Background: There are currently no effective drugs to mitigate the ischemia/reperfusion injury caused by fluid resuscitation after hemorrhagic shock (HS). The aim of this study was to explore the potential of the histone deacetylase 6 (HDAC6)-specific inhibitor tubastatin A (TubA) to suppress nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome activation in macrophages under hypoxia/reoxygenation (H/R) conditions.
Methods: The viability of RAW264.7 cells subjected to H/R after treatment with different concentrations of TubA was assessed using a cell-counting kit-8 (CCK8) assay. Briefly, 2.5 μmol/L TubA was used with RAW264.7 cells under H/R condition. RAW264.7 cells were divided into three groups, namely the control, H/R, and TubA groups. The levels of reactive oxygen species (ROS) in the cells were detected using fluorescence microscopy. The protein expression of HDAC6, heat shock protein 90 (Hsp90), inducible nitric oxide synthase (iNOS), NLRP3, gasdermin-D (GSDMD), Caspase-1, GSDMD-N, and Caspase-1 p20 was detected by western blotting. The levels of interleukin-1β (IL-1β) and IL-18 in the supernatants were detected using enzyme-linked immunosorbent assay (ELISA).
Results: HDAC6, Hsp90, and iNOS expression levels were significantly higher (<0.01) in the H/R group than in the control group, but lower in the TubA group than in the H/R group (<0.05). When comparing the H/R group to the control group, ROS levels were significantly higher (<0.01), but significantly reduced in the TubA group (<0.05). The H/R group had higher NLRP3, GSDMD, Caspase-1, GSDMD-N, and Caspase-1 p20 expression levels than the control group (<0.05), however, the TubA group had significantly lower expression levels than the H/R group (<0.05). IL-1β and IL-18 levels in the supernatants were significantly higher in the H/R group compared to the control group (<0.01), but significantly lower in the TubA group compared to the H/R group (<0.01).
Conclusion: TubA inhibited the expression of HDAC6, Hsp90, and iNOS in macrophages subjected to H/R. This inhibition led to a decrease in the content of ROS in cells, which subsequently inhibited the activation of the NLRP3 inflammasome and the secretion of IL-1β and IL-18.
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http://dx.doi.org/10.5847/wjem.j.1920-8642.2024.059 | DOI Listing |
Chem Biodivers
December 2023
Institute of Chemistry, VAST, 18 Hoang Quoc Viet, Cau Giay, Hanoi, 10000, Vietnam.
Epaltes australis Less. has been traditionally used to treat fever and snake bites, whereas Lindera myrrha (Lour.) Merr.
View Article and Find Full Text PDFChin J Nat Med
June 2023
School of Pharmaceutical Sciences, Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, China. Electronic address:
Acute lung injury (ALI) is a prevalent and severe clinical condition characterized by inflammatory damage to the lung endothelial and epithelial barriers, resulting in high incidence and mortality rates. Currently, there is a lack of safe and effective drugs for the treatment of ALI. In a previous clinical study, we observed that Jinyinqingre oral liquid (JYQR), a Traditional Chinese Medicine formulation prepared by the Taihe Hospital, Affiliated Hospital of Hubei University of Medicine, exhibited notable efficacy in treating inflammation-related hepatitis and cholecystitis in clinical settings.
View Article and Find Full Text PDFJ Hepatol
August 2014
Swiss Hepato-Pancreatico-Biliary Center, Department of Surgery, University Hospital Zürich, CH-8091 Zürich, Switzerland. Electronic address:
Background & Aims: Fasting and calorie restriction are associated with a prolonged life span and an increased resistance to stress. The protective effects of fasting have been exploited for the mitigation of ischemic organ injury, yet the underlying mechanisms remain incompletely understood. Here, we investigated whether fasting protects liver against ischemia reperfusion (IR) through energy-preserving or anti-inflammatory mechanisms.
View Article and Find Full Text PDFZhonghua Shi Yan He Lin Chuang Bing Du Xue Za Zhi
October 2013
Objective: To investigate the effect of RNA interfering TLR4 signal pathway on phagocytosis of Kupffer cells.
Methods: RAW2647 mice mononuclear macrophage leukemia cells were observed. The tested group was interfered by Tlr4-mus-1567 RNA which had the best result confirmed by QPCR, cells interfered by Negative Control RNA as NC group, and normal cell as control.
J Immunol
March 2009
Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas, and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Valladolid, Spain.
Macrophages can be activated through TLRs for a variety of innate immune responses. In contrast with the wealth of data existing on TLR-dependent gene expression and resultant cytokine production, very little is known on the mechanisms governing TLR-mediated arachidonic acid (AA) mobilization and subsequent eicosanoid production. We have previously reported the involvement of both cytosolic group IVA phospholipase A(2) (cPLA(2)) and secreted group V phospholipase A(2) (sPLA(2)-V) in regulating the AA mobilization response of macrophages exposed to bacterial LPS, a TLR4 agonist.
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