Effect of ischemia-reperfusion injury on elafin levels in rat liver.

BACKGROUND: The aim of this study was to quantify serum levels of elafin, a serine protease inhibitor, and to assess its effects on histopathological and biochemical parameters in hepatic ischemia-reperfusion injury. METHODS: Forty female Wistar albino rats were divided into five groups: Group 1 served as the control group. Liver ischemia was induced for 30 minutes in the other four groups. An additional 1-hour, 2-hour, and 3-hour reperfusion was induced in Groups 3, 4, and 5, respectively. At the end of the experiment, intracardiac blood samples were obtained for biochemical examination, and tissue samples from the liver were taken for histopathological examination. Levels of elafin, ischemia-modified albumin (IMA), total antioxi-dant status (TAS), and total oxidant status (TOS) were also examined. RESULTS: Serum elafin levels decreased beginning from Group 2, with the lowest level reached in Group 5 (p<0.01). The IMA level was the lowest in the control group and the highest in Group 5 (p<0.01). TOS, aspartate aminotransferase (AST), and alanine amino-transferase (ALT) levels were lowest in the control group and highest in Group 5 (p<0.01). Group 5 had the highest IMA/albumin ratio, although no significant differences were found between these four groups. The lowest TAS level was found in the control group, but a stable and significant increase was not detected in the other groups. No significant differences were found between the groups in terms of alkaline phosphatase (ALP) and albumin levels. A negative correlation was observed between serum elafin levels and AST, ALT, and TOS levels (p<0.01). The number of Grade 1 histopathological results was found to be higher in the groups with reperfusion (Groups 3, 4, 5). In histopathological subgroup analysis, while the elafin level was lower in Grade 1 group, AST, ALT, and TOS levels were higher (p<0.01). Additionally, the IMA/albumin ratio was found to be higher in the Grade 1 group (p=0.02). CONCLUSION: In hepatic ischemia-reperfusion injury, elafin levels decreased as the reperfusion time increased. As the reperfusion time increased, both hepatocyte damage and oxidant capacity increased, with a negative correlation observed between these findings and elafin levels. Therefore, elafin may play a protective role in hepatic ischemia-reperfusion injury and could assist clinicians in assessing liver injury.

Association of inflammation-related markers and diabetic retinopathy severity in the aqueous humor, but not serum of type 2 diabetic patients.

Diabetic retinopathy (DR) is a frequent microvascular complication of diabetes mellitus, and inflammatory pathways have been linked to its pathogenesis. In this retrospective, observational pilot study, we aimed to compare the concentrations of four inflammation-related proteins, ZAG, Reg-3a, elafin and RBP-4, in the serum and aqueous humor of healthy controls and diabetic patients with different stages of DR. The concentrations of VEGF-A, IL-8, IL-6 were determined in parallel as internal controls. In the serum, we did not find significant differences in the concentrations of target proteins. In the aqueous humor, higher levels of ZAG, RBP-4, Reg-3a and elafin were observed in advanced nonproliferative DR (NPDR)/ proliferative DR (PDR) compared to controls. The levels of ZAG and RBP-4 were also higher in advanced NPDR/PDR than in nonapparent DR. Normalization of target protein concentrations to the aqueous humor total protein demonstrates that a spill-over from serum due to breakage of the blood-retina barrier only partially accounts for increased inflammation related markers in later stages. In conclusion, we found elevated levels of Reg-3a, RBP-4, elafin and ZAG in advanced stages of diabetic retinopathy. Higher levels of pro-inflammatory proteins, Reg-3a and RBP-4, might contribute to the pathogenesis of diabetic retinopathy, as the parallel increased concentrations of anti-inflammatory molecules elafin and ZAG might indicate a compensatory mechanism.

Pathological roles of antimicrobial peptides and pro-inflammatory factors secreted from the cervical epithelium in Gardnerella vaginalis-abundant vaginal flora in pregnancy.

