Imperial College London

DrDesWalsh

Faculty of MedicineFaculty of Medicine Centre

Director of Research Strategy
 
 
 
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Contact

 

+44 (0)20 7594 9846d.walsh

 
 
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Location

 

Faculty BuildingSouth Kensington Campus

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Summary

 

Publications

Publication Type
Year
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24 results found

Anderson PJB, Watts HR, Jen S, Gentleman SM, Moncaster JA, Walsh DT, Jen L-Set al., 2009, Differential effects of interleukin-1beta and S100B on amyloid precursor protein in rat retinal neurons., Clin Ophthalmol, Vol: 3, Pages: 235-242, ISSN: 1177-5467

PURPOSE: Interleukin-1beta (IL-1beta) and S100B calcium binding protein B (S100B) have been implicated in the pathogenesis of Alzheimer's disease. Both are present in and around senile plaques and have been shown to increase levels of amyloid precursor protein (APP) mRNA in vitro. However, it is not known how either of these substances affects APP in vivo. METHODS: We have studied the effects of IL-1beta and S100B on the expression and processing of APP using a retinal-vitreal model. We have also investigated the effect of amyloid beta peptide (Abeta) on APP in the same system and the regulation of S100B production by Abeta and IL-1beta from retinal glial cells. RESULTS: Retinal ganglion cells constitutively express APP. However, after intravitreal injection of IL-1beta or Abeta there was a marked reduction in APP levels as detected by Western blotting and IL-1beta produced a decrease in APP immunoreactivity (IR). Nissl staining showed that the integrity of the injected retinas was unchanged after injection. Two days after S100B injection, there was a small reduction in APP-IR but this was accompanied by the appearance of some intensely stained large ganglion cells and there was some up-regulation in APP holoprotein levels on Western blot. Seven days post-S100B injection, these large, highly stained cells had increased in number throughout the retina. Injection of Abeta and IL-1beta also caused an increase in S100B production within the retinal Müller glial cells. CONCLUSION: These results support the hypothesis that S100B (a glial-derived neurotrophic factor) and IL-1beta (a pro-inflammatory cytokine) can modulate the expression and processing of APP in vivo and so may contribute to the progression of Alzheimer's disease.

Journal article

Watts HR, Vince V, Walsh DT, Bresciani LG, Gentleman SM, Jen L-S, Anderson PJBet al., 2007, Alterations in presenilin 1 processing by amyloid-beta peptide in the rat retina, EXPERIMENTAL BRAIN RESEARCH, Vol: 181, Pages: 69-77, ISSN: 0014-4819

Journal article

Swales KE, Korbonits M, Carpenter R, Walsh DT, Warner TD, Bishop-Bailey Det al., 2006, The farnesoid X receptor is expressed in breast cancer and regulates apoptosis and aromatase expression, CANCER RESEARCH, Vol: 66, Pages: 10120-10126, ISSN: 0008-5472

Journal article

Walsh DT, Kung K, Legg E, Anderson PBJ, Gentleman SM, Jen LSet al., 2006, Induction of possible progenitor cells within nonneurogenic regions of the brain, 107th Meeting of the British-Neuropathological-Society, Publisher: BLACKWELL PUBLISHING, Pages: 240-241, ISSN: 0305-1846

Conference paper

Walsh DT, Bresciani L, Saunders D, Manca MF, Jen A, Gentleman SM, Jen LSet al., 2005, Amyloid beta peptide causes chronic glial cell activation and neuro-degeneration after intravitreal injection, NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY, Vol: 31, Pages: 491-502, ISSN: 0305-1846

Journal article

Moncaster JA, Walsh DT, Gentleman SM, 2004, Regulation of amyloid precursor protein (APP) processing by ion channel activity in an in vivo rat retinal system, 9th International Conference on Alzheimers Disease and Related Disorders, Publisher: ELSEVIER SCIENCE INC, Pages: S227-S227, ISSN: 0197-4580

Conference paper

Bishop-Bailey D, Walsh DT, Warner TD, 2004, Expression and activation of the farnesoid X receptor in the vasculature, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 101, Pages: 3668-3673, ISSN: 0027-8424

Journal article

Croucher MJ, Patel H, Walsh DT, Moncaster JA, Gentleman SM, Fazal A, Jen LSet al., 2003, Up-regulation of soluble amyloid precursor protein fragment secretion in the rat retina in vivo by metabotropic glutamate receptor stimulation, NEUROREPORT, Vol: 14, Pages: 2271-2274, ISSN: 0959-4965

