Mouse Model Of Sensitization Research Articles

Modulation effect of Lactobacillus acidophilus KLDS 1.0738 on gut microbiota and TLR4 expression in β-lactoglobulin-induced allergic mice model

Objectivesβ-lactoglobulin (β-Lg)-sensitized mice model was employed to investigate the correlation between Lactobacillus acidophilus KLDS 1.0738 (Lap KLDS 1.0738) modulating gut microbiota and inducting Toll-like receptors (TLRs) expression. MethodsThe alterations of mice fecal microbiota were analyzed by 16S rRNA gene sequencing. The serum cytokines production and TLR4/NF-κB mRNA expression in the colon tissues were measured by ELISA kit and quantitative RT-PCR, respectively. ResultsThe results showed that Lap KLDS 1.0738 pretreatment attenuated β-Lg-induced hypersensitivity, accompanied with a diminished expression of TLR4/NF-κB signaling. Moreover, oral administration of Lap KLDS 1.0738 improved the richness and diversity of fecal microbiota, which was characterized by fewer Proteobacteria phylum and Helicobacteraceae family, and higher Firmicutes phylum and Lachnospiraceae family than allergic group. Notably, TLR4/NF-κB expression was positively correlated with the family of Helicobacteraceae in allergic group, but negatively correlated with the family of Lachnospiraceae, Ruminococcaceae and anti-inflammatory cytokines level. A significant positive correlation was observed between TLR4/NF-κB expression and the production of histamine, total IgE and pro-inflammatory cytokines. ConclusionsIntake of Lap KLDS 1.0738 can influence the gut bacterial composition, which might result in recognizing TLRs signaling so as to inhibit allergic response.

Incomplete inactivation of atypical scrapie following recommended autoclave decontamination procedures.

Prions are highly resistant to the decontamination procedures normally used to inactivate conventional pathogens. This is a challenging problem not only in the medical and veterinary fields for minimizing the risk of transmission from potentially infective sources but also for ensuring the safe disposal or subsequent use of animal by-products. Specific pressure autoclaving protocols were developed for this purpose, but different strains of prions have been reported to have differing resistance patterns to established prion decontamination procedures, and as additional TSE strains are identified it is necessary to determine the effectiveness of such procedures. In this study we assessed the efficacy of sterilization using the EU recommended autoclave procedure for prions (133°C, 3 Bar for 20min) on the atypical or Nor98 (AS/Nor98) scrapie strain of sheep and goats. Using a highly sensitive murine mouse model (tg338) that overexpresses ovine PrPC , we determined that this method of decontamination reduced the infectivity titre by 1010 . Infectivity was nonetheless still detected after applying the recommended autoclaving protocol. This shows that AS/Nor98 can survive the designated legislative decontamination conditions, albeit with a significant decrease in titre. The infectivity of a classical scrapie isolate subjected to the same decontamination conditions was reduced by 106 suggesting that the AS/Nor98 isolate is less sensitive to decontamination than the classical scrapie source.

Function of complement factor H and imaging of small molecules by MALDI-MSI in a methamphetamine behavioral sensitization model.

At present, the harm of new-type drug, methamphetamine (METH), has gradually exceeded that of the traditional opioid drugs, and METH abuse has become a serious public health and social problem. In our previous study, complement factor H (CFH) was found to be upregulated in the sera of METH-addicted patients and rats and in certain brain regions in the rats. We used ELISA and immunofluorescence to confirm the changes in CFH in the serum and hippocampus of a METH behavioral sensitization mouse model, and C1q expression was also detected by immunofluorescence in the hippocampus. We aimed to elucidate the involvement of CFH and C1q in the mechanism of METH addiction. We also detected the distribution of various small molecules by matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) in select brain regions: the nucleus accumbens, the hippocampus and the ventral tegmental area. The expression of CFH was upregulated in the serum and hippocampus of METH behavioral sensitization model mice, consistent with our previous research on conditioned place preference rats. In contrast, C1q decreased dramatically in the mossy fibers of the hippocampus. The results of small-molecule imaging by MALDI-MSI showed that the levels of K+, antioxidants, neurotransmitters, and ATP metabolism-related molecules were altered in different regions. These results indicate the involvement of the complement system in the mechanism of METH addiction and validate the presence of oxidative stress, energy metabolism changes during addiction. This suggests the utility of further investigation into the above aspects.

