Marcel Henrique Marcondes Sari

Syzygium cumini extract decrease adenosine deaminase, 5'nucleotidase activities and oxidative damage in platelets of diabetic patients.

Diabetes mellitus, a chronic metabolic disorder, has assumed epidemic proportions and its long-term complications can have devastating consequences. The oxidative stress in diabetes was greatly increased due to prolonged exposure to hyperglycemia and impairment of oxidant/antioxidant equilibrium. Syzygium cumini is being widely used to treat diabetes by the traditional practitioners over many centuries. Adenosine deaminase (ADA) and 5′-Nucleotidase (5′NT) are enzymes of purine nucleoside metabolism that play an important role in the regulation of adenosine (Ado) levels. In this study, we investigated the effect of Syzygium cumini aqueous leaves extract (ASc) on ADA and 5′NT activities and on parameters of oxidative stress under in vitro conditions, using platelets of patients with Type 2 diabetes mellitus. Platelet-Rich Plasma (PRP) was assayed by ADA, 5′NT, Catalase (CAT), Superoxide Dismutase (SOD) activities and Thiobarbituric acid reactive substances (TBARS) levels. We observed that ADA, 5′NT activities and TBARS levels were significantly higher when compared to the control group, and ASc (100 and 200 µg/mL) prevented these effects. Our study demonstrates that ASc was able to remove oxidant species generated in diabetic conditions and modulates in the Ado levels. Then, ASc may promote a compensatory response in platelet function, improving the susceptibility-induced by the diabetes mellitus.

Contribution of dopaminergic and adenosinergic systems in the antinociceptive effect of p-chloro-selenosteroid

This study investigated the antinociceptive action of p-chloro-selenosteroid (PCS), administered by intragastric route (i.g.) to mice against acute models. The contribution of adenosinergic, dopaminergic, serotonergic, nitric oxide and opioid systems was investigated. It was evaluated if the administration of PCS triggers toxic effect. Treatment with PCS (10mg/kg) reduced writhing induced by acetic acid and its effect lasts up to 48 h after treatment. The compound caused an inhibition in neurogenic and inflammatory phases of nociception and in paw edema induced by formalin. The licking behavior triggered by glutamate was reduced by PCS. In the tail-immersion test, PCS elicited an increase in delta latency response. Pretreatment with caffeine (3mg/kg, intraperitoneally [i.p.]) and SCH58261 (3mg/kg, i.p.), antagonist at adenosinergic receptors, SCH23390 (0.05 mg/kg, i.p.) and sulpiride (5mg/kg, i.p.), antagonist at dopaminergic receptors, caused a reduction in the antinociceptive action of PCS in the glutamate test. By contrast, pretreatment with WAY100635 (0.7 mg/kg, i.p.), ketanserin (0.3mg/kg, i.p.), ondasentron (0.5mg/kg, i.p.), l-arginine (600 mg/kg, i.p.) and naloxone (1mg/kg, subcutaneous [s.c.]) did not abolish the antinociceptive effect caused by PCS (10mg/kg, i.g.) administration. The animals treated with PCS did not show alterations in locomotor and exploratory activities, in biochemical parameters evaluated, food and water consumption, as well as in the body weight. These results clearly showed the antinociceptive action of PCS in different animal models without causing acute toxic effects in mice. Adenosinergic and dopaminergic systems seem to be related to the mechanisms by which PCS elicits antinociception.

