Non-Insulin-Dependent Diabetes : Optimising Oral Therapy

Beaven, D.W. Medical Publications Korea 1990 Medical Progress Vol.12 No.9

Human Insulin : Is it Making Life Sweeter for the Diabetic

Beaven, D.W. Medical Publications Korea 1987 Medical Progress Vol.9 No.10

Magnetically Controlled Growing Rods: The Experience of Mechanical Failure from a Single Center Consecutive Series of 28 Children with a Minimum Follow-up of 2 Years

Alastair Beaven,Adrian C. Gardner,David S. Marks,,Jwalant S. Mehta,Matthew Newton-Ede,,Jonathan B. Spilsbury 대한척추외과학회 2018 Asian Spine Journal Vol.12 No.5

Study Design: Retrospective observational study of a continuous series of 28 children. Purpose: To determine the mechanical failure rate in our cohort of children treated with magnetically controlled growth rods (MCGRs). Overview of Literature: Previous studies report a MCGR mechanical failure rate of 0%–75%. Methods: All patients with MCGR implantation between 2012 and 2015 were examined and followed up for a minimum of 2 years. A retrospective evaluation of contemporaneously documented clinical findings was conducted, and radiographs were retrospectively examined for mechanical failure. The external remote controller (ERC)-specified length achieved in the clinic was compared to the length measured on subsequent radiographs. Results: Fourteen mechanical failures were identified in 28 children (50%) across a total of 52 rods (24 pairs and four single constructs). Mechanical failures were due to: failure to lengthen under general anesthesia (seven children), actuator pin fracture (four), rod fracture (one), foundation screw failure (one), and ran out of rod length (one). Of the 14 mechanical failures, six were treated with final fusion operations (reflecting limited further growth potential), and eight patients were treated with the intention for further lengthening. We therefore consider these eight patients to represent the true incidence of mechanical failure in our cohort (29%). The difference between the ERC length and radiographic length was found to be identical in 11% cases; 35% were overestimates, and 54% were underestimates. The median underestimate was 2.45 mm whereas the median overestimate was 3.1 mm per distraction episode. In total, 95% of all ERC distractions were within ±10 mm of the radiographic length achieved over a median of nine distraction episodes. Conclusions: Our series is the most comprehensive MCGR series published to date, and we present a mechanical failure rate of 29%. Clinicians should be mindful of the discrepancies between ERC length and radiographic measurements of rod length; other modalities may be more helpful in this regard.

Biophysical and functional characterization of Norrin signaling through Frizzled4

Bang, Injin,Kim, Hee Ryung,Beaven, Andrew H.,Kim, Jinuk,Ko, Seung-Bum,Lee, Gyu Rie,Lee, Hasup,Im, Wonpil,Seok, Chaok,Chung, Ka Young,Choi, Hee-Jung National Academy of Sciences 2018 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.115 No.35

<P>Wnt signaling is initiated by Wnt ligand binding to the extracellular ligand binding domain, called the cysteine-rich domain (CRD), of a Frizzled (Fzd) receptor. Norrin, an atypical Fzd ligand, specifically interacts with Fzd4 to activate ss-catenin-dependent canonical Wnt signaling. Much of the molecular basis that confers Norrin selectivity in binding to Fzd4 was revealed through the structural study of the Fzd4(CRD)-Norrin complex. However, how the ligand interaction, seemingly localized at the CRD, is transmitted across full-length Fzd4 to the cytoplasm remains largely unknown. Here, we show that a flexible linker domain, which connects the CRD to the transmembrane domain, plays an important role in Norrin signaling. The linker domain directly contributes to the high-affinity interaction between Fzd4 and Norrin as shown by similar to 10-fold higher binding affinity of Fzd4(CRD) to Norrin in the presence of the linker. Swapping the Fzd4 linker with the Fzd5 linker resulted in the loss of Norrin signaling, suggesting the importance of the linker in ligand-specific cellular response. In addition, structural dynamics of Fzd4 associated with Norrin binding investigated by hydrogen/deuterium exchange MS revealed Norrin-induced conformational changes on the linker domain and the intracellular loop 3 (ICL3) region of Fzd4. Cell-based functional assays showed that linker deletion, L430A and L433A mutations at ICL3, and C-terminal tail truncation displayed reduced ss-catenin-dependent signaling activity, indicating the functional significance of these sites. Together, our results provide functional and biochemical dissection of Fzd4 in Norrin signaling.</P>

