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Diabetes and Inflammation
Published in Awanish Kumar, Ashwini Kumar, Diabetes, 2020
One recent study showed that high glucose concentration or hyperglycaemia results in significant increase in the expression of TLR-2 and TLR-4 in human monocytes cell lines and the monocytes isolated from diabetic subjects, resulting in NF-κB activation and eventual inflammatory response. TLR-2 and TLR-4 expression is also observed in a variety of other cells such as endothelial cells, coronary artery smooth muscle cells, adipocytes and pancreatic islets. It was also found experimentally that high glucose induced increased TLR-2 and TLR-4 expression persists for around 2–3 days before coming back to normal if hyperglycaemia is reduced to normal levels. It was also shown that hyperglycaemia leads to increased superoxide release from monocytes, which is a potent oxidising agent [6]. This increase in TLR expression is positively correlated with insulin resistance, N-carboxymethyllysine (N-CML), which is an important physiological AGE and FFA. The concentration and number of ligands for these two TLRs, such as heat shock protein 60 (HSP 60), HSP 70 and HMGB1, are also increased and were consistent with hyperglycaemia. HMGB1 is a chromatin protein similar to histone which is released by immune cells, mostly monocytes, macrophages and dendritic cells. In a few reported studies, it was shown that certain drug classes such as thiazolidinediones (TZDs), statins and angiotensin receptor blockers (ARBs) decrease the TLR expression [24] (Figure 2.1).
Senescent Cells as Drivers of Age-Related Diseases
Published in Shamim I. Ahmad, Aging: Exploring a Complex Phenomenon, 2017
Cielo Mae D. Marquez, Michael C. Velarde
HMGB1 is also implicated in cellular senescence. While HMGB1 is initially found in the nucleus, it becomes redistributed to the extracellular milieu as a secreted alarmin, shortly after DNA damage and activation of a p53-dependent growth arrest [23,106]. HMGB1 secretion occurs in a p53-dependent manner and does not require ATM or p16 activation. HMGB1 release stimulates cytokine secretion and promotes senescence-associated inflammation by signaling through the toll-like receptor-4 (TLR-4) [23].
Principles of Clinical Pathology
Published in Pritam S. Sahota, James A. Popp, Jerry F. Hardisty, Chirukandath Gopinath, Page R. Bouchard, Toxicologic Pathology, 2018
Niraj K. Tripathi, Jacqueline M. Tarrant
High-mobility group box 1 protein (HMGB1) is a non-histone chromatin-associated protein that is widely expressed in the body, highly conserved between rodents and humans, and present in high concentration in the nucleus. Post-translational modifications including acetylation and redox changes of HMGB1 govern the biological functions of this molecule and contribute to the understanding of mechanistic effects in liver toxicity. HMGB1 is hyperacetylated in activated monocytes, macrophages, and natural killer cells, and mature dendritic cells, which results in its translocation from the nucleus to the cytosol and active secretion where it acts as a proinflammatory cytokine (Lotze and Tracey 2005). Whereas hypoacetylated HMGB1 is loosely bound to the nuclear chromatin and only appears in the circulation when leaked from the cell as a consequence of hepatocellular necrosis. Total HMGB1 can be measured by immunoassay, however mass spectrometry is required to detect hyperacetylated forms. HMGB1 has only recently been investigated as a mechanistic biomarker for DILI. Total HMGB1 was reported to increase earlier than ALT and had similar accuracy for detection of acetaminophen toxicity in mice as ALT. The acetylated forms of HMGB1 were useful in distinguishing the pathologic processes and chronologic profile of toxicity in this model. Hypoacetylated HMGB1 reflected the early stage of active necrosis, with a fast appearance and decline in the circulation. In comparison, the hyperacetylated form showed a protracted rise associated with inflammation and hepatocellular regeneration (Antoine et al. 2009). Total HMGB1 could predict the development of acute liver toxicity on admission to the hospital and hyperacetylated HMGB1 was prognostic for a poor outcome in patients with acetaminophen overdose (Antoine et al. 2012, 2013).