Evaluation of the pharmacological properties of salicylic acid-derivative organoselenium: 2-Hydroxy-5-selenocyanatobenzoic acid as an anti-inflammatory and antinociceptive compound☆☆☆

The present study evaluated the antinociceptive and anti-inflammatory effects of per oral (p.o.) administration of salicylic acid-derivative organoselenium compounds in chemical models of nociception in mice. The compounds (50 mg/kg; p.o.) were administered 30 and 60 min before the nociceptive behavior and compared to the positive-control, acetylsalicylic acid (ASA; 200 mg/kg; p.o.). In addition, a dose-response curve (25-100 mg/kg) for compounds was carried out in the formalin test. When assessed in the chemical models, acetic acid-induced writhing behavior, formalin and glutamate tests, the compounds showed the following antinociceptive profile 1B>2B>1A>2A, suggesting a chemical structure-dependent relationship. Then, the anti-inflammatory properties and toxicological potential of compound 1B were investigated. Compound 1B, similar to the positive-control, ASA, diminished the edema formation and decreased the myeloperoxidase activity induced by croton oil (2.5%) in the ear tissue. The results also indicate that a single oral administration of 1B caused neither signs of acute toxicity nor those of gastrointestinal injury. The administration of 1B did not alter the water and food intakes, plasma alanine and aspartate aminotransferase activities or urea levels and cerebral or hepatic δ-aminolevulinate dehydratase activity. Salicylic acid-derivative organoseleniums, mainly compound 1B, have been found to be novel compounds with antinociceptive/anti-inflammatory properties; nevertheless, more studies are required to examine their therapeutic potential for pain treatment.

Pomegranate seed oil nanoemulsions improve the photostability and in vivo antinociceptive effect of a non-steroidal anti-inflammatory drug

The combination of pomegranate seed oil and ketoprofen in nanoemulsions aiming to improve the antinociceptive effect was evaluated according to the writhing test and Complete Freuds Adjuvant induced paw inflammation in mice. The formulations showed adequate characteristics and improved ketoprofens photostability against UVC radiation exposure. The dialysis bag technique showed that 100% of the drug was released from the nanoemulsions after 3h and the oil amount had no influence on the releasing. Furthermore, time- and dose-response curves were obtained to determine the antinociceptive effect of the formulations. In the post-test, the nanoemulsion containing ketoprofen significantly reduced abdominal constrictions in time-response curve, showing effect up to 12h while the free ketoprofen showed effect up to 3h. In addition, the blank nanoemulsion presented a reduction of abdominal constriction up to 1h of pre-treatment. Regarding the dose-response curve, the free ketoprofen presents effect at 0.5mg/Kg dose and nanoemulsion at 1.0mg/Kg dose. Time- and dose-response curves were performed to determine the antinociceptive effect in inflammatory pain. After the evaluation of mechanical allodynia testing at the Von Frey Hair, the free ketoprofen showed effect up to 6h while nanoemulsions presented effect up to 10h. Moreover, acute toxicity was performed with ALT and AST activity evaluations and urea levels. After 7 days of treatment, no toxic effects for nanoemulsions were found. In conclusion, ketoprofen-loaded pomegranate seed oil nanoemulsions presented adequate characteristics and a high antinociceptive activity in the animal models tested.

Antiviral Action of Diphenyl Diselenide on Herpes Simplex Virus 2 Infection in Female BALB/c Mice.

Diphenyl diselenide, (PhSe)2, is an organoselenium compound with pharmacological actions mostly related to antioxidant and anti‐inflammatory properties. The study investigated its antiviral and virucidal actions against herpes simplex virus 2 (HSV‐2) infection in vitro and in a vaginal infection model in mice. The plaque reduction assay indicated that (PhSe)2 showed virucidal and antiviral actions reducing infectivity in 70.8% and 47%, respectively. The antiviral action of (PhSe)2 against HSV‐2 vaginal infection was performed by infecting mice (105 PFU/ml−1) at day 6. The treatment with (PhSe)2 (5 mg/kg/day, intragastric [i.g.]) followed 5 days before and for more 5 days after infection. The extravaginal lesion score was evaluated from days 6 to 10. At day 11, animals were killed, and histological evaluation, determination of viral load, and TNF‐α and IFN‐γ levels were performed in supernatants of homogenized vaginal tissue. The levels of reactive species (RS), protein carbonyl, non‐protein thiols (NPSH), nitrate/nitrite (NOx), and malondialdehyde (MDA), and the activities of myeloperoxidase (MPO), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR) were determined. (PhSe)2 reduced the histological damage, extravaginal lesion scores, the viral load of vaginal tissue, and the activity of MPO, but increased the levels of TNF‐α, IFN‐γ. (PhSe)2 attenuated the increase of RS, MDA, NOx levels and the activity of GR caused by infection. (PhSe)2 also attenuated the reduction of NPSH content and the inhibition of CAT, SOD, and GPx activities. The antiviral action of (PhSe)2 against HSV‐2 infection was related to its immunomodulatory, antioxidant, and anti‐inflammatory properties. J. Cell. Biochem. 117: 1638–1648, 2016.