Journal article

Moncaster JA, Walsh DT, Jen LS, Gentleman SMet al., 2003, N-methyl-D-aspartate (NMDA) differentially affects amyloid precursor protein (APP) cleavage in the rat retinal-vitreal model, NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY, Vol: 29, Pages: 523-524, ISSN: 0305-1846

Journal article

Bishop-Bailey D, Walsh DT, Warner TD, 2003, Farnesoid X receptor (FXR) as a novel target in vascular smooth muscle cells, Meeting of the British-Pharmacological-Society-Clinical-Pharmacology-Section, Publisher: NATURE PUBLISHING GROUP, Pages: U30-U30, ISSN: 0007-1188

Conference paper

Aruoma OI, Moncaster JA, Walsh DT, Gentleman SM, Ke B, Liang YF, Higa T, Jen LSet al., 2003, The antioxidant cocktail, effective microorganism X (EM-X), protects retinal neurons in rats against N-methyl-D-aspartate excitotoxicity in vivo, FREE RADICAL RESEARCH, Vol: 37, Pages: 91-97, ISSN: 1071-5762

Journal article

Croucher MJ, Patel H, Walsh DT, Moncaster JA, Gentleman SM, Fazal A, Jen LSet al., 2003, Up-regulation of soluble amyloid precursor protein fragment secretion in the rat retina in vivo by metabotropic glutamate receptor stimulation, NeuroReport, Vol: 14, Pages: 708-716, ISSN: 0959-4965

Journal article

Bresciani LG, Walsh DT, Gentleman SM, Jen LSet al., 2002, Developmental regulation and possible alternative cleavage of presenilin 1 in the rat retina, MOLECULAR AND CELLULAR NEUROSCIENCE, Vol: 21, Pages: 239-249, ISSN: 1044-7431

Journal article

Moncaster JA, Walsh DT, Gentleman SM, Jen LS, Aruoma OIet al., 2002, Ergothioneine treatment protects neurons against N-methyl-D-aspartate excitotoxicity in an in vivo rat retinal model, NEUROSCIENCE LETTERS, Vol: 328, Pages: 55-59, ISSN: 0304-3940

Journal article

Walsh DT, Montero RM, Bresciani LG, Jen AYT, Leclercq PD, Saunders D, El-Amir AN, Gbadamoshi L, Gentleman SM, Jen LSet al., 2002, Amyloid-beta peptide is toxic to neurons in vivo via indirect mechanisms, NEUROBIOLOGY OF DISEASE, Vol: 10, Pages: 20-27, ISSN: 0969-9961

Journal article

Walsh DT, Betmouni S, Perry VH, 2001, Absence of detectable IL-1 beta production in murine prion disease: A model of chronic neurodegeneration, JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY, Vol: 60, Pages: 173-182, ISSN: 0022-3069

Journal article

Bresciani LG, Walsh DT, Leclercq PD, Jen LS, Gentleman SMet al., 2000, Characterisation of presenilin 1 expression in the developing rat retina, EUROPEAN JOURNAL OF NEUROSCIENCE, Vol: 12, Pages: 111-111, ISSN: 0953-816X

Journal article

Walsh DT, Bresciani L, Leclercq PD, Montero R, Gentleman SM, Jen LSet al., 2000, Intra-vitreal injection of A-beta 1-42 causes alterations in glial cell function in the rat retina, EUROPEAN JOURNAL OF NEUROSCIENCE, Vol: 12, Pages: 378-378, ISSN: 0953-816X

Journal article

Minghetti L, Walsh DT, Levi G, Perry VHet al., 1999, In vivo expression of cyclooxygenase-2 in rat brain following intraparenchymal injection of bacterial endotoxin and inflammatory cytokines, JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY, Vol: 58, Pages: 1184-1191, ISSN: 0022-3069

Journal article

Walsh DT, Yagaloff KA, Williams TJ, Nourshargh Set al., 1996, The role of LTB(4) and LTD(4) in substance P-induced eosinophil accumulation in guinea-pig skin as determined by novel and specific antagonists, BRITISH JOURNAL OF PHARMACOLOGY, Vol: 119, Pages: P53-P53, ISSN: 0007-1188