DJ-1 regulates mast cell activation and IgE-mediated allergic responses

Kim, D.K.,Kim, H.S.,Kim, A.R.,Kim, J.H.,Kim, B.,Noh, G.,Kim, H.S.,Beaven, M.A.,Kim, Y.M.,Choi, W.S. Mosby 2013 The Journal of allergy and clinical immunology Vol.131 No.6

Background: DJ-1 is an antioxidant protein known to reduce levels of reactive oxygen species (ROS), but its presence or function in mast cells and allergic diseases is unknown. Objectives: We sought to determine the role and mechanism of DJ-1 in allergic responses in vitro and in vivo. Methods: ROS and DJ-1 levels in serum or culture medium were measured with ELISA kits. The role of DJ-1 was evaluated in mast cell cultures and passive cutaneous anaphylaxis in normal or DJ-1 knockout (KO) mice. The mechanism of DJ-1 action was examined by using immunoblotting, immunoprecipitation, RT-PCR, and other molecular biological approaches. Results: Patients with atopic dermatitis had increased levels of ROS and diminished levels of DJ-1. DJ-1 KO mice exhibited enhanced passive cutaneous anaphylaxis and augmented ROS levels in sera and bone marrow-derived mast cells (BMMCs). Furthermore, antigen-induced degranulation and production of TNF-α and IL-4 were significantly amplified in DJ-1 KO and anti-DJ-1 small interfering RNA-transfected BMMCs compared with that seen in wild-type (WT) BMMCs. Studies with these cells and BMMCs transfected with small interfering RNAs against the phosphatases Src homology domain 2-containing protein tyrosine phosphatase (SHP) 1 and SHP-2 revealed that the DJ-1 KO phenotype could be attributed to suppression of SHP-1 activity and enhancement of SHP-2 activity, leading to strengthened signaling through linker for activation of T cells, phospholipase Cγ, and mitogen-activated protein kinases. Conclusions: A deficiency or constitutive activation of DJ-1 can have implications in mast cell-driven allergic diseases, such as asthma and anaphylaxis.

Curcumin, a constituent of curry, suppresses IgE-mediated allergic response and mast cell activation at the level of Syk

Lee, Jun Ho,Kim, Jie Wan,Ko, Na Young,Mun, Se Hwan,Her, Erk,Kim, Bo Kyung,Han, Jeung Whan,Lee, Hoi Young,Beaven, Michael A.,Kim, Young Mi,Choi, Wahn Soo Elsevier 2008 The journal of allergy and clinical immunology Vol.121 No.5

<P><B>Background</B></P><P>Activation of mast cells through the high-affinity receptor for IgE (FcϵRI) underlies atopic allergic reactions. Curcumin can block this activation, but the mechanism and the effects of curcumin on IgE-mediated allergic reactions are unknown.</P><P><B>Objectives</B></P><P>We sought to determine the antiallergic activity of curcumin <I>in vivo</I> and its mechanism of action in mast cells.</P><P><B>Methods</B></P><P>The antiallergic activity of curcumin was evaluated in mast cell cultures and the passive cutaneous anaphylaxis model. The effects of curcumin on mast cell signaling events were examined by using immunoblotting, immunoprecipitation, RT-PCR, and other molecular biologic approaches.</P><P><B>Results</B></P><P>Curcumin inhibited antigen-mediated activation of mast cells and passive cutaneous anaphylaxis in mice. Suppression of degranulation and secretion of TNF-α and IL-4 was apparent at concentrations as low as 3 μmol/L curcumin in activated mast cells. Similar concentrations of curcumin suppressed Syk-dependent phosphorylations of the adaptor proteins linker of activated T cells and Grb2-associated binder 2, which are critical for mast cell activation. Although curcumin did not inhibit the phosphorylation of Syk itself, it directly inhibited Syk kinase activity <I>in vitro</I>. Further downstream, activating phosphorylations of Akt and the mitogen-activated protein kinases p38, p44/42 (extracellular signal-regulated kinase 1/2), and c-Jun N-terminal kinase, which are critical for the production of inflammatory cytokines, were also inhibited.</P><P><B>Conclusions</B></P><P>Curcumin inhibits Syk kinase–dependent signaling events in mast cells and might thus contribute to its antiallergic activity. Therefore curcumin might be useful for the treatment of mast cell–related immediate and delayed allergic diseases.</P>

Interleukin-10–producing CD5⁺ B cells inhibit mast cells during immunoglobulin E–mediated allergic responses