Bacterial vaginosis due to Gardnerella vaginalis (GV) is one of the main causes of preterm birth. Antimicrobial function of the cervical glands prevents ascending pathogen infection. This study investigated the effect of GV on the cervical gland cells. We examined the correlation between GV and neutrophil elastase in the cervical mucous obtained from pregnant women's clinical samples. Culture supernatants (sup) of GV and Lactobacillus crispatus (LC) were added to human immortalized cervical gland cells (EndoCx). Quantitative reverse transcription PCR (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA) were used to examine the effects on the production of antimicrobial peptides (AMPs), secretory leukocyte peptidase inhibitor (SLPI), and Elafin. mRNA microarray analysis revealed the expression profile of GV-exposed EndoCx. Moreover, the antimicrobial activity of Elafin against LC and GV was investigated. In the clinical samples, neutrophil elastase was increased in the GV-positive cervical mucous. In an in vitro assay, RT-qPCR and ELISA showed that GV-sup enhanced the secretion of Elafin, but not SLPI, from EndoCx, whereas LC-sup did not. mRNA microarray assay and ELISA results demonstrated that GV-sup enhanced the proinflammatory pathway and interleukin (IL)- 8 secretion from EndoCx as well as cell adhesion and tight junction pathways. Moreover, GV-sup directly enhanced Elafin and IL-8 secretion from the cervical gland cells. In the GV-abundant vaginal flora, IL-8 level increased the neutrophil elastase activity and Elafin inhibited the elastase activity to protect from tissue damage and infection. Thus, the balance of IL-8-induced neutrophil and Elafin-induced antiprotease activities may be crucial in preterm labor.

Elafin and its precursor trappin-2: What is their therapeutic potential for intestinal diseases?

Elafin and its precursor trappin-2 are known for their contribution to the physiological mucosal shield against luminal microbes. Such a contribution seems to be particularly relevant in the gut, where the exposure of host tissues to heavy loads of microbes is constant and contributes to mucosa-associated pathologies. The expression of trappin-2/elafin has been shown to be differentially regulated in diseases associated with gut inflammation. Accumulating evidence has demonstrated the protective effects of trappin-2/elafin in gut intestinal disorders associated with acute or chronic inflammation, or with gluten sensitization disorders. The protective effects of trappin-2/elafin in the gut are discussed in terms of their pleiotropic modes of action: acting as protease inhibitors, transglutaminase substrates, antimicrobial peptides or as a regulator of pro-inflammatory transcription factors. Further, the question of the therapeutic potential of trappin-2/elafin delivery at the intestinal mucosa surface is raised. Whether trappin-2/elafin mucosal delivery should be considered to ensure intestinal tissue repair is also discussed.

Endogenous Retroviral Elements Generate Pathologic Neutrophils in Pulmonary Arterial Hypertension.

Rationale: The role of neutrophils and their extracellular vesicles (EVs) in the pathogenesis of pulmonary arterial hypertension is unclear. Objectives: To relate functional abnormalities in pulmonary arterial hypertension neutrophils and their EVs to mechanisms uncovered by proteomic and transcriptomic profiling. Methods: Production of elastase, release of extracellular traps, adhesion, and migration were assessed in neutrophils from patients with pulmonary arterial hypertension and control subjects. Proteomic analyses were applied to explain functional perturbations, and transcriptomic data were used to find underlying mechanisms. CD66b-specific neutrophil EVs were isolated from plasma of patients with pulmonary arterial hypertension, and we determined whether they produce pulmonary hypertension in mice. Measurements and Main Results: Neutrophils from patients with pulmonary arterial hypertension produce and release increased neutrophil elastase, associated with enhanced extracellular traps. They exhibit reduced migration and increased adhesion attributed to elevated ß1-integrin and vinculin identified by proteomic analysis and previously linked to an antiviral response. This was substantiated by a transcriptomic IFN signature that we related to an increase in human endogenous retrovirus K envelope protein. Transfection of human endogenous retrovirus K envelope in a neutrophil cell line (HL-60) increases neutrophil elastase and IFN genes, whereas vinculin is increased by human endogenous retrovirus K deoxyuridine triphosphate diphosphatase that is elevated in patient plasma. Neutrophil EVs from patient plasma contain increased neutrophil elastase and human endogenous retrovirus K envelope and induce pulmonary hypertension in mice, mitigated by elafin, an elastase inhibitor. Conclusions: Elevated human endogenous retroviral elements and elastase link a neutrophil innate immune response to pulmonary arterial hypertension.