Identification of circular RNA circVPS33A as a modulator in house dust mite-induced injury in human bronchial epithelial cells
Published in Experimental Lung Research, 2021
Yinghao Su, Limei Geng, Yunlei Ma, Xiangyan Yu, Ziyi Kang, Zenglu Kang
Extracellular HMGB1, a ubiquitous nuclear protein, operates as a contributor in the cellular inflammatory response.26 Targeting HMGB1 has been proposed as a therapeutic strategy against some inflammatory disorders.18,26 Furthermore, HMGB1 has an essential role in promoting inflammatory response implicated in the occurrence and progression of asthma.19,20,25 In this paper, we first demonstrated that miR-192-5p directly targeted HMGB1 and miR-192-5p-mediated suppression of HMGB1 attenuated Der p1-driven cell injury. Lou and colleagues highlighted the involvement of miR-192-5p in asthma development depending on the repression of matrix metalloproteinase-16 (MMP-16) and autophagy related 7 (ATG7).17 Additionally, previous evidence reported that several other miRNAs, such as miR-143-3p and miR-216-5p, involved in the pathogenesis of asthma via targeting HMGB1.27,37. Our data also identified circVPS33A as a post-transcriptional modulator of HMGB1 through miR-192-5p. The HMGB1/toll-like receptor 4 (TLR4)/NF-κB pathway performs a crucial function in controlling the pathogenesis of asthma,38,39 which suggests that the circVPS33A/miR-192-5p/HMGB1 axis might regulate Der p1-driven cell injury via the TLR4/NF-κB signaling. However, further investigations are needed.
Immunological mechanisms underlying sterile inflammation in the pathogenesis of atherosclerosis: potential sites for intervention
Published in Expert Review of Clinical Immunology, 2021
Roland Truong, Finosh G. Thankam, Devendra K. Agrawal
HMGB1 has significant relevance for drug targeted therapies. Release of HMGB1 from nucleus to cytosol requires JAK/STAT pathway. Resveratrol has been suggested to reduce HMGB1 release via modulating the JAK/STAT signaling pathway and is considered a potential useful agent for atherosclerosis and inflammatory diseases [137]. Lu et al. reported that the pharmacological inhibition of JAK/STAT pathway did not decrease proinflammatory cytokines suggesting a potential therapy to inhibit HMGB1 release without affecting the innate immune system [138]. However, the JAK/STAT pathway plays a role in many fundamental processes and the faulty JAK/STAT signaling may result in autoimmune disorders or cancer. Irey et al. demonstrated that although JAK/STAT inhibition exhibits antitumor effects, the inhibition increases pro-tumorigenic inflammatory factors in the tumor microenvironment promoting therapeutic resistance [139]. Therefore, while there are anti-inflammatory effects by inhibiting the JAK/STAT pathway, further investigations are warranted to elucidate the risks and benefits of targeting the JAK/STAT pathway in atherosclerosis.
Ethyl pyruvate ameliorates heat stroke-induced multiple organ dysfunction and inflammatory responses by induction of stress proteins and activation of autophagy in rats
Published in International Journal of Hyperthermia, 2021
Je-Ming Hu, Chih-Hsueng Hsu, Yu-Chun Lin, Ching-Wen Kung, Shu-Ying Chen, Wen-Ting Lin, Pao-Yun Cheng, Hsin-Hsueh Shen, Yen-Mei Lee
HO-1 exerts its antioxidant capacity mediated by the degradation of pro-oxidant free heme and the generation of biliverdin and bilirubin, the major components for antioxidant action [11]. We have previously shown that EP induced HO-1 expression to alleviate lung injury in endotoxemic rats [16]. Similar report also indicated that EP inhibited LPS-stimulated macrophages from releasing iNOS and HMGB1 [32]. HMGB1 is a ubiquitous nuclear protein and late inflammatory mediator in sepsis that can be secreted by immune cells, including macrophages and neutrophils. Emerging evidence supports that EP significantly inhibits the release of HMGB1 from stimulated macrophages [33] and acts an ROS scavenger [13,14]. In this study, EP may exert its antioxidant action by induction of HSP70 and HO-1, and by scavenging free radicals, leading to the attenuation of oxidative stress and inflammatory responses in HS rats.