Ketoprofen-loaded pomegranate seed oil nanoemulsion stabilized by pullulan: Selective antiglioma formulation for intravenous administration

This study aimed to prepare pomegranate seed oil nanoemulsions containing ketoprofen using pullulan as a polymeric stabilizer, and to evaluate antitumor activity against in vitro glioma cells. Formulations were prepared by the spontaneous emulsification method and different concentrations of pullulan were tested. Nanoemulsions presented adequate droplet size, polydispersity index, zeta potential, pH, ketoprofen content and encapsulation efficiency. Nanoemulsions were able to delay the photodegradation profile of ketoprofen under UVC radiation, regardless of the concentration of pullulan. In vitro release study indicates that nanoemulsions were able to release approximately 95.0% of ketoprofen in 5h. Free ketoprofen and formulations were considered hemocompatible at 1 μg/mL, in a hemolysis study, for intravenous administration. In addition, a formulation containing the highest concentration of pullulan was tested against C6 cell line and demonstrated significant activity, and did not reduce fibroblasts viability. Thus, pullulan can be considered an interesting excipient to prepare nanostructured systems and nanoemulsion formulations can be considered promising alternatives for the treatment of glioma.

Caffeine and diphenyl diselenide improve long-term memory impaired in middle-aged rats

The aim of the present study was to evaluate the effects of diphenyl diselenide (PhSe)2 supplemented diet (10ppm) associated to the administration of caffeine (15mg/kg; i.g.) for 30days on the novel object recognition memory in middle-aged rats. The present findings showed that (PhSe)2-supplemented diet enhanced short-term memory, but not long-term memory, of middle-aged rats in the novel object recognition task. The (PhSe)2 supplemented diet associated with caffeine administration improved long-term memory, but did not alter short-term memory, impaired in middle-aged rats. Daily caffeine administration to middle-aged rats had no effect on the memory tasks. Diet supplemented with (PhSe)2 plus caffeine administration increased the number of crossings and rearings reduced in middle-aged rats. Caffeine administration plus (PhSe)2 diets were effective in increasing the number of rearings and crossings, respectively, in middle-aged rats, [(3)H] glutamate uptake was reduced in hippocampal slices of rats from (PhSe)2 and caffeine plus (PhSe)2 groups. In addition, animals supplemented with (PhSe)2 showed an increase in the pCREB/CREB ratio whereas pAkt/Akt ratio was not modified. These results suggest that the effects of (PhSe)2 on the short-term memory may be related to its ability to decrease the uptake of glutamate, influencing the increase of CREB phosphorylation. (PhSe)2-supplemented diet associated to the administration of caffeine improved long-term memory impaired in middle-aged rats, an effect independent of CREB and Akt phosphorylation.

Enhanced photostability, radical scavenging and antitumor activity of indole-3-carbinol-loaded rose hip oil nanocapsules

