Unraveling the neuroprotective mechanisms of naltrexone against aluminum-induced neurotoxicity.

Aluminum (Al) is a known neurotoxic trace element linked to Alzheimer's disease (AD). Naltrexone, an opioid antagonist, has shown promising effects in reducing neuroinflammation at lower doses than those prescribed for addiction. This study aimed to determine the neuroprotective effects of naltrexone on Al-induced neurotoxicity in an in vitro AD model. The SH-SY5Y cells were first cultivated in a standard growth medium. Subsequently, the cells were induced to differentiate by decreasing the concentration of fetal bovine serum and introducing retinoic acid (RA) into the culture media. Subsequently, the inclusion of brain-derived neurotrophic factor (BDNF) was implemented in conjunction with RA. The process of differentiation was concluded on the seventh day. Study groups (n = 3) were designed as the control group, naltrexone group, Al group, Al-Nal group, Alzheimer' model (AD) group, Alzheimer model + Al-exposed group (AD-Al), Alzheimer model + Nal applied group (AD-Nal) and Alzheimer model + Al-exposed + Nal applied group (AD-Al-Nal). Hyperphosphorylated Tau protein as the specific marker of AD was measured in all groups. Glycogen synthase kinase-3 (GSK-3)ß, Protein phosphatase 2A (PP2A), Akt and Wnt signaling pathways were analyzed comparatively. In addition, oxidative stress parameters (total antioxidant capacity, lipid peroxidase, protein carbonyl and reactive oxygen species) were measured comparatively in the study groups. The results showed that naltrexone reduced hyperphosphorylated tau protein levels by regulating GSK-3ß, PP2A, Akt and Wnt signaling. Also, exposure to naltrexone decreased oxidative stress parameters. Based on these results, naltrexone shows promise as a potential therapy for AD, subject to additional clinical assessments.

Antioxidant dihydrolipolic acid protects against in vitro aluminum-induced toxicity.

Dihydrolipoic acid (DHLA) is a natural antioxidant known for its ability to counteract metal toxicity and oxidative stress. It has shown the potential to safeguard cells from harmful environmental substances. It may hold therapeutic benefits in treating neurodegenerative disorders by defending against oxidative damage and chronic inflammation. Thus, this study aimed to explore the potential neuroprotective effects of DHLA against aluminum (Al)-induced toxicity using an Alzheimer's disease (AD) model in vitro. The study focused on two important pathways: GSK-3ß and the Wnt signaling pathways. The SH-SY5Y cell line was differentiated to establish AD, and the study group were as follows: control, Al, DHLA, Al-DHLA, AD, AD-Al, AD-DHLA, and AD-Al-DHLA. The impact of DHLA on parameters related to oxidative stress was assessed. The activity of the GSK-3ß pathway was measured by evaluating the levels of PPP1CA, PP2A, GSK-3ß, and Akt. The Wnt signaling pathway was assessed by measuring Wnt/ß-catenin in the different study groups. Exposure to DHLA significantly reduced oxidative stress by effectively decreasing the levels of reactive oxygen species, thereby protecting against protein oxidation and limiting the production of malonaldehyde. Moreover, the DHLA-treated groups exhibited a remarkable increase in the total antioxidant capacity. Furthermore, the study observed an upregulation of the Wnt signaling pathway and a downregulation of the GSK-3ß pathway in the groups treated with DHLA. In summary, the neuroprotective effects of DHLA, primarily achieved by reducing oxidative stress and modulating critical imbalanced pathways associated with AD, indicate its potential as a promising addition to the treatment regimens of AD patients.

Role of aluminum exposure on Alzheimer's disease and related glycogen synthase kinase pathway.

Aluminum (Al) is an environmentally abundant metal that is not essential for life. There is considerable evidence that Al as a neurotoxic xenobiotic may play a role in the pathogenesis of neurodegenerative diseases like Alzheimer's disease (AD). Exposure to aluminum has been shown to cause neuronal damage that resembles the symptoms of AD. In this review, we will summarize recent data about Al as the possible risk of incidence of AD. Then glycogen synthase kinase-3 beta (GSK3ß) contributes to the hyperphosphorylation of Tau protein, the main component of neurofibrillary tangles, one of the hallmarks of AD as one of the mechanisms behind Al neurotoxicity will be covered. Overall, there is still a need for epidemiological studies and more in vivo and in vitro studies to determine the exact mechanisms of its neurotoxicity and the role of GSK3ß in both Al toxic effect and AD.

