Hedgehog (Hh) signaling is deregulated in multiple human cancers including pancreatic ductal adenocarcinoma (PDA). Because KRAS mutation represents one of the earliest genetic alterations and occurs almost universally PDA, we hypothesized that oncogenic promotes tumorigenesis part through activation Hh pathway. Here, report activates hedgehog PDA cells, utilizing a downstream effector pathway mediated by RAF/MEK/MAPK but not phosphatidylinositol 3-kinase (PI3K)/AKT. Oncogenic transformation...

The recent discovery of Epac, a novel cAMP receptor protein, opens up new dimension in studying cAMP-mediated cell signaling. It is conceivable that many the functions previously attributed to cAMP-dependent protein kinase (PKA) are fact also Epac-dependent. finding an additional intracellular provides opportunity further dissect divergent roles exerts different types. In this study, we probed cross-talk between signaling and phosphatidylinositol 3-kinase/PKB pathways. Specifically, examined...

Respiratory syncytial virus (RSV) is the major cause of acute bronchiolitis in infancy, a syndrome characterized by wheezing, respiratory distress, and pathologic findings peribronchial mononuclear cell infiltration release inflammatory mediators basophil eosinophil leukocytes. Composition activation this cellular response are thought to rely on discrete target selectivity C-C chemokines. We demonstrate that infection vitro human epithelial cells lower tract RSV induced dose- time-dependent...

Abstract The electrospinning of gelatin aqueous solution was successfully carried out by elevating the spinning temperature. effects temperature and concentration were investigated on morphology nanofibers in current study. To improve stability mechanical properties moist state, nanofibrous membrane chemically crosslinked 1‐ethyl‐3‐dimethyl‐aminopropyl carbodiimide hydrochloride N ‐hydroxyl succinimide. crosslinker optimized measuring swelling degree weight loss. Nanofibrous structure...

Abstract Poly‐ L ‐lactic acid (PLLA)/hydroxyapatite (HA) hybrid membranes were fabricated via electrospinning of the PLLA/HA dispersion for use in bone tissue regeneration. The structural properties and morphologies PLLA membrane investigated by measuring Brunauer‐Emmett‐Teller specific surface area, observations SEM, TEM. integrating HA nanoparticles studied energy X‐ray analysis FTIR. mechanical also measured tensile tests. For exploring biological behaviors membrane, vitro degradation...

Exchange protein directly activated by cAMP (EPAC) and cAMP-dependent kinase (PKA) are two intracellular receptors that mediate the effects of prototypic second messenger cAMP. Identifying pharmacological probes for selectively modulating EPAC activity represents a significant unmet need within research field. Herein, we report identification characterization 3-(5-<i>tert</i>-butyl-isoxazol-3-yl)-2-[(3-chloro-phenyl)-hydrazono]-3-oxo-propionitrile (ESI-09), novel noncyclic nucleotide...

A new type of C2-symmetric chiral bisguanidine was designed as a highly efficient catalyst in the inverse-electron-demand hetero-Diels−Alder reaction chalcones with azlactones for first time. wide variety γ,δ-unsaturated δ-lactone derivatives α-quaternary-β-tertiary stereocenters were obtained high yields (up to 88%) excellent enantioselectivities 99% ee). Hydrogen bonds considered be crucial activation and stereoinduction reaction. In all cases, major HDA adducts, which single diastereomer...

Significant effort has been devoted to fabricating various biomaterials satisfy specific clinical requirements. In this study, we developed a new type of guided tissue regeneration (GTR) membrane by electrospinning suspension consisting poly(l-lactic acid), multiwalled carbon nanotubes, and hydroxyapatite (PLLA/MWNTs/HA). MWNTs/HA nanoparticles were uniformly dispersed in the membranes, degradation characteristics far improved. Cytologic research revealed that PLLA/MWNTs/HA enhanced adhesion...

The major physiological effects of cAMP in mammalian cells are transduced by two ubiquitously expressed intracellular receptors, protein kinase A (PKA) and exchange directly activated (EPAC), as well cyclic nucleotide-gated ion channels certain tissues. Although a large number PKA inhibitors available, there no reported EPAC-specific antagonists, despite extensive research efforts. Here we report the identification characterization noncyclic nucleotide EPAC antagonists that exclusively...

Significance Chronic pain represents a massive therapeutic challenge that requires understanding of underlying mechanisms to develop novel treatments. We show genetic deletion the Rap1 guanine-nucleotide exchange factor Epac1 protects against chronic inflammatory mechanical hyperalgesia. Moreover, an orally active Epac inhibitor reverses existing without affecting normal sensitivity. Epac1-mediated is controlled by G protein kinase 2 (GRK2) through inhibition Epac1-to-Rap1 signaling and...

Abstract The cAMP signaling cascade is one of the most frequently targeted pathways for development pharmaceutics. A plethora recent genetic and pharmacological studies suggest that exchange proteins directly activated by (EPACs) are implicated in multiple pathologies. Selective EPAC inhibitors have been recently developed. One specific inhibitor, ESI-09, has shown to block activity functions, as well recapitulate phenotypes knockout mice when applied vivo . However, a study raised concern...

