Search

Purpose: Aluminum trichloride (AlCl 3 ) exposure was proven to encourage some behavioral deficits and eventually induces anxiety and depression in rodents animals. Therefore, this experiment aimed to scout about the effects of pomegranate juice on anxiety- and depression-like behaviors caused by AlCl 3 in male mice., Methods: Six groups of male mice were administrated orally for 35 days by PJ and AlCl3. The control group (G-I) received tap water, while the PJ groups (G-II and G-III) were treated with 20 % and 40 % PJ, respectively. The AlCl 3 group (G-IV) was treated with 400 mg/kg/day of AlCl 3, and the last two groups (G-V and G-VI) were treated with AlCl 3 and 20 % PJ or 40 % PJ, respectively. Then, the open-field (O-F), elevated plus maze (EPM), tail suspension (TS), forced swimming (FS), and light/dark box (L/DB) tests were applied for anxiety- and depression-like behavior studies. In addition, neurotransmitters and oxidative parameters in the brain were evaluated. The plasma cortisol was measured at the end of the experiment., Results: Behavioral analyses showed that PJ inhibited AlCl 3 -induced depressive and anxiogenic effects in the O-F, EPM, TS, FS, L/DB tests. In addition, neurochemical results indicated that PJ at 20 % concentration minimized the AlCl 3 toxicity on dopamine (DOP), serotonin (SER), and acetylcholinesterase (AChE) levels in the for-brain of male mice. Moreover, PJ moderated the AlCl 3 effects by decreasing the level of thiobarbituric acid reactive substances (TBARS), and enhancing catalase (CAT), superoxide dismutase (SOD), glutathione S-transferase (GST) and glutathione (GSH) activities. The plasma cortisol increased in male mice treated with AlCl3 and in a group treated with a high dose of PJ., Conclusion: Our results proposed that the anxiety- and depression-like behaviors induced by AlCl 3 exposure in male mice can be ameliorated by PJ treatment, probably through the inhibition of oxidative damage and minimizing the changes in neurotransmitters and hormonal activity., (Copyright © 2021 Elsevier GmbH. All rights reserved.)

Amyloid-β (Aβ) peptides play a key role in Alzheimer's disease (AD), the most common type of dementia. In this study, a polysaccharide from Bletilla striata (BSP), with strong antioxidant and anti-inflammatory properties, was extracted using a low-temperature method and tested for its efficacy against AD, in vitro using N2a and BV-2 cells, and in vivo using an AD rat model. The characterization of the extracted BSP for its molecular structure and functional groups demonstrated the effectiveness of the modified method for retaining its bioactivity. In vitro, BSP reduced by 20% reactive oxygen species (ROS) levels in N2a cells ( p = 0.0082) and the expression levels of inflammation-related genes by 3-fold TNF-α ( p = 0.0048), 4-fold IL-6 ( p = 0.0019), and 2.5-fold IL-10 ( p = 0.0212) in BV-2 cells treated with Aβ fibrils. In vivo, BSP recovered learning memory, ameliorated morphological damage in the hippocampus and cortex, and reduced the expression of the β-secretase protein in AlCl 3 -induced AD rats. Collectively, these findings demonstrated the efficacy of BSP for preventing and alleviating the effects of AD.

Myrcene (Myr) has been reported to show neuroprotective effects in cerebral ischemia. In this research work, we investigated the Myr effect on neurobehavioural, and neuropathological alteration in mice induced by Aluminium trichloride (AlCl 3 ) and D - galactose. The administration of AlCl 3 (5 mg/kg; p. o.), and D - galactose (60 mg/kg; i. p.) for 90 days in mice resulted in spatial learning and memory deficits, cognitive decline, as well as neurotoxicity. The treatments with Myr low dose (100 mg/kg), Myr high dose (200 mg/kg), donepezil (2 mg/kg), and Myr low dose + donepezil (100 + 2 mg/kg) were administered via intraperitoneal route for 30 days significantly reversed the neurobehavioral, and neuropathological effects of AlCl 3 and D - galactose in mice. The results of behavioural tests such as Morris water maze, elevated plus maze, and locomotor; biochemical analysis such as malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), nitrite, and acetylcholinesterase (AChE); and ELISA tests such as mouse β - secretase (BACE), amyloid-beta peptide 1-42 (Aβ 1 - 42 ), tumor necrosis factor - α (TNF-α), interleukin - 6 (IL-6), and brain-derived neurotrophic factor (BDNF) demonstrated a significant (p < 0.05) neuroprotective effect of the Myr and donepezil co-treatments. In addition, hematoxylin and eosin staining of the cerebral cortex and hippocampus revealed eosinophilic lesions and hyperchromatic nuclei in Alzheimer's disease mice, but treatments with Myr low dose, Myr high dose, donepezil, and Myr low dose + donepezil reversed these neurodegenerative effects. Myr showed these activities by enhancing synaptic plasticity and cholinergic activity, as well as reducing oxidative damage, neuroinflammation, Aβ 1-42 aggregations, and histopathological damage. Myr alone and in combination with donepezil may serve as a potential candidate for the treatment of Alzheimer's disease., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Neurological disturbances including cholinergic dysfunction, oxidative stress, neuroinflammation, and cognitive impairments are the well-reported consequences of old age-related disorders like Alzheimer's disease (AD) or dementia. Bisphosphonates were shown to ameliorate dementia in osteoporotic patients, neuroinflammation, and cholinesterase activity in rodents. Thus, the present study has been designed to examine the role of alendronate against cognitive and neurological disturbances in mice induced by a combined oral dose of d-galactose and aluminum chloride (AlCl 3 ) for 6 weeks. d-galactose acts as a senescence agent, whereas AlCl 3 is a neurotoxin and in combination generates neuropathologies and cognitive depletion resembling aging and AD. It was found that memory was markedly impaired in d-galactose + AlCl 3 -treated mice as assessed in different behavioral paradigms. Additionally, d-galactose + AlCl 3 led to neurotoxicity assessed on the basis of neuroinflammation, oxidative stress, glial cell activation, neuronal damage, and augmented GSK-3β level in mice hippocampus. Consequently, alendronate administration orally for 15 days in d-galactose + AlCl 3 -exposed mice prominently reversed all these behavioral and neuropathological changes. These findings show that alendronate can be a potential therapeutic molecule with multiple targets for the management of age-related neurological disorders such as AD., (© 2021 John Wiley & Sons, Ltd.)