Human Inflammatory Neutrophils Express Genes Encoding Peptidase Inhibitors: Production of Elafin Mediated by NF-κB and CCAAT/Enhancer-Binding Protein ß.

The concept of plasticity of neutrophils is highlighted by studies showing their ability to transdifferentiate into APCs. In this regard, transdifferentiated neutrophils were found at inflammatory sites of autoimmune arthritis (AIA). Exposure of neutrophils to inflammatory stimuli prolongs their survival, thereby favoring the acquisition of pathophysiologically relevant phenotypes and functions. By using microarrays, quantitative RT-PCR, and ELISAs, we showed that long-lived (LL) neutrophils obtained after 48 h of culture in the presence of GM-CSF, TNF, and IL-4 differentially expressed genes related to apoptosis, MHC class II, immune response, and inflammation. The expression of anti-inflammatory genes mainly of peptidase inhibitor families is upregulated in LL neutrophils. Among these, the PI3 gene encoding elafin was the most highly expressed. The de novo production of elafin by LL neutrophils depended on a synergism between GM-CSF and TNF via the activation and cooperativity of C/EBPß and NF-κB pathways, respectively. Elafin concentrations were higher in synovial fluids (SF) of patients with AIA than in SF of osteoarthritis. SF neutrophils produced more elafin than blood counterparts. These results are discussed with respect to implications of neutrophils in chronic inflammation and the potential influence of elafin in AIA.

Eugenol-piperine loaded polyhydroxy butyrate/polyethylene glycol nanocomposite-induced apoptosis and cell death in nasopharyngeal cancer (C666-1) cells through the inhibition of the PI3K/AKT/mTOR signaling pathway.

Nasopharyngeal cancer is a malignancy developing from the nasopharynx epithelium due to smoking and nitrosamine-containing foods. Nasopharyngeal cancer is highly endemic to Southeast Asia. Eugenol and piperine have shown many anticancer activities on numerous cancer types, like colon, lung, liver, and breast cancer. In this study, we amalgamated eugenol and piperine loaded with a polyhydroxy butyrate/polyethylene glycol nanocomposite (Eu-Pi/PHB-PEG-NC) for better anticancer results against nasopharyngeal cancer (C666-1) cells. In the current study, nasopharyngeal cancer cell lines C666-1 were utilized to appraise the cytotoxic potential of Eug-Pip-PEG-NC on cell propagation, programmed cell death, and relocation. Eu-Pi/PHB-PEG-NC inhibits cellular proliferation on C666-1 cells in a dose-dependent manner, and when compared with 20 µg/ml, 15 µg/ml of loaded mixture evidently restrained the passage aptitude of C666-1 cells, this was attended with a downregulated expression of mitochondrial membrane potential. Treatment with 15 µg/ml Eu-Pi/PHB-PEG-NC suggestively amplified cell apoptosis in the C666-1 cells. Furthermore, its cleaved caspase-3, 8, and 9 and Bax gene expression was augmented and Bcl-2 gene expression was diminished after Eu-Pi/PHB-PEG-NC treatment. Additionally, our data established that the collective effect of Eu-Pi/PHB-PEG-NC loaded micelles inhibited the expansion of C666-1 cells augmented apoptosis connected with the intrusion of PI3K/Akt/mTOR signaling pathway.

Evaluation of trappin-2 in cervicovaginal secretions as predictor of spontaneous preterm birth in asymptomatic high-risk women: Nested case-control study.

