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.

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.

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.

Effects of Fluoride on Submandibular Glands of Mice: Changes in Oxidative Biochemistry, Proteomic Profile, and Genotoxicity.

Although fluoride (F) is well-known to prevent dental caries, changes in cell processes in different tissues have been associated with its excessive exposure. Thus, this study aimed to evaluate the effects of F exposure on biochemical, proteomic, and genotoxic parameters of submandibular glands. Twenty one old rats (n = 30) were allocated into three groups: 60 days administration of drinking water containing 10 mgF/L, 50 mgF/L, or only deionized water (control). The submandibular glands were collected for oxidative biochemistry, protein expression profile, and genotoxic potential analyses. The results showed that both F concentrations increased the levels of thiobarbituric acid-reactive substances (TBARS) and reduced glutathione (GSH) and changed the proteomic profile, mainly regarding the cytoskeleton and cellular activity. Only the exposure to 50 mgF/L induced significant changes in DNA integrity. These findings reinforce the importance of continuous monitoring of F concentration in drinking water and the need for strategies to minimize F intake from other sources to obtain maximum preventive/therapeutic effects and avoid potential adverse effects.

Imaging Microstructural Damage and Alveolar Bone Loss in Rats Systemically Exposed to Methylmercury: First Experimental Evidence.

The alveolar bone is an important mineralized structure of the periodontal support apparatus, and information about the methylmercury (MeHg) effects on the structural integrity is scarce. Therefore, this study aimed to investigate whether systemic, chronic, and low-dose exposure to MeHg can change the alveolar bone microstructure of rats. Adult Wistar rats (n = 30) were exposed to 0.04 mg/kg/day of MeHg or vehicle through intragastric gavage. The animals were euthanized after 60 days, and blood samples were collected for trolox equivalent antioxidant capacity (TEAC), glutathione (GSH), lipid peroxidation (LPO), and comet assays. The mandible of each animal was collected and separated into hemimandibles that were used to determine the total Hg level in the bone and to analyze microstructural damage and alveolar bone loss in terms of trabecular number (Tb.N), trabecular thickness (Tb.Th), bone volume fraction (BV/TV), and exposed root area of the second molars. MeHg exposure triggered oxidative stress in blood represented by lower levels of GSH and TEAC and the increase in LPO and DNA damage of the blood cells. High total Hg levels were found in the alveolar bone, and the microstructural analyses showed a reduction in Tb.N, Tb.Th, and BV/TV, which resulted in an increase in the exposed root area and a decrease in bone height. Long-term MeHg exposure promotes a systemic redox imbalance associated with microstructural changes and alveolar bone loss and may indicate a potential risk indicator for periodontal diseases.

Long-Term Exposure to Inorganic Mercury Leads to Oxidative Stress in Peripheral Blood of Adult Rats.

Mercury chloride (HgCl2) is a compound found in the environment that presents low risk due to low liposolubility. Considering the importance of blood as access rout to the systemic distribution of this toxicant to the organism as well as functions performed by it, this study aimed to investigate the effects of HgCl2 on the peripheral blood of rats, evaluating the oxidative biochemistry, blood count, and morphology of cell populations. For this, 20 adult Wistar male rats were divided into control (n = 10) and exposed (n = 10) groups and received distilled water or HgCl2 at a dose of 0.375 mg/kg for 45 days, respectively, through intragastric gavage. Then, the animals were euthanized and the blood was collected for total mercury (Hg) levels determination, complete blood and reticulocyte count, oxidative biochemistry by Trolox Equivalent Antioxidant Capacity (TEAC), reduced glutathione (GSH) levels, superoxide dismutase activity (SOD), thiobarbituric acid reactive substances (TBARS), and nitric oxide (NO), in blood cells and plasma. Long-term exposure increased total Hg in plasma and blood cells. In blood cells, only TEAC has decreased; in plasma, the HgCl2 increased TBARS and NO levels, followed by a decrease in TEAC and GSH levels. There were no quantitative changes in reticulocytes, erythrocytes, and hemoglobin; however, the number of leukocytes have increased and platelets have decreased. Our results suggest that even in the face of low toxicity when compared with other mercury species, HgCl2 at low doses is able to modulate the systemic redox balance and affect some blood cell populations.

Aluminum-Induced Toxicity in Salivary Glands of Mice After Long-term Exposure: Insights into the Redox State and Morphological Analyses.

Several studies indicate aluminum (Al) as a potent toxicant, mainly related to central nervous system disorders. However, investigations about the Al effects over salivary glands are still scarce. In this way, the present study aimed to investigate whether the Al chloride (AlCl3) is able of triggering oxidative stress in parotid and submandibular glands of mice and also, if any morphological impairment is observed. For this, twenty mice were divided into two groups: Exposed group (EG), which received 18.5 mg/kg of AlCl3 by intragastric gavage for 60 days and control group (CG), which received distilled water by intragastric gavage during the same period of time. After that, levels of reduced glutathione (GSH) and malonaldehyde (MDA) were analyzed and we performed morphological analyses by evaluating the area of parenchyma, stroma, acini, and ducts in both glands. Statistical analyses were performed by Student's t test and two-way ANOVA, adopting p < 0.05. No abnormal body weight was observed and data indicates that although both major salivary glands are susceptible to Al-induced oxidative stress, by increasing MDA and reducing GSH, only submandibular glands decreased the parenchyma and increased stroma area. Moreover, the submandibular glands showed smaller total area of acini and higher total area of ducts, in comparison with the control group. Notably, AlCl3 induces oxidative stress in both glands, however, submandibular glands showed to be more susceptible to Al effects than parotid glands. Our study gives evidences about Al toxicity in parotid and submandibular glands and claims for new investigations to understand more mechanisms of Al-induced toxicity.

