SOCS box-containing protein 2 (Asb2). Asb2 promotes the ubiquitination of Notch targets such as E2A and Janus kinase (Jak) 2, and a dominant-negative (DN) mutant of Asb2 blocks Notch-induced degradation of these proteins. Asb2 likely binds Jak2 directly but associates with E2A through Skp2. We next provide evidence to suggest that Asb2 bridges the formation of non-canonical cullin-based complexes through interaction with not only ElonginB/C and Cullin (Cul) 5, but also the F-box-containing protein, Skp2, which is known to associate with Skp1 and Cul1. Consistently, ablating the function of Cul1 or Cul5 using DN mutants or siRNAs protected both E2A and Jak2 from Asb2-mediated or Notch-induced degradation. By shifting monomeric E3 ligase complexes to dimeric forms through activation of Asb2 transcription, Notch could effectively control the turnover of a variety of substrates and it exerts diverse effects on cell proliferation and differentiation.