Aluminium in cosmetics and personal care products.

Usage of inorganic ingredients like aluminium salts in cosmetics and personal care products has been a concern for producers and consumers. Although aluminium is used to treat hyperhidrosis, some worries have been raised about aluminium's role in breast cancer, breast cyst and Alzheimer's disease. The human population is exposed to aluminium from vaccines, diet, and drinking water, but the frequent use of aluminium-based cosmetics might add additional local exposure. This paper reviews literature to determine if aluminium-based products may pose potential harm to the body. The dermal absorption of aluminium is not widely understood. It is not yet known whether aluminium can travel from the skin to brain to cause Alzheimer's disease. Aluminium may cause gene instability, alter gene expression or enhance oxidative stress, but the carcinogenicity of aluminium has not been proved yet. Until now, epidemiological researches were based on oral information, which lacks consistency, and the results are conflicting. Future studies should target real-life-based long-time exposure to antiperspirants and other aluminium-containing cosmetics and personal care products.

The effects of season and gender on the serum aflatoxins and ochratoxin A levels of healthy adult subjects from the Central Anatolia Region, Turkey.

PURPOSE: This study was undertaken to determine the effects of season and gender on serum aflatoxin (AF) levels (AFG1, AFB1, AFG2 and AFB2) and ochratoxin A (OTA) concentrations of healthy adult population living in Central Anatolia Region of Turkey. METHODS: AF levels were measured by high-performance liquid chromatography (HPLC) and OTA levels were measured by enzyme-linked immunosorbent assay (ELISA) in serum samples of healthy adults (n = 233). RESULTS: In summer and winter, total AF levels in females were 0.98 ± 0.10 and 0.94 ± 0.12 ng/ml and in males 1.35 ± 0.17 and 0.93 ± 0.11 ng/ml, respectively. Male subjects had significantly higher serum total AF levels in summer compared with females (~38%). There was no marked seasonal change in AFG1, AFB1 and AFG2 concentrations in the whole population, except AFB2. Both of the genders had significantly higher OTA levels in winter compared with summer (~60%). CONCLUSIONS: Overall results suggest that Central Anatolia residents are continuously exposed to AFs and OTA. Besides, season and gender can be effective in mycotoxin exposure.

Serum aflatoxin levels of the healthy adult population living in the north and south regions of Turkey.

OBJECTIVE: To determine the serum concentrations of aflatoxin B1 (AFB1), aflatoxin B2 (AFB2), aflatoxin G1 (AFG1) and aflatoxin G2 (AFG2) in the healthy adult population living in both the Black Sea and Mediterranean regions of Turkey and to investigate the regional, seasonal and gender variability in aflatoxins (AF) exposure in these regions. DESIGN: Serum AFB1, AFB2, AFG1 and AFG2 concentrations were analysed by HPLC. Settings In total, four hundred and eighty-four serum samples were analysed. SUBJECTS: Four hundred and eighty-four healthy adult volunteers living in rural areas of the Black Sea and Mediterranean regions of Turkey were studied. RESULTS: The mean serum concentration of total AF in the Black Sea region was 1·33 ppb (min-max 0·15-3·38 ppb) and 0·90 ppb (min-max 0·18-2·48 ppb) for summer and winter, respectively. In the Mediterranean region, the mean serum concentration of total AF was determined as 0·55 ppb (range 0·04-1·72 ppb) for summer and 0·45 ppb (range 0·12-1·43 ppb) for winter. The total AF concentrations in serum samples were statistically higher in summer compared with winter for the two regions. The differences between the regions were statistically significant concerning all samples, with higher total AF concentrations in the Black Sea region. CONCLUSIONS: The overall results suggest that the Turkish population living in these two regions is continuously exposed to AF, particularly in the summer, and that mycotoxin contamination in food should be monitored routinely for food safety and human health.

Urinary lipid and protein oxidation products upon halothane, isoflurane, or sevoflurane anesthesia in humans: potential biomarkers for a subclinical nephrotoxicity.

