Chlorogenic acid reduces liver inflammation and fibrosis through inhibition of toll-like receptor 4 signaling pathway

Shi, Haitao; Liu, Dong; Jiang, Jiong; Zhao, Jiawei; Zhao, Gang; Dang, Xiaoyan; Lu, Xiaolan; Miao, Jia

doi:10.1016/j.tox.2012.10.025

Cited by 220 publications

(148 citation statements)

References 47 publications

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“…Instead, doxorubicin caused chronic and much more destructive inflammation that usually includes the activation of TNF signaling pathway, generation of massive ROS and persistent expression of multiple proinflammatory cytokines-all of which belong to typical characteristics of inflammatory responses against endotoxin (27,28). In addition, the central role of TLR4 in mediating this pathologic process-as demonstrated by both our and other studies-further suggests that endotoxin is the most likely antigen to trigger tissue inflammation, because the principal function of this receptor is to recognize the component of invaded bacteria, notably including endotoxin (17,29).…”

Section: Discussionsupporting

confidence: 59%

“…S3). The DGMþDOXþ2 mg/kg LPS mice and DGMþDOXþ5 mg/kg LPS mice had significantly higher levels of CK (2, 29.57 U/L) than DGMþDOX mice. These findings indicated that endotoxin in circulation could be a direct cause of doxorubicin to the cardiac (CK and LDH), renal (BUN), and hepatic (ALT) tissues, respectively ( Supplementary Fig.…”

Section: Endotoxin From Gut Microbiota Causes Inflammation and Tissuementioning

confidence: 88%

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Doxorubicin-Induced Systemic Inflammation Is Driven by Upregulation of Toll-Like Receptor TLR4 and Endotoxin Leakage

et al. 2016

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Doxorubicin is one of the most effective chemotherapeutic agents used for cancer treatment, but it causes systemic inflammation and serious multiorgan side effects in many patients. In this study, we report that upregulation of the proinflammatory Toll-like receptor TLR4 in macrophages by doxorubicin is an important step in generating its toxic side effects. In patient serum, doxorubicin treatment resulted in leakage of endotoxin and inflammatory cytokines into circulation. In mice, doxorubicin damaged the intestinal epithelium, which also resulted in leakage of endotoxin from the gut flora into circulation. Concurrently, doxorubicin increased TLR4 expression in macrophages both in vitro and in vivo, which further enhanced the sensitivity of these cells to endotoxin. Either depletion of gut microorganisms or blockage of TLR4 signaling effectively decreased doxorubicininduced toxicity. Taken together, our findings suggest that doxorubicin-triggered leakage of endotoxin into the circulation, in tandem with enhanced TLR4 signaling, is a candidate mechanism underlying doxorubicin-induced systemic inflammation. Our study provides new insights for devising relevant strategies to minimize the adverse effects of chemotherapeutic agents such as doxorubicin, which may extend its clinical uses to eradicate cancer cells. Cancer Res; 76(22); 6631-42. Ó2016 AACR.

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Section: Discussionsupporting

confidence: 59%

Section: Endotoxin From Gut Microbiota Causes Inflammation and Tissuementioning

confidence: 88%

Doxorubicin-Induced Systemic Inflammation Is Driven by Upregulation of Toll-Like Receptor TLR4 and Endotoxin Leakage

et al. 2016

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“…CGA ameliorates LPS-induced hepatic injury in mice with decreased TLR4 or TNF-a production in liver tissues (22), as well as LPS-induced pulmonary injury with attenuated leukocyte infiltration into the airway alveolar fluid (34). CGA reduces CCl 4 -induced hepatic inflammation and fibrosis in rats, in which it inhibits NF-kB-activating pathways such as IkBa phosphorylation, IkBa degradation and nuclear import of NF-kB downregulates expression of TNF-a, IL-1b, IL-6, or iNOS in liver tissues (35). CGA also protects against adjuvant-induced arthritis in rats with decreased TNF-a or IL-1b production in knee joints (36).…”

Section: Discussionmentioning

confidence: 99%

IRAK4 as a Molecular Target in the Amelioration of Innate Immunity–Related Endotoxic Shock and Acute Liver Injury by Chlorogenic Acid

Park

Baek

Yun

et al. 2015

The Journal of Immunology

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Mice lacking the IL-1R–associated kinase 4 (IRAK4) are completely resistant to LPS-induced endotoxic disorder or the TLR9 agonist CpG DNA plus d-galactosamine–induced acute liver injury (ALI), whereas wild-type strains succumb. However, translational drugs against sepsis or ALI remain elusive. Lonicerae flos extract is undergoing the clinical trial phase I in LPS-injected healthy human volunteers for sepsis treatment. In the current study, chlorogenic acid (CGA), a major anti-inflammatory constituent of lonicerae flos extract, rescued endotoxic mortality of LPS-intoxicated C57BL/6 mice, as well as ameliorated ALI of LPS/d-galactosamine–challenged C57BL/6 mice. As a mechanism, CGA inhibited various TLR agonist–, IL-1α–, or high-mobility group box-1–stimulated autophosphorylation (activation) of IRAK4 in peritoneal macrophages from C57BL/6 or C3H/HeJ mice via directly affecting the kinase activity of IRAK4, a proximal signal transducer in the MyD88-mediated innate immunity that enhances transcriptional activity of NF-κB or AP-1. CGA consequently attenuated protein or mRNA levels of NF-κB/AP-1 target genes encoding TNF-α, IL-1α, IL-6, and high-mobility group box-1 in vivo under endotoxemia or ALI. Finally, this study suggests IRAK4 as a molecular target of CGA in the treatment of innate immunity–related shock and organ dysfunction following insult of various TLR pathogens from bacteria and viruses.

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“…In addition, CGA could inhibit lipopolysaccharide (LPS)-induced microglial activation and improve the survival of dopaminergic neurons (21). CGA could also reduce carbon tetrachloride-induced liver fibrosis in rats through inhibition of the Toll-like receptor 4 signaling pathway (22,23) and through the suppression of oxidative stress in liver and hepatic stellate cells (24).…”

mentioning

confidence: 99%

Antischistosomiasis Liver Fibrosis Effects of Chlorogenic Acid through IL-13/miR-21/Smad7 Signaling Interactions In Vivo and In Vitro

Wang

Yang

Xue

et al. 2017

Antimicrob Agents Chemother

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Chlorogenic acid reduces liver inflammation and fibrosis through inhibition of toll-like receptor 4 signaling pathway

Cited by 220 publications

References 47 publications

Doxorubicin-Induced Systemic Inflammation Is Driven by Upregulation of Toll-Like Receptor TLR4 and Endotoxin Leakage

Doxorubicin-Induced Systemic Inflammation Is Driven by Upregulation of Toll-Like Receptor TLR4 and Endotoxin Leakage

IRAK4 as a Molecular Target in the Amelioration of Innate Immunity–Related Endotoxic Shock and Acute Liver Injury by Chlorogenic Acid

Antischistosomiasis Liver Fibrosis Effects of Chlorogenic Acid through IL-13/miR-21/Smad7 Signaling Interactions In Vivo and In Vitro

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