Journal article

Walsh DT, Weg VB, Williams TJ, Nourshargh Set al., 1995, Substance P-induced inflammatory responses in guinea-pig skin: the effect of specific NK1 receptor antagonists and the role of endogenous mediators., Br J Pharmacol, Vol: 114, Pages: 1343-1350, ISSN: 0007-1188

1. The sensory neuropeptide substance P (SP), when released from sensory nerves, has been implicated in the development of neurogenic inflammation. In the present study, using an in vivo model system, we have characterized and investigated the mechanisms underlying SP-induced leukocyte accumulation and oedema formation in the guinea-pig. 2. Intradermally injected SP (i.d., 10(-13) - 10(-9) mol per site), induced a dose- and time-dependent accumulation of 111In-neutrophils, 111In-eosinophils and oedema formation as measured by the local accumulation of i.v. injected 125I-albumin. The leukocyte accumulation evoked by SP was significant at 10(-10) and 10(-9) mol per site, whereas oedema formation was significant at the lowest dose tested (10(-13) mol per site). 3. The NK1 receptor antagonists, CP-96,345 (1 mg kg-1, i.v.) and RP-67,580 (10 micrograms per site, i.d.), significantly attenuated the oedema formation induced by the lower doses of SP. Oedema formation and leukocyte accumulation induced by 10(-9) mol per site SP were unaffected by either antagonist. 4. SP-elicited responses were not significantly affected by the platelet activating factor (PAF) receptor antagonist, UK-74,505 (2.5 mg kg-1, i.v.) or the H1 histamine receptor antagonist, chlorpheniramine (10(-8) mol per site, i.d.). However, the 111In-eosinophil accumulation, but not the 111In-neutrophil accumulation or oedema formation, induced by SP was significantly inhibited by the specific 5-lipoxygenase (5-LO) inhibitor, ZM-230,487 (10(-8) mol per site, i.d.). 5. The accumulation of both 111 In-neutrophils and 111 In-eosinophils induced by SP was abolished in guinea-pigs treated i.v. with an anti-CD18 monoclonal antibody 6.5E F(ab')2 (2.5 mg kg-1). The oedema response was unaffected in these animals.6. These results suggest that SP-induced inflammatory events may be mediated via two mechanisms involving NK1 receptor-dependent and independent pathways. Oedema formation induced by the lower doses of SP may be

Journal article

Weg VB, Walsh DT, Faccioli LH, Williams TJ, Feldmann M, Nourshargh Set al., 1995, LPS-induced 111In-eosinophil accumulation in guinea-pig skin: evidence for a role for TNF-alpha., Immunology, Vol: 84, Pages: 36-40, ISSN: 0019-2805

Lipopolysaccharide (LPS) is a major component of the cell wall of Gram-negative bacteria with powerful pro-inflammatory activities. Although the mechanisms involved in LPS-induced neutrophil accumulation have been studied extensively, few reports have focused on the effects of LPS on eosinophil infiltration. In this study we have used an in vivo model of local 111In-eosinophil accumulation in the guinea-pig to investigate the mechanisms of LPS-induced eosinophilia. Using a 4-hr in vivo test period, the intradermal injection of LPS (50-1000 ng/site) led to a marked and dose-dependent accumulation of 111In-eosinophils into guinea-pig skin sites. Time-course experiments revealed that this cell infiltration was delayed in onset, becoming significant 1 hr after the intradermal administration of LPS. The slow development of the response and its sensitivity to the locally administered protein synthesis inhibitor, actinomycin D, suggested that the LPS-induced 111In-eosinophil accumulation in vivo is mediated by the generation of de novo proteins. The intravenous pretreatment of guinea-pigs with a soluble tumour necrosis factor-alpha (TNF-alpha) receptor fusion protein (TNFR-IgG, 1 mg/kg), potently inhibited the 111In-eosinophil accumulation induced by LPS. Our results demonstrate that LPS can induce 111In-eosinophil accumulation in vivo in guinea-pig skin, and that this process is mediated by TNF-alpha.