OBJECTIVE: To investigate whether lipid and protein oxidation products are elevated and correlated with routine clinical markers of hepatic and renal function in patients anesthetized with halothane, isoflurane, or sevoflurane. METHODS: Urine and blood samples were collected from patient groups. Excretion of aldehydes, acetone, and o,o'-dityrosine was measured before and after anesthesia. Blood samples were analysed for clinical markers. RESULTS: Urinary concentrations of aldehydes, acetone, o,o'-dityrosine and glucose were significantly increased after anesthesia in halothane and sevoflurane groups earlier than clinical markers. Significant correlations were found in sevoflurane group. CONCLUSION: Lipid and protein oxidation contributes to subclinical sevoflurane nephrotoxicity. Oxidation products may serve as early biomarkers.

Evaluation of tetrahydrobiopterin pathway in operating room workers: changes in biopterin status and tryptophan metabolism.

The aim of the study was to evaluate the effect of anesthetics as operating room contaminants on tetrahydrobiopterin pathway in 40 operating room personnel and 30 healthy controls by measuring biopterin, dihydrobiopterin reductase, tryptophan, kynurenine and serotonin. Biopterin concentrations were 124 ± 12.3 µmol/mol creatinine in workers and 88 ± 5.7 µmol/mol creatinine in controls whereas kynurenine concentrations were 1.75 ± 0.09 µM and 1.95 ± 0.06 µM, respectively (both, p < 0.05). It can be claimed that enhanced biopterin and diminished kynurenine levels may play a triggering role in disruption of metabolic events in operating room personnel.

Mechanistic Biomarkers in Toxicology

Biomarkers are important parameters that are reliable, applicable, reproducible, and generally inexpensive. All biomarkers have a significant role in human health, especially mechanistic biomarkers, which are the most important for the prevention of toxic effects and diseases. They demonstrate the possibility of diagnosis, prognosis, recurrence, and spread of disease. Furthermore, they show the exposure levels to numerous chemical, biological, and physical agents. To date, the development and application of biomarkers require the knowledge of mechanisms underlying their production. Therefore, the present study focused on the possible mechanistic biomarkers.

N-acetylcysteine, a thiol antioxidant, decreases alveolar bone loss in experimental periodontitis in rats.

BACKGROUND: The purpose of this study was to analyze the morphometric and histopathologic changes associated with experimental periodontitis in rats in response to systemic administration of N-acetylcysteine (NAC). METHODS: Forty-three Wistar rats were divided into five experimental groups: non-ligated (NL) group (n = 10), ligature only (LO) group (n = 10), and groups that were administered NAC systemically (7, 35, or 70 mg/kg body weight per day [NAC7, NAC35, and NAC70 groups, respectively]; n = 8, 9, and 6). Silk ligatures were placed at the gingival margin of the lower first molars in a mandibular quadrant. The study duration was 11 days, and the animals were sacrificed at the end of this period. Changes in alveolar bone levels were measured clinically and tissues were histopathologically examined to assess the differences among the study groups. RESULTS: At the end of 11 days, the alveolar bone loss was significantly higher in the LO group compared to NL, NAC7, NAC35, and NAC70 groups (P <0.05). There was no statistically significant difference in the osteoclast numbers among the study groups (P >0.05), whereas the effect of NAC was dose-dependent. CONCLUSION: NAC prevented alveolar bone loss in the rat model, in a dose-dependent manner, when administered systemically.

Traditional Techniques Applied in Olive Oil Production Results in Lower Quality Products in Northern Cyprus.

OBJECTIVES: Olive oil production and its consumption is one of the traditional characteristics of Northern Cyprus. To date, no research has been conducted to analyze the quality of traditionally produced olive oil. Therefore, within this study, we aimed to analyze the olive oil produced within the island concomitant to the determination and comparison of its quality indices. MATERIALS AND METHODS: The standard olive oil analysis techniques acknowledged by the IOOC and ISO were employed. Accordingly, the fatty acid content, peroxide level, total phenol content, the levels of carotenoids and chlorophyll, as well as status of oxidation were all tested concomitant to statistical analysis. RESULTS: In contrast to the regional belief and consideration, the results indicated that the olive oil produced locally is highly exposed to oxidation and therefore, it is of lower quality according to the ISO guidelines. CONCLUSION: The traditional techniques employed for the production, distribution, and storage of olive oil within Northern Cyprus must be re-evaluated and controlled to satisfy the current standards required and employed globally.

