Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The antiinflammatory and antiapoptotic effects of chondroitin sulfate (CS) are being used to treat osteoarthritis. Recent evidence has revealed that those peripheral effects of CS may also have therapeutic interest in diseases of the central nervous system (CNS). We review here such evidence. Perineuronal nets (PNNs) formed by chondroitin sulfate proteoglycans (CSPGs) may have a neuroprotective action against oxidative stress potentially involved in neurodegeneration. On the other hand, in human neuroblastoma SH-SY5Y cells CS has antioxidant and neuroprotective effects by activating the signaling pathway PKC/PI3K/Akt and inducing the antioxidant enzyme hemoxygenase-1. Consistent with this is the observation that protein kinase C (PKC) blockade overcomes inhibition of neurite outgrowth elicited by CSPGs. In addition, CS protects cortical neurons against excytotoxic death by phosphorylation of intracellular signals and the suppression of caspase-3 activation. Of interest is the finding that a disaccharide derived from CSPG degradation (CSGP-DS) protects neurons against toxicity both in vitro and in vivo. Furthermore, CSGP-DS efficiently protects against neuronal loss in experimental autoimmune encephalomyelitis and uveitis, decreases secretion of tumor necrosis factor-alpha (TNF-alpha) and block necrosis factor kappa B (NF-kappaB) translocation. In conclusion, CS may have neuroprotective properties linked to its antioxidant and antiinflammatory effects.
Osteoarthritis Cartilage 2010 Jun
PMID:Antioxidant, antiinflammatory and neuroprotective actions of chondroitin sulfate and proteoglycans. 2039 98

Neural crest stem/progenitor cells (NCSCs) populate a variety of tissues, and their dysregulation is implicated in several human diseases including craniosynostosis and neuroblastoma. We hypothesised that small molecules that inhibit NCSC induction or differentiation may represent potential therapeutically relevant drugs in these disorders. We screened 640 FDA-approved compounds currently in clinical use for other conditions to identify those which disrupt development of NCSC-derived skeletal elements that form the zebrafish jaw. In the primary screen, we used heterozygous transgenic sox10:gfp zebrafish to directly visualise NCSC-derived jaw cartilage. We noted partial toxicity of this transgene in relation to jaw patterning, suggesting that our primary screen was sensitised for NCSC defects, and we confirmed 10 novel, 4 previously reported, and 2 functional analogue drug hits in wild-type embryos. Of these drugs, 9/14 and 7/14, respectively, are known to target pathways implicated in osteoarthritis pathogenesis or to cause reduced bone mineral density/increased fracture risk as side effects in patients treated for other conditions, suggesting that our screen enriched for pathways targeting skeletal tissue homeostasis. We selected one drug that inhibited NCSC induction and one drug that inhibits bone mineralisation for further detailed analyses which reflect our initial hypotheses. These drugs were leflunomide and cyclosporin A, respectively, and their functional analogues, teriflunomide and FK506 (tacrolimus). We identified their critical developmental windows of activity, showing that the severity of defects observed related to the timing, duration, and dose of treatment. While leflunomide has previously been shown to inhibit NCSC induction, we demonstrate additional later roles in cartilage remodelling. Both drugs altered expression of extracellular matrix metalloproteinases. As proof-of-concept, we also tested drug treatment of disease-relevant mammalian cells. While leflunomide treatment inhibited the viability of several human NCSC-derived neuroblastoma cell lines coincident with altered expression of genes involved in ribosome biogenesis and transcription, FK506 enhanced murine calvarial osteoblast differentiation and prevented fusion of the coronal suture in calvarial explants taken from Crouzon syndrome mice.
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PMID:An FDA-Approved Drug Screen for Compounds Influencing Craniofacial Skeletal Development and Craniosynostosis. 3097 83

Cytokine-like protein 1 (Cytl1), also named Protein C17 or C4orf4 is located on human chromosome 4p15-p16 and encodes a polypeptide of 126 amino acid residues that displays characteristics of a secretory protein. Cytl1 is expressed by a sub-population of CD34+ human mononuclear cells from bone marrow and cord blood, and by chondrocytes (cartilage-forming cells). In this review, we explore evidence suggesting that Cytl1 may be involved in the regulation of chondrogenesis, cartilage homeostasis and osteoarthritis progression, accompanied by the modulation of Sox9 and insulin-like growth factor 1 expression. In addition, Cytl1 exhibits chemotactic and pro-angiogenic biological effects. Interestingly, CCR2 (C-C chemokine receptor type 2) has been identified as a likely receptor for Cytl1, which mediates the ERK signalling pathway. Cytl1 also appears to mediate the TGF-beta-Smad signalling pathway, which is hypothetically independent of the CCR2 receptor. More recently, studies have also potentially linked Cytl1 with a variety of conditions including cardiac fibrosis, smoking, alcohol dependence risk, and tumours such as benign prostatic hypertrophy, lung squamous cell carcinoma, neuroblastoma and familial colorectal cancer. Defining the molecular structure of Cytl1 and its role in disease pathogenesis will help us to design therapeutic approaches for Cytl1-associated pathological conditions.
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PMID:Protein Cytl1: its role in chondrogenesis, cartilage homeostasis, and disease. 3108 46