Mechanisms of TQ-6, a Novel Ruthenium-Derivative Compound, against Lipopolysaccharide-Induced In Vitro Macrophage Activation and Liver Injury in Experimental Mice: The Crucial Role of p38 MAPK and NF-κB Signaling

Abstract

Several studies have reported that metal complexes exhibit anti-inflammatory activities; however, the molecular mechanism is not well understood. In this study, we used a potent ruthenium (II)-derived compound, [Ru(η6-cymene)2-(1H-benzoimidazol-2-yl)-quinoline Cl]BF4 (TQ-6), to investigate the molecular mechanisms underlying the anti-inflammatory effects against lipopolysaccharide (LPS)-induced macrophage activation and liver injury in mice. Treating LPS-stimulated RAW 264.7 cells with TQ-6 suppressed nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) expression in a concentration-dependent manner. The LPS-induced expression of tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) were reduced in TQ-6-treated cells. TQ-6 suppressed, LPS-stimulated p38 MAPK phosphorylation, IκBα degradation, and p65 nuclear translocation in cells. Consistent with the in vitro studies, TQ-6 also suppressed the expression of iNOS, TNF-α, and p65 in the mouse model with acute liver injury induced by LPS. The present study showed that TQ-6 could protect against LPS-induced in vitro inflammation in macrophage and in vivo liver injury in mice, and suggested that NF-κB could be a promising target for protecting against LPS-induced inflammation and liver injury by TQ-6. Therefore, TQ-6 can be a potential therapeutic agent for treating inflammatory diseases.

GDF3 Protects Mice against Sepsis-Induced Cardiac Dysfunction and Mortality by Suppression of Macrophage Pro-Inflammatory Phenotype

“…Given the reduced pro-inflammatory cytokine secretion mediated by rGDF3, we next tested whether GDF3 influenced macrophage phenotype. RT-PCR analysis of macrophage polarization markers (i.e., iNOS for M1 and Arg1 for M2) showed that LPS stimulation remarkably activated iNOS expression, whereas greatly inhibited Arg1 expression in BMDMs ( Figure 4A,B), which are consistent with previous reports [19]. However, treatment of LPS-macrophages with rGDF3 resulted in a significantly reduction of iNOS expression ( Figure 4A) and elevation of Arg-1 mRNA levels ( Figure 4B), compared to control cells.…”

Thymoquinone Protects Neurons in the Cerebellum of Rats through Mitigating Oxidative Stress and Inflammation Following High-Fat Diet Supplementation

“…Further study supported TQ inhibiting NF-kappaB and NO activation [44]. Consistent with this finding, [53] reported that TQ inhibited NO production by reducing the expression of iNOS to reveal its anti-inflammatory response. It has been suggested that by inhibiting COX, NO, and NF-kappaB, TQ has strong anti-inflammatory potential.…”

Hepatoprotective Effects of a Ruthenium(II) Schiff Base Complex in Rats with Diet-Induced Prediabetes

“…In addition, treatment with the metal compound with dietary intervention displayed more effective results in terms of lowering ALT levels in prediabetic rats. A recent study by Hsia et al 22 demonstrated the anti-inflammatory properties of a novel ruthenium compound, via inhibiting inflammatory mediators (nitric oxide and nitric oxide synthase) and proinflammatory cytokines (tumor necrosis factor-α and interleukin-1β)in RAW 264.7 cells. Additionally, the metal compound also displayed protective effect against lipopolysaccharide-induced liver injury in mice, thus protecting progressive liver damage 22 .…”

“…A recent study by Hsia et al 22 demonstrated the anti-inflammatory properties of a novel ruthenium compound, via inhibiting inflammatory mediators (nitric oxide and nitric oxide synthase) and proinflammatory cytokines (tumor necrosis factor-α and interleukin-1β)in RAW 264.7 cells. Additionally, the metal compound also displayed protective effect against lipopolysaccharide-induced liver injury in mice, thus protecting progressive liver damage 22 . Moreover, the findings of the study could suggest that the integration of the Schiff base ligand within the coordination sphere of this ruthenium(II) complex could possibly protect the liver from toxic and proinflammatory effects because metal compounds complexed with organic ligands have been found to be less toxic 25 .…”

“…Patients taking these drugs should be closely monitored due to possible contraindications with diabetes mellitus medications and the vulnerable condition of the liver during the drug detoxification process 20 , 21 . Ruthenium (II)-derived complex has been shown to possess anti-inflammatory properties and exhibited protective effect against lipopolysaccharide-induced liver injury in mice through mediation the inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells signaling pathways 22 . Furthermore, recent studies have reported that ruthenium(II) complex with a diimine uracil chelating ligand possesses antidiabetes properties that improved glycemic control, insulin sensitivity, and decreased risk of developing diabetes-related cardiovascular diseases in diet-induced prediabetic rats 23 , 24 .…”