Introduction: Aluminum is a kind of chemical contaminants in food which can induce neurotoxicity. Aluminum exposure is closely related to neurodegenerative diseases (ND), in which neuroinflammation might involve. However, the molecular mechanism of aluminum-induced neuroinflammation through pyroptosis is not fully clarified yet., Material and Methods: The mice model of subacute exposure to aluminum chloride (AlCl 3 ) was established. BV2 microglia cells was treated with AlCl 3 in vitro. Resveratrol (Rsv) was adopted as intervention agent., Results: Our results showed that aluminum induced cognitive impairment, destroying blood brain barrier (BBB), and causing nerve injury in mice. Meanwhile, aluminum could stimulate nucleotide oligomerization domain-like receptor family pyrin domain containing protein 3 (NLRP3) inflammasome assembly and activate caspase-1 (CASP1), inducing gasdermin D (GSDMD)-mediated pyroptosis signaling, releasing cytokines IL-1β and IL-18, further promoting the activation of glial cells to magnify neuroinflammatory response. Moreover, DEAD-box helicase 3 X-linked (DDX3X) and stress granule RasGAP SH3-domain-binding protein 1 (G3BP1) both participated in neuroinflammation induced by aluminum. When co-treated with Rsv, these injuries were alleviated to some extent., Conclusion: Aluminum exposure could induce nerve cell pyroptosis and neuroinflammation by DDX3X-NLRP3 inflammasome signaling pathway, which could be rescued via Rsv activating sirtuin 1 (SIRT1)., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases characterized by a progressive loss of memory and other cognitive functions among elder people. Nowadays, natural antioxidants have been used to recover the quality of life for those with AD. In this study, we investigated, for the first time, the combined effect of docosahexaenoic acid (DHA) and Ginkgo bilobastandardized extract (EGb761) on AD mice. AD was induced in adult male albino mice with AlCl 3 (20 mg/kg b.w, i.g.) and D-galactose (D-gal; 120 mg/kg, i.p.) for 90 days. 30 days after induction, mice were treated with DHA (200 mg/kg b.w., i.g.) and EGb761 (200 mg/kg b.w., i.g.) for two months. Our data revealed that the dual treatment of DHA and EGb761 significantly improved cognitive memory and spatial learning abilities in AD-induced mice. The drug treatments preserved the hippocampal CA3 architecture and restored neuronal ultrastructural alterations. Expression of protein phosphatase 2A (PP2A), the most implicated protein phosphatase in AD neurodegeneration, was highly upregulated in the CA3 hippocampus of AD mice treated with DHA and EGb761. Intriguingly, TNF-α expression was significantly reduced in the same group. In conclusion, our findings proved that the combined effect of DHA and EGb761 tended to be potent against the neurodegenerative effect of AlCl 3 and D-gal. The applied treatment enhanced neuronal survival and cognitive functions via upregulation of PP2A and restoration of TNF-α expression., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Aluminum (Al) is known to be hepatotoxic. Oxidative stress is the main mechanism of liver injury caused by Al, and can also lead to mitochondrial damage. Mitochondrial damage is a prerequisite for mitochondrial quality control (MQC) dysregulation. Parkin can activate MQC and maintain mitochondrial homeostasis. However, the role of Parkin-mediated MQC in Al-induced liver damage has not been elucidated. In this study, forty male wild type (WT) C57BL/6N mice were treated with 0, 44.825, 89.65 or 179.3 mg/kg body weight AlCl 3 in drinking water for 90 days, respectively. We found that Al induced mitophagy and disrupted mitochondrial dynamics and mitochondrial biogenesis. Then, twenty male WT C57BL/6N mice and twenty male Parkin knockout (Parkin -/- ) C57BL/6N mice were divided into four groups and treated with 0, 89.65, 0, 89.65 mg/kg body weight AlCl 3 in drinking water for 90 days, respectively. We found that Parkin -/- inhibited mitophagy and further disrupted mitochondrial dynamics and mitochondrial biogenesis. These results indicated that Parkin-mediated MQC could be disrupted by Al and protected against Al-induced liver damage., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Chromosome instability (CIN) consists of high rates of structural and numerical chromosome abnormalities and is a well-known hallmark of cancer. Aluminum is added to many industrial products of frequent use. Yet, it has no known physiological role and is a suspected human carcinogen. Here, we show that V79 cells, a well-established model for the evaluation of candidate chemical carcinogens in regulatory toxicology, when cultured in presence of aluminum-in the form of aluminum chloride (AlCl 3 ) and at concentrations in the range of those measured in human tissues-incorporate the metal in a dose-dependent manner, predominantly accumulating it in the perinuclear region. Intracellular aluminum accumulation rapidly leads to a dose-dependent increase in DNA double strand breaks (DSB), in chromosome numerical abnormalities (aneuploidy) and to proliferation arrest in the G2/M phase of the cell cycle. During mitosis, V79 cells exposed to aluminum assemble abnormal multipolar mitotic spindles and appear to cluster supernumerary centrosomes, possibly explaining why they accumulate chromosome segregation errors and damage. We postulate that chronic aluminum absorption favors CIN in mammalian cells, thus promoting carcinogenesis.

