Colorless granular crystal
(1S,4E,12S,13S)-5,10-Dimethyl-8,14,16-trioxatetracyclo[10.2.2.0.0]hexadeca-4,7(11),9-trien-15-one/2H-10,1a-(Epoxymethano)oxireno[4,5]cyclodeca[1,2-b]furan-12-one, 3,6,10,10a-tetrahydro-5,9-dimethyl-, (1aS,4E,10S,10aS)-
Methanol; Acetontrile; Ethyl Acetate; DMSO
434.5±45.0 °C at 760 mmHg
HS Code Reference
Personal Projective Equipment
For Reference Standard and R&D, Not for Human Use Directly.
provides coniferyl ferulate(CAS#:13476-25-0) MSDS, density, melting point, boiling point, structure, formula, molecular weight etc. Articles of coniferyl ferulate are included as well.>> amp version: coniferyl ferulate
Type-I interferons (IFNs) play a key role in the immune defences against viral and bacterial infections, and in cancer immunosurveillance. We have established that clathrin-dependent endocytosis of the type-I interferon (IFN-α/β) receptor (IFNAR) is required for JAK/STAT signalling. Here we show that the internalized IFNAR1 and IFNAR2 subunits of the IFNAR complex are differentially sorted by the retromer at the early endosome. Binding of the retromer VPS35 subunit to IFNAR2 results in IFNAR2 recycling to the plasma membrane, whereas IFNAR1 is sorted to the lysosome for degradation. Depletion of VPS35 leads to abnormally prolonged residency and association of the IFNAR subunits at the early endosome, resulting in increased activation of STAT1- and IFN-dependent gene transcription. These experimental data establish the retromer complex as a key spatiotemporal regulator of IFNAR endosomal sorting and a new factor in type-I IFN-induced JAK/STAT signalling and gene transcription.
Type-I interferons (IFN-α/β) are key cytokines for cellular responses in innate and acquired immunity to diseases including cancer and infection1. The type-I IFNs activate the canonical Janus kinase/signal transducers and activators of transcription (JAK/STAT) signalling pathway, which relies on ubiquitously expressed type I IFN-α/β receptors (IFNAR), Janus family kinases (JAK1 and TYK2), and STAT1 and STAT2. IFN-α/β binding results in IFNAR1 and IFNAR2 subunits rearrangement and dimerization, followed by auto- and transphosphorylation and activation of TYK2 and JAK1, which are respectively pre-associated with IFNAR1 and IFNAR2 (refs 1, 2). JAK-mediated IFNAR phosphorylation leads to the recruitment and activation of cytoplasmic STAT1 and STAT2, which in association with IFN-regulatory factor 9, are translocated to the nucleus as a trimolecular complex called IFN-stimulated gene (ISG) factor 3 that binds DNA to initiate the transcription of ISGs.
As many as 17 different but related type-I IFNs elicit numerous and complex activities through binding to the same IFNAR receptor complex, raising the question of the molecular mechanisms that control the selectivity of type-I IFN signalling. Several studies have established various regulatory mechanisms at the level of gene transcription, epigenetics or signalling cross-talks3,4,5. Endocytosis has long been viewed as a simple means to control receptor signalling by down-modulation of receptor numbers at the plasma membrane. Pioneering studies on the epidermal growth factor receptor have challenged this passive role of endocytosis6 and led to a new paradigm where the endocytic network is directly connected to the control of receptor signalling7. If increasing evidence suggests that endosomes may function as signalling platforms, the challenge today is to identify the molecular machinery that controls the endocytosis signalling nexus8. This particular aspect of receptor signalling regulation by membrane trafficking has received little attention for IFNAR and JAK/STAT signalling9,10. Nevertheless, we previously established that IFNAR endocytosis through clathrin-coated pits was required for the activation of JAK/STAT signalling and the antiviral and antiproliferative activities of type-I IFNs11.
In this study, we aimed to elucidate how the delivery of IFNAR to the endosomal network may play a role in the control of JAK/STAT signalling induced by IFN-α/β. We consequently uncover a new role for the retromer complex in JAK/STAT signalling termination. We found that the retromer subunit vacuolar protein sorting-associated protein 35 (VPS35) binds IFNAR2 and thereby controls the spatiotemporal dissociation of the IFNAR1 and IFNAR2 subunits of the IFNAR complex at the early endosome. This interaction is critical for the proper regulation of JAK/STAT signalling and gene transcription induced by IFN-α/β.