OBJECTIVE: To evaluate trappin-2 levels in cervicovaginal secretions for prediction of spontaneous preterm birth (sPTB) and compare it with transvaginal sonography (TVS) cervical length in asymptomatic women at risk of PTB. METHODS: Trappin-2 levels assessed in cervicovaginal secretions collected from 80 asymptomatic pregnant women at high risk for preterm delivery and cervical length measured by TVS, first at 14-20 weeks of pregnancy and repeated 8 weeks later. On the basis of delivery outcomes, participants were divided into cases (delivery <37 weeks) and controls (delivery at 37-41 weeks). RESULTS: The mean value of cervicovaginal trappin-2 was significantly higher in women who delivered preterm (n = 40), compared with the term group (n = 40: P < 0.001) both at 14-20 weeks and at 22-28 weeks. The critical cut-off value for cervicovaginal trappin-2 at 14-20 weeks was 4620 pg/mL, above which participants delivered prematurely with sensitivity, specificity, and positive and negative predictive values of 82.5%, 71.0%, 78.5%, and 81.5% respectively, whereas TVS cervical length in this window period was not significantly associated with preterm birth. At 22-28 weeks a trappin-2 value of 6900 pg/mL had similar predictive accuracy. CONCLUSION: Raised cervicovaginal trappin-2 levels can be used as an early tool for prediction of PTB as early as 14-20 weeks (earlier than TVS) in asymptomatic high-risk women.

USP18 promotes cell proliferation and suppressed apoptosis in cervical cancer cells via activating AKT signaling pathway.

BACKGROUND: The deubiquitinating (DUB) enzyme ubiquitin-specific protease 18 (USP18), also known as UBP43, is an ubiquitin-specific protease linked to several human malignancies. However, USP18's underlying function in human cervical cancer remains unclear. In the current study, we aimed to analyse the role of USP18 and its signalling pathways in cervical cancer. METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemical staining were performed to analyse USP18 levels in cervical cancer and matched to adjacent normal tissues. Moreover, RNA interference (RNAi) and lentiviral-mediated vector transfections were performed to silence and overexpress USP18, respectively, in cervical cancer cells. Further, Cell Counting Kit-8 (CCK-8) and Annexin V/PI staining assays were used to assess its biological function in cell proliferation and apoptosis, respectively. A xenograft model was used to examine USP18's function in vivo. RESULTS: The present findings demonstrated that USP18 was overexpressed in cervical cancer specimens and cell lines. Silencing USP18 in SiHa and Caski cervical cancer cell lines inhibited cell proliferation, induced apoptosis, and promoted cleaved caspase-3 expression. In contrast, USP18 overexpression showed the opposite effects in human HcerEpic cells. A Gene Set Enrichment Analysis revealed that USP18 was enriched in the PI3K/AKT signalling pathway in cervical cancer. Hence, the PI3K/AKT inhibitor LY294002 was used to determine the relationship between USP18 and AKT in cervical cancer cells. Importantly, LY294002 significantly abolished the effects of USP18 overexpression in cervical cancer cells. In vivo, USP18 silencing inhibited human cervical cancer cells' tumorigenicity. CONCLUSIONS: The current study indicates that USP18 is an oncogenic gene in cervical cancer. Our findings not only deepened the understanding of USP18's biological function in cervical cancer pathogenesis, but we also provided novel insight for cervical cancer therapy. TRIAL REGISTRATION: Retrospectively registered.

Blockade of RANKL/RANK signaling pathway by epigallocatechin gallate alleviates mast cell-mediated inflammatory reactions.

Receptor activator of NF-κB ligand (RANKL) as an osteoclast differentiation factor induces inflammatory reactions via production of thymic stromal lymphopoietin (TSLP). Epigallocatechin gallate (EGCG) is the major and the most active compound in green tea and has anti-inflammatory, anti-cancer, anti-oxidant, and neuroprotective effects. However, the effect and molecular mechanisms of EGCG are still unknown in RANKL-induced inflammatory reactions. Here we investigated the immuno-regulatory effects and its molecular mechanisms of epigallocatechin gallate (EGCG) in RANKL-stimulated human mast cell line, HMC-1 cells. In this study, EGCG prevented expression of PI3 Kinase and phosphorylation of mitogen-activated protein (MAP) Kinases in RANKL-stimulated HMC-1 cells. EGCG prevented caspase-1 activity and decreased transcriptional activity of nuclear factor (NF)-κB by suppressing inhibitory protein κBα phosphorylation in RANKL-stimulated HMC-1 cells. EGCG has been shown to prevent production and mRNA expression of TSLP, interleukin (IL)-1ß, IL-6, and IL-8 by RANKL without cytotoxicity. Furthermore, EGCG prevented degranulation of mast cell in RANKL-stimulated HMC-1 cells. Overall, these results suggest that EGCG acts as a natural agent for preventing and treating RANKL-mediated inflammatory diseases by targeting PI3 Kinase, MAP Kinase, caspase-1, and NF-κB signaling cascade in mast cells.