A sufficient quantitative understanding of aluminium (Al) toxicokinetics (TK) in man is still lacking, although highly desirable for risk assessment of Al exposure. Baseline exposure and the risk of contamination severely limit the feasibility of TK studies administering the naturally occurring isotope 27 Al, both in animals and man. These limitations are absent in studies with 26 Al as a tracer, but tissue data are limited to animal studies. A TK model capable of inter-species translation to make valid predictions of Al levels in humans-especially in toxicological relevant tissues like bone and brain-is urgently needed. Here, we present: (i) a curated dataset which comprises all eligible studies with single doses of 26 Al tracer administered as citrate or chloride salts orally and/or intravenously to rats and humans, including ultra-long-term kinetic profiles for plasma, blood, liver, spleen, muscle, bone, brain, kidney, and urine up to 150 weeks; and (ii) the development of a physiology-based (PB) model for Al TK after intravenous and oral administration of aqueous Al citrate and Al chloride solutions in rats and humans. Based on the comprehensive curated 26 Al dataset, we estimated substance-dependent parameters within a non-linear mixed-effect modelling context. The model fitted the heterogeneous 26 Al data very well and was successfully validated against datasets in rats and humans. The presented PBTK model for Al, based on the most extensive and diverse dataset of Al exposure to date, constitutes a major advancement in the field, thereby paving the way towards a more quantitative risk assessment in humans., (© 2021. The Author(s).)

Aluminum (Al), as a common environmental pollutant, causes osteoblast (OB) dysfunction and then leads to Al-related bone diseases (ARBD). One of the mechanisms of ARBD is oxidative stress, which leads to an increase in the production of reactive oxygen species (ROS). ROS can induce mitochondrial damage, thereby inducing mitophagy and apoptosis. But whether mitophagy and apoptosis mediated by ROS, and the role of ROS in AlCl 3 -induced MC3T3-E1 cell dysfunction is still unclear. In this study, MC3T3-E1 cells used 0 mM Al (control group), 2 mM Al (Al group), 5 mM N-acetyl cysteine (NAC) (NAC group), 2 mM Al and 5 mM NAC (Al + NAC group) for 24 h. We found AlCl 3 -induced MC3T3-E1 cell dysfunction accompanied by oxidative stress, apoptosis, and mitophagy. While NAC, a ROS scavenger treatment, restored cell function and alleviated the mitophagy and apoptosis. These results suggested that mitophagy and apoptosis mediated by ROS participate in AlCl 3 -induced MC3T3-E1 cell dysfunction., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Edaravone (Eda) is a free radical scavenger used in clinical trials for the treatment of ischemic stroke and amyotrophic lateral sclerosis. However, how Eda exerts its neuroprotective effects remains to be elucidated. We investigated the neuroprotective effects of Eda in cultured hippocampal neurons and in a mouse model of AlCl 3 /D-galactose-induced cognitive impairment. Eda protected hippocampal neurons by eliminating H 2 O 2 or glutamate-induced toxicity, leading to decreased cell viability and neurite shortening. Consistently, Eda restored impaired levels of BDNF, FGF2 and their associated signaling axes (including TrkB, p-Akt and Bcl-2) to attenuate neuronal death. In a mouse model of chemically-induced cognitive impairment, Eda restored the levels of BDNF, FGF2 and TrkB/Akt signaling axis to attenuate neuronal apoptosis, thereby ameliorating cognitive impairment. Meanwhile, the pro-inflammation was eliminated due to the restoration of pro-inflammatory factors such as TNF-α, IL-6, IL-1β, and NOS2. In summary, Eda is an effective drug for protecting neurons from neurotoxic injury. BDNF, FGF2, and their regulated pathways may be potential therapeutic targets for neuroprotection., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD) is a multifactorial neurological disorder associated with neuropathological and neurobehavioral changes, like cognition and memory loss. Pathological hallmarks of AD comprise oxidative stress, formation of insoluble β-amyloid (Aβ) plaques, intracellular neurofibrillary tangles constituted by hyperphosphorylated tau protein (P-tau), neurotransmitters dysbalanced (DA, NE, 5-HT, GABA and Glutamate) and metal deposition. Chronic exposure to metals like aluminium and copper causes accumulation of Aβ plaques, promotes oxidative stress, neuro-inflammation, and degeneration of cholinergic neurons results in AD-like symptoms. In the present study, rats were administered with aluminium chloride (200 mg/kg p.o) and copper sulfate (0.5 mg/kg p.o) alone and in combination for 28 days. Allicin (10 and 20 mg/kg i.p) was administered from day 7 to day 28. Spatial and recognition memory impairment analysis was performed using Morris water maze, Probe trial, and Novel Object Recognition test. Animals were sacrificed on day 29, brain tissue was isolated, and its homogenate was used for biochemical (lipid peroxidation, nitrite, and glutathione), neuro-inflammatory (IL-1β, IL-6 and TNF- α), neurotransmitters (DA, NE, 5-HT, GABA and Glutamate), Aβ (1-42) level, Al concentration estimation, and Na + /K + -ATPase activity. In the present study, aluminium chloride and copper sulfate administration increased oxidative stress, inflammatory cytokines release, imbalanced neurotransmitters' concentration, and promoted β-amyloid accumulation and Na + /K + -ATPase activity. Treatment with allicin dose-dependently attenuated these pathological events via restoration of antioxidants, neurotransmitters concentration, and inhibiting cytokine release and β-amyloid accumulation. Moreover, allicin exhibited the neuroprotective effect through antioxidant, anti-inflammatory, neurotransmitters restoration, attenuation of neuro-inflammation and β-amyloid-induced neurotoxicity.