Immunotherapy-specific miRNA Expression Profiles In Spleenic CD4+ T-cells In A Peanut Sensitized Mouse Model Treated With Oral Or Epicutaneous Immunotherapy

Immunotherapy-specific miRNA Expression Profiles In Spleenic CD4+ T-cells In A Peanut Sensitized Mouse Model Treated With Oral Or Epicutaneous Immunotherapy

Comparison of Ovalbumin Sensitized Mice Model for Allergy: A Preliminary Study

Allergy diseases tend to increase with variety of clinical manifestations. To date, pharmacotherapy do not treat the underlying disease. Many researches concerned to study new approach of allergy therapy which need allergy mouse model for evaluation. This study was aimed to compare the effectiveness of two treatment methods by using ovalbumin for allergy sensitization. This study was conducted in PT.Bimana Indomedical animal facility Bogor on June until September 2016. Six mice were divided into 2 groups. First group was sensitized by ovalbumin 100ug subcutaneous (sc) day-0, 50 ug intra peritoneal (ip) day-14 and 100 ug intranasal (in) day-21. Second group was sensitized by ovalbumin 10 ug ip day-0 and day-7, 10 ug in day-21, 22, and 23. Body weight, hematology parameters (red blood cells, white blood cells, hemoglobin and hematocrit) and total IgE concentration of day-0 (pre-treatment) and day 24 (post-treatment) were measured. The results showed that there was an increase of mice body weight of both treatment group, while hematology changes of pre and post treatment were not significantly different (paired t-test). Whereas the increase in total IgE pre and post treatment was significantly different between the two groups (paired t-test). In conclusion, the second allergy sensitization method is better than the first allergy sensitization method.

Oxidative stress mediates renal endothelial cell damage in trichloroethylene-sensitized mice.

The purpose of this study was to explore whether renal endothelial cell injury is associated with oxidative stress in trichloroethylene (TCE)-induced immune kidney damage by detecting adhesion molecules and oxidative stress indexes. In this study, a mouse model of skin sensitization with the antioxidant Tempol was used to explore the mechanism. Blood urea nitrogen (BUN), creatinine (Cre), and histological examination were used for kidney function evaluation. Kidney homogenates were used for detecting renal nitric oxide (NO), nitric oxide synthase (NOS), superoxide dismutase (SOD) and malondialdehyde (MDA). Renal endothelial nitric oxide synthase (eNOS), E-selectin, vascular cell adhesion molecule (VCAM-1) and intercellular adhesion molecule (ICAM-1) protein levels were measured by immunohistochemical and Western blot. We found that BUN and Cre levels increased in the TCE sensitization positive group and the TCE+Tempol sensitization positive group. In the TCE sensitization positive group, a partial area of vacuolar degeneration and lysed epithelial cells were observed in renal tubules. In TCE+Tempol sensitization positive group, small areas were also found to be vacuolar degenerated and renal tubules were dissolved. Renal NO, NOS, SOD and eNOS levels decreased and MDA levels increased, renal E-selectin, VCAM-1and ICAM-1 protein levels increased in the TCE sensitization positive group and the TCE+Tempol sensitization positive group. Tempol attenuated TCE induced up-regulation of MDA, E-selectin, VCAM-1and ICAM-1 and down-regulation of NO, NOS, SOD and eNOS. In conclusion, trichloroethylene-sensitized mice renal immune injury is associated with the renal endothelial cells' oxidative stress state.

Isolation of maltol derivatives from Stellera chamaejasme and the anti-atopic properties of maltol on skin lesions in DNCB-stimulated mice.