Journal article

Sanz MJ, Weg VB, Walsh DT, Williams TJ, Nourshargh Set al., 1994, Differential effects of the PAF receptor antagonist UK-74,505 on neutrophil and eosinophil accumulation in guinea-pig skin., Br J Pharmacol, Vol: 113, Pages: 513-521, ISSN: 0007-1188

1. The effect of the dihydropyridine, platelet activating factor (PAF) receptor antagonist, UK-74,505, on leucocyte accumulation and oedema formation in guinea-pig skin was investigated. The inflammatory reactions studied were elicited by exogenous mediators, a passive cutaneous anaphylactic (PCA) reaction and zymosan particles. 2. Leucocyte accumulation and oedema formation were measured as the local accumulation of i.v. administered 111In-labelled neutrophils or eosinophils together with 125I-labelled albumin. UK-74,505 was either administered i.v. or used to pretreat the radiolabelled leucocytes in vitro prior to their last wash and injection into recipient animals. 3. In vitro, UK-74,505 inhibited PAF-induced elevations in cytoplasmic levels of Ca2+ ([Ca2+]i) in fura-2-loaded guinea-pig neutrophils and eosinophils with IC50 values of 10(-9) M and 7 x 10(-9) M respectively. Neutrophils and eosinophils pretreated with 10(-7) M and 10(-6) M UK-74,505 respectively, and maintained at 37 degrees C, were unresponsive to PAF for the 4 h period investigated. 4. In vivo, using 2 h test periods, i.v. UK-74,505 (0.5 and 2.5 mg kg-1) inhibited the accumulation of 111In-neutrophils, 111In-eosinophils and oedema formation induced by intradermal PAF, but had no effect on responses elicited by leukotriene B4 (LTB4) and zymosan-activated plasma (ZAP, used as a source of C5a des Arg). UK-74,505 (2.5 mg kg-1) was also without an effect on response induced by a PCA reaction but significantly suppressed the 111In-eosinophil accumulation following the intradermal administration of zymosan particles. The 111In-neutrophil accumulation induced by zymosan particles was not, however, affected by UK-74,505. 5. In a second series of in vivo experiments, "'In-leucocytes were pretreated in vitro with UK-74,505 prior to their last wash and injection into recipient animals. Radiolabelled neutrophils, and eosinophils were pretreated with 10-7 M and 10-6 M UK-74,505 respectively, concentratio

Journal article

Jose PJ, Griffiths-Johnson DA, Collins PD, Walsh DT, Moqbel R, Totty NF, Truong O, Hsuan JJ, Williams TJet al., 1994, Eotaxin: a potent eosinophil chemoattractant cytokine detected in a guinea pig model of allergic airways inflammation., Journal of Experimental Medicine, Vol: 179, Pages: 881-887, ISSN: 1540-9538

Eosinophil accumulation is a prominent feature of allergic inflammatory reactions, such as those occurring in the lung of the allergic asthmatic, but the endogenous chemoattractants involved have not been identified. We have investigated this in an established model of allergic inflammation, using in vivo systems both to generate and assay relevant activity. Bronchoalveolar lavage (BAL) fluid was taken from sensitized guinea pigs at intervals after aerosol challenge with ovalbumin. BAL fluid was injected intradermally in unsensitized assay guinea pigs and the accumulation of intravenously injected 111In-eosinophils was measured. Activity was detected at 30 min after allergen challenge, peaking from 3 to 6 h and declining to low levels by 24 h. 3-h BAL fluid was purified using high performance liquid chromatography techniques in conjunction with the skin assay. Microsequencing revealed a novel protein from the C-C branch of the platelet factor 4 superfamily of chemotactic cytokines. The protein, "eotaxin," exhibits homology of 53% with human MCP-1, 44% with guinea pig MCP-1, 31% with human MIP-1 alpha, and 26% with human RANTES. Laser desorption time of flight mass analysis gave four different signals (8.15, 8.38, 8.81, and 9.03 kD), probably reflecting differential O-glycosylation. Eotaxin was highly potent, inducing substantial 111In-eosinophil accumulation at a 1-2 pmol dose in the skin, but did not induce significant 111In-neutrophil accumulation. Eotaxin was a potent stimulator of both guinea pig and human eosinophils in vitro. Human recombinant RANTES, MIP-1 alpha, and MCP-1 were all inactive in inducing 111In-eosinophil accumulation in guinea pig skin; however, evidence was obtained that eotaxin shares a binding site with RANTES on guinea pig eosinophils. This is the first description of a potent eosinophil chemoattractant cytokine generated in vivo and suggests the possibility that similar molecules may be important in the human asthmatic lung.

Journal article

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