Effects of EPHX1 and CYP3A4*22 genetic polymorphisms on carbamazepine metabolism and drug response among Tunisian epileptic patients

The aim of this study was to evaluate the impact of polymorphisms in the EPHX1 (c.416A?>?G, c.337T?>?C) and CYP3A4*22 genes involved in carbamazepine (CBZ) metabolism and pharmacoresistance among 118 Tunisian patients with epilepsy under maintenance dose of CBZ. These genetic polymorphisms were analyzed by PCR-RFLP. Associations between plasma CBZ concentration, CBZ-E concentration, maintenance doses and metabolic ratio (CBZ-E:CBZ, CBZ-D:CBZ-E) were analyzed with each polymorphism. Both variants of EPHX1 c.416A?>?G and c.337T?>?C are significantly associated with higher metabolic ratio CBZ-E:CBZ and seem to decrease the activity of the epoxide hydrolase. The CYP3A4*22 variant allele is significantly associated with lower CBZ-D:CBZ-E ratio and seems also to be associated with less activity of the cytochrome. Our data suggest that certain polymorphisms of metabolizing enzyme genes could influence inter-individual variability of CBZ metabolism.     

Immunomodulatory effects of Santolina chamaecyparissus leaf extracts on human neutrophil functions

Context: Santolina chamaecyparissus L. (Asteraceae) is an aromatic plant wide spread in the Mediterranean region. It is used in folk medicine for its anti-inflammatory properties.

Objective: The effects of S. chamaecyparissus aqueous extract (SCAE) and polyphenolic extract (SCPE) on human polymorphonuclear neutrophil (PMN) degranulation, chemotaxis, phagocytosis, and microbicidal capacity were examined in vitro.

Materials and methods: Aqueous and polyphenolic extracts were prepared from S. chamaecyparissus leaves. The elastase release was used as a marker for measuring PMN degranulation, while chemotaxis was performed using a 48-microwell chemotaxis chamber. The phagocytosis and the microbicidal capacity were evaluated using fresh cultures of Candida albicans.

Results: The treatment of neutrophils with different concentrations (10–200?µg/ml) of SCAE and SCPE caused a significant (p?<?0.001) and dose-dependent inhibitory effect on elastase release in fMLP/Cytochalasin B (CB)-stimulated neutrophils. Indeed, 100?µg/ml of SCAE exerted an inhibitory effect of 51.97?±?6.2%, whereas SCPE at the same concentration abolished completely PMN degranulation. Moreover, both extracts inhibited markedly (p?<?0.01) fMLP-induced chemotactic migration. At 200?µg/ml, SCAE and SCPE exerted an inhibitory effect of 54.61?±?7.3% and 57.71?±?7.44%, respectively. In addition, a decline in both phagocytosis and microbicidal capacity against Candida albicans was observed when PMNs were exposed to 100 and 200?µg/ml of SCAE or SCPE.

Conclusion: The exerted effects on neutrophil functions support the anti-inflammatory activity and show new mechanisms of action and effectiveness of S. chamaecyparissus leaf extracts. This plant may be considered as an interesting source of anti-inflammatory and immunomodulatory agents.     

Maternal stress and hair cortisol among pregnant women following hurricane Florence

Natural disasters represent major stressors, resulting in psychological distress and physiological responses such as increased cortisol. During pregnancy, this impacts not only maternal well-being, but also fetal development. In 2018, Hurricane Florence caused extensive damage across the eastern United States. Studies indicated that compared to married pregnant women, unmarried pregnant women had higher risk of distress. Here we assess hair cortisol among a subsample of participants, and variations based on marital status.

Methods

We analyzed multiple stress measures among 37 participants who were pregnant during Hurricane Florence. We used questionnaires modeled on previous studies to assess hardship associated with the hurricane, psychological distress, sociodemographic characteristics, social support, and food security. We analyzed cortisol concentrations in proximal and distal hair sections, representing stress around the time of the disaster (distal) and 3–4 months following the disaster (proximal). We used linear regression to test relationships between hair cortisol and self-report stress measures, and variations based on marital status.