This study aimed to develop poly(ε-caprolactone) nanocapsules loaded with indole-3-cabinol (I3C) using rose hip oil (RHO) or medium chain triglycerides (MCT) as oil core. In vitro radical scavenging activity (DPPH method), hemolysis, and antitumor effects on breast (MCF-7) and glioma (C6) cells were conducted. Preformulation evaluations revealed that RHO is suitable to prepare the nanocapsules considering the log P determination and dissolution/swelling experiments of polymer films. The nanocapsules were prepared and presented adequate physicochemical characteristics as mean size around 250nm, polydispersity index values <0.2, zeta potential negative values and I3C encapsulation efficiency around 42%, without any influence of the oil core (RHO or MCT) on these parameters. However, the photodegradation study demonstrated that RHO nanocapsules showed less degree of I3C degradation in comparison to MCT nanocapsules. The in vitro release profile showed that both nanocapsule suspensions demonstrated an initial burst effect followed by a prolonged I3C release. In addition, the formulations were considered hemocompatibles at 10μg/mL and showed an enhanced radical scavenging activity in comparison to free I3C. Moreover, nanocapsules prepared with RHO increased about two times the antitumor effect of I3C on MCF-7 and C6 cells without significant reduction of astrocyte cell viability. In conclusion, nanocapsule formulations developed in this study might be considered promising for cancer treatment.

2-Phenylethynyl-butyltellurium attenuates amyloid-β peptide(25-35)-induced learning and memory impairments in mice.

Our previous study demonstrated that 2‐phenylethynyl‐butyltellurium (PEBT), an organotellurium compound, enhances memory in mice. In this study, the effects of PEBT on cognitive impairment induced by Aβ25–35 were assessed by Morris water maze and step‐down inhibitory avoidance tasks. Mice received a single intracerebroventricular injection of Aβ25–35 (3 nmol/3 μl/per site) and a daily oral administration of PEBT (1 mg/kg, for 10 days). PEBT significantly improved Aβ‐induced learning deficits on the training session in the Morris water maze. At the probe trial session, PEBT significantly decreased the escape latency and increased the number of crossings in the platform local compared with the Aβ‐treated group. PEBT significantly improved Aβ‐induced memory impairment in the step‐down inhibitory avoidance task. General locomotor activity was similar in all groups. This study showed that PEBT ameliorated the impairments of spatial and nonspatial long‐term memory evaluated on Morris water maze and step‐down inhibitory avoidance tasks, respectively. The results suggest that PEBT could be considered a candidate for the prevention of memory deficits such as those observed in Alzheimers disease.

Bisphenol A impairs the memory function and glutamatergic homeostasis in a sex-dependent manner in mice: Beneficial effects of diphenyl diselenide

&NA; Bisphenol A (BPA) is a compound integrated in commodities, which consequently increases the human exposure to this toxicant. The deleterious effects of BPA exposure during periods of brain development have been documented mainly concerning the impairment in memory functions. Diphenyl diselenide (PhSe)2, an organoselenium compound, shows protective/restorative effects against memory deficits in experimental models. Thus, this study investigated the effects of (PhSe)2 on the memory impairments induced by BPA exposure to male and female mice and the possible involvement of glutamatergic system in these effects. Three‐week‐old male and female Swiss mice received BPA (5 mg/kg), intragastrically, from 21st to 60th postnatal day. After, the animals were intragastrically treated with (PhSe)2 (1 mg/kg) during seven days. The mice performed the behavioral memory tests and the [3H] glutamate uptake and NMDA receptor subunits (2A and 2B) analyses were carried out in the hippocampus and cerebral cortex of mice. The results demonstrated that the BPA exposure induced impairment of object recognition memory in both sexes. However, it caused impairments in spatial memory in female and in the passive avoidance memory in male mice. Besides, BPA caused a decrease in the [3H] glutamate uptake and NMDA receptor subunit levels in the cortical and hippocampal regions depending on the sex. Treatment with (PhSe)2 reversed in a sex‐independent manner the behavioral impairments and molecular alterations. In conclusion, BPA had a negative effect in different memory types as well as in the glutamatergic parameters in a sex‐dependent manner and (PhSe)2 treatment was effective against these alterations. Graphical abstract Figure. No caption available. HighlightsBPA exposure induced memory impairment in a sex dependent manner in mice.(PhSe)2 reversed memory impairments caused by BPA exposure in mice.(PhSe)2 modulated hippocampal and cortical [3H]glutamate uptake in mice.(PhSe)2 restored the hippocampal and cortical NMDA receptor subunits levels.