Stimulation of soluble guanylate cyclase exerts antiinflammatory actions in the liver through a VASP/NF-κB/NLRP3 inflammasome circuit

Soluble guanylate cyclase (sGC) catalyzes the conversion of guanosine triphosphate into cyclic guanosine-3′,5′-monophosphate, a key second messenger in cell signaling and tissue homeostasis. It was recently demonstrated that sGC stimulation is associated with a marked antiinflammatory effect in the liver of mice with experimental nonalcoholic steatohepatitis (NASH). Here, we investigated the mechanisms underlying the antiinflammatory effect of the sGC stimulator praliciguat (PRL) in the liver. Therapeutic administration of PRL exerted antiinflammatory and antifibrotic actions in mice with choline-deficientl-amino acid-defined high-fat diet-induced NASH. The PRL antiinflammatory effect was associated with lower F4/80- and CX3CR1-positive macrophage infiltration into the liver in parallel with lower Ly6CHigh- and higher Ly6CLow-expressing monocytes in peripheral circulation. The PRL antiinflammatory effect was also associated with suppression of hepatic levels of interleukin (IL)-1β, NLPR3 (NACHT, LRR, and PYD domain-containing protein 3), ASC (apoptosis-associated speck-like protein containing a caspase-recruitment domain), and active cleaved-caspase-1, which are components of the NLRP3 inflammasome. In Kupffer cells challenged with the classical inflammasome model of lipopolysaccharide plus adenosine triphosphate, PRL inhibited the priming (expression ofIl1bandNlrp3) and blocked the release of mature IL-1β. Mechanistically, PRL induced the protein kinase G (PKG)-mediated phosphorylation of the VASP (vasodilator-stimulated phosphoprotein) Ser239 residue which, in turn, reduced nuclear factor-κB (NF-κB) activity andIl1bandNlrp3gene transcription. PRL also reduced active cleaved-caspase-1 levels independent of pannexin-1 activity. These data indicate that sGC stimulation with PRL exerts antiinflammatory actions in the liver through mechanisms related to a PKG/VASP/NF-κB/NLRP3 inflammasome circuit.

Evaluation of the neuroprotective effects of ozone in an experimental spine injury model

OBJECTIVEThe pathophysiology of spine injury consists of primary and secondary damage mechanisms. The vast majority of treatments aim to prevent or at least stop the progression of secondary neurotoxic events during the acute period. Ozone has been found to have potent antiinflammatory effects, to activate the immune system, and to have a substantial impact on the antioxidant system. In this study the authors aimed to evaluate the neuroprotective effects of ozone and their possible roles in recovery from spine injury, assessed based on biochemical, histological, and neurological parameters using an experimental spine injury model in rats.METHODSThe study included 31 female Wistar albino rats. The rats were divided randomly into 5 groups, with 7 rats in each group except the sham group, which contained 3 rats, as follows: group 1 (sham), laminectomy; group 2 (control), laminectomy and spinal trauma with no medical treatment (0.5 ml isotonic saline applied 1 hour postsurgery); group 3, single medical treatment with 30 mg/kg methylprednisolone applied intraperitoneally 1 hour after laminectomy and trauma; group 4, single medical treatment with 60 μg/ml ozone at 0.7 mg/kg applied intraperitoneally 1 hour after laminectomy and trauma; and group 5, double medical treatment with 30 mg/kg methylprednisolone and 60 μg/ml ozone at 0.7 mg/kg applied intraperitoneally 1 hour after laminectomy and trauma. After neurosurgery, neurobehavioral tests were performed in all groups. After 7 days of follow-up, all the rats were killed. Biopsy specimens obtained from trauma sites were examined using H & E, cresyl violet, immunohistochemical (anticonnexin-43), and TUNEL staining processes. Levels of interleukin (IL)–1β, IL-6, and tumor necrosis factor–α (TNF-α) and total oxidant status (TOS) and total antioxidant status (TAS) were measured in blood samples.RESULTSThe level of neurobehavioral healing was the highest in the double-treatment group (group 5), and the difference between the groups was significant. The minimum IL-6 level was found in group 5, indicating that the antiinflammatory impact was the most significant in this group (p = 0.01). Additionally, ozone was found to reduce oxidant stress more effectively than methylprednisolone (p = 0.03). Although methylprednisolone was superior to ozone in terms of the antiinflammatory effect, this effect was greater in group 5. Nevertheless, the number of neurons in group 5 was close to that of the control group, and the number of apoptotic cells was the least in group 5 (p < 0.001).CONCLUSIONSIn acute spinal injury, the combined application of methylprednisolone and ozone was found to have a greater antiinflammatory effect, hasten clinical recovery, and increase histological recovery compared with methylprednisolone therapy alone. This study showed that this combination therapy of methylprednisolone with the addition of ozone might have a more beneficial effect in the treatment of spinal injury than methylprednisolone therapy alone.