Elafin inhibits obesity, hyperglycemia, and liver steatosis in high-fat diet-treated male mice.

Elafin is an antimicrobial and anti-inflammatory protein. We hypothesize that elafin expression correlates with diabetes. Among non-diabetic and prediabetic groups, men have significantly higher serum elafin levels than women. Men with type 2 diabetes mellitus (T2DM) have significantly lower serum elafin levels than men without T2DM. Serum elafin levels are inversely correlated with fasting blood glucose and hemoglobin A1c levels in men with T2DM, but not women with T2DM. Lentiviral elafin overexpression inhibited obesity, hyperglycemia, and liver steatosis in high-fat diet (HFD)-treated male mice. Elafin-overexpressing HFD-treated male mice had increased serum leptin levels, and serum exosomal miR181b-5p and miR219-5p expression. Transplantation of splenocytes and serum exosomes from elafin-overexpressing HFD-treated donor mice reduced food consumption and fat mass, and increased adipose tissue leptin mRNA expression in HFD-treated recipient mice. Elafin improved leptin sensitivity via reduced interferon-gamma expression and induced adipose leptin expression via increased miR181b-5p and miR219-5p expression. Subcutaneous and oral administration of modified elafin inhibited obesity, hyperglycemia, and liver steatosis in the HFD-treated mice. Circulating elafin levels are associated with hyperglycemia in men with T2DM. Elafin, via immune-derived miRNAs and cytokine, activates leptin sensitivity and expression that subsequently inhibit food consumption, obesity, hyperglycemia, and liver steatosis in HFD-treated male mice.

Cervicovaginal natural antimicrobial expression in pregnancy and association with spontaneous preterm birth.

There is much interest in the role of innate immune system proteins (antimicrobial peptides) in the inflammatory process associated with spontaneous preterm birth (sPTB). After promising pilot work, we aimed to validate the association between the antimicrobial peptides/proteins elafin and cathelicidin and sPTB. An observational cohort study of 405 women at high-risk, and 214 women at low-risk of sPTB. Protein concentrations of elafin and cathelicidin, and the enzyme human neutrophil elastase (HNE) were measured in over 1,000 cervicovaginal fluid (CVF) samples (10 to 24 weeks' gestation). Adjusted CVF cathelicidin and HNE concentrations (but not elafin) were raised in high-risk women who developed cervical shortening and who delivered prematurely and were predictive of sPTB < 37 weeks, with an area under the curve (AUC) of 0.75 (95% CI 0.68 to 0.81) for cathelicidin concentration at 14 to 15+6 weeks. Elafin concentrations were affected by gestation, body mass index and smoking. CVF elafin in early pregnancy was modestly predictive of sPTB < 34 weeks (AUC 0.63, 0.56-0.70). Alterations in innate immune response proteins in early pregnancy are predictive of sPTB. Further investigation is warranted to understand the drivers for this, and their potential to contribute towards clinically useful prediction techniques.

Upregulation of elafin expression in the fallopian tube of ectopic tubal pregnancies compared to the normal tubes.

