Caffeic Acid-Zinc Basic Salt/Chitosan Nanohybrid Possesses Controlled Release Properties and Exhibits In Vivo Anti-Inflammatory Activities.

Caffeic acid (CA) exhibits a myriad of biological activities including cardioprotective action, antioxidant, antitumor, anti-inflammatory, and antimicrobial properties. On the other hand, CA presents low water solubility and poor bioavailability, which have limited its use for therapeutic applications. The objective of this study was to develop a nanohybrid of zinc basic salts (ZBS) and chitosan (Ch) containing CA (ZBS-CA/Ch) and evaluate its anti-edematogenic and antioxidant activity in dextran and carrageenan-induced paw edema model. The samples were obtained by coprecipitation method and characterized by X-ray diffraction, Fourier transform infrared (FT-IR), scanning electron microscope (SEM) and UV-visible spectroscopy. The release of caffeate anions from ZBS-CA and ZBS-CA/Ch is pH-dependent and is explained by a pseudo-second order kinetics model, with a linear correlation coefficient of R2 ≥ 0.99 at pH 4.8 and 7.4. The in vivo pharmacological assays showed excellent anti-edematogenic and antioxidant action of the ZBS-CA/Ch nanoparticle with slowly releases of caffeate anions in the tissue, leading to a prolongation of CA-induced anti-edematogenic and anti-inflammatory activities, as well as improving its inhibition or sequestration antioxidant action toward reactive species. Overall, this study highlighted the importance of ZBS-CA/Ch as an optimal drug carrier.

Alpha-Lipoic Acid and Its Enantiomers Prevent Methemoglobin Formation and DNA Damage Induced by Dapsone Hydroxylamine: Molecular Mechanism and Antioxidant Action.

Dapsone (DDS) therapy can frequently lead to hematological side effects, such as methemoglobinemia and DNA damage. In this study, we aim to evaluate the protective effect of racemic alpha lipoic acid (ALA) and its enantiomers on methemoglobin induction. The pre- and post-treatment of erythrocytes with ALA, ALA isomers, or MB (methylene blue), and treatment with DDS-NOH (apsone hydroxylamine) was performed to assess the protective and inhibiting effect on methemoglobin (MetHb) formation. Methemoglobin percentage and DNA damage caused by dapsone and its metabolites were also determined by the comet assay. We also evaluated oxidative parameters such as SOD, GSH, TEAC (Trolox equivalent antioxidant capacity) and MDA (malondialdehyde). In pretreatment, ALA showed the best protector effect in 2.5 µg/mL of DDS-NOH. ALA (1000 µM) was able to inhibit the induced MetHb formation even at the highest concentrations of DDS-NOH. All ALA tested concentrations (100 and 1000 µM) were able to inhibit ROS and CAT activity, and induced increases in GSH production. ALA also showed an effect on DNA damage induced by DDS-NOH (2.5 µg/mL). Both isomers were able to inhibit MetHb formation and the S-ALA was able to elevate GSH levels by stimulating the production of this antioxidant. In post-treatment with the R-ALA, this enantiomer inhibited MetHb formation and increased GSH levels. The pretreatment with R-ALA or S-ALA prevented the increase in SOD and decrease in TEAC, while R-ALA decreased the levels of MDA; and this pretreatment with R-ALA or S-ALA showed the effect of ALA enantiomers on DNA damage. These data show that ALA can be used in future therapies in patients who use dapsone chronically, including leprosy patients.

Polybia occidentalis and Polybia fastidiosa venom: a cytogenotoxic approach of effects on human and vegetal cells.