Lycopene restores trace element levels in ochratoxin A-treated rats.

This study was designed to investigate the in vivo effects of ochratoxin A (OTA) and/or lycopene on the levels of selenium, zinc, and copper in the liver, kidneys, and testes of male Sprague-Dawley rats. The rats were treated with OTA (0.5 mg kg-1 day-1) and/or lycopene (5 mg kg-1 day-1) by gavage for 7 or 14 days. Trace element levels were measured by atomic absorption spectrometry. OTA significantly lowered selenium (20 % in the liver, 17 % in the kidney, and 40 % in the testis), zinc (24 % in the liver, 23 % in the kidney, and 26 % in the testis), and copper levels (40 % in the liver and 10 % in the kidney). Lycopene alone did not affect the trace element levels in any of the organs. In combination with OTA, however, it significantly restored liver, kidney, and testis selenium and zinc levels compared to the group treated with OTA alone. Our results have confirmed that depletion of trace elements in different organs is one of the mechanisms of action of OTA. They also suggest that lycopene interferes with this depleting effect and restores trace element levels, the implications of which need to be further investigated.

Assessment of Aflatoxin M1 and Heavy Metal Levels in Mothers Breast Milk in Famagusta, Cyprus.

Breast milk contributes towards optimal nutrition for infants. However, studies showed that it can also contain different toxins and heavy metals, which reduce its health benefits. The aim of this study is to determine the level of contaminants such as aflatoxin M1 (AFM1), Pb, Cd, As, and Hg in breast milk samples from Famagusta, Cyprus. Correlations between moldy food consumption, smoking habits of the mothers, and contaminant levels in breast milk were also investigated. Breast milk samples from 50 lactating mothers in rural and urban areas of Famagusta District were analyzed for AFM1 by ELISA. Eighty percent of them were found to be contaminated with AFM1 with the mean measurement of 7.84 ± 1.72 ng/l. Socio-demographic status, moldy food consumption habits, and smoking status do not have any effect on the AFM1 levels observed in breast milk. Heavy metal levels in breast milk were examined by inductively coupled plasma mass spectrometry, and the mean measurements were1.19 ± 1.53 ppm for Pb, 0.73 ± 0.58 ppm for As, 0 ± 0.20 ppm for Hg, and 0.45 ± 0.23 ppm for Cd. This study indicates that the levels of these contaminants in breast milk samples obtained in Famagusta District are well within the acceptable levels. However, the presence of AFM1 and heavy metals still may pose risks for infant health.

Effect of folic acid supplementation on aluminum accumulation in rats.

OBJECTIVE: Exposure to many xenobiotics may cause depletion of folic acid (folate), which is an essential vitamin for humans. Replacement of folate can be effective in protection against some diseases and in partial or total prevention of adverse effects related to xenobiotics. Aluminum (Al) is the most widely distributed metal in the outer crust of the earth. Its toxicity in humans is well known. However, there is no evidence that folate can decrease accumulation of Al to which humans can be exposed in many ways. The aim of the present study was to quantify organ Al accumulation and to evaluate whether there is any protective (or reductive) effect of folic acid on Al accumulation. METHODS: Male Wistar rats were assigned oral Al chloride (200 mg x kg(-1) x d(-1), n = 10, group 1) alone or in combination with folic acid (20 mg x kg(-1) x d(-1), n = 10, group 2) for 8 wk. At the end of the period, bone, kidney, brain, and blood samples were collected, and Al concentrations were determined by electrothermal atomic absorption spectrophotometry. RESULTS: Mean values of Al in the tissue samples from group 1 were higher than those from group 2 (all P < 0.05). No difference was observed in serum Al levels between groups (P > 0.05). CONCLUSION: These results suggest that folate supplementation might be useful to decrease Al accumulation in its main target organs, i.e., bone, kidney, and brain.

Effect of ionizing radiation on the pteridine metabolic pathway and evaluation of its cytotoxicity in exposed hospital staff.