Aluminum (Al) is known for its neurotoxicity for over a century and is reported to have specifically high toxicity for cholinergic system. The effect of Al on muscarinic acetylcholine receptors is widely reported, but its effect on nicotinic acetylcholine receptors (nAChRs) is less well known. The aim of this study was to determine the effects of Al on hippocampus dependent learning and memory, function and expression of nAChRs in the hippocampus. Al concentration and neurodegeneration were also measured in the hippocampus following Al treatment. The mice were treated with 250 mg/kg AlCl 3 .6H 2 O in drinking water for a period of 42 days. Results show that Al treated animals have significantly reduced spatial reference memory as compared to control animals in Morris water maze test. Similarly, Al treated animals showed reduced contextual memory for Pavlovian fear compared to control animals. Al treated animals show higher anxiety in elevated plus maze as compared to control animals. The analysis of nAChR expression via RT-PCR showed reduced expression of α7 , α4 and β2 nAChR gene expression in the hippocampus of Al treated animals. High Al accumulation was observed in Al-treated animals (688.14 ± 242.82 μg/g) compared to the control group (115.14 ± 18.18 μg/g) that resulted in severe neurodegeneration in the hippocampus. These results demonstrated that Al exposure caused neurotoxicity in mice hippocampus which is manifested by reduced memory and elevated anxiety. The results were further validated by high Al accumulation in the hippocampus, severe neurodegeneration and reduced expression of nAChRs.

Aluminum is well recognized as a nephrotoxic agent. Its hazardous effects arise from the high risk of daily exposure. The consumption of fructose also represents a critical health issue that might negatively impact different organs, including the kidneys. To pursue our previous work, this study aimed to investigate the potential renoprotective effects of glycyrrhizic acid (GLYA) on aluminum-induced nephrotoxicity in insulin-resistant rats. Insulin resistance (IR) was induced by adding fructose (10%) in drinking water for 18 weeks. Male Wistar rats were divided into five groups: control (CTRL), aluminum chloride (ALM, 34 mg/kg/day), fructose (FRCT), aluminum plus fructose (AL/FR), and GLYA (rats received AL/FR and treated with 40 mg/kg GLYA daily). AL/FR resulted in abnormal renal function tests and renal tissue injury. This was associated with increased oxidative stress and inflammation in the renal tissue. Moreover, the expressions of the toll-like receptor 4 (TLR4) and its adaptor proteins were increased in AL/FR group. The administration of GLYA mollified AL/FR-induced renal injury, oxidative stress, activation of the TLR4 signaling pathway, and inflammation. In conclusion, we provide evidence for the promising renoprotective effect of GLYA against AL/FR-induced kidney damage in rats. The renoprotection is attributed to the suppression of oxidative stress and inhibition of the TLR4/NF-κB signaling pathway in the kidneys.

This study aimed to evaluate the effect of daily sublethal doses of aluminum (Al) on hematological, physiological, biochemical, and behavioral changes in male albino Wistar rats. In addition, Al tissue accumulation and histopathological changes in the cerebral cortex, liver, and kidney were examined. The rats were randomly separated into three groups. Group 1 included rats who received the median deadly dose (LD 50 ) of aluminum chloride (AlCl 3 ), group 2 served as the control, and group 3 was treated with a non-lethal dose of AlCl 3 (1.5 mg/kg) intraperitoneally for 45 days. At defined time intervals, hepatic and renal specific enzymes and biochemical activity were measured. In addition, we examined Al accumulation, the condition of the liver via histological methods, and the impact on the cerebral cortex. In comparison to the controls, rats treated with AlCl 3 exhibited a rise in AST, ALT, and ALP enzyme activity. We also saw a significant decrease in body weight and a decrease in total protein, lipids, cholesterol, acetylcholinesterase (AChE), RBCs, and Hb levels compared to the control group. Histopathological examination suggested severe changes in the liver, kidney, and cerebral cortex of the rats. The current study indicates that sublethal daily exposure to AlCl 3 causes hazardous effects, as increased Al concentration in the body is shown to induce detrimental biochemical and histological changes as well as decreased body weight. Therefore, careful attention should be given to treatments requiring long exposure in patients and the potential for accumulation via food and drinking.