The venoms of wasps are a complex mixture of biologically active compounds, such as low molecular mass compounds, peptides, and proteins. The aim of the study was to evaluate the action of wasp venoms, Polybia occidentalis and Polybia fastidiosa, on the DNA of human leukocytes and on the cell cycle and genetic material of the plant model Lactuca sativa L. (lettuce). The cultured leukocytes were treated with the venoms and then evaluated by the comet assay. On another assay, seeds were exposed to a venom solution; the emitted roots were collected and the occurrence of cell cycle alterations (CCAs) and DNA fragmentation were evaluated by agarose gel electrophoresis and TUNEL assay. The results demonstrated that the venom of both wasps induces several CCAs and reduces the mitotic index (MI) on treated cells. They induced damage on human leukocytes DNA. High frequencies of fragments were observed in cells exposed to P. occidentalis venom, while those exposed to P. fastidiosa showed a high frequency of non-oriented chromosome. Both venoms induced the occurrence of various condensed nuclei (CN). This alteration is an excellent cytological mark to cell death (CD). Additionally, CD was evidenced by positive signals in TUNEL assay, by DNA fragmentation in agarose gel electrophoresis with vegetal cells, and by DNA fragmentation of the human leukocytes evaluated. Furthermore, human leukocytes exposed to the venom of P. fastidiosa had high rate of damage. The data demonstrate that both vegetal and human cells are adequate to evaluate the genotoxicity induced by venoms.

Preclinical evidences of aluminum-induced neurotoxicity in hippocampus and pre-frontal cortex of rats exposed to low doses.

Aluminum (Al) is a neurotoxicant agent implicated in several behavioral, neuropathological and neurochemical changes associated with cognitive impairments. Nevertheless, mechanisms of damage and safety concentrations are still very discussed. Thus, the main purpose of this study was to investigate whether two aluminum low doses were able to produce deleterious effects on cognition of adult rats, including oxidative stress in hippocampus and prefrontal cortex, two important areas for cognition. For this, thirty adult Wistar rats were divided into three groups: Al1 (8.3 mg/kg/day), Al2 (32 mg/kg/day) and Control (Ultrapure Water), in which all three groups received their solutions containing or not AlCl3 by intragastric gavage for 60 days. After the experimental period, the short- and long-term memories were assessed by the object recognition test and step-down inhibitory avoidance. After euthanizing, prefrontal cortex and hippocampus samples were dissected for Al levels measurement and evaluation of oxidative biochemistry. Only Al2 increased Al levels in hippocampal parenchyma significantly; both concentrations did not impair short-term memory, while long-term memory was affected in Al1 and Al2. In addition, oxidative stress was observed in prefrontal and hippocampus in Al1 and Al2. Our results indicate that, in a translational perspective, humans are subjected to deleterious effects of Al over cognition even when exposed to low concentrations, by triggering oxidative stress and poor long-term memory performance.

Safety and Effectiveness of Copaiba Oleoresin (C. reticulata Ducke) on Inflammation and Tissue Repair of Oral Wounds in Rats.

In traditional communities of the Brazilian Amazon, the copaiba oleoresin (C. reticulata Ducke) is widely known for its therapeutic activity, especially its wound healing and anti-inflammatory actions. Our study aimed to evaluate these effects in oral lesions and the safety of the dosage proposed. A punch biopsy wound was induced on the ventral surface of the tongue of forty-five male Wistar rats under anesthesia. Animals were randomly allocated to one of three groups based on the treatment: control, corticoid and copaiba. A daily dose of each treatment and vehicle was administrated by oral gavage for three consecutive days. Sample collections took place on the third, seventh and 15th days post-wounding for clinical and histopathological analyses. Blood was collected on the third and seventh days for kidneys and liver function tests. Semi-quantitative analyses were performed based on scores of inflammation and reepithelization. Tissue collagen deposition was detected by PicroSirius red staining. Copaiba-treated wounds revealed a smaller wound area, decreased of acute inflammatory reaction and enhanced reepithelization. The levels of kidney and liver function tests did not reveal presence of damage post-treatments. Our findings suggest that copaiba oleoresin is a safe and effective alternative therapy for inflammation and tissue repair of oral wounds in this animal model.

Hippocampal Impairment Triggered by Long-Term Lead Exposure from Adolescence to Adulthood in Rats: Insights from Molecular to Functional Levels.

Lead (Pb) is an environmental and occupational neurotoxicant after long-term exposure. This study aimed to investigate the effects of systemic Pb exposure in rats from adolescence to adulthood, evaluating molecular, morphologic and functional aspects of hippocampus. For this, male Wistar rats were exposed to 50 mg/kg of Pb acetate or distilled water for 55 days by intragastric gavage. For the evaluation of short-term and long-term memories, object recognition and step-down inhibitory avoidance tests were performed. At the end of the behavioral tests, the animals were euthanized and the hippocampus dissected and processed to the evaluation of: Pb content levels in hippocampal parenchyma; Trolox equivalent antioxidant capacity (TEAC), glutathione (GSH) and malondialdehyde (MDA) levels as parameters of oxidative stress and antioxidant status; global proteomic profile and neuronal degeneration by anti-NeuN immunohistochemistry analysis. Our results show the increase of Pb levels in the hippocampus of adult rats exposed from adolescence, increased MDA and GSH levels, modulation of proteins related to neural structure and physiology and reduced density of neurons, hence a poor cognitive performance on short and long-term memories. Then, the long-term exposure to Pb in this period of life may impair several biologic organizational levels of the hippocampal structure associated with functional damages.