The aim of this study was to isolate maltol derivatives from S. chamaejasme and to investigate the anti-atopic dermatitis (anti-AD) effect of maltol in a 2,4-dinitrochlorobenzene (DNCB)-sensitized mouse model of AD. A novel compound, maltol 3-O-(4′-O-cis-p-coumaroyl)-β-d-glucoside (named isosoyamaloside I), and two known maltol derivatives (maltol and soyamaloside I) were isolated from S. chamaejasme using chromatographic methods. Dermal application of maltol to DNCB-sensitized AD mice reduced erythema, pruritus, and lichenification scores. Histopathological examinations revealed significant decline in mast cell infiltration in maltol-treated AD mice. In addition, maltol accelerated skin barrier recovery by reducing TEWL and skin pH and increasing skin hydration. Maltol was also found to suppress atopy-induced IL-4 and IgE elevations in serum, which are known to be essential for the development of atopy. The results of this study show that maltol is a potential therapeutic candidate for the treatment of AD-related skin diseases.

Immunocompetent and Immunodeficient Mouse Models for Enterovirus 71 Pathogenesis and Therapy.

Enterovirus 71 (EV71) is a global health threat. Children infected with EV71 could develop hand-foot-and-mouth disease (HFMD), encephalitis, paralysis, pulmonary edema, and death. At present, no effective treatment for EV71 is available. We reviewed here various mouse models for EV71 pathogenesis and therapy. Earlier studies relied on the use of mouse-adapted EV71 strains. To avoid artificial mutations arising de novo during the serial passages, recent studies used EV71 clinical isolates without adaptation. Several human receptors for EV71 were shown to facilitate viral entry in cell culture. However, in vivo infection with human SCARB2 receptor transgenic mice appeared to be more limited to certain strains and genotypes of EV71. Efficacy of oral infection in these transgenic models is extremely low. Intriguingly, despite the lack of human receptors, immunodeficient neonatal mouse models can still be infected with EV71 clinical isolates via oral or intraperitoneal routes. Crossbreeding between SCARB2 transgenic and stat1 knockout mice generated a more sensitive and user-friendly hybrid mouse model. Infected hybrid mice developed a higher incidence and earlier onset of CNS disease and death. Different pathogenesis profiles were observed in models deficient in various arms of innate or humoral immunity. These models are being actively used for antiviral research.

The optimal age for epicutaneous sensitization following tape-stripping in BALB/c mice

BackgroundDirect contact of food proteins with eczematous lesions is thought to be the main cause of epicutaneous sensitization. To further investigate the development and pathogenesis of food allergy in vivo, a good mouse model of epicutaneous sensitization is needed. However, a fundamental problem in that regard is that the optimal age for epicutaneous sensitization of mice is unknown. In this study, we attempted to elucidate that optimal age. MethodsDorsal skin of wild-type BALB/c female mice (1, 3, 8 and 24 weeks old) was shaved, depilated and tape-stripped. A Finn chamber containing a 20-μl-aliquot of 20-mg/ml (OVA) was applied to the tape-stripped skin on 3 consecutive days/week, for 3 weeks. The body temperature was measured after intraperitoneal OVA challenge. Serum OVA-specific IgE titers and OVA-induced cytokine production by spleen cells were measured by ELISA. Dendritic cells (DCs) that migrated to the draining lymph nodes were quantified by FITC-labeled OVA and flow cytometry. The mRNA expression levels in the dorsal skin were measured by qPCR. ResultsA significant age-dependent body temperature decline was observed after OVA challenge. The serum OVA-specific IgE titer, OVA-induced cytokine production (i.e., IL-4, IL-5 and IL-13) by spleen cells, and number of FITC-OVA-engulfing DCs increased with age. In addition, mRNA for IL-33, but not TSLP or IL-25, was significantly induced in the skin by tape-stripping and increased with age. ConclusionsTwenty-four-week-old mice showed the greatest DC migration, Th2 polarization, IgE production and body temperature decline. Skin-derived IL-33 is likely to play key roles in those changes.