Background: Aluminum toxicity induces neurodegenerative changes in the brain and results in Alzheimer's disease (AD)., Objective: Here, the aim was to evaluate the antioxidant therapeutic effects of ellagic acid (EA) and EA-loaded nanoparticles (EA-NP) in an aluminum chloride-induced AD rat model., Methods: The nanoparticles' loading of EA was 0.84/1 w/w. The in vitro release kinetics of EA from EA-NP in fetal bovine serum showed 60% release in the first 1-5 hours, followed by sustained release at 60-70% over 6-24 hours. Six groups were implemented; group 1 served as the control, group 2 received EA, group 3 received EA-NP, group 4 was the AD rat model administered AlCl3 (50 mg/kg) for 4 weeks, groups 5 (AD+EA) and 6 (AD+EA-NP) were treated with EA and EA-NP, respectively, for 2 weeks after AlCl3 was stopped. The neurotoxicity in the rat brain was examined by measuring the brain antioxidant biomarkers catalase, glutathione, and total antioxidant activity and lipid peroxidation (thiobarbituric acid, TBA). Histopathological studies using hematoxylin and eosin, cresyl violet, silver stains, and the novel object recognition test were examined., Results: Data revealed significant increase of antioxidant biomarkers and decreased TBA in the EA-NP group. The pathological hallmarks of AD-vacuolation of the neurons, chromatolysis, neurofibrillary tangles, and the senile plaques in brains of the AD rat model were decreased and restoration of Nissl granules was noted. The calculated discrimination index in the behavioral test increased more in cases treated with EA-NP., Conclusion: The treatment of AD with EA-NP was more effective than EA in alleviating the oxidative neurotoxic effects on AD rat brains., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

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 AlCl 3 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., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Growing evidences suggest the presence of several similarities in the molecular mechanisms underlying the neurodegenerative diseases and metabolic abnormalities. Adults who develop Metabolic Syndrome (MS) are at a higher risk of developing Alzheimer's disease (AD). Pharmacological agents, like dipeptidyl peptidase-4 (DPP-4) inhibitors that increase the levels of glucagon like peptide 1 (GLP-1) and ameliorate symptoms of MS, have become an auspicious candidate as disease modifying agents in the treatment of AD. The present study investigates the beneficial effects of Vildagliptin, a DPP-4 inhibitor in counteracting cognitive decline in different models of dementia targeting the AKT, JAK/STAT signaling pathways and hippocampal Klotho expression, to judge the neuroprotective, anti-apoptotic and anti-inflammatory effects of the drug. Cognitive decline was induced by either administration of high fat high sugar (HFHS) diet for 45 days alone, or with oral administration of AlCl 3 (100 mg/kg/day) for 60 days. Rats were orally administered Vildagliptin (10 mg/kg) for 60 days along with AlCl 3 administration. Vildagliptin treatment improved spatial memory and activities in morris water maze (MWM) test and open field test respectively. Results revealed an increase of both hippocampal klotho and Bcl-2 expressions along with an increase in both AKT and ERK1/2 phosphorylation. In contrast, Vildagliptin treatment decreased hippocampal contents of inflammatory, apoptotic and oxidative stress biomarkers as TNF-α, caspase-3 and FOXO1 along with restoring metabolic abnormalities. A significant decrease in BAX expressions with JAK2/STAT3 inhibition was observed. These findings demonstrate that the neuroprotective role of vildagliptin is possibly via modulating Klotho protein together with AKT pathway., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Accumulation of aluminium (Al) in the brain is known to be a toxic insult that result in neurodegenerative diseases and melatonin is known to have neuroprotective role. The present study was designed to investigate the neuroprotective effects of melatonin for aluminium chloride (AlCl 3 )-induced neurotoxicity in rats. Twelve-week old male Wistar rats were orally received 175 mg/kg AlCl 3 with or without 5 mg/kg melatonin intraperitoneal pretreatment. Group 3 intraperitoneally recieved 5 mg/kg melatonin and group 4 rats were orally treated with saline solution for 8 weeks. A series of behavioral tests, biochemical analysis and expression of AD-associated proteins in the brain were determined after 7 weeks of all treatments. Our results indicated that AlCl 3 treatment tends to induce memory and cognitive impairment. However, melatonin treatment attenuated amyloid beta (Aβ) (1-42) level by decreasing β-secretase, augmented low-density lipoprotein receptor-related protein 1, and neprilysin protein expression. Moreover, AlCl 3 -induced endoplasmic reticulum (ER) stress and oxidative stress was attenuated by melatonin supplementation. In conclusion, these findings demonstrate a protective role of melatonin against Aβ peptide accumulation, ER stress and oxidative stress in the AlCl 3 -treated AD model. Hence, the melatonin supplement might be an alternative way to alleviate the development of AD., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The present study was designed to investigate the nephroprotective effect of bromelain against oxidative stress stimulated by aluminium chloride in rats. Rats were grouped as follows; group one was used as control while groups 2, 3 and 4 were treated orally with bromelain (250 mg/kg, daily), aluminium chloride (AlCl 3 ; 34 mg/kg BW, every other day) and bromelain plus AlCl 3 for 30 days, respectively. Administration of AlCl 3 caused a significant reduction in rats' body and kidney weights, and increased Al accumulation in kidney tissue. Also, AlCl 3 treatment elevated thiobarbituric acid reactive substances, hydrogen peroxide, kidney functions biomarkers levels and lactate dehydrogenase activity. While enzymatic (SOD, CAT, GPx, GR, GST) and non-enzymatic (GSH) antioxidants, protein content, and alkaline phosphatase activity were significantly decreased. In addition, significant alterations in lipid and protein profiles were detected. Furthermore, histopathological and immunohistochemical variations were seen in kidney sections supporting the obtained biochemical changes. Otherwise, rats supplemented with bromelain singly declined lipid peroxidation and improved most of the studied parameters. Moreover, rats pretreated with bromelain followed by AlCl 3 intoxication showed significant alleviation in lipid peroxidation, antioxidant status and biochemical indices with respect to AlCl 3 treated group. Conclusively, bromelain has beneficial protective effects and has the capability to counteract the toxic influence of AlCl 3 . So, bromelain might represent a novel approach in the therapy of metal toxicity because of its antioxidant and chelating properties., (Copyright © 2020 Elsevier B.V. All rights reserved.)