Kim, Hyuk Soon,Kim, A-Ram,Kim, Do Kyun,Kim, Hyun Woo,Park, Young Hwan,Jang, Geun Hyo,Kim, Bokyung,Park, Yeong Min,You, Jueng Soo,Kim, Hyung Sik,Beaven, Michael A.,Kim, Young Mi,Choi, Wahn Soo AAAS 2015 Science signaling Vol.8 No.368

<P>Subsets of B cells inhibit various immune responses through their production of the cytokine interleukin-10 (IL-10). We found that IL-10-producing CD5(+) B cells suppressed the immunoglobulin E (IgE)- and antigen-mediated activation of mast cells in vitro as well as allergic responses in mice in an IL-10-dependent manner. Furthermore, the suppressive effect of these B cells on mast cells in vitro and in vivo depended on direct cell-to-cell contact through the costimulatory receptor CD40 on CD5(+) B cells and the CD40 ligand on mast cells. This contact enhanced the production of IL-10 by the CD5(+) B cells. Through activation of the Janus-activated kinase-signal transducer and activator of transcription 3 pathway, IL-10 decreased the abundance of the kinases Fyn and Fgr and inhibited the activation of the downstream kinase Syk in mast cells. Together, these findings suggest that an important function of IL-10-producing CD5(+) B cells is inhibiting mast cells and IgE-mediated allergic responses.</P>

The Scaffold Protein Prohibitin Is Required for Antigen-Stimulated Signaling in Mast Cells

Kim, Do Kyun,Kim, Hyuk Soon,Kim, A-Ram,Jang, Geun Hyo,Kim, Hyun Woo,Park, Young Hwan,Kim, Bokyung,Park, Yeong Min,Beaven, Michael A.,Kim, Young Mi,Choi, Wahn Soo AAAS 2013 Science signaling Vol.6 No.292

<P><B>How to Prohibit Mast Cell Activation</B></P><P>Mast cells are the major effector cells of the allergic response. Binding of antigen to immunoglobulin E (IgE) molecules bound to the cell-surface, high-affinity IgE receptor FcεRI results in receptor clustering, mast cell activation, and degranulation, resulting in the release of factors that mediate the allergic response. Phosphorylation and activation of the Src family kinases Lyn and Syk are critical for mast cell activation. Kim <I>et al</I>. found that the scaffold protein prohibitin (PHB), which mediates functions such as mitochondrial biogenesis and transcriptional regulation (see commentary by Yurugi and Rajalingam), was abundant in intracellular granules in mouse mast cells. Stimulation of mast cells with antigen resulted in the translocation of PHB to plasma membrane lipid rafts, which was required for the association of FcεRI with Syk, the activation of Syk, and degranulation. Knockdown of PHB in mice inhibited mast cell activation and anaphylaxis, suggesting that targeting PHB therapeutically may reduce allergic responses.</P>

Interleukin-33 stimulates formation of functional osteoclasts from human CD14(+) monocytes.

Mun, Se Hwan,Ko, Na Young,Kim, Hyuk Soon,Kim, Jie Wan,Kim, Do Kyun,Kim, A-Ram,Lee, Seung Hyun,Kim, Yong-Gil,Lee, Chang Keun,Lee, Seoung Hoon,Kim, Bo Kyung,Beaven, Michael A,Kim, Young Mi,Choi, Wahn So Birkhäuser ; Springer 2010 Cellular and molecular life sciences Vol.67 No.22

<P>Interleukin (IL)-33 is a recently described pro-inflammatory cytokine. Here we demonstrate IL-33 as a regulator of functional osteoclasts (OCs) from human CD14(+) monocytes. IL-33 stimulates formation of tartrate-resistant acid phosphatase (TRAP)(+) multinuclear OCs from monocytes. This action was suppressed by anti-ST2 antibody, suggesting that IL-33 acts through its receptor ST2, but not by the receptor activator of NF-κB ligand (RANKL) decoy, osteoprotegerin, or anti-RANKL antibody. IL-33 stimulated activating phosphorylations of signaling molecules in monocytes that are critical for OC development. These included Syk, phospholipase Cγ2, Gab2, MAP kinases, TAK-1, and NF-κB. IL-33 also enhanced expression of OC differentiation factors including TNF-α receptor-associated factor 6 (TRAF6), nuclear factor of activated T cells cytoplasmic 1, c-Fos, c-Src, cathepsin K, and calcitonin receptor. IL-33 eventually induced bone resorption. This study suggests that the osteoclastogenic property of IL-33 is mediated through TRAF6 as well as the immunoreceptor tyrosine-based activation motif-dependent Syk/PLCγ pathway in human CD14(+) monocytes.</P>