Ibrutinib suppresses alloantibody responses in a mouse model of allosensitization

BackgroundIbrutinib is a Bruton's tyrosine Kinase (BTK) antagonist that inhibits B cell receptor (BCR) signaling. Complete BTK deficiency is associated with absence of B-cells. Ibrutinb is currently approved by FDA for treatment of B-cell malignancies, including Waldenström macroglobulinaemia. We recently carried out studies to determine if ibrutinib could modify alloantibody responses. Materials and methodsA mouse model of allogenic sensitization using a C57BL/6 mouse as the recipient of a skin allograft from an HLA-A2 transgenic mouse was utilized to examine the effects of ibrutinib on alloantibody responses and B cell effector functions. Donor-specific antibody (DSA) levels were measured in a flow-cytometric antibody binding assay. Splenic T and B cell subsets and plasma cells were analyzed in flow cytometry. ResultsControl mice developed peak levels of DSA IgM at day 14 PTx while the ibrutinib treated mice had significantly lower levels of DSA IgM (p=0.0047). Control mice developed HLA.A2-specific IgG antibodies at day 14 (230±60 MFI) and reached peak levels at day 21 (426±61 MFI). In contrast, mice in the treatment group had low levels of HLA.A2-specific IgG at day 14 (109±59 MFI, p=0.004) and day 21 (241±86 MFI, p=0.003). FACS analysis found a reduction of B220+ or CD19+ B cell population (p<0.05). In addition, ibrutinib attenuated recall DSA IgG responses to re-sensitization (p<0.05) and reduced CD38+CD138+ plasma cells (p<0.05) in the spleens. ConclusionsIbrutinib is effective in suppressing alloantibody responses through blocking BTK-mediated BCR signaling, leading to reduction of B cells and short-lived plasma cells in the spleens. Use of ibrutinib may provide benefits to HLA-sensitized transplant patients for alloantibody suppression.

Indoleamine 2,3-dioxygenase and inducible nitric oxide synthase mediate immune tolerance induced by CTLA4Ig and anti-CD154 hematopoietic stem cell transplantation in a sensitized mouse model

Cytotoxic T-lymphocyte-associated protein 4 immunoglobulin (CTLA4Ig) and anti-cluster of differentiation 154 (anti-CD154) are able to block B7/CD28 and CD40/CD154 co-stimulatory signals in T cells. Additionally, they promote hematopoietic stem cell transplantation (HSCT) in sensitized recipients and are able to induce immune tolerance and complete hematopoietic reconstitution. Indoleamine 2, 3-dioxygenase (IDO) and nitric oxide (NO) have been implicated in T cell immune tolerance. The aim of the present report was to study the in vivo tolerogenic mechanisms by which CTLA4Ig and anti-CD154 induce transplantation survival in mice receiving HSCT. BALB/c mice were sensitized via splenocyte transfusion and pretreated with CTLA4Ig plus anti-CD154 on day-7. IDO and inducible nitric oxide synthase (iNOS) inhibitors were applied on days-7 to 0 and the mice were divided into 4 groups (n=10) and injected with IDO every other day. The mice were sacrificed on day 0, and splenocytes were separated to identify CD11c+ antigen-presenting cells, which were subsequently assessed for IDO expression and activity. The concentration of NO was tested using a nitrate reductase kit. Following the acceptance of allogeneic HSCT, mice were tested for homing and engraftment, as well as survival rate. Application of the IDO inhibitor increased the concentration of NO, whereas a decrease in NO resulted in increased IDO activity. Immune tolerance was abrogated in the presence of both IDO and iNOS inhibitors, whereas this effect was not observed with either compound alone. CTLA4Ig and anti-CD154 may induce immune tolerance by affecting the activity of IDO and iNOS. This tolerance was abrogated in the presence of both IDO and iNOS inhibitors. A cross-regulatory pathway was observed between the IDO and NO pathways, in which the inhibition of IDO stimulated the iNOS pathway and vice versa.