Investigations carried out to estimate the effect of long-term occupational exposure to low levels of external ionizing radiation indicated that exposed hospital staff showed an increase in chromosome aberrations. The purpose of this study was to evaluate whether genomic instability or an alteration in pteridine synthesis could be used as a marker of the potential hazard of ionizing radiation in hospital workers. Twenty gamma-radiation- and 33 X-ray-exposed technicians working in radiotherapy and radio-diagnostic units were included in this study, along with 22 healthy matched individuals. Plasma concentrations of nitrite plus nitrate (NO(x)) were measured to estimate reactive nitrogen species. Urinary neopterin, biopterin and creatinine concentrations were measured by high-performance liquid chromatography to determine metabolic activity along the pteridine pathway. Sister chromatid exchange was used as a measure of mutagenicity. Apoptosis was evaluated morphologically and also with a DNA-fragmentation test. The plasma NO(x) levels of both gamma-radiation- and X-ray-exposed technicians were significantly higher than those of the healthy controls (p<0.05). While the urinary biopterin concentrations were significantly higher in radiation-exposed groups compared with the healthy subjects (p<0.05), urinary neopterin concentrations remained unchanged. The apoptosis rates of gamma-radiation- and X-ray-exposed workers were significantly elevated in comparison with those in the control group (both p<0.05). Also, the increase in sister chromatid exchange frequency was significant in each of the radiation-exposed groups (exposed groups versus controls; p<0.05). These results indicate that long-term exposure to low-dose ionizing radiation, even below the permitted levels, could result in increased oxidative stress, which may lead to DNA damage and mutagenicity.

Aflatoxin and ochratoxin in various types of commonly consumed retail ground samples in Ankara, Turkey.

To detect aflatoxin (AF) or ochratoxin A (OTA) contamination, 25 retail ground samples of 12 different types of seed-, pulses-, and cereal-flours and starches were randomly collected from markets and traditional bazaars in Ankara, Turkey. The levels of AF in the retail ground samples were determined by high performance liquid chromatography (HPLC) and ranged from 0.03-3.16 ppb. The percentage of contaminated samples for aflatoxin B(1), B(2), G(1), and G(2) were 64, 60, 72, and 76 %, respectively. The determination of OTA level was performed by enzyme-linked immunosorbent assay (ELISA), and they were ranged between 0.27-4.07 ppb (n=24). However, the screened mycotoxin levels in the samples were under the permission limits of Turkey, the daily intake of these products corresponds to at least 50 % of daily diet in our country. Routine measurements of the toxin levels in foods and feeds should be carried out to prevent their harmful effects on health.

Hepatoprotective effect of 17ß-estradiol as antioxidant modulators against stress damage.

BACKGROUND: Liver is one of the most important organs affected by exercise. According to the literature a few study to date has investigated the effects of estrogen supplementation on exercise-induced oxidative stress in liver tissue of rats. OBJECTIVES: We aimed to investigate the effects of estrogen supplementation on oxidative stress markers in liver tissue of exercised rats. MATERIALS AND METHODS: Male rats (n = 35) were divided as estrogen supplemented (n = 18) and non-supplemented groups (n = 17); these groups were further divided as rest and eccentric exercised groups. Eccentric exercise groups were further divided as rats killed after 1 hour and 48 hours of eccentric exercise. Estrogen (10 mg/kg) was administered subcutaneously for 30 days. Eccentric exercise was applied as treadmill run (15° downhill, 20 m/min) consisting of periods of "5 min" run and 2 min rest repeated 18 times. The rat liver was examined biochemically and histologically. Activities of GST, GSH-Px, CAT, SOD and MDA concentration were also measured spectrophotometrically. RESULTS: Some disruptions were detected in experimental groups compared with the control group. Additionally, exercise training caused an increase in SOD and decrease in GSH-Px activities in some experimental groups. SOD activities increased significantly in group 3 (Estrogen (-), eccentric exercise (+) killed (after 1 h), compared with group 5 (Estrogen (-), eccentric exercise (+) killed (after 48 h). On the other hand, GSH-Px activities were also significantly decreased in groups 3, 4 and 5 compared with the control group. Leukocyte infiltration in liver increased after 48 hours compared with after 1 hour and estrogen supplementation was not able to prevent this infiltration. CONCLUSIONS: Estrogen seemed to be not very effective to prevent eccentric exercise-induced liver damage.

Effects of the metals on dihydropteridine reductase activity.