Mitochondrial Dysfunction and Alpha-Lipoic Acid: Beneficial or Harmful in Alzheimer's Disease?

Alzheimer's disease (AD) is a neurodegenerative disorder characterised by impairments in the cognitive domains associated with orientation, recording, and memory. This pathology results from an abnormal deposition of the ß-amyloid (Aß) peptide and the intracellular accumulation of neurofibrillary tangles. Mitochondrial dysfunctions play an important role in the pathogenesis of AD, due to disturbances in the bioenergetic properties of cells. To date, the usual therapeutic drugs are limited because of the diversity of cellular routes in AD and the toxic potential of these agents. In this context, alpha-lipoic acid (α-LA) is a well-known fatty acid used as a supplement in several health conditions and diseases, such as periphery neuropathies and neurodegenerative disorders. It is produced in several cell types, eukaryotes, and prokaryotes, showing antioxidant and anti-inflammatory properties. α-LA acts as an enzymatic cofactor able to regulate metabolism, energy production, and mitochondrial biogenesis. In addition, the antioxidant capacity of α-LA is associated with two thiol groups that can be oxidised or reduced, prevent excess free radical formation, and act on improvement of mitochondrial performance. Moreover, α-LA has mechanisms of epigenetic regulation in genes related to the expression of various inflammatory mediators, such PGE2, COX-2, iNOS, TNF-α, IL-1ß, and IL-6. Regarding the pharmacokinetic profile, α-LA has rapid uptake and low bioavailability and the metabolism is primarily hepatic. However, α-LA has low risk in prolonged use, although its therapeutic potential, interactions with other substances, and adverse reactions have not been well established in clinical trials with populations at higher risk for diseases of aging. Thus, this review aimed to describe the pharmacokinetic profile, bioavailability, therapeutic efficacy, safety, and effects of combined use with centrally acting drugs, as well as report in vitro and in vivo studies that demonstrate the mitochondrial mechanisms of α-LA involved in AD protection.

Comparison of the Effects of Brazil Nut Oil and Soybean Oil on the Cardiometabolic Parameters of Patients with Metabolic Syndrome: A Randomized Trial.

Recent evidence suggests that replacing saturated fat with unsaturated fat is beneficial for cardiovascular health. This study compared the effects of Brazil nut oil (BNO) and soybean oil (SO) supplementation for 30 days on anthropometric, blood pressure, biochemical, and oxidative parameters in patients with metabolic syndrome (MS). Thirty-one patients with MS were randomly allocated to receive 30 sachets with 10 mL each of either BNO (n = 15) or SO (n = 16) for daily supplementation. Variables were measured at the beginning of the study and after 30 days of intervention. No change in anthropometric and blood pressure variables were observed (p > 0.05). Total (p = 0.0253) and low-density lipoprotein (p = 0.0437) cholesterol increased in the SO group. High-density lipoprotein cholesterol decreased (p = 0.0087) and triglycerides increased (p = 0.0045) in the BNO group. Malondialdehyde levels decreased in the BNO group (p = 0.0296) and total antioxidant capacity improved in the SO group (p = 0.0110). Although the addition of oils without lifestyle interventions did not affect anthropometric findings or blood pressure and promoted undesirable results in the lipid profile in both groups, daily supplementation of BNO for 30 days decreased lipid peroxidation, contributing to oxidative stress reduction.

Neuroprotective Mechanisms of Resveratrol in Alzheimer's Disease: Role of SIRT1.

Alzheimer's disease (AD) is a progressive and neurodegenerative disorder of the cortex and hippocampus, which eventually leads to cognitive impairment. Although the etiology of AD remains unclear, the presence of ß-amyloid (Aß) peptides in these learning and memory regions is a hallmark of AD. Therefore, the inhibition of Aß peptide aggregation has been considered the primary therapeutic strategy for AD treatment. Many studies have shown that resveratrol has antioxidant, anti-inflammatory, and neuroprotective properties and can decrease the toxicity and aggregation of Aß peptides in the hippocampus of AD patients, promote neurogenesis, and prevent hippocampal damage. In addition, the antioxidant activity of resveratrol plays an important role in neuronal differentiation through the activation of silent information regulator-1 (SIRT1). SIRT1 plays a vital role in the growth and differentiation of neurons and prevents the apoptotic death of these neurons by deacetylating and repressing p53 activity; however, the exact mechanisms remain unclear. Resveratrol also has anti-inflammatory effects as it suppresses M1 microglia activation, which is involved in the initiation of neurodegeneration, and promotes Th2 responses by increasing anti-inflammatory cytokines and SIRT1 expression. This review will focus on the antioxidant and anti-inflammatory neuroprotective effects of resveratrol, specifically on its role in SIRT1 and the association with AD pathophysiology.