BACKGROUND: Ectopic pregnancy is one of the most important causes of maternal deaths and fallopian tubes are the location of 95% of ectopic pregnancies. Elafin is a natural antimicrobial molecule that plays an important role as an anti-inflammatory agent in mucosal surfaces and has been found in the female reproductive tract. OBJECTIVES: The aim of this study was to investigate elafin expression, in the fallopian tube mucosa of ectopic pregnancies compared to the normal tubes using immunohistochemistry (IHC) techniques and quantitative reverse transcription (qRT)-PCR. METHODS: In this case-control study, uterine tube samples were obtained from patients with an indication for surgical removal of the tubes. The case group (n = 20) consisted of patients who were undergoing salpingectomy due to an ectopic pregnancy, the control group (n = 20) included patients who had a salpingectomy and hysterectomy. Using qRT-PCR and IHC, the expression of elafin was investigated in both study groups. RESULTS: Immunohistochemical expression of elafin in the epithelium and connective tissue was significantly increased in the implantation site of the patients in comparison with the control group (P < 0.001). The level of elafin mRNA increased in the mucous membrane of the fallopian tube from patients with the ectopic pregnancy compared to the normal mucosa (P < 0.001). CONCLUSION: Increasing expression of elafin during an ectopic pregnancy may be a mechanism for enhancing innate immune response and be involved in related pathological conditions such as infection and ectopic implantation.

Recombinant Human Elafin Ameliorates Chronic Hyperoxia-Induced Lung Injury by Inhibiting Nuclear Factor-Kappa B Signaling in Neonatal Mice.

The study aimed to investigate whether recombinant human elafin can prevent hyperoxia-induced pulmonary inflammation in newborn mice, and to explore the mechanism underlying the inhibitory effects of elafin on nuclear factor-kappa B (NF-κB) signaling pathway. Neonatal C57BL/6J mice were exposed to 85% O2 for 1, 3, 7, 14, or 21 days. Then, elafin was administered daily for 20 days through intraperitoneal injection. After treatment, morphometric analysis, quantitative real-time polymerase chain reaction, terminal deoxynucleotidyl transferase dUTP nick end labeling staining, and Western blotting were carried out to determine the key markers involved in inflammatory process and the potential signaling pathways in hyperoxia-exposed newborn mice treated with elafin. In neonatal bronchopulmonary dysplasia (BPD) mice, hyperoxia induced apoptosis by increasing Bcl-2-associated X protein expression, and triggered inflammation by upregulating the expression levels of interleukin (IL)-1ß, IL-6, IL-8, and tumor necrosis factor-α. Moreover, hyperoxia activated NF-κB signaling pathway by promoting the nuclear translocation of p65 in lung tissue. However, all these changes could be inhibited or reversed by elafin at least partially. Elafin reduced apoptosis, suppressed inflammation cytokines, and improved NF-κB p65 nuclear accumulation in hyperoxia-exposed neonatal mice, indicating that this recombinant protein can serve as a novel target for the treatment of BPD.

High circulating elafin levels are associated with Crohn's disease-associated intestinal strictures.

BACKGROUND: Antimicrobial peptide expression is associated with disease activity in inflammatory bowel disease (IBD) patients. IBD patients have abnormal expression of elafin, a human elastase-specific protease inhibitor and antimicrobial peptide. We determined elafin expression in blood, intestine, and mesenteric fat of IBD and non-IBD patients. METHODS: Serum samples from normal and IBD patients were collected from two UCLA cohorts. Surgical resection samples of human colonic and mesenteric fat tissues from IBD and non-IBD (colon cancer) patients were collected from Cedars-Sinai Medical Center. RESULTS: High serum elafin levels were associated with a significantly elevated risk of intestinal stricture in Crohn's disease (CD) patients. Microsoft Azure Machine learning algorithm using serum elafin levels and clinical data identified stricturing CD patients with high accuracy. Serum elafin levels had weak positive correlations with clinical disease activity (Partial Mayo Score and Harvey Bradshaw Index), but not endoscopic disease activity (Mayo Endoscopic Subscore and Simple Endoscopic Index for CD) in IBD patients. Ulcerative colitis (UC) patients had high serum elafin levels. Colonic elafin mRNA and protein expression were not associated with clinical disease activity and histological injury in IBD patients, but stricturing CD patients had lower colonic elafin expression than non-stricturing CD patients. Mesenteric fat in stricturing CD patients had significantly increased elafin mRNA and protein expression, which may contribute to high circulating elafin levels. Human mesenteric fat adipocytes secrete elafin protein. CONCLUSIONS: High circulating elafin levels are associated with the presence of stricture in CD patients. Serum elafin levels may help identify intestinal strictures in CD patients.