Metals are the oldest toxins known to human. Particularly, occupational and environmental exposure to aluminium, lead, mercury, cadmium, and manganese cause serious health problems by interaction with biological systems. Cellular targets of these metals are mostly specific biochemical processes (enzymes) and/or membranes of cells and organelles. To prevent and/or reduce the untoward or irreversible toxic effects of the metals by using biomarkers are as important as to know and to understand of their toxicity mechanisms. Dihydropteridine reductase (DHPR), which possessed essential thiol groups at the activity site, plays a crucial role in the maintenance of tetrahydrobiopterin (BH4). BH4 is the cofactor in the synthesis and regulation of neurotransmitters. A limited number of the evidences have shown that DHPR may be a target for the metals. Therefore, the present study was designed to assess possible in vitro effects of the commonly exposed metals on the enzyme activity. It was found that aluminium, cadmium, mercury, di-phenyl mercury, lead, diethyl lead, in chloride forms, and manganese, in sulphate form, led to statistically significant decreases in DHPR activity, in a concentration-dependent manner, in vitro.

Level of neopterin, a marker of immune cell activation in gingival crevicular fluid, saliva, and urine in patients with aggressive periodontitis.

BACKGROUND: Neopterin, a marker of cellular immune activation, is produced by human macrophages after induction by interferon gamma that is secreted by T lymphocytes. Neopterin concentrations in diverse body fluids have been reported to increase in parallel with bacteria in the clinical course of infections. Therefore, determination of neopterin in body fluids was thought to be useful for predicting the prognosis and diagnosis of aggressive forms of periodontal disease, in which the cell-mediated immune response plays an important role in immunopathogenesis. The aim of the present study was to observe the role of neopterin in the pathogenesis of aggressive periodontitis (AgP). METHODS: Thirteen individuals who were systemically and periodontally healthy and 16 systemically healthy individuals diagnosed with AgP were recruited for this study. Mixed saliva and urine samples were collected from each subject. Gingival crevicular fluid (GCF) samples were obtained from 6 teeth with > or =5 mm probing depth (PD). After evaluation of GCF amount from paper strips, enzyme-linked immunosorbent assay (ELISA) was employed to determine the amount of neopterin in urine, saliva, and GCF. RESULTS: The amount of neopterin in urine and saliva measured 235.77+/-405.31 micromol neopterin/mol creatinine and 9.85+/-7.66 nmol/l, respectively, for the AgP group and 225.45+/-100.72 micromol neopterin/mol creatinine and 5.25+/-5.76 nmol/l, respectively, for controls. The present data demonstrate that, while salivary neopterin levels were found to be significantly different between periodontitis and control subjects, there were non-significant differences in urine neopterin levels. The amount and concentration of neopterin in GCF measured was 18+/-12.75 nmol/l and 3.67+/-2.40 nmol/ml for the AgP group and 2.51+/-1.72 nmol/l and 3.88+/-4.50 nmol/ml for the control group. When total amounts of neopterin are taken into consideration, a significant difference between AgP and controls is shown; however, no significant difference in net concentration of neopterin was found between both groups. CONCLUSIONS: This study is the first report to evaluate the involvement of neopterin in AgP and this might be considered of value in understanding periodontal disease mechanisms.

Accumulation of aluminum in rat brain: does it lead to behavioral and electrophysiological changes?

The present study was undertaken to examine possible aluminum (Al) accumulation in the brain of rats and to investigate whether subchronic exposure to the metal leads to behavioral and neurophysiological changes in both treated and control groups. Each of the groups consisted of 10 animals. Aluminum chloride (AlCl3) at a low (50 mg/kg/d) or high (200 mg/kg/d) dose was applied to male Wistar rats by gavage for 8 wk. Al-free water by gavage was given to the control group throughout the experiment. Behavioral effects were evaluated by open-field (OF) motor activity and by acoustic startle response (ASR). Electrophysiological examination was done by recording spontaneous activity and sensory-evoked potentials from the visual, somatosensory, as well as auditory cortex. The Al content of each whole brain was determined by electrothermal atomic absorption spectrophotometry. Subchronic Al exposure slightly caused some changes in the evoked potentials and electrocorticograms and in the OF and ASR performance, but these results were not statistically significant. The brain Al levels of the control and the low and high dose of Al-exposed groups were measured as 0.717+/-0.208 microg/g (wet weight), 0.963+/-0.491 microg/g (wet weight) and 1.816+/-1.157 microg/g (wet weight), respectively.