Spatiotemporal control of interferon-induced JAK/STAT signalling and gene transcription by the retromer complex
Daniela Chmiest,1,2,3 Nanaocha Sharma,4 Natacha Zanin,1,2,3 Christine Viaris de Lesegno,1,2,3 Massiullah Shafaq-Zadah,2,3,5 Vonick Sibut,6,7,8 Florent Dingli,9 Philippe Hupe,6,7,8,10 Stephan Wilmes,11 Jacob Piehler,11 Damarys Loew,9 Ludger Johannes,2,3,5 Gideon Schreiber,4 and Christophe Lamazea,1,2,3
2016 Dec 5
A longstanding and still-increasing threat to the effective treatment of infectious diseases is resistance to antimicrobial countermeasures. Potentially, the targeting of host proteins and pathways essential for the detrimental effects of pathogens offers an approach that may discover broad-spectrum anti-pathogen countermeasures and circumvent the effects of pathogen mutations leading to resistance. Here we report implementation of a strategy for discovering broad-spectrum host-oriented therapies against multiple pathogenic agents by multiplex screening of drugs for protection against the detrimental effects of multiple pathogens, identification of host cell pathways inhibited by the drug, and screening for effects of the agent on other pathogens exploiting the same pathway. We show that a clinically used antimalarial drug, Amodiaquine, discovered by this strategy, protects host cells against infection by multiple toxins and viruses by inhibiting host cathepsin B. Our results reveal the practicality of discovering broadly acting anti-pathogen countermeasures that target host proteins exploited by pathogens.
Whereas medical treatments generally target specific cellular functions of patients to cure or mitigate the effects of diseases, the strategy underlying treatment of infectious disease treatment is to target the infecting pathogen1. Inevitably, and not surprisingly, the targeting of pathogens has led to the emergence and spread among pathogens of mutational resistance to countermeasures. Such resistance, together with a desire to expand the utility of countermeasures by increasing their range of therapeutic efficacy, has in recent years sparked interest in agents aimed at host functions that pathogens exploit to enter or be released from host cells1. Not infrequently, multiple pathogens or toxins that affect hosts by different mechanisms use the same host pathways2, raising the prospect that multiplex strategies that concurrently or sequentially screen for host functions exploited by multiple pathogenic agents may lead to the discovery of broadly active and host-oriented infectious disease countermeasures.
Here we report the discovery, using a cell-based multiplex approach to screen a library of FDA-approved drugs for the ability to interfere with disparately acting pathogens. We report here, that a compound used clinically as an antimalarial agent, inhibits both the detrimental effects of multiple bacterial toxins and the entry of Ebola and other viruses into host cells. We further show that the broad antipathogenic actions of Amodiaquine result from its ability to interfere with the functioning of the host protein, cathepsin B.
Identification of agents effective against multiple toxins and viruses by host-oriented cell targeting
Leeor Zilbermintz,1,* William Leonardi,1,* Sun-Young Jeong,2 Megan Sjodt,3 Ryan McComb,1 Chi-Lee C. Ho,5 Cary Retterer,4 Dima Gharaibeh,4 Rouzbeh Zamani,4 Veronica Soloveva,4 Sina Bavari,4 Anastasia Levitin,1 Joel West,1 Kenneth A. Bradley,5 Robert T. Clubb,3 Stanley N. Cohen,2 Vivek Gupta,1 and Mikhail Martchenkoa,1
2015 Aug 27
Treatment of large bone defects is a challenging clinical situation that may be benefited from cell therapies based on regenerative medicine. This study was conducted to evaluate the effect of local injection of bone marrow-derived mesenchymal stromal cells (BM-MSCs) or adipose tissue-derived MSCs (AT-MSCs) on the regeneration of rat calvarial defects. BM-MSCs and AT-MSCs were characterized based on their expression of specific surface markers; cell viability was evaluated after injection with a 21-G needle. Defects measuring 5 mm that were created in rat calvaria were injected with BM-MSCs, AT-MSCs, or vehicle-phosphate-buffered saline (Control) 2 weeks post-defect creation. Cells were tracked by bioluminescence, and 4 weeks post-injection, the newly formed bone was evaluated by µCT, histology, nanoindentation, and gene expression of bone markers. BM-MSCs and AT-MSCs exhibited the characteristics of MSCs and maintained their viability after passing through the 21-G needle. Injection of both BM-MSCs and AT-MSCs resulted in increased bone formation compared to that in Control and with similar mechanical properties as those of native bone. The expression of genes associated with bone formation was higher in the newly formed bone induced by BM-MSCs, whereas the expression of genes involved in bone resorption was higher in the AT-MSC group. Cell therapy based on local injection of BM-MSCs or AT-MSCs is effective in delivering cells that induced a significant improvement in bone healing. Despite differences observed in molecular cues between BM-MSCs and AT-MSCs, both cells had the ability to induce bone tissue formation at comparable amounts and properties. These results may drive new cell therapy approaches toward complete bone regeneration.
Subject terms: Regeneration, Mesenchymal stem cells
Cell Therapy: Effect of Locally Injected Mesenchymal Stromal Cells Derived from Bone Marrow or Adipose Tissue on Bone Regeneration of Rat Calvarial Defects
Gileade P. Freitas,1 Helena B. Lopes,1 Alann T. P. Souza,1 Paula G. F. P. Oliveira,1 Adriana L. G. Almeida,1 Lucas E. B. Souza,2 Paulo G. Coelho,3,4 Marcio M. Beloti,1 and Adalberto L. Rosacorresponding author1
2019 Sep 17.