Basophils and mast cells are crucial for reactions due to epicutaneous sensitization to ovalbumin.

The prevalence of food allergies worldwide has increased recently. Epicutaneous sensitization to antigen could be a method to study food allergy. To clarify the mechanisms of food allergy, we established a mouse model of epicutaneous sensitization using ovalbumin (OVA). BALB/c mice were sensitized by three-time application of OVA to tape-stripped skin (1-week sensitization at 2-week intervals) and oral challenge of OVA undertaken. Rectal temperature was monitored. Blood and tissue (skin and jejunum) of challenged mice were taken. Numbers of mast cells (MCs) and basophils were counted. Serum and/or tissue levels of OVA -specific IgE and IgG antibodies and several cytokines were measured using enzyme-linked immunoassay kits. MC and basophil depletion experiments were undertaken. In OVA/epicutaneous-sensitized and orally challenged mice, systemic anaphylaxis (as evidenced by reduced rectal temperature) was observed. Levels of OVA-specific IgE and IgG antibodies were increased in these mice, as were increased number of MCs and basophils. Serum levels of MC protease 1 were increased significantly. Basophil and MC depletion experiments revealed that they both participate in reactions. Increased production of thymic stromal lymphopoietin (TSLP) at skin sites of OVA sensitization was noted. We speculate that TSLP produced from epidermal cells during antigen sensitization can enable basophils to promote a T helper (Th)2 immune reaction, leading to and systemic anaphylaxis by antigen-specific IgE-bearing MCs. This TSLP-basophils-MC axis could be a novel therapeutic target against food allergy.

(1142) - Use of Exosome for Alloantibody Suppression: A Study in a Mouse Model of HLA-A2 Sensitization

(1142) - Use of Exosome for Alloantibody Suppression: A Study in a Mouse Model of HLA-A2 Sensitization

No Effect of Dietary Aspartame or Stevia on Pancreatic Acinar Carcinoma Development, Growth, or Induced Mortality in a Murine Model.

Pancreatic cancer has an extremely poor prognosis, largely due to a poor record for early detection. Known risk factors for pancreatic cancer include obesity, diet, and diabetes, implicating glucose consumption and regulation as a key player. The role of artificial sweeteners may therefore be pertinent to disease kinetics. The oncogenic impact of artificial sweeteners is a highly controversial area. Aspartame, one of the most studied food additives, is widely recognized as being generally safe, although there are still specific areas where research is incomplete due to study limitations. Stevia, by contrast, has been the subject of relatively few studies, and the potential health benefits are based on extrapolation rather than direct testing. Here, we used longitudinal tracking of pancreatic acinar carcinoma development, growth, and lethality in a sensitized mouse model. Despite exposure to aspartame and stevia from the in utero stage onward, we found no disease modification activity, in either direction. These results contribute to the data on aspartame and stevia safety, while also reducing confidence in several of the purported health benefits.

Diet Matters: Endotoxin in the Diet Impacts the Level of Allergic Sensitization in Germ-Free Mice.

Germ-free animals have been used to define the vital role of commensal bacteria on the maturation of the host immune system. However, the role of bacterial residues in diet in this setting is poorly understood. Here we investigated the effect of bacterial contamination in sterile diet on the level of allergic sensitization in germ-free mice. Sterile grain-based diets ST1 and R03 were tested for the level of bacterial contamination. ST1 contained higher amount of bacterial DNA, approximately ten times more endotoxin, and induced higher, TLR4-dependent, cytokine production in dendritic cells compared to R03. In a germ-free mouse model of sensitization to the major birch pollen allergen Bet v 1, feeding on ST1 for at least two generations was associated with decreased production of allergen-specific IgE and IgG1 antibodies in sera in comparison to R03. Furthermore, reduced levels of allergen-specific and ConA-induced cytokines IL-4, IL-5 and IL-13 accompanied by increased levels of IFN-γ were detected in splenocytes cultures of these mice. Our results show that contamination of experimental diet with bacterial residues, such as endotoxin, significantly affects the development of allergic sensitization in germ-free mice. Therefore, careful selection of sterile food is critical for the outcomes of germ-free or gnotobiotic experimental models of immune-deviated diseases.

