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Kc R.,Rush University Medical Center | Li X.,Rush University Medical Center | Kroin J.S.,Rush University Medical Center | Liu Z.,Rush University Medical Center | And 11 more authors.
Annals of the Rheumatic Diseases | Year: 2016

Objectives A key clinical paradox in osteoarthritis (OA), a prevalent age-related joint disorder characterised by cartilage degeneration and debilitating pain, is that the severity of joint pain does not strictly correlate with radiographic and histological defects in joint tissues. Here, we determined whether protein kinase Cδ (PKCδ), a key mediator of cartilage degeneration, is critical to the mechanism by which OA develops from an asymptomatic joint-degenerative condition to a painful disease. Methods OA was induced in 10-week-old PKCδ null (PKCδ-/-) and wild-type mice by destabilisation of the medial meniscus (DMM) followed by comprehensive examination of the histology, molecular pathways and knee-pain-related-behaviours in mice, and comparisons with human biopsies. Results In the DMM model, the loss of PKCδ expression prevented cartilage degeneration but exacerbated OA-associated hyperalgesia. Cartilage preservation corresponded with reduced levels of inflammatory cytokines and of cartilage-degrading enzymes in the joints of PKCδ-deficient DMM mice. Hyperalgesia was associated with stimulation of nerve growth factor (NGF) by fibroblast-like synovial cells and with increased synovial angiogenesis. Results from tissue specimens of patients with symptomatic OA strikingly resembled our findings from the OA animal model. In PKCd null mice, increases in sensory neuron distribution in knee OA synovium and activation of the NGF-tropomyosin receptor kinase (TrkA) axis in innervating dorsal root ganglia were highly correlated with knee OA hyperalgesia. Conclusions Increased distribution of synovial sensory neurons in the joints, and augmentation of NGF/TrkA signalling, causes OA hyperalgesia independently of cartilage preservation. © 2016 BMJ Publishing Group Ltd & European League Against Rheumatism.


Brass D.,Alomone Labs Ltd. | Grably M.R.,Alomone Labs Ltd. | Bronstein-Sitton N.,Alomone Labs Ltd. | Gohar O.,Alomone Labs Ltd. | Meir A.,Alomone Labs Ltd.
Purinergic Signalling | Year: 2012

The broad expression pattern of the G protein-coupled P2Y receptors has demonstrated that these receptors are fundamental determinants in many physiological responses, including neuromodulation, vasodilation, inflammation, and cell migration. P2Y receptors couple either G q or G i upon activation, thereby activating different signaling pathways. Ionotropic ATP (P2X) receptors bind extracellular nucleotides, a signal which is transduced within the P2X protein complex into a cation channel opening, which usually leads to intracellular calcium concentration elevation. As such, this family of proteins initiates or shapes several cellular processes including synaptic transmission, gene expression, proliferation, migration, and apoptosis. The ever-growing range of applications for antibodies in the last 30 years attests to their major role in medicine and biological research. Antibodies have been used as therapeutic tools in cancer and inflammatory diseases, as diagnostic reagents (flow cytometry, ELISA, and immunohistochemistry, to name a few applications), and in widespread use in biological research, including Western blot, immunoprecipitation, and ELISPOT. In this article, we will showcase several of the advances that scientists around the world have achieved using the line of antibodies developed at Alomone Labs for P2Y and P2X receptors. © 2011 The Author(s).


PubMed | Alomone Labs Ltd
Type: | Journal: Toxicon : official journal of the International Society on Toxinology | Year: 2013

Voltage dependent sodium (Na(V)) channels are large membrane spanning proteins which lie in the basis of action potential generation and propagation in excitable cells and hence are essential mediators of neuronal signaling. Inhibition of Na(V) channel activity is one of the core mechanisms to treat conditions related to neuronal hyperexcitability, such as epilepsy in the clinic. Na(V) channel blockers are also extensively used to locally inhibit action potential generation and related pain perceptions in the form of local anesthetics. Here we describe the isolation, biochemical characterization, synthesis and in vitro characterization of two potent Na(V) channel blockers from the venom of the Paraphysa scrofa (Phrixotrichus auratus) tarantula spider. Both Voltage sensor toxin 3 (VSTx-3, -theraphotoxin-Gr4a) and GTx1-15 (Toxin Gtx1-15), were originally isolated from the venom of the related tarantula Grammostola rosea and described as K(V) and Ca(V) channel blockers, respectively. In our hands, GTx1-15 was shown to be a potent inhibitor of tetrodotoxin (TTX)-sensitive channels (IC 0.007 M for hNa(V)1.7 and 0.12 M for hNa(V)1.3 channels), with very little effect on TTX-resistant (Na(V)1.5 and NaV1.8) channels. VSTx-3 was demonstrated to be a potent, TTX-sensitive sodium channel blocker and especially, potent blocker of Na(V)1.8 channels (IC 0.19 M for hNa(V)1.3, 0.43 M for hNa(V)1.7 and 0.77 M for hNa(V)1.8 channels). Such potent inhibitors with differential selectivity among Na(V) channel isoforms may be used as tools to study the roles of the different channels in processes related to hyperexcitability and as lead compounds to treat pathological pain conditions.


PubMed | Alomone Labs Ltd.
Type: Journal Article | Journal: Purinergic signalling | Year: 2012

The broad expression pattern of the G protein-coupled P2Y receptors has demonstrated that these receptors are fundamental determinants in many physiological responses, including neuromodulation, vasodilation, inflammation, and cell migration. P2Y receptors couple either G(q) or G(i) upon activation, thereby activating different signaling pathways. Ionotropic ATP (P2X) receptors bind extracellular nucleotides, a signal which is transduced within the P2X protein complex into a cation channel opening, which usually leads to intracellular calcium concentration elevation. As such, this family of proteins initiates or shapes several cellular processes including synaptic transmission, gene expression, proliferation, migration, and apoptosis. The ever-growing range of applications for antibodies in the last 30years attests to their major role in medicine and biological research. Antibodies have been used as therapeutic tools in cancer and inflammatory diseases, as diagnostic reagents (flow cytometry, ELISA, and immunohistochemistry, to name a few applications), and in widespread use in biological research, including Western blot, immunoprecipitation, and ELISPOT. In this article, we will showcase several of the advances that scientists around the world have achieved using the line of antibodies developed at Alomone Labs for P2Y and P2X receptors.

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