The protective effects of naringenin, a citrus flavonoid, non-complexed or complexed with hydroxypropyl-ß-cyclodextrin against multiorgan damage caused by neonatal endotoxemia.

BACKGROUND: Endotoxemia is a severe and dangerous clinical syndrome that results in elevated morbidity, especially in intensive care units. Neonates are particularly susceptible to endotoxemia due to their immature immune systems. There are few effective treatments for neonatal endotoxemia. One group of compounds with potential in the treatment of neonatal inflammatory diseases such as endotoxemia is the flavonoids, mainly due to their antioxidant and anti-inflammatory properties. Among these, naringenin (NGN) is a citrus flavonoid which has already been reported to have anti-inflammatory, antioxidant, anti-nociceptive and anti-cancer effects. Unfortunately, its clinical application is limited by its low solubility and bioavailability. However, cyclodextrins (CDs) have been widely used to improve the solubility of nonpolar drugs and enhance the bioavailability of these natural products. OBJECTIVE: We, therefore, aimed to investigate the effects of NGN non-complexed and complexed with hydroxypropyl-ß-cyclodextrin (HPßCD) on neonatal endotoxemia injuries in a rodent model and describe the probable molecular mechanisms involved in NGN activities. METHOD: We used exposure to a bacterial lipopolysaccharide (LPS) to induce neonatal endotoxemia in the mice. RESULTS: It was found that NGN (100 mg/kg i.p.) exposure during the neonatal period reduced leukocyte migration and decreased pro-inflammatory cytokine (TNF-α, IL-1ß and IL-6) levels in the lungs, heart, kidneys or cerebral cortex. In addition, NGN upregulated IL-10 production in the lungs and kidneys of neonate mice. The administration of NGN also enhanced antioxidant enzyme catalase and SOD activity, reduced lipid peroxidation and protein carbonylation and increased the reduced sulfhydryl groups in an organ-dependent manner, attenuating the oxidative damage caused by LPS exposure. NGN decreased ERK1/2, p38MAPK and COX-2 activation in the lungs of neonate mice. Moreover, NGN complexed with HPßCD was able to increase the animal survival rate. CONCLUSION: NGN attenuated inflammatory and oxidative damage in the lungs, heart and kidneys caused by neonatal endotoxemia through the MAPK signaling pathways regulation. Our results show that NGN has beneficial effects against neonatal endotoxemia and could be useful in the treatment of neonatal inflammatory injuries.

The effects of flavonoids in experimental sepsis: A systematic review and meta-analysis.

Sepsis is a host's dysregulated immune response to an infection associated with systemic inflammation and excessive oxidative stress, which can cause multiple organ failure and death. The literature suggests that flavonoids, a broad class of secondary plant metabolites, have numerous biological activities which can be valuable in the treatment of sepsis. This study aimed to review the effects of flavonoids on experimental sepsis, focusing mainly on survival rate, and also summarizing information on its mechanisms of action. We searched in the main databases up to November 2022 using relevant keywords, and data were extracted and analyzed qualitatively and quantitatively. Thirty-two articles met the study criteria for review and 29 for meta-analysis. Overall, 30 different flavonoids were used in the studies. The flavonoids were able to strongly inhibit inflammatory response by reducing the levels of important pro-inflammatory mediators, for example, tumor necrosis factor-alpha and interleukin-1ß, oxidative stress, and showed antibacterial and anti-apoptotic actions. The meta-analysis found an increase of 50% in survival rate of the animals treated with flavonoids. They appear to act as multi-target drugs and may be an excellent therapeutic alternative to reduce a number of the complications caused by sepsis, and consequently, to improve survival rate.

Lyotropic liquid crystal mesophases as transdermal delivery systems for lipophilic drugs: A comparative study.

The present work aimed to evaluate different Liquid Crystal Mesophases (LCM) as transdermal drug delivery systems (TDDS) for nifedipine (NFD), a lipophilic drug model. The formulations composed of water, Citrus sinensis essential oil (CSEO), PPG-5-CETETH-20, and Olive oil ester PEG-7 were obtained and characterized by polarized light microscopy (PLM), rheology, small-angle x-ray scattering (SAXS), Fourier transform infrared coupled with an attenuated total reflection accessory (FTIR-ATR) and in vitro assays: bioadhesion, drug release, skin permeation, and retention tests. As a result, changes in component proportions led to several transparent viscous systems with an anisotropic profile. PLM and SAXS proved the presence of lamellar (S1), hexagonal (S3), and lamellar + hexagonal (S2) LCM, and rheology showed a high viscoelasticity profile. LCMs were able to adhere to the skin, and S2 achieved higher adhesion strength. NFD (5 mg/mL) has not modified the organization of LCMs. Results also showed that S3 promoted higher permeation and retention and higher disorganization of stratum corneum lipids, which is the main permeation-enhancing mechanism. Thus, the formulations obtained can carry and improve drug delivery through the skin and are promising TDDS for lipophilic drug administration, such as NFD.