Blood Oxidative Stress Modulates Alveolar Bone Loss in Chronically Stressed Rats.

We aimed to investigate the effects of chronic stress (CS) on experimental periodontitis (EP) in rats. For this, 28 Wistar rats were divided into four groups: control, ligature-induced experimental periodontitis (EP), chronic stress (CS; by physical restraint model) and CS+EP (association of chronic stress and ligature-induced periodontitis). The experimental period lasted 30 days, including exposure to CS every day and ligature was performed on the 15th experimental day. After 30 days, the animals were submitted to the behavioral test of the elevated plus maze (EPM). Next, rats were euthanized for blood and mandible collection in order to evaluate the oxidative biochemistry (by nitric oxide (NO), reduced-glutathione activity (GSH), and thiobarbituric acid reactive substance levels (TBARS)) and alveolar bone characterization (by morphometric, micro-CT, and immunohistochemistry), respectively. The behavioral parameters evaluated in EPM indicated higher anxiogenic activity in the CS and CS+EP, groups, which is a behavioral reflex of CS. The results showed that CS was able to change the blood oxidative biochemistry in CS and CS+EP groups, decrease GSH activity in the blood, and increase the NO and TBARS concentrations. Thus, CS induces oxidative blood imbalance, which can potentialize or generate morphological, structural, and metabolic damages to the alveolar bone.

Phloroglucinol derivatives from Hypericum species trigger mitochondrial dysfunction in Leishmania amazonensis.

Bioactive molecules isolated from plants are promising sources for the development of new therapies against leishmaniasis. We investigated the leishmanicidal activity of cariphenone A (1), isouliginosin B (2) and uliginosin B (3) isolated from Hypericum species. Promastigotes and amastigotes of Leishmania amazonensis were incubated with compounds 1-3 at concentrations 1-100 µm for 48 h. The anti-promastigote effect of compounds was also tested in combinations. The cytotoxicity against macrophages and human erythrocytes were determined using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) method and hemolysis assay, respectively. The compounds 1-3 showed high leishmanicidal activity against promastigotes, IC50 values of 10.5, 17.5 and 11.3 µm, respectively. Synergistic interactions were found to the associations of compounds 1 and 2 [Σ fractional inhibitory concentration (FIC) = 0.41], and 2 and 3 (ΣFIC = 0.28) on promastigotes. All Hypericum compounds induced mitochondrial hyperpolarization and reactive oxygen species production in promastigotes. The compounds showed low cytotoxicity toward mammalian cells, high selectivity index and killed intracellular amastigotes probably mediated by oxidative stress. These results indicate that these compounds are promising candidates for the development of drugs against leishmaniasis.

Immune modulation of some autoimmune diseases: the critical role of macrophages and neutrophils in the innate and adaptive immunity.

Macrophages and neutrophils are key components involved in the regulation of numerous chronic inflammatory diseases, infectious disorders, and especially certain autoimmune disease. However, little is known regarding the contribution of these cells to the pathogenesis of autoimmune disorders. Recent studies have aimed to clarify certain important factors affecting the immunogenicity of these cells, including the type and dose of antigen, the microenvironment of the cell-antigen encounter, and the number, subset, and phenotype of these cells, which can prevent or induce autoimmune responses. This review highlights the role of macrophage subsets and neutrophils in injured tissues, supporting their cooperation during the pathogenesis of certain autoimmune diseases.

Dual Behavior of Exosomes in Septic Cardiomyopathy.