Influenza A Virus Pre-Infection Exacerbates Pseudomonas aeruginosa-Mediated Lung Damage Through Increased MMP-9 Expression, Decreased Elafin Production and Tissue Resilience.

Individuals with impaired immune responses, such as ventilated and cystic fibrosis patients are often infected with Pseudomonas aeruginosa (P.a) bacteria, and a co-infection with the Influenza virus (IAV) is often present. It has been known for many years that infection with IAV predisposes the host to secondary bacterial infections (such as Streptococcus pneumoniae or Staphylococcus aureus), and there is an abundance of mechanistic studies, including those studying the role of desensitization of TLR signaling, type I IFN- mediated impairment of neutrophil chemokines and antimicrobial production, attenuation of IL1ß production etc., showing this. However, little is known about the mechanistic events underlying the potential deleterious synergy between Influenza and P.a co-infections. We demonstrate here in vitro in epithelial cells and in vivo in three independent models (two involving mice given IAV +/- P.a, and one involving mice given IAV +/- IL-1ß) that IAV promotes secondary P.a-mediated lung disease or augmented IL-1ß-mediated inflammation. We show that IAV-P.a-mediated deleterious responses includes increased matrix metalloprotease (MMP) activity, and MMP-9 in particular, and that the use of the MMP inhibitor improves lung resilience. Furthermore, we show that IAV post-transcriptionally inhibits the antimicrobial/anti-protease molecule elafin/trappin-2, which we have shown previously to be anti-inflammatory and to protect the host against maladaptive neutrophilic inflammation in P.a infections. Our work highlights the capacity of IAV to promote further P.a-mediated lung damage, not necessarily through its interference with host resistance to the bacterium, but by down-regulating tissue resilience to lung inflammation instead. Our study therefore suggests that restoring tissue resilience in clinical settings where IAV/P.a co-exists could prove a fruitful strategy.

[Biology and signaling pathways involved in the oncogenesis of desmoid tumors]. / Biologie et voies de signalisations impliquées dans l'oncogenèse des tumeurs desmoïdes.

Desmoid tumors (TDs) are derived from mesenchymal stem cells and their pathogenesis is strongly linked to the Wingless/Wnt cascade where the deregulation of ß-catenin plays a major role. A mutation of the CTNNB1 encoding ß-catenin is found in the majority of sporadic TD cases and constitutional mutations of APC have been described in heritable forms in patients with familial adenomatous polyposis (FAP). Estrogens could also play a role in pathogenesis and this is the basis for the use of hormone therapy. Other signaling pathways have been involved in the development of TDs such as Notch, Hedgehog, JAK/STAT, PI3 Kinase/AKT and mTOR. Metalloproteases are expressed in TDs and play a role in invasiveness. TGF-ß, as a growth factor, stimulates the transcriptional activity of ß-catenin. Future studies will need to focus on better describing and understanding the immune environment of TDs. One of the major difficulties for the experimental study of TDs is the virtual absence of a preclinical model, either in vitro or in vivo. This is partly why the interactions between the different signaling pathways presented here and their consequences for the development of TDs are still poorly understood.

A novel curcumin-loaded composite dressing facilitates wound healing due to its natural antioxidant effect.

PURPOSE: To prepare a novel wound dressing to facilitate cutaneous wound healing. METHODS: Curcumin (Cur) was added to the ring-shaped ß-cyclodextrin (CD) to form a ß-CD-Cur inclusion complex (CD-Cur). CD-Cur was then integrated into a composite chitosan-alginate (CA) mix. Finally, CA-CD-Cur was generated with a freeze-drying technique. Water-uptake capacity, degradation rate, and drug-release kinetics of the newly formed dressing were investigated in vitro. In animal studies, cutaneous wounds in rats were created, treated with CA-CD-Cur, then compared to CA-Cur, CA, and gauze. RESULTS: CA-CD-Cur-treated wounds showed accelerated closure rates, improved histopathological results, and lower SOD, lipid peroxidation, pI3K, and pAktkt levels than other groups. On the contrary, catalase, IκBα, and TGFß1 levels were higher than others. CONCLUSION: CA-CD-Cur may facilitate cutaneous wound dressing that facilitate wound healing.