Epac belongs to a new family of proteins that can directly mediate the action intracellular second messenger cAMP by activating downstream small GTPase Rap1. The Epac/Rap1 pathway represents novel cAMP-signaling cascade is independent cAMP-dependent protein kinase (PKA). In this study, we have used fluorescence microscopy probe targeting during different stages cell division cycle and structural features are important for localization. Our results suggest Epac, endogenous or expressed as...

L1 is a multidomain transmembrane neural recognition molecule essential for neurohistogenesis. While moieties in the immunoglobulin-like domains of have been implicated both heterophilic and homophilic binding, function fibronectin (FN)-like repeats remains largely unresolved. Here, we demonstrate that third FN-like repeat (FN3) spontaneously homomultimerizes to form trimeric higher order complexes. Remarkably, these complexes support direct RGD-independent interactions with several...

Cellular transformation is a complex process involving genetic alterations associated with multiple signaling pathways. Development of model using defined elements has provided an opportunity to elucidate the role oncogenes and tumor suppressor genes in initiation development ovarian cancer. To study cellular molecular mechanisms Ras-mediated oncogenic epithelial cells, we used proteomic approach two-dimensional electrophoresis mass spectrometry profile two cell lines, one immortalized SV40...

The neural cell adhesion molecule L1 has been shown to function as a homophilic ligand in variety of dynamic neurological processes. Here we demonstrate that the sixth immunoglobulin-like domain human (L1-Ig6) can heterophilic for multiple members integrin superfamily including αvβ3, αvβ1, α5β1, and αIIbβ3. interaction between L1-Ig6 αIIbβ3 was found support rapid attachment activated platelets, whereas corresponding with αvβ3 αvβ1 supported umbilical vein endothelial cells. Mutation single...

Carbon nanomaterials (CNMs), such as carbon nanotube (CNT) and graphene, are highlighted in bone regeneration because of their osteoinductive properties. Their combinations with nanofibrous polymeric scaffolds, which mimic the morphology natural extracellular matrix bone, arouse keen interest tissue engineering. To this end, CNM were incorporated into poly(l-lactic acid) scaffolds by thermal-induced phase separation. The CNM-containing composite biologically evaluated both vitro co-culture...

Significance Our studies combining genetic and pharmacological manipulations provide convincing evidence that exchange protein directly activated by cAMP (Epac) 1 plays a critical role in fatal spotted fever group rickettsioses. Inhibition of Epac1 suppresses bacterial adhesion and/or invasion. Most importantly, we show small-molecule Epac inhibitor can prevent suppress rickettsial infection. results demonstrate Epac1-mediated signaling represents mechanism for host–pathogen interactions is...

The prototypic second messenger cyclic AMP (cAMP) is essential for controlling cellular metabolism, including glucose and lipid homeostasis.In mammals, the majority of cAMP functions are mediated by cAMP-dependent protein kinase (PKA) exchange proteins directly activated (Epacs).To explore physiological Epac1, we generated Epac1 knockout mice.Here report that null mutants have reduced white adipose tissue plasma leptin levels but display heightened sensitivity.Epac1-deficient mice more...

Natural Killer (NK) cells are effector lymphocytes involved in tumor immunosurveillance, however, the specific mechanism hepatocellular carcinoma (HCC) has not been well understood. In present study, we estimated relative abundances of NK HCC using gene expression data, and found that cell abundance was lower tissues than adjacent normal tissues. With common subclasses, also three subclasses had distinct cells. Moreover, strong association between genes encoding immune checkpoint proteins,...

CD8+ T cells mediate some of the damage to lung epithelium following respiratory syncytial virus (RSV) infection. Since recognize antigen-laden class I MHC molecules on target cells, we examined in this study expression by RSV-infected epithelial cells. Respiratory cell lines and bronchial from normal human tissue responded RSV infection with an increased as determined flow cytometry immunoprecipitation metabolically radiolabeled The increase was dependent infectious, replicating virus....

Abstract To investigate the potential application of bone marrow stromal cells (BMSCs) and an injectable sodium alginate/gelatin scaffold for tissue engineering (BTE). The phenotype osteogenic BMSCs was examined by mineralized nodules formation type I collagen expression. Cell proliferation evaluated MTT assay. biocompatibility were hematoxylin eosin (H&amp;E) staining. Ectopic as well closure rabbit calvarial critical‐sized defects following scaffold‐cell implantation analyzed histological...

Epac2, a guanine nucleotide exchange factor, regulates wide variety of intracellular processes in response to second messenger cAMP. In this study, we have used peptide amide hydrogen/deuterium mass spectrometry probe the solution structural and conformational dynamics full-length Epac2 presence absence The results support mechanism which cAMP-induced activation is mediated by major hinge motion centered on C terminus cAMP binding domain. This change realigns regulatory components away from...

EPAC1 and EPAC2, two isoforms of exchange proteins directly activated by cAMP (EPAC), respond to the second messenger regulate a wide variety intracellular processes under physiological pathophysiological circumstances. Herein, we report chemical design, synthesis, pharmacological characterization three different scaffolds (diarylsulfones, N,N-diarylamines, arylsulfonamides) as highly potent selective antagonists EPAC2. Several EPAC2 have been identified including 20i (HJC0350), which has an...