A large number of studies showed that aluminum (Al) has potential neurotoxicity to human and animal bodies. Al-treated animals showed anxiety-like behavior, oxidative stress, neuroinflammation and γ-aminobutyric acid (GABA) changes. Bergamot essential oil (BEO) is a kind of well-known plant extract from the fresh fruit of bergamot. Previous studies suggested that BEO improved mood and relieved symptoms of stress-induced anxiety. This study was designed to study the effects of BEO on anxiety-like behavior, oxidative stress, neuroinflammation and GABA system in aluminum trichloride (AlCl 3 ) treated rats. Results showed that AlCl 3 exposure induced anxiety-like behavior in the elevated plus maze and the open field test. Moreover, AlCl 3 exposure decreased the level of GABA and the activity of glutathione peroxidase (GPx), catalase (CAT) and superoxide dismutase (SOD) in the hippocampus (HP) and the frontal cortex (FC). In addition, AlCl 3 exposure increased the levels of malondialdehyde (MDA) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) and the levels of interleukin-1 beta (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) in the HP and the FC. To the contrary, co-administration of BEO and AlCl 3 improved the anxiety-like behavior, GABA system, oxidative stress and neuroinflammation. These results indicated that BEO can alleviate the anxiety-like behavior of AlCl 3 -exposed rats through the combined action of antioxidant, anti-inflammatory and GABA regulation., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The study was to investigate the effects of flavonoids (rutin, puerarin, and silymarin) on learning and memory function in rats exposed to aluminum chloride (AlCl 3 ). Wistar rats were administered flavonoids at a dose of 100 mg/(kg·bw)/day or 200 mg/(kg·bw)/day after exposed to 281.40 mg/(kg·bw)/day AlCl 3 ·6H 2 O. The results of Morris water maze suggested that rutin and puerarin increased the frequency of crossing the platform and swimming time spent in the target quadrant of AlCl 3 -induced rats significantly. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay indicated that three flavonoids could alleviate apoptosis of hippocampal neurons induced by AlCl 3 . Real time-PCR and western blot suggested that rutin, puerarin and 100 mg/(kg·bw)/day silymarin could decrease the AlCl 3 -induced high expression of Bcl-2 associated X protein (Bax) mRNA and protein in hippocampus, but the expression of B cell lymphoma/leukemia-2 (Bcl-2) mRNA and protein was not significantly different among groups. Flavonoids could up regulate the low expression of autophagy related proteins (Beclin 1 (Bcl-2-interacting protein with a coiled-coil domain 1) and LC3 (microtubule-associated protein 1 light chain 3)) caused by AlCl 3 exposure. Flavonoids could also adjust the change in adenosine triphosphatase, superoxide dismutase, glutathione peroxidase and malondialdehyde induced by intake of AlCl 3 . The results of inductively coupled plasma atomic emission spectroscopy (ICP-AES) suggested that flavonoids could effectively reduce the high Al level in brain and serum of AlCl 3 exposed rats. In conclusion, three flavonoids may improve learning and memory function by inhibiting excessive apoptosis and oxidative stress in AlCl 3 exposed rats., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Methylphenidate (MPH), a psychotropic medication is commonly used for children with attention deficit hyperactivity disorder (ADHD). In this study we elucidated the neuroprotective and anti-inflammatory effects of MPH and Rosmarinus officinalis (rosemary) extract, an ancient aromatic herb with several applications in traditional medicine. Briefly, six groups of mice (n = 8 each group), were specified for the study and behavioral analysis was performed to analyze spatial memory followed by histological assessment and gene expression analysis of synaptic (Syn I, II and III) and inflammatory markers (IL-6, TNFα and GFAP) via qRT-PCR, in an AlCl 3 -induced mouse model for neurotoxicity. The behavioral analysis demonstrated significant cognitive decline, memory defects and altered gene expression in AlCl 3 -treated group. Rosemary extract significantly decreased the expression of inflammatory and synaptic markers to the similar levels as that of MPH. The present findings suggested the neuroprotective potential of Rosmarinus officinalis extract. However, further characterization of its anti-inflammatory and neuroprotective properties and MPH is required to strategize future treatments for several neurological and neurodegenerative disorders, including Alzheimer's disease.

