Aloin Reduces HMGB1-Mediated Septic Responses and Improves Survival in Septic Mice by Activation of the SIRT1 and PI3K/Nrf2/HO-1 Signaling Axis.

Abstract

High mobility group box 1 (HMGB1) is recognized as a late mediator of sepsis, and the inhibition of HMGB1 release and recovery of vascular barrier integrity have emerged as attractive therapeutic strategies for the management of sepsis. We tested the hypothesis that aloin induces sirtuin 1 (SIRT1) and heme oxygenase (HO)-1, which inhibit HMGB1 release in lipopolysaccharide (LPS)-stimulated cells, thereby inhibiting HMGB1-induced hyperpermeability and increasing the survival of septic mice. Aloin was administered after LPS or HMGB1 challenge, and the antiseptic activity of aloin was determined from measurements of permeability, activation of pro-inflammatory proteins and production of markers for tissue injury in HMGB1-activated human umbilical vein endothelial cells (HUVECs) and a cecal ligation and puncture (CLP)-induced sepsis mouse model. Aloin significantly reduced HMGB1 release in LPS-activated HUVECs via SIRT1-mediated HMGB1 deacetylation and the PI3K/Nrf2/heme oxygenase (HO)-1 signaling axis. Aloin also suppressed the production of tumor necrosis factor (TNF)- α and interleukin (IL)-6, as well as the activation of nuclear factor (NF)- κ B and extracellular signal-regulated kinase 1/2 (ERK 1/2) by HMGB1. Moreover, aloin restored HMGB1-mediated vascular disruption and inhibited vascular hyperpermeability in mice. In addition, treatment with aloin reduced the CLP-induced release of HMGB1, sepsis-related mortality and tissue injury in vivo. Our results suggest that aloin reduces HMGB1 release and sepsis-related mortality by activating SIRT1 and PI3K/Nrf2/HO-1 signals, indicating that aloin has potential for the treatment of sepsis.

• Authors: Sumin Yang, Wonhwa Lee, Bong-Seon Lee, Changhun Lee, Eui Kyun Park, Sae-Kwang Ku, Jong-Sup Bae
• Journal: The American journal of Chinese medicine (Am J Chin Med) Vol. 47 Issue 3 Pg. 613-633 ( 2019) ISSN: 1793-6853 [Electronic] Singapore
• PMID: 30966773 (Publication Type: Journal Article)

Chemical References

• HMGB1 Protein
• NF-E2-Related Factor 2
• Nfe2l2 protein, mouse
• Heme Oxygenase-1
• Phosphatidylinositol 3-Kinases
• Sirtuin 1
• Emodin
• alloin

Topics

• Aloe (chemistry)
• Animals
• Disease Models, Animal
• Emodin (administration & dosage, analogs & derivatives, pharmacology)
• HMGB1 Protein (antagonists & inhibitors, metabolism)
• Heme Oxygenase-1 (metabolism)
• Human Umbilical Vein Endothelial Cells (metabolism)
• Humans
• Male
• Mice, Inbred C57BL
• NF-E2-Related Factor 2 (metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phytotherapy
• Sepsis (drug therapy, etiology, genetics, metabolism)
• Signal Transduction (drug effects)
• Sirtuin 1 (metabolism)