Hesperetin-Based Hydrogels Protect the Skin against UV Radiation-Induced Damage.

UV radiation can cause damages, such as erythema, skin photoaging, and carcinogenesis. The adoption of protective measures against sun exposure is essential to prevent these damages, and the interest in using natural substances as an alternative for photoprotection is growing. Thus, hesperetin with antioxidant, anti-inflammatory, and anticancer properties is a promising substance to be used with photochemopreventive action and to protect the skin from damage induced by UV radiation. Therefore, the present study aimed to develop a topical formulation based on AAMVPC gel containing hesperetin and evaluate its photoprotective effect on the skin of rats exposed to UVA-UVB radiation. The animals were submitted to the irradiation protocol UVA-UVB, and at the end, erythema, lipid peroxidation, and activity of the antioxidant enzyme catalase and superoxide dismutase were evaluated. Additionally, it evaluated the activity of myeloperoxidase and histological changes. The formulation presented a rheological and spreadability profile suitable for cutaneous application. In vivo results demonstrated that the topical formulation of AAMVPC gel containing hesperetin at a concentration of 10% protected the skin from damage induced by UVA-UVB radiation, with the absence of erythema, lipid lipoperoxidation, and inflammation (low myeloperoxidase activity), and increased catalase and superoxide dismutase activities. The morphology and architecture of the dermo-epidermal tissue of these animals were like those observed under normal conditions (non-irradiated animals). Thus, the results showed that hesperetin was able to protect the animals' skin against UV radiation-induced skin damage and the protection mechanisms may be related to the antioxidant and anti-inflammatory properties of this natural product.

The anticonvulsant effect of geraniol and inclusion complex geraniol: beta-cyclodextrin / El efecto anticonvulsivo de geraniol y la inclusión de geraniol complejo: beta-ciclodextrina

Geraniol (GR) is an acyclic monoterpene alcohol present in essential oils of aromatic plant species used in Brazilian folk medicine for the treatment of epilepsy. The present study was designed to evaluate the anticonvulsant effect of GR and of the inclusion complex geraniol:beta-cyclodextrin (GR:beta-CD). Mice were treated with GR or with GR:beta-CD (50, 100 and 200 mg/kg) 30 min before pentylenetetrazole (PTZ) or strychnine (STN). GR at 200 mg/kg and GR:beta-CD at the doses of 100 and 200 mg/kg significantly increased the latency for the first PTZ-induced convulsion and reduced the percentage of animals that convulsed. The pretreatment of flumazenil did not revert the anticonvulsant effect of GR in the PTZ-induced convulsion model. In the STN-induced convulsion model, the effects of GR were investigated and no difference was found against control. The results demonstrated an anticonvulsant activity of GR in the PTZ-model, which was potentialized by the complexation with beta-CD...

Geraniol (GR) es un alcohol monoterpeno acíclico presentes en los aceites esenciales de las especies de plantas aromáticas utilizadas en la medicina popular brasileña para el tratamiento de la epilepsia. El presente estudio fue diseñado para evaluar el efecto anticonvulsivo del GR y de la inclusión de geraniol complejo: beta-ciclodextrina (GR:beta-CD). Los ratones fueron tratados con GR o con GR:beta- CD (50, 100 y 200 mg/kg) 30 minutos antes de pentylenotetrazole (PTZ) o strichinine (STN). GR a 200 mg/kg y GR:beta-CD en las dosis de 100 y 200 mg/kg aumentó significativamente la latencia para la primera convulsión inducida PTZ-y redujo la porcentaje de animales que convulsionó. El tratamiento previo de flumazenil no revirtió el efecto anticonvulsivo de GR en el modelo de convulsión inducida con PTZ. En el modelo de convulsión inducida com STN, los efectos de GR fueron investigados y no se encontró ninguna diferencia contra el control. Los resultados demostraron una actividad anticonvulsiva de geraniol en el modelo de PTZ, que fue potenciada por la formación de complejos con beta-CD...

Structure­activity relationship of terpenes with anti-inflammatory profile ­ a systematic review.

