Pro-inflammatory GPR75 and anti-apoptotic phospholipase signaling pathways contribute to the ameliorating effect of soluble epoxide hydrolase inhibition on chronic experimental autoimmune encephalomyelitis in mice.

Soluble epoxide hydrolase (sEH) inhibition has currently emerged as a therapeutic target in the treatment of various neuroinflammatory neurodegenerative diseases, including multiple sclerosis. Previously, we reported that treatment of mice with a sEH-selective inhibitor, 1-(1-propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea; TPPU), ameliorated chronic experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein 35-55 peptide immunization followed by injection of pertussis toxin to mice via regulating pro-inflammatory and anti-inflammatory pathways in the central nervous system. This study tested the hypothesis that the pro-inflammatory G protein-coupled receptor (GPR) 75 and anti-apoptotic phospholipase C (PLC) signaling pathways also contribute to the ameliorating effect of TPPU on chronic EAE.

NLRX1 ligand, docosahexaenoic acid, ameliorates LPS-induced inflammatory hyperalgesia by decreasing TRAF6/IKK/IkB-a/NF-kB signaling pathway activity.

The nucleotide-binding oligomerization domain-like receptor X1 (NLRX1) has been associated with various anti-inflammatory mechanisms. We investigated whether the NLRX1 ligand docosahexaenoic acid (DHA) ameliorates lipopolysaccharide (LPS)-induced inflammatory hyperalgesia by interacting with tumor necrosis factor receptor-associated factor 6 (TRAF6)/inhibitor of kB (IkB) kinase (IKK)/IkB-a/nuclear factor-κB (NF-κB) signaling pathway in the central nervous system. Reaction time to thermal stimuli within 30 seconds was measured in male mice injected with saline, lipopolysaccharide (LPS), and/or DHA after 6 hours using the hot plate test.

Activation of GPR75 Signaling Pathway Contributes to the Effect of a 20-HETE Mimetic, 5,14-HEDGE, to Prevent Hypotensive and Tachycardic Responses to Lipopolysaccharide in a Rat Model of Septic Shock.

The orphan receptor, G protein-coupled receptor (GPR) 75, which has been shown to mediate various effects of 20-hydroxyeicosatetraenoic acid (20-HETE), is considered as a therapeutic target in the treatment of cardiovascular diseases in which changes in the production of 20-HETE play a key role in their pathogenesis. Our previous studies showed that 20-HETE mimetic, N -(20-hydroxyeicosa-5[Z],14[Z]-dienoyl)glycine (5,14-HEDGE), protects against vascular hyporeactivity, hypotension, tachycardia, and arterial inflammation induced by lipopolysaccharide (LPS) in rats. This study tested the hypothesis that the GPR75 signaling pathway mediates these effects of 5,14-HEDGE in response to systemic exposure to LPS.

mTOR inhibition as a possible pharmacological target in the management of systemic inflammatory response and associated neuroinflammation by lipopolysaccharide challenge in rats.

Neuroinflammation plays a critical role during sepsis triggered by microglial activation. Mammalian target of rapamycin (mTOR) has gained attraction in neuroinflammation, however, the mechanism remains unclear. Our goal was to assess the effects of mTOR inhibition by rapamycin on inflammation, microglial activation, oxidative stress, and apoptosis associated with the changes in the inhibitor-κB (IκB)-α/nuclear factor-κB (NF-κB)/hypoxia-inducible factor-1α (HIF-1α) pathway activity following a systemic challenge with lipopolysaccharide (LPS).

Soluble epoxide hydrolase inhibitor trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea prevents hyperalgesia through regulating NLRC4 inflammasome-related pro-inflammatory and anti-inflammatory signaling pathways in the lipopolysaccharide-induced pain mouse model.

Epoxyeicosatrienoic acids (EETs) have anti-inflammatory effects and soluble epoxide hydrolase (sEH) inhibition might be a useful therapeutic approach to manage inflammatory disorders. The purpose of the study was to investigate whether nucleotide-binding and oligomerization domain-like receptor (NLR) C4 inflammasome-related pro-inflammatory and anti-inflammatory signaling pathways in the central nervous system (CNS) participates in the effect of trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea (TPPU), a potent sEH inhibitor, to prevent hyperalgesia in the LPS-induced pain mouse model. The latency of pain within 30 s was measured by the hot plate test in male mice injected with saline, lipopolysaccharide (LPS) (10 mg/kg), and/or TPPU (0.

Suppression of TLR4/MyD88/TAK1/NF-κB/COX-2 Signaling Pathway in the Central Nervous System by Bexarotene, a Selective RXR Agonist, Prevents Hyperalgesia in the Lipopolysaccharide-Induced Pain Mouse Model.

A selective RXR agonist, bexarotene, has been shown to have anti-inflammatory, anti-nociceptive, and neuroprotective effects in several models of numerous neurological diseases characterized by systemic inflammation. The mechanisms underlying these effects remains unknown. To elucidate these mechanisms, we investigated whether the TLR4/MyD88/TAK1/NF-κB/COX-2 signaling pathway in the CNS mediates the effect of bexarotene to prevent hyperalgesia in the LPS-induced inflammatory pain mouse model.