Synthesis of Some New Hydroxytriazenes and their Antimicrobial and Anti-inflammatory Activities

Background: Hydroxytriazenes and their derivatives have been studied for the biological and pharmacological applications in the past few years. These compounds possess antibacterial, antifungal, anti-inflammatory, analgesic and wound healing activities. In this study, we report the synthesis of ten hydroxytriazenes in two series derived from disubstituted aniline and studied for antimicrobial and anti-inflammatory activities. Methods: For this purpose, 2-methyl-5-chloroaniline and 2-trifluoromethyl-5-chloroaniline were used to synthesize compounds A1-5 and B1-5 series, respectively. All compounds were synthesized by the reported method which involves three steps of the method (i) Reduction, (ii) Diazotization, (iii) Coupling. All synthesized compounds were characterized by various techniques CHN elemental analysis, FTIR, 1H NMR, and MASS spectral analysis. The antibacterial activities of the compounds were screened against S. aureus, S. pyogenes, E. coli, P. aeruginosa, and antifungal activities were against C. albicans, A. clavatus by the zone of inhibition method. In addition, anti-inflammatory activity was also evaluated by carrageenan-induced paw edema method and results were reported as % inhibition. Results: All the synthesized compounds were obtained in pure form and their spectral data are in good agreement with their structure. The synthesized compounds have shown good antimicrobial activity and zone of inhibition was ranging 21 to 24 mm. Further antiinflammatory effect of the compounds was 96.58 to 98.71 % inhibition. Conclusion: The results of the present study indicate that chloro and trifluoromethyl substitution at hydroxytriazenes skeleton could improve anti-inflammatory and antimicrobial activities.

Analgesic and antiinflammatory activities of the capilliposide derived from Lysimachia capillipes Hemsl., a traditional Chinese medicinal herb

Pain and inflammation are associated with the pathophysiology of different clinical conditions. The Lysimachia capillipes Hemsl. capilliposide (LCc) is the main bioactive component of this Chinese medicinal herb, which is widely used as a remedy for the treatment of colds and arthritis. This study investigated the analgesic and antiinflammatory activities of LCc in an animal model. LCc had no significant influence on the spleen, lung, liver and stomach coefficients in mice. Pharmacological studies showed that LCc at all doses (40, 60 and 90 mg/kg) increased the latency period of paw licking induced by thermal stimulation, and at the dose of 40 mg/kg it significantly suppressed abdominal writhing episodes of mice induced by intraperitoneal (i.p.) injection of acetic acid. LCc also had antiinflammatory effect on inflammation models. Doses of 60 and 90 mg/kg suppressed paw edema induced by subcutaneous (s.c.) injection of carrageenan. Mechanistic studies revealed that the antiinflammatory effect of LCc was associated with inhibition of the production of malondialdehyde (MDA), prostaglandin E2 (PGE2), tumor necrosis factor (TNF-?), cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) in paw tissue of carrageenan-injected mice. These results show that LCc has analgesic and antiinflammatory effects in mice.