Since the industrial revolution, all living beings have become susceptible to numerous sources of aluminum (Al) exposure. In addition to causing proven toxicity in many organs and systems, Al can also have estrogenic activity when absorbed by the body. The reproductive organs are commonly affected by environmental pollutants with estrogenic activity, but little is known about the effects of Al on the prostate and gonads. Therefore, the aim of this study was to evaluate the effects of subchronic Al exposure on the prostate and gonads of male and female adult gerbils. After 30 days of oral exposure to aluminum chloride (10 mg/kg/day), the animals were euthanized and the organs processed for cytochemical, ultrastructural, and biochemical assays. Ventral male prostates exposed to Al became hyperplastic and showed signs of cell aging. In addition, the male prostate showed decreased catalase (CAT) and superoxide dismutase (SOD) activity. The female prostate was structurally more affected than the ventral male prostate, since it presented hyperplasia and punctual foci of inflammation and prostatic intraepithelial neoplasia. However, CAT and SOD activities did not change in this gland. In the testis, Al promoted immature germ cell detachment and degeneration, as well as reduced CAT activity. In the ovaries, Al caused reduction in folliculogenesis and decreased SOD activity. Together, these results indicate that Al is toxic to the prostate and gonads of adult gerbils and that continuous exposure to this metal can impair the fertility of individuals of both sexes., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Manufactured nanoparticles (NPs) can potentially cause negative effects on molecular (proteins and nucleic acids), subcellular, cellular, tissue, organ, and organism due to their unusual physicochemical characteristics. Ionizable NPs in water (e.g., Al 2 O 3 -NPs) may create toxic effects on aquatic animals. The present research determined the influences of Al 2 O 3 -NPs and appropriate concentrations of ionizing Al(III) using water-soluble AlCl 3 in zebrafish larvae (72 h post-fertilization, Danio rerio ) by analyzing transcriptional alterations of stress-associated genes ( rad51 , p53 , mt2 ) with quantitative real-time PCR (qRT-PCR). In addition, genotoxic effects of Al(III) and Al 2 O 3 -NPs were evaluated. The lethal concentrations that cause death of 50% (LC 50 ) of zebrafish larvae when exposed to 0-50 mg/l Al(III) and 0-500 mg/l Al 2 O 3 -NPs were 3.26 ± 0.38 and 130.19 ± 5.59 mg/l, respectively, for 96 h. A concentration-dependent increase was observed in the genotoxicity in cells of larvae exposed to Al(III) and Al 2 O 3 -NPs for 96 h. DNA damage was more severe in larvae exposed to Al(III) (41.0% tail) than that of Al 2 O 3 -NPs (21.8% tail). A complex induction of stress-associated genes was observed in fish and this induction was not directly related to the concentrations of Al(III) and Al 2 O 3 -NPs, although a significant induction was detected in mt2 gene of larvae exposed to Al(III) and Al 2 O 3 -NPs relative to control group. The induction levels of mt2 were 4.13 ± 0.1 and 2.13 ± 0.1-fold change (mean ± S.E.M.) in larvae at 15 mg/l of Al(III) and 100 mg/l of Al 2 O 3 -NP concentrations, respectively.

Objective: To explore the role of calcium/calmodulin-dependent protein kinase Ⅱ(CaMK-Ⅱ) and protein phosphatase-2 A(PP2 A) on hyperphosphorylation of tau induced by AlCl&#95;3 in SH-SY5 Y cell., Methods: SH-SY5 Y cells were assigned to the control group, AlCl&#95;3 low, middle, high exposed groups(200, 400800 μmol/L Al~(3+)), KN93 intervention group(800 μmol/L Al~(3+)+0. 5 μmol/L KN93) and sphingosine intervention group(800 μmol/L Al~(3+)+5 nmol/L sphingosine). After 48 h of exposure and intervention, the viabilities of cells were measured by CCK-8 assay, the contents of CaMK-Ⅱ and PP2 A were determined by ELISA, and the expression of tau5 and phosphorylation of Thr-181, Thr-231, Ser-262 and Ser-396 were detected by Western-Blot., Results: The viabilities of cells in AlCl&#95;3 middle and high exposed groups were significantly lower than that of the control group(P&lt;0. 05). Compared with the AlCl&#95;3 high exposed group, the viabilities of cells in KN93 intervention group and sphingosine intervention group were significantly increased(P&lt;0. 05), as well as the difference of the cell viability between sphingosine intervention group and the control group was not statistically significant. Compared with the control group, the contents of CaMK-Ⅱin AlCl&#95;3 low, middle, high exposed groups were significantly increased(P&lt;0. 05), while the contents of PP2 A in those groups were significantly decreased(P&lt;0. 05). Compared with AlCl&#95;3 high exposed group, the contents of CaMK-Ⅱ in KN93 intervention group and sphingosine intervention group were significantly decreased(P&lt;0. 05), and PP2 A in those groups were significantly increased(P&lt;0. 05). The expression of tau5 and phosphorylation of Thr-181, Thr-231, Ser-396 in AlCl&#95;3 low, middle, high exposed group showed significantly higher than those of the control group(P&lt;0. 05), while the phosphorylation of Ser-262 in AlCl&#95;3 high exposed group showed significantly higher than that of the control group(P&lt;0. 05). After intervention with KN93 and sphingosine, the expression of tau5, and phosphorylation of Thr-181, Thr-231, Ser-262, Ser-396 in KN93 intervention group and sphingosine intervention group were significantly lower than those of AlCl&#95;3 high exposed group( P&lt;0. 05), as well as compared with the control group, the phosphorylation of Ser-262 in KN93 intervention group and Thr-181, Thr-231 and Ser-396 in sphingosine intervention group were not statistical difference., Conclusion: AlCl&#95;3 could increase the phosphorylation of Thr-181, Thr-231, Ser-262 and Ser396 in SH-SY5 Y cells, which mechanism may relate to the changes of CaMK-Ⅱand PP2 A. CaMK-Ⅱ mainly regulates the phosphorylation of Ser-262 induced by AlCl&#95;3, while PP2 A mainly regulates the phosphorylation of Thr-181, Thr-231 and Ser-396 induced by AlCl&#95;3. It is suggested that hyperphosphorylated tau protein induced by AlCl&#95;3 is closely related to PP2 A.