Pharmacological inhibition of soluble epoxide hydrolase attenuates chronic experimental autoimmune encephalomyelitis by modulating inflammatory and anti-inflammatory pathways in an inflammasome-dependent and -independent manner.

We aimed to determine the effect of soluble epoxide hydrolase (sEH) inhibition on chronic experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS), associated with changes in inflammasome-dependent and -independent inflammatory and anti-inflammatory pathways in the CNS of mice. C57BL/6 mice were used to induce chronic EAE by using an injection of MOG peptide/PT. Animals were observed daily and scored for EAE signs for 25 days after immunization.

Eicosanoids derived from cytochrome P450 pathway of arachidonic acid and inflammatory shock.

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Septic shock, the most common form of vasodilatory shock, is a subset of sepsis in which circulatory and cellular/metabolic abnormalities are severe enough to increase mortality. Inflammatory shock constitutes the hallmark of sepsis, but also a final common pathway of any form of severe long-term tissue hypoperfusion.

NF-κB activation mediates LPS-or zymosan-induced hypotension and inflammation reversed by BAY61-3606, a selective Syk inhibitor, in rat models of septic and non-septic shock.

We have previously demonstrated that the activation of the spleen tyrosine kinase (Syk)/inhibitory-κB (IκB)-α/nuclear factor-κB (NF-κB) p65 signalling pathway contributes to hypotension and inflammatory response in a rat models of zymosan (ZYM)-induced non-septic shock. The purpose of this study was to further examine the possible mechanism underlying the effect of inhibition of Syk by BAY61-3606 via NF-κB activity at the level of nuclear translocation regarding the production of vasodilator and proinflammatory mediators in lipopolysaccharide (LPS) (septic)- and ZYM (non-septic)-induced shock. Administration of LPS (10 mg/kg, ip) or ZYM (500 mg/kg, ip) to male Wistar rats decreased mean arterial pressure and increased heart rate that was associated with an increase in the activities of cyclooxygenase and nitric oxide synthase, tumour necrosis factor-α, and interleukin-8 levels, and NF-κB activation and nuclear translocation in sera and/or cardiovascular and renal tissues.

Inhibition of NLRP3 Inflammasome Prevents LPS-Induced Inflammatory Hyperalgesia in Mice: Contribution of NF-κB, Caspase-1/11, ASC, NOX, and NOS Isoforms.

The nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3), an intracellular signaling molecule that senses many environmental- and pathogen/host-derived factors, has been implicated in the pathogenesis of several diseases associated with inflammation. It has been suggested that NLRP3 inflammasome inhibitors may have a therapeutic potential in the treatment of NLRP3-related inflammatory diseases. The aim of this study was to determine whether inhibition of NLRP3 inflammasome prevents inflammatory hyperalgesia induced by lipopolysaccharide (LPS) in mice as well as changes in expression/activity of nuclear factor κB (NF-κB), caspase-1/11, nicotinamide adenine dinucleotide phosphate oxidase (NOX), and endothelial/neuronal/inducible nitric oxide synthase (eNOS/nNOS/iNOS) that may regulate NLRP3/apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC)/pro-caspase-1 inflammasome formation and activity by using a selective NLRP3 inflammasome inhibitor, MCC950.

Quality of life, clinical effectiveness, and satisfaction in patients with beta thalassemia major and sickle cell anemia receiving deferasirox chelation therapy.

Objectives: There is a need to remove excess iron with iron chelation therapy (ICT) to avoid the serious clinical sequelae associated with iron overload in patients with beta thalassemia major (BTM) and sickle cell anemia (SCA). Due to the effects of the diseases and their treatments, ICT is still a major reason for unsatisfactory compliance. The aim of this single-center observational study was to evaluate the quality of life, clinical effectiveness, and satisfaction in pediatric and adult patients with BTM and SCA receiving deferasirox (DFX) chelation therapy.

Contribution of PPARα/β/γ, AP-1, importin-α3, and RXRα to the protective effect of 5,14-HEDGE, a 20-HETE mimetic, against hypotension, tachycardia, and inflammation in a rat model of septic shock.

Objectives: We have previously demonstrated that downregulation of the MyD88/TAK1-dependent signaling pathway associated with increased CYP4A1 expression and 20-HETE formation participates in the protective effect of N-(20-hydroxyeicosa-5[Z],14[Z]-dienoyl)glycine (5,14-HEDGE), a 20-HETE mimetic, against vascular hyporeactivity, hypotension, tachycardia, inflammation, and mortality in a rodent model of septic shock. The aim of this study was to determine whether increased renal and cardiovascular expression of PPARα/β/γ and RXRα associated with decreased expression and/or activity of AP-1 and importin-α3 participates in the protective effect of 5,14-HEDGE in response to systemic administration of lipopolysaccharide (LPS).

Methods: Conscious male Wistar rats received saline (4 ml/kg) or LPS (10 mg/kg) at time 0.