An FGFR3 Autocrine Loop Sustains Acquired Resistance to Trastuzumab in Gastric Cancer Patients.

The majority of gastric cancer patients who achieve an initial response to trastuzumab-based regimens develop resistance within 1 year of treatment. This study was aimed at identifying the molecular mechanisms responsible for resistance. A HER2+-trastuzumab sensitive NCI-N87 gastric cancer orthotopic nude mouse model was treated with trastuzumab until resistance emerged. Differentially expressed transcripts between trastuzumab-resistant and sensitive gastric cancer cell lines were annotated for functional interrelatedness by Ingenuity Pathway Analysis software. Immunohistochemical analyses were performed in pretreatment versus posttreatment biopsies from gastric cancer patients receiving trastuzumab-based treatments. All statistical tests were two-sided. Four NCI-N87 trastuzumab-resistant (N87-TR) cell lines were established. Microarray analysis showed HER2 downregulation, induction of epithelial-to-mesenchymal transition, and indicated fibroblast growth factor receptor 3 (FGFR3) as one of the top upregulated genes in N87-TR cell lines. In vitro, N87-TR cell lines demonstrated a higher sensitivity than did trastuzumab-sensitive parental cells to the FGFR3 inhibitor dovitinib, which reduced expression of pAKT, ZEB1, and cell migration. Oral dovitinib significantly (P = 0.0006) reduced tumor burden and prolonged mice survival duration in N87-TR mouse models. A higher expression of FGFR3, phosphorylated AKT, and ZEB1 were observed in biopsies from patients progressing under trastuzumab-based therapies if compared with matched pretreatment biopsies. This study identified the FGFR3/AKT axis as an escape pathway responsible for trastuzumab resistance in gastric cancer, thus indicating the inhibition of FGFR3 as a potential strategy to modulate this resistance. Clin Cancer Res; 22(24); 6164-75. ©2016 AACR.

Technical Note: Contrast free angiography of the pulmonary vasculature in live mice using a laboratory x-ray source.

Purpose:In vivo imaging of the pulmonary vasculature in small animals is difficult yet highly desirable in order to allow study of the effects of a host of dynamic biological processes such as hypoxic pulmonary vasoconstriction. Here the authors present an approach for the quantification of changes in the vasculature.Methods:A contrast free angiography technique is validated in silico through the use of computer-generated images and in vivo through microcomputed tomography (μCT) of live mice conducted using a laboratory-based x-ray source. Subsequent image processing on μCT data allowed for the quantification of the caliber of pulmonary vasculature without the need for external contrast agents. These measures were validated by comparing with quantitative contrast microangiography in the same mice.Results:Quantification of arterial diameters from the method proposed in this study is validated against laboratory-based x-ray contrast microangiography. The authors find that there is a high degree of correlation (R = 0.91) between measures from microangiography and their contrast free method.Conclusions:A technique for quantification of murine pulmonary vasculature without the need for contrast is presented. As such, this technique could be applied for longitudinal studies of animals to study changes to vasculature without the risk of premature death in sensitive mouse models of disease. This approach may also be of value in the clinical setting.

Uricase Inhibits Nitrogen Dioxide-Promoted Allergic Sensitization to Inhaled Ovalbumin Independent of Uric Acid Catabolism.