Human exposure to aluminum (Al) mainly occurs through food intake. However, influences of Al on the gastrointestinal tract have been rarely reported. In particular, the effect of Al on the metastasis and angiogenesis of colorectal cancer cells has not been studied. Thus, we investigated the effect of Al on the metastatic proclivity using the human colorectal cancer cell line, HT-29. Cells were exposed to 1-16 mM AlCl 3 for 3-72 h. The effects of AlCl 3 on HT-29 cells for migration/invasion/adhesion, and metastasis-associated protein and gene expression were evaluated. AlCl 3 promoted cell migration and invasion, whereas it suppressed cell adhesion. AlCl 3 -exposed cells showed decreased E-cadherin and increased vimentin and Snail. AlCl 3 increased transforming growth factor-beta (TGF-β) mRNA expression and Smad2/3 nuclear translocation. AlCl 3 -treated cells had a higher mRNA expression of matrix metalloproteinase (MMP)-7 and -9 than the control. Particularly, AlCl 3 -treated HT-29 cells promoted the angiogenesis of endothelial cells via increasing the secretion of vascular endothelial growth factor. Taken together, AlCl 3 can promote the metastatic proclivity of colorectal cancer cells through MMP-7, -9, and TGF-β/Smad2/3 pathway. Our data suggest that Al exposure of the gastrointestinal tract may be a risk factor for metastasis initiation in colorectal cancer cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by the formation of insoluble deposits of β-amyloid (Aβ) plaques within the parenchyma of the brain. The present study aimed to investigate the neuroprotective role of ethyl pyruvate against in vitro and in vivo model of aluminum chloride (AlCl 3 )-induced AD. Effect of ethyl pyruvate (5, 10, 20, 40 mM) against AlCl 3 (1250 μM)-induced neurotoxicity in primary neuron-glial mixed cell culture was evaluated using cell viability assays (MTT assay as well as calcein-AM/propidium iodide fluorescent dyes). In vivo model, AlCl 3 (50 mg/kg) were given through intraperitoneal route (i.p.) once daily for 4 weeks in rats and after 2 weeks, ethyl pyruvate (50, 100, 200 mg/kg/day) was co-administered with AlCl 3 once daily via the oral route. The present study, in addition to perform histopathology of the brain, also estimated oxidant and antioxidant parameters as well as memory impairment using pole test, plus maze, and Morris water maze test. The binding mode of ethyl pyruvate in the hMD-2 was also studied. Results of in vitro studies showed that the AlCl 3 administration resulted in neuronal cell death. AlCl 3 administration in rats resulted in memory loss, oxidative stress (increased lipid peroxide and nitric oxide), impairment of antioxidant mechanisms (superoxide dismutase, catalase, and reduced glutathione), and deposition of amyloid plaques in cerebral cortex region of the brain. AlCl 3 also resulted in the overexpression of the TLR4 receptors in the brain tissues. Administration of ethyl pyruvate ameliorated the AlCl 3 -induced neurotoxicity in neuron-glial mixed cell culture as well as histopathological, neurochemical, and behavioral consequences of chronic administration of AlCl 3 in the rat. Ethyl pyruvate showed a docking score of 4.048. Thus, ethyl pyruvate is effective against in vitro and in vivo models of AlCl 3 -induced AD.

Aluminum is a potent neurotoxin used in animal models of neurodegenerative diseases like Alzheimer's disease (AD), in which oxidative stress mediates tissue pathogenesis in vivo. N-acetyl cysteine (NAC) is a glutathione precursor with reported antioxidant and neuroprotective potentials. Recent therapy for combating AD is known to provide only symptomatic relief thus necessitating the discovery of new drugs and their mechanism of action. This study was aimed to demonstrate the in vivo neuroprotective effect of NAC against aluminum (Al 3+ )-induced neuro-degeneration in rats (a model for AD). Twenty- five (25) adult male Wistar rats used for this study were divided into 5 groups: Group A = Control, B = Aluminum chloride (200 mg/kg), C = 1000 mg/kg of NAC + Aluminum chloride (200 mg/kg), D = 