The in vitro anti-inflammatory activity of N-antipyrine-3,4-dichloromaleimide derivatives is due to an immunomodulatory effect on cytokines environment.

BACKGROUND AND AIM: Inflammation is the immune response to a harmful stimulus, and its purpose is to destroy foreign agents so that the affected site can be repair. When uncontrolled or unresolved, inflammation can lead to significant tissue damage. Many classes of compounds are used today as anti-inflammatory drugs. However, there is an ongoing demand for new, more effective molecules with higher safety margins. In this regard, the anti-inflammatory effect of six synthetic compounds of N-antipyrine-3,4-dichloromaleimide was evaluated. METHODS: RAW 264.7 cells were used to evaluate the cytotoxicity and the anti-inflammatory activity, by measuring the effect of these molecules on nitric oxide, IL-1ß, IL-6, MCP-1 (CCL2), TNF-α, INF-γ, IL-4, and IL-13 levels, as well as under NF-κB activation. RESULTS: Some of the tested compounds showed significant cytotoxicity (CC50 < 100 µM). Subsequently, the potential of nitric oxide (NO) inhibition as screening for potential anti-inflammatory action was evaluated. Three of the compounds tested showed a promising profile (1, 3, and 5). When the effect of these compounds was evaluated on the production of IL-1ß, IL-6, MCP-1 (CCL2), TNF-α, and INF-γ, only N-antipyrine-3,4-dichloromaleimide (1) and N-antipyrine-3-chloro-4-(3,4-dichloroaniline) maleimide (3) showed significant inhibition profiles. These two compounds were also able to increase the production of cytokines known for having an anti-inflammatory profile (IL-4 and IL-13) and inhibit the phosphorylation of the p-p65 NF-κB subunit significantly. CONCLUSION: In conclusion, these two compounds present a significant and unusual anti-inflammatory mechanism (increasing the production of anti-inflammatory mediators). They are therefore considered promising prototypes for the development of new anti-inflammatory drugs with immunomodulatory characteristics.

Perinatal exposure to a glyphosate pesticide formulation induces offspring liver damage.

The present study investigated the effects of perinatal exposure to glyphosate-based herbicide (GBH) in offspring's liver. Pregnant Wistar rats were exposed to GBH (70 mg glyphosate/Kg body weight/day) in drinking water from gestation day 5 to postnatal day 15. The perinatal exposure to GBH increased 45Ca2+ influx in offspring's liver. Pharmacological tools indicated a role played by oxidative stress, phospholipase C (PLC) and Akt pathways, as well as voltage-dependent Ca2+ channel modulation on GBH-induced Ca2+ influx in offspring's liver. In addition, changes in the enzymatic antioxidant defense system, decreased GSH content, lipid peroxidation and protein carbonylation suggest a connection between GBH-induced hepatotoxic mechanism and redox imbalance. The perinatal exposure to GBH also increased the enzymatic activities of transaminases and gamma-glutamyl transferase in offspring's liver and blood, suggesting a pesticide-induced liver injury. Moreover, we detected increased iron levels in liver, blood and bone marrow of GBH-exposed rats, which were accompanied by increased transferrin saturation and decreased transferrin levels in blood. The levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were increased in the liver of rats perinatally exposed to GBH, which were associated with. Increased phospho-p65NFκB immunocontent. Therefore, we propose that excessive amounts of iron in offspring's liver, blood and bone marrow induced by perinatal exposure to GBH may account for iron-driven hepatotoxicity, which was associated with Ca2+ influx, oxidative damage and inflammation. Further studies will clarify whether these events can ultimately impact on liver function.

Phenolic Compounds Isolated from Calea uniflora Less. Promote Anti-Inflammatory and Antioxidant Effects in Mice Neutrophils (Ex Vivo) and in Mice Pleurisy Model (In Vivo).

The literature shows that phenolic compounds possess important antioxidant and anti-inflammatory activities; however, the mechanism underlying these effects is not elucidated yet. The genus Calea is used in folk medicine to treat rheumatism, respiratory diseases, and digestive problems. In this context, some phenolic compounds were isolated with high purity from Calea uniflora Less. and identified as noreugenin (NRG) and α-hydroxy-butein (AH-BU). The aim of this study was to analyze the effect of these compounds on cell viability, the activity of myeloperoxidase (MPO), and apoptosis of mouse neutrophils using ex vivo tests. Furthermore, the effect of these compounds on the cytokines, interleukin 1 beta (IL-1ß), interleukin 17A (IL-17A), and interleukin 10 (IL-10), and oxidative stress was investigated by analyzing lipid peroxidation (the concentration of thiobarbituric acid reactive substances (TBARS)) and activities of antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT), and glutathione S-transferase (GST), using a murine model of neutrophilic inflammation. The NRG and AH-BU reduce MPO activity and increase neutrophil apoptosis (p < 0.05). These compounds reduced the generation of oxygen reactive species and IL-1ß and IL-17A levels but increased IL-10 levels (p < 0.05). This study demonstrated that NRG and AH-BU show a significant anti-inflammatory effect by inhibiting the MPO activity and increasing neutrophil apoptosis in primary cultures of mouse neutrophils. These effects were at least partially associated with blocking reactive species generation, inhibiting IL-1ß and IL-17A, and increasing IL-10 levels.

Molecular mechanism of action of Pelargonidin-3-O-glucoside, the main anthocyanin responsible for the anti-inflammatory effect of strawberry fruits.

Fragaria x ananassa Duch., popularly called strawberry, is known for its worldwide consumption and important biological activities, and these effects are related to its high concentration of anthocyanins. Pelargonidin-3-O-glucoside (P3G) is a major anthocyanin found in strawberry, and was evaluated for its anti-inflammatory action in experimental models. The effect of strawberry extract and P3G, on leukocyte migration, exudation levels and many inflammatory mediators, was therefore evaluated in an in vivo model. An in vitro study was also carried out to characterize the effect of P3G on mitogen-activated protein kinases, and on nuclear transcript factors NF-κB and AP-1. The results revealed that the strawberry and P3G have important anti-inflammatory proprieties, and the anti-inflammatory mechanism of P3G involves the arrest of IkB-α activation and reduction in JNKMAPK phosphorylation. The results reinforce that strawberry fruits are functional foods that can act as an adjuvant in the treatment of inflammatory conditions.