Sepsis is one of the main causes of ICU hospitalization worldwide, with a high mortality rate, and is associated with a large number of comorbidities. One of the main comorbidities associated with sepsis is septic cardiomyopathy. This process occurs mainly due to mechanisms of damage in the cardiovascular system that will lead to changes in cardiovascular physiology, such as decreased Ca2+ response, mitochondrial dysfunction and decreased ß-adrenergic receptor response. Within this process the exosomes play an important role in the pathophysiology of this disease, in which the exosomal content is related to mechanisms that will trigger its development. After platelet activation through ROS exposition, exosomes containing high concentrations of NADPH are released in heart blood vessels, those exosomes will be internalized in endothelial cells leading to cell death and cardiac dysfunction. On the opposite, exosomes derived from mesenchymal stem cells contain miR-223, that have anti-inflammatory properties, are released in less quantities in septic patients causing an imbalance that leads to cardiac dysfunction.

Action mechanism and cardiovascular effect of anthocyanins: a systematic review of animal and human studies.

Cardiovascular diseases (CVD) are an important cause of death worldwide. Anthocyanins are a subgroup of flavonoids found in berries, flowers, fruits and leaves. In epidemiological and clinical studies, these polyphenols have been associated with improved cardiovascular risk profiles as well as decreased comorbidities. Human intervention studies using berries, vegetables, parts of plants and cereals (either fresh or as juice) or purified anthocyanin-rich extracts have demonstrated significant improvements in low density lipoproteins oxidation, lipid peroxidation, total plasma antioxidant capacity, and dyslipidemia as well as reduced levels of CVD molecular biomarkers. This review discusses the use of anthocyanins in animal models and their applications in human medicine, as dietary supplements or as new potent drugs against cardiovascular disease.

Antimicrobial bioassay-guided fractionation of a methanol extract of Eupatorium triplinerve.

CONTEXT: Eupatorium triplinerve Vahl (Asteraceae), popularly known as Japana, is widely used in folk medicine, due its analgesic, anticoagulant, antianorexic, antiparasitic, anthelmintic, sedative, antifungal, and antibacterial properties. OBJECTIVE: The present study evaluated the chemical composition and antimicrobial activity of E. triplinerve extracts from different parts of the plant and identified the extract with the highest antimicrobial potential. MATERIALS AND METHODS: Extracts were obtained by maceration of all parts of plant, and subjected to bioassay-guided fractionation of methanol extract by partition column chromatography. The major chemical groups, saponins, reducing sugars, alkaloids, steroids, triterpenoids, phenols, tannins, flavonoids, and others were screened by standard techniques. The antimicrobial activity of the different extracts was performed by microdilution assay and the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values were reported. RESULTS: Phytochemical screening of hydroalcoholic extract from all parts of E. triplinerve identified mainly steroids, coumarins, alkaloids, saponins, tannins, depsides and absence of polysaccharides and flavonoids. The methanol extract of leaves presented the highest content of coumarins and lower MIC values of 62 and 75 µg/mL against Enterococcus faecalis and Staphylococcus aureus, respectively. In addition, its non-polar fractions showed antimicrobial activity with MIC ranging from 16 to 125 µg/mL against Gram-negative bacteria, mainly Escherichia coli. DISCUSSION AND CONCLUSION: Data showed that non-polar fractions of E. triplinerve methanolic extract has better antimicrobial activity and most likely depends on the presence of several compounds, such as depsidones, coumarins, saponins, and triterpenes on crude extract. The results can be exploited largely in research of new antibacterial agents.

Is there any association between the presence of biomarkers and apical periodontitis? A systematic review.

This systematic review aimed to verify whether there is evidence of an association between apical periodontitis and the presence of systemic biomarkers. This study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses - PRISMA. For this, the acronym PECO was used; population (P) of adult humans exposed (E) to the presence of apical periodontitis, compared (C) to adult humans without apical periodontitis, and the outcome (O) of the presence of biomarkers was observed. The articles were searched in PubMed, Scopus, Web of Science, LILACS, Cochrane Library, OpenGray, and Google Scholar grey databases. Subsequently, studies were excluded based on title, abstract, and full article reading, following the eligibility criteria. The methodological quality of the selected studies was evaluated using the Newcastle-Ottawa qualifier. After exclusion, 656 studies were identified, resulting in 17 final articles that were divided into case-control, cross-sectional, and cohort studies. Eight studies were considered to have a low risk of bias, one had a medium risk of bias, and eight had a high risk of bias. In addition, 12 articles evaluated biomarkers in blood plasma, four evaluated them in saliva, and only one evaluated them in gingival crevicular fluid. The results of these studies indicated an association between apical periodontitis and the systemic presence of biomarkers. These markers are mainly related to inflammation, such as interleukins IL-1, IL-2, and IL-6, oxidative markers, such as nitric oxide and superoxide anions, and immunoglobulins IgG and IgM. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier (CRD42023493959).