Inflammation is a complex biological response that in spite of having available treatments, their side effects limit their usefulness. Because of this, natural products have been the subject of incessant studies, among which the class of terpenes stands out. They have been the source of study for the development of anti-inflammatory drugs, once their chemical diversity is well suited to provide skeleton for future anti-inflammatory drugs. This systematic review reports the studies present in the literature that evaluate the anti-inflammatory activity of terpenes suffering any change in their structures, assessing whether these changes also brought changes in their effects. The search terms anti-inflammatory agents, terpenes, and structure­activity relationship were used to retrieve English language articles in SCOPUS, PUBMED and EMBASE published between January 2002 and August 2013. Twenty-seven papers were found concerning the structural modification of terpenes with the evaluation of antiinflammatory activity. The data reviewed here suggest that modified terpenes are an interesting tool for the development of new anti-inflammatory drugs.

The influence of trait anxiety on the elevation of arterial pressure induced by L-NAME in rats.

Due to the high prevalence of anxiety disorders and hypertension comorbidity in the general population, the establishment of anxiety as a risk factor for elevated blood pressure, or the reverse, is of great relevance. In this context, animal models can be of great scientific value, as they permit the control of several variables. Bearing this in mind, the influence of anxiety, not as a state, but as a personality trait (trait anxiety), on blood pressure elevation and vice versa were investigated for the first time in rats, using the free-exploratory paradigm (FEP). Sixty adult male Wistar rats were evaluated on FEP and categorized according to their levels of anxiety. From this sample, 24 animals with high (n=12) and low (n=12) trait anxiety were allocated to two treatment groups: (1) l-NAME (N(G)-nitro-l-arginine methyl ester, 20mg/kg, p.o., for 7 days to increase blood pressure; n=6/anxiety category); (2) CTRL (tap water, p.o., for 7 days; n=6/anxiety category). During treatment, measurements of systolic blood pressure (SBP) were taken daily. After treatment, the animals were again tested on FEP. SBP and trait anxiety levels were compared pre- and post-treatment. Additionally, correlations between trait anxiety levels and SBP increases (l-NAME group) were analyzed. The results showed that l-NAME was able to induce significant SBP elevation, but only for the high-anxious animals, while SBP elevation did not significantly interfere with anxiety levels. A significant correlation between anxiety levels and SBP peaks in response to l-NAME was also shown. No differences were observed between the levels of anxiety before and after treatment. These findings suggest that individuals with high trait anxiety are more susceptible to increases in blood pressure, but that high blood pressure does not affect the levels of trait anxiety.

Synthesis and pharmacological evaluation of carvacrol propionate.

This study aimed at synthesizing the carvacrol propionate (CP) and evaluating its pharmacological profile. CP was obtained from carvacrol and propionyl chloride through an esterification reaction. Male Swiss mice were treated with CP (25, 50, or 100 mg/kg). We evaluated the analgesic effect, mechanical hyperalgesia, and anti-inflammatory effect. Pre-treatment with CP inhibited (p<0.01 and 0.001) the formalin-induced nociception in both phases. CP inhibited (p<0.05, 0.01, and 0.001) the development of mechanical hyperalgesia. CP was able to decrease the leukocyte recruitment (p<0.001) and the amount of TNF-α (p<0.001), IL-1ß (p<0.05), and protein leakage (p<0.01) into the pleural cavity. In addition, the paw edema was inhibited by CP (p<0.05, 0.01, and 0.001). The CP attenuates nociception, mechanical hyperalgesia, and inflammation, through an inhibition of cytokines.

Antidiabetic effect of the Chrysobalanus icaco L. aqueous extract in rats.

Chrysobalanus icaco L. is a medicinal plant popularly known in Brazil as "Grageru" or "Abageru." It is used in African and American continents as medicinal food in the treatment of several diseases, including diabetes. This study used phytochemical screening to determine the antioxidant and α-amylase inhibitor activities of the aqueous extract (AECI) of C. icaco, and evaluated its antidiabetic potential in rodents. Phytochemical screening was performed using colorimetric tests with specific reagents. The in vitro antioxidant activity was evaluated by the scavenging activity of 2,2-diphenyl-1-picril-hydrazyl. The lethality test and behavioral screening was performed using an oral administration of 5 g/kg of AECI. The antidiabetic potential of AECI was evaluated through the oral glucose tolerance test (OGTT) and chronic hypoglycemic test at the doses of 100, 200, and 400 mg/kg (orally). Metformin was used as a reference drug in all tests. Diabetes was induced by injection of alloxan (40 mg/kg; intravenously). Phytochemical screening showed the presence of various compounds, including tannins, flavones, triterpenoids, steroids, saponins, and alkaloids. The in vitro antioxidant test demonstrated that AECI presented potent antioxidant activity. The lethality test and behavioral screening did not show lethality signs. In the OGTT test, AECI administration was not able to inhibit the elevation of glycemia. However, chronically administrated, it was able to cause a significant (P<.05) reduction of glycemia from 335±27 up to 197±15 mg/dL. These results demonstrate that the AECI presents a potential beneficial effect for diabetes.