Results

Self-report measures of distress and hardship were similar among married and unmarried participants. Mean cortisol levels in distal and proximal sections were higher among unmarried participants. Controlling for confounding variables, hardship was not associated with hair cortisol. Distress predicted cortisol in distal sections (β = .482, p = .018), with a trend for proximal sections (β = .368, p = .055). Marital status was a significant predictor of distal (β = .388, p = .027) and proximal (β = .333, p = .047) hair cortisol, explaining 8.6%–11.7% of unique variance.

Conclusions

Preexisting and intersecting risk factors likely place unmarried pregnant individuals at risk of stress during and following a disaster.     

Effect of Cleome arabica Leaf Extract on Rat Paw Edema and Human Neutrophil Migration

The anti-inflammatory activity of Cleome arabica leaf extract was studied in vivo and in vitro. Firstly, the extract was examined for its anti-inflammatory activity using carrageenan-induced rat paw edema as a model of acute inflammation. A subplantar injection of 0.1 ml of carrageenan 1% induced a progressive swelling of the rat paw in all time points, that reached a maximal volume in placebo group within 5 h. Results showed that pre-treatment of rats by Cleome arabica leaf extract, 1 h prior the injection of the phlogogenic agent, prevented the increase of the edema in dose-dependent manner with an ED 50 of 231 mg/kg, body weight. The extract doses 100, 200 and 300 mg/kg, reduced edema to 65.54 ± 5.2%, 57.86 ± 8%, and 41.54 ± 3.6%, respectively, 5 h after the carrageenan injection. Secondly, we have examined the effect of Cleome arabica leaf extract on human neutrophil migration induced by fMLP (10 -7 M), using 48-well chemotaxis chamber. Results showed that the extract inhibited neutrophil chemotaxis significantly (p &lt; 0.01) and in a dose-dependent manner. Neutrophil migration was reduced to 16.71 ± 4.6% in presence of 50µg/ml of Cleome arabica leaf extract. It appears that the antiinflammatory activity of Cleome arabica leaf extract, observed in vivo as well as in vitro, could be due to its high flavonoid content (19%). These results may contribute to explain the use of this plant in folk medicine.     

Anti-inflammatory effect of rutin on rat paw oedema, and on neutrophils chemotaxis and degranulation

BACKGROUND: Rutin, a natural flavone derivative, is known for its pharmacological properties. We have previously reported that this flavonol exerted a potent inhibitory effect on respiratory burst of fMet-Leu-Phe-stimulated neutrophils, as well as on phosphoinositide 3-kinase gamma activity in a cell free system. In the present study, the anti-inflammatory effect of rutin was investigated in vivo and in vitro. METHODS: rutin or aspirin (100 mg/kg, body weight) were given orally to rats 1 hour before paw oedema induction, using lambda-carrageenan 1%. The rat paw volume was measured by mean of plethysmometer, initially and during 6 hours. The chemotaxis of neutrophils towards 10(-7) M fMet-Leu-Phe was performed using 48-well chemotaxis chamber. Neutrophils that migrated through 5 microm pore size polycarbonate filter, in presence or in absence of rutin, were counted microscopically. Elastase exocytosis of either phorbol 12-myristate 13-acetate or fMet-Leu-Phe/cytochalasin B-stimulated neutrophils was assessed in absence or in presence of rutin using the synthetic substrate N-Suc-Ala-Ala-Ala-p-nitroanilide. The absorbance of released p-nitroaniline was measured at 405 nm using microplate reader. RESULTS: The maximal swelling in placebo group was observed at 5 hours, after lambda-carrageenan injection. Oral administration of rutin reduced rat paw swelling starting 2 hours after lambda-carrageenan injection. Rutin reduced significantly (p < 0.05) and in a dose-dependant manner the polymorphonuclear neutrophils chemotaxis to fMet-Leu-Phe. Furthermore, elastase exocytosis, induced by both stimuli, was partially inhibited by rutin up to 25 microM. CONCLUSION: The present study revealed that rutin possesses anti-inflammatory properties.