Endotoxin tolerance and low activation of TLR-4/NF-κB axis in monocytes of COVID-19 patients.

Higher endotoxin in the circulation may indicate a compromised state of host immune response against coinfections in severe COVID-19 patients. We evaluated the inflammatory response of monocytes from COVID-19 patients after lipopolysaccharide (LPS) challenge. Whole blood samples of healthy controls, patients with mild COVID-19, and patients with severe COVID-19 were incubated with LPS for 2 h. Severe COVID-19 patients presented higher LPS and sCD14 levels in the plasma than healthy controls and mild COVID-19 patients. In non-stimulated in vitro condition, severe COVID-19 patients presented higher inflammatory cytokines and PGE-2 levels and CD14 + HLA-DRlow monocytes frequency than controls. Moreover, severe COVID-19 patients presented higher NF-κB p65 phosphorylation in CD14 + HLA-DRlow, as well as higher expression of TLR-4 and NF-κB p65 phosphorylation in CD14 + HLA-DRhigh compared to controls. The stimulation of LPS in whole blood of severe COVID-19 patients leads to lower cytokine production but higher PGE-2 levels compared to controls. Endotoxin challenge with both concentrations reduced the frequency of CD14 + HLA-DRlow in severe COVID-19 patients, but the increases in TLR-4 expression and NF-κB p65 phosphorylation were more pronounced in both CD14 + monocytes of healthy controls and mild COVID-19 patients compared to severe COVID-19 group. We conclude that acute SARS-CoV-2 infection is associated with diminished endotoxin response in monocytes. KEY MESSAGES: Severe COVID-19 patients had higher levels of LPS and systemic IL-6 and TNF-α. Severe COVID-19 patients presented higher CD14+HLA-DRlow monocytes. Increased TLR-4/NF-κB axis was identified in monocytes of severe COVID-19. Blunted production of cytokines after whole blood LPS stimulation in severe COVID-19. Lower TLR-4/NF-κB activation in monocytes after LPS stimulation in severe COVID-19.

Exposure to tolerable concentrations of aluminum triggers systemic and local oxidative stress and global proteomic modulation in the spinal cord of rats.

The tolerable aluminum (Al) intake levels for humans are constantly under review by regulatory agencies due to novel pre-clinical evidence on the neurotoxicity of prolonged Al exposure; however, little is known about the effects of Al on the spinal cord. This study aimed to investigate potential adverse effects on both spinal cord and systemic biochemical balance after prolonged exposure to a low dose of Al. Twenty adult rats were distributed in the control (distilled water) and exposed group (8.3 mg of AlCl3/kg/day). After 60 days, both blood and spinal cord samples were collected for oxidative stress and proteomic analyses. In plasma and erythrocytes, glutathione level was not different between groups; however, exposure to AlCl3 significantly decreased glutathione level in the spinal cord. Thiobarbituric acid reactive substances levels in the plasma and spinal cord of animals from the control group were significantly lower than those animals exposed to AlCl3. Exposure to AlCl3 significantly modulated the expression of proteins associated with the cell cycle, stimulus-response, cytoskeleton, nervous system regulation, protein activity, and synaptic signaling. Therefore, prolonged exposure to a low dose of Al triggered oxidative stress and proteomic changes that may affect spinal cord homeostasis.

BmooMPα-I, a Metalloproteinase Isolated from Bothrops moojeni Venom, Reduces Blood Pressure, Reverses Left Ventricular Remodeling and Improves Cardiac Electrical Conduction in Rats with Renovascular Hypertension.

