Modulation of diabetes-related liver injury by the HMGB1/TLR4 inflammatory pathway
J. physiol. biochem
; 74(2): 345-358, mayo 2018.
Artigo
em Inglês
| IBECS
| ID: ibc-178990
Biblioteca responsável:
ES1.1
Localização: BNCS
ABSTRACT
Chronic inflammation plays an essential role in the development of diabetic complications. Understanding the molecular mechanisms that support inflammation is a prerequisite for the design of novel anti-inflammatory therapies. These would take into consideration circulating levels of cytokines and damage-associated molecular patterns (DAMPs) that include the high mobility group box 1 (HMGB1) protein which, in part, promotes the inflammatory response through TLR4 signaling. The liver, as the source of circulating cytokines and acute-phase proteins, contributes to the control of systemic inflammation. We previously found that liver injury in streptozotocin-induced diabetic rats correlated with the level of oxidative stress, increased expression of HMGB1, and with the activation of TLR4-mediated cell death pathways. In the present work, we examined the effects of ethyl pyruvate (EP), an inhibitor of HMGB1 release/expression, on the modulation of activation of the HMGB1/TLR4 inflammatory cascade in diabetic liver. We observed that increased expression of inflammatory markers, TNF-α, IL-6, and haptoglobin in diabetic liver was associated with increased HMGB1/TLR4 interaction, activation of MAPK (p38, ERK, JNK)/NF-κB p65 and JAK1/STAT3 signaling pathways, and with decreased expression of Nrf2-regulated antioxidative enzymes. The reduction in HMGB1 expression as the result of EP administration reduced the pro-inflammatory activity of HMGB1 and exerted a protective effect on diabetic liver, which was observed as improved liver histology and antioxidant and inflammatory statuses. Our results suggest that prevention of HMGB1 release and blockage of the HMGB/TLR4 axis represents a potentially effective therapeutic strategy aimed at ameliorating diabetes-induced inflammation and ensuing liver injury
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Coleções:
Bases de dados nacionais
/
Espanha
Base de dados:
IBECS
Assunto principal:
Proteína HMGB1
/
Diabetes Mellitus Experimental
/
Receptor 4 Toll-Like
/
Inflamação
/
Hepatopatias
Limite:
Animais
/
Humanos
Idioma:
Inglês
Revista:
J. physiol. biochem
Ano de publicação:
2018
Tipo de documento:
Artigo
Instituição/País de afiliação:
University of Belgrade/Republic of Serbia