"Go upstream, young man": lessons learned from the p38 saga

Hammaker, Deepa; Firestein, Gary S.

doi:10.1136/ard.2009.119479

Cited by 194 publications

(173 citation statements)

References 75 publications

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“…They comprise three groups; p38, c-Jun N-terminal kinase (JNK) and extracellular-regulated protein kinase (ERK) with p38 the most explored for treatment potential. Inhibition of various p38 inhibitors proved therapeutic in CIA and other models of arthritis, but numerous p38 inhibitors did not progress past phase III RA trials with both toxicity and poor efficacy cited for their failure in the clinic (Hammaker and Firestein, 2010).…”

Section: (B) Small Moleculesmentioning

confidence: 99%

Animal models of rheumatoid arthritis: How informative are they?

McNamee

Williams

Seed

2015

European Journal of Pharmacology

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Animal models of arthritis are widely used to de-convolute disease pathways and to identify novel drug targets and therapeutic approaches. However, the high attrition rates of drugs in Phase II/III rates means that a relatively small number of drugs reach the market, despite showing efficacy in pre-clinical models. There is also increasing awareness of the ethical issues surrounding the use of animal models of disease and it is timely, therefore, to review the relevance and translatability of animal models of arthritis. In this paper we review the most commonly used animal models in terms of their pathological similarities to human rheumatoid arthritis as well as their response to drug therapy. In general, the ability of animal models to predict efficacy of biologics in man has been good. However, the predictive power of animal models for small molecules has been variable, probably because of differences in the levels of target knockdown achievable in vivo.3

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Section: (B) Small Moleculesmentioning

confidence: 99%

Animal models of rheumatoid arthritis: How informative are they?

McNamee

Williams

Seed

2015

European Journal of Pharmacology

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“…Of note, several targets for gene therapy such as IL-1Ra, TNF-, and IL-17 have already yielded DMARBDs or other forms of neutralizing compounds which are either currently being assessed in pre-clinical studies, tested in RA clinical trials or routinely used in the treatment of RA in clinical practice (Genovese et al, 2010;Finckh & Gabay, 2008;Gibbons & Hyrich, 2009;Ishiguro et al, 2011;Sênolt et al, 2009;Toh et al, 2010). However, the positive results obtained with various gene therapy strategies in cell cultures and/or in animal models of arthritis must always be cautiously interpreted as the previous supportive results with inhibitors of p38 kinase in arthritis animal models (Böhm et al, 2009;Hammaker & Firestein, 2010) which provided the impetus for the clinical testing of p38 kinase inhibitors proved to be disappointing in terms of clinical outcomes in human RA trials (Genovese, 2009). Thus, it remains to be seen if the biopharmaceutical industry will use pertinent targets for RA intervention such as IL-10, BAFF, MMP-9, etc.…”

Section: Discussionmentioning

confidence: 99%

Gene Therapy Outcomes in Experimental Models of Inflammatory Arthritis

Malemud¹

2011

Gene Therapy Applications

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“…Dtk, morfogenez, hücre büyümesi, migrasyon ve yaşamda kalma gibi endotel hücrelerin işlevlerinde kritik bir rol oynamakta ve in vivo koşullarda damar bütünlüğü-nün sürdürülmesine katkıda bulunmaktadır (4,5 leştiren ITAM'leri fosforile etmektedir. Etkinleşen Dtk, MAPK, fosfoinozitit-3-kinaz (phosphoinositide-3-kinase; PI3K) ve fosfolipaz C (phospholipase C, PLC) gibi çoklu sinyal ileti yolları aracılığı ile enflamasyonu düzenlemektedir (52). IgE reseptörü aracılığıyla antijen tarafından uyarılan mast hücrelerinde Dtk, sitoplazmik FLA 2 'nin etkinleşmesi için gereklidir (53).…”

Section: Dtk'nin Ekspresyonu Ve Etkinliğinin Düzenlenmesiunclassified

Signal Transduction of Zymosan and Spleen Tyrosine Kinase

Ünsal¹,

Temiz²,

Tunçtan³

et al. 2014

MUSBED

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Zimosan sinyal iletisi ve dalak tirozin kinazıZimosan, Saccharomyces cerevisiae'nin hücre duvarından elde edilen, polisakkarit zincirlerinden oluşan bir bileşendir. Zimosan, başlıca 1,3-β-glukan, 1,6-β-glukan ve α-mannan gibi çapraz bağlı polisakkaritlerden oluşmaktadır. Zimosan, fungal sepsis, septik olmayan şok, çoklu organ yetmezliği, akut peritonit, irritabl bağırsak sendromu gibi enflamatuvar hastalıkların patojenezinde rol oynamakta ve ilgili deneysel modellerde kullanılmaktadır. Zimosanın monosit, makrofaj ve dendritik hücreler gibi immün sistem hücrelerindeki etkilerine toll-like receptor 2, dektin-1, mannoz ve kompleman reseptörleri gibi çeşitli reseptörler aracılık etmektedir. Dalak tirozin kinazı (Dtk), 72 kDa ağırlığında reseptör ile kenetli olmayan bir intraselüler tirozin kinazdır. Dtk'nin, mast hücreleri, nötrofiller, makrofajlar ve trombositler gibi tüm hematopoetik hücrelerde ve fibroblastlar, epitel, sinir ve damar endotel hücreleri gibi hematopoetik olmayan hücrelerde eksprese edildiği gösterilmiştir. Dtk, zimosanın dektin-1 reseptörü aracılığıyla oluşturduğu hücresel yanıtlara aracılık eden önemli bir kinazdır. Bu derlemede, zimosan sinyal iletisinde Dtk'nin rolü değerlendirilmiştir. Anahtar sözcükler: Zimosan, Dalak tirozin kinazı, dektin-1, enflamasyon ABS TRACT Signal transduction of zymosan and spleen tyrosine kinaseZymosan is a component produced by polysaccharide which is obtained from cell wall of Saccharomyces cerevisiae. Zymosan consists of crosslinked polysaccharides such as 1,3-β glucan, 1,6-β glucan, and α-mannan. Zymosan plays a role in inflammmatory diseases such as fungal sepsis, non-septic shock, multiple organ dysfunction syndrome, acute peritonitis, irritable bowel syndrome and it is used in related experimental models. Toll-like receptor 2, dectin-1, mannose, and compleman receptors mediate zymosan's effects on immune system cells such as monocytes, macrophages, and dendritic cells. Spleen tyrosine kinase (Syk) is a cytosolic, intracellular, 72-kDa protein tyrosine kinase. It is demonstrated that Syk is expressed in hematopoietic cells such as mast cells, neutrophils, macrophages, B cells, leukocytes, and platelets and in non-hematopoietic cells such as epithelial, fibroblast, neuronal cells, and vascular endothelial cells. Spleen tyrosine kinase is a critical kinase that mediates cellular responses through dectin-1 receptor by zymosan. In this review, the role of syk in is evaluated in the signal transduction of zymosan.

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"Go upstream, young man": lessons learned from the p38 saga

Abstract: Despite the success of biological therapies in rheumatoid arthritis

Cited by 194 publications

References 75 publications

Animal models of rheumatoid arthritis: How informative are they?

Animal models of rheumatoid arthritis: How informative are they?

Gene Therapy Outcomes in Experimental Models of Inflammatory Arthritis

Signal Transduction of Zymosan and Spleen Tyrosine Kinase

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