BmooMPα-I has kininogenase activity, cleaving kininogen releasing bradykinin and can hydrolyze angiotensin I at post-proline and aspartic acid positions, generating an inactive peptide. We evaluated the antihypertensive activity of BmooMPα-I in a model of two-kidney, one-clip (2K1C). Wistar rats were divided into groups: Sham, who underwent sham surgery, and 2K1C, who suffered stenosis of the right renal artery. In the second week of hypertension, we started treatment (Vehicle, BmooMPα-I and Losartan) for two weeks. We performed an electrocardiogram and blood and heart collection in the fourth week of hypertension. The 2K1C BmooMPα-I showed a reduction in blood pressure (systolic pressure: 131 ± 2 mmHg; diastolic pressure: 84 ± 2 mmHg versus 174 ± 3 mmHg; 97 ± 4 mmHg, 2K1C Vehicle, p < 0.05), improvement in electrocardiographic parameters (Heart Rate: 297 ± 4 bpm; QRS: 42 ± 0.1 ms; QT: 92 ± 1 ms versus 332 ± 6 bpm; 48 ± 0.2 ms; 122 ± 1 ms, 2K1C Vehicle, p < 0.05), without changing the hematological profile (platelets: 758 ± 67; leukocytes: 3980 ± 326 versus 758 ± 75; 4400 ± 800, 2K1C Vehicle, p > 0.05), with reversal of hypertrophy (left ventricular area: 12.1 ± 0.3; left ventricle wall thickness: 2.5 ± 0.2; septum wall thickness: 2.3 ± 0.06 versus 10.5 ± 0.3; 2.7 ± 0.2; 2.5 ± 0.04, 2K1C Vehicle, p < 0.05) and fibrosis (3.9 ± 0.2 versus 7.4 ± 0.7, 2K1C Vehicle, p < 0.05). We concluded that BmooMPα-I improved blood pressure levels and cardiac remodeling, having a cardioprotective effect.

Effects of long-term fluoride exposure are associated with oxidative biochemistry impairment and global proteomic modulation, but not genotoxicity, in parotid glands of mice.

BACKGROUND: Fluoride has become widely used in dentistry because of its effectiveness in caries control. However, evidence indicates that excessive intake interferes with the metabolic processes of different tissues. Thus, this study aimed to investigate the effects of long-term exposure to F on the parotid salivary gland of mice, from the analysis of oxidative, proteomic and genotoxic parameters. MATERIALS AND METHODS: The animals received deionized water containing 0, 10 or 50 mg/L of F, as sodium fluoride, for 60 days. After, parotid glands were collected for analysis of oxidative biochemistry, global proteomic profile, genotoxicity assessment and histopathological analyses. RESULTS: The results revealed that exposure to fluoride interfered in the biochemical homeostasis of the parotid gland, with increased levels of thiobarbituric acid reactive species and reduced glutathione in the exposed groups; as well as promoted alteration of the glandular proteomic profile in these groups, especially in structural proteins and proteins related to oxidative stress. However, genotoxic assessment demonstrated that exposure to fluoride did not interfere with DNA integrity in these concentrations and durations of exposure. Also, it was not observed histopathological alterations in parotid gland. CONCLUSIONS: Thus, our results suggest that long-term exposure to fluoride promoted modulation of the proteomic and biochemical profile in the parotid glands, without inducing damage to the genetic component. These findings reinforce the importance of rationalizing the use of fluorides to maximize their preventative effects while minimizing the environmental risks.

Repeated Cycles of Binge-Like Ethanol Exposure Induces Neurobehavioral Changes During Short- and Long-Term Withdrawal in Adolescent Female Rats.

Alcohol consumption is spread worldwide and can lead to an abuse profile associated with severe health problems. Adolescents are more susceptible to addiction and usually consume ethanol in a binge drinking pattern. This form of consumption can lead to cognitive and emotional disorders, however scarce studies have focused on long-term hazardous effects following withdrawal periods after binge drinking in adolescents. Thus, the present study aims at investigating whether behavioral and cognitive changes persist until mid and late adulthood. Female Wistar rats (9-10 animals/group) received intragastric administration of four cycles of ethanol binge-like pattern (3.0 g/kg/day, 20% w/v; 3 days-on/4 days-off) from 35th to 58th days old, followed withdrawal checkpoints 1 day, 30 days, and 60 days. At each checkpoint period, behavioral tests of open field, object recognition test, elevated plus maze, and forced swimming test were performed, and blood and hippocampus were collected for oxidative biochemistry and brain-derived neurotrophic factor (BDNF) levels analysis, respectively. The results demonstrated that adolescent rats exposed to binge drinking displayed anxiogenic- and depressive-like phenotype in early and midadulthood, however, anxiety-like profile persisted until late adulthood. Similarly, short-term memory was impaired in all withdrawal periods analysed, including late adult life. These behavioral data were associated with oxidative damage in midadulthood but not BDNF alterations. Taken together, the present work highlights the long-lasting emotional and cognitive alterations induced by ethanol binge drinking during adolescence, even after a long period of abstinence, which might impact adult life.