Nitrogen dioxide (NO2) is an environmental air pollutant and endogenously generated oxidant that contributes to the exacerbation of respiratory disease and can function as an adjuvant to allergically sensitize to an innocuous inhaled Ag. Because uric acid has been implicated as a mediator of adjuvant activity, we sought to determine whether uric acid was elevated and participated in a mouse model of NO2-promoted allergic sensitization. We found that uric acid was increased in the airways of mice exposed to NO2 and that administration of uricase inhibited the development of OVA-driven allergic airway disease subsequent to OVA challenge, as well as the generation of OVA-specific Abs. However, uricase was itself immunogenic, inducing a uricase-specific adaptive immune response that occurred even when the enzymatic activity of uricase had been inactivated. Inhibition of the OVA-specific response was not due to the capacity of uricase to inhibit the early steps of OVA uptake or processing and presentation by dendritic cells, but occurred at a later step that blocked OVA-specific CD4(+) T cell proliferation and cytokine production. Although blocking uric acid formation by allopurinol did not affect outcomes, administration of ultra-clean human serum albumin at protein concentrations equivalent to that of uricase inhibited NO2-promoted allergic airway disease. These results indicate that, although uric acid levels are elevated in the airways of NO2-exposed mice, the powerful inhibitory effect of uricase administration on allergic sensitization is mediated more through Ag-specific immune deviation than via suppression of allergic sensitization, a mechanism to be considered in the interpretation of results from other experimental systems.

NFIB overexpression cooperates with Rb/p53 deletion to promote small cell lung cancer.

Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumor type that is typically metastatic upon diagnosis. We have a poor understanding of the factors that control SCLC progression and metastasis. TheNFIB transcription factor is frequently amplified in mouse models of SCLC, but clear evidence that NFIB promotes SCLC in vivo is lacking. We report that in mouse models, Nfib amplifications are far more frequent in liver metastases over primary SCLC, suggesting roles in tumor progression/metastasis. Overexpression of Nfib in a sensitized mouse model led to acceleration of SCLC, indicating that Nfib functions as a bona fide oncogene. Suppression of Nfib expression in cell lines derived from the doxycycline-inducible Rb/p53/TET-Nfib model led to increased apoptosis and suppression of proliferation. Transcriptional analysis revealed that Nfib regulates the expression of genes related to axon guidance, focal adhesion and extracellular matrix-receptor interactions. These data indicate that Nfib is a potent oncogene in SCLC, and the enrichment of Nfib amplifications in liver metastases over primary SCLC points to Nfib as a candidate driver of SCLC metastasis.

2-(4-{2-[(phenylthio)acetyl]carbonohydrazonoyl}phenoxy)acetamide as a new lead compound for management of allergic rhinitis.

We selected a hit compound, 2-(4-{2-[(phenylthio)acetyl]-carbonohydrazonoyl}-phenoxy)acetamide (PA), by a molecular docking simulation between 636,565 compounds and caspase-1 protein. We examined the effect of PA on allergic rhinitis (AR) animal model. We assessed the therapeutic effects and the regulatory mechanisms of ovalbumin (OVA)-sensitized mouse model of AR. A molecular docking simulation and a kinetic assay indicated that PA regulates the caspase-1 activation through the interaction with the caspase-1 active site. In the AR animal model, PA significantly reduced the rub scoring increased by OVA. The up-regulated IgE, histamine, interleukin (IL)-1β, and thymic stromal lymphopoietin (TSLP) levels in the serum of OVA-sensitized mice were significantly decreased by the treatment with PA. Protein levels of IL-1β, IL-5, IL-6, IL-13, tumor necrosis factor-α, TSLP, cyclooxygenase-2, macrophage inflammatory protein-2, and intercellular adhesion molecule-1 were also significantly inhibited by the treatment with PA in the nasal mucosa tissues of the OVA-sensitized mice. In the PA-treated mice, the number of eosinophils and mast cells infiltrated by OVA-sensitization were also reduced. In addition, PA reduced the mast cell-derived caspase-1 activity and expression in the nasal mucosa tissues of the OVA-sensitized mice. PA showed the possibility to regulate AR in OVA-induced AR models, suggesting that it has therapeutic potential for the management of AR as a lead compound.