Imidazolium salts as an alternative for anti-Leishmania drugs: Oxidative and immunomodulatory activities.

In this study we explored the previously established leishmanicidal activity of a complementary set of 24 imidazolium salts (IS), 1-hexadecylimidazole (C16Im) and 1-hexadecylpyridinium chloride (C16PyrCl) against Leishmania (Leishmania) amazonensis and Leishmania (Leishmania) infantum chagasi. Promastigotes of L. amazonensis and L. infantum chagasi were incubated with 0.1 to 100 µM of the compounds and eight of them demonstrated leishmanicidal activity after 48 h - C10MImMeS (IC50 L. amazonensis = 11.6), C16MImPF6(IC50 L. amazonensis = 6.9), C16MImBr (IC50 L. amazonensis = 6), C16M2ImCl (IC50 L. amazonensis = 4.1), C16M4ImCl (IC50 L. amazonensis = 1.8), (C10)2MImCl (IC50 L. amazonensis = 1.9), C16Im (IC50 L. amazonensis = 14.6), and C16PyrCl (IC50 L. amazonensis = 4).The effect of IS on reactive oxygen species production, mitochondrial membrane potential, membrane integrity and morphological alterations of promastigotes was determined, as well as on L. amazonensis-infected macrophages. Their cytotoxicity against macrophages and human erythrocytes was also evaluated. The IS C10MImMeS, C16MImPF6, C16MImBr, C16M2ImCl, C16M4ImCl and (C10)2MImCl, and the compounds C16Im and C16PyrCl killed and inhibited the growth of promastigote forms of L. amazonensis and L. infantum chagasi in a concentration-dependent manner, contributing to a better understanding of the structure-activity relationship of IS against Leishmania. These IS induced ROS production, mitochondrial dysfunction, membrane disruption and morphological alterations in infective forms of L. amazonensis and killed intracellular amastigote forms in very low concentrations (IC50 amastigotes ≤ 0.3), being potential drug candidates against L. amazonensis.

A preliminary study on the association of tamoxifen, endoxifen, and 4-hydroxytamoxifen with blood lipids in patients with breast cancer.

The long-term treatment with tamoxifen can alter the lipid profile of patients with breast cancer. Only a few studies associated the plasma concentrations of tamoxifen, endoxifen, and 4-hydroxytamoxifen with blood lipids, which is relevant as the distribution of these compounds for the tissues can be changed, negatively affecting the treatment. The variations in lipids also can account for the high interindividual variation in plasma concentrations of these compounds. The aim of this preliminary study was to associate the plasma levels of tamoxifen and the active metabolites with the lipid levels. An observational study of cases was conducted in patients with breast cancer using tamoxifen in a daily dose of 20 mg. The lipids were measured by spectrophotometric methods and the plasma concentrations of tamoxifen, endoxifen, and 4-hydroxytamoxifen by high-performance liquid chromatography. A total of 20 patients were included in the study. The median plasma concentrations of tamoxifen, 4-hydroxytamoxifen and endoxifen were 62 ng/mL, 1.04 ng/mL and 8.79 ng/mL. Triglycerides levels ranged from 59 to 352 mg/dL, total cholesterol from 157 to 321 mg/dL, LDL-c from 72 mg/dL to 176 mg/dL and HDL-C from 25.1 mg/dL to 62.8 mg/dL. There were no significant associations between the plasma concentrations of tamoxifen, 4-hydroxytamoxifen, and endoxifen with the levels of triglycerides and total cholesterol. The multivariate analysis revealed a weak association between plasma concentrations of tamoxifen and the active metabolites with HDL-c, LDL-c and VLDL-c. This finding provides preliminary evidence of the low impact of lipoproteins levels in the exposure to tamoxifen, 4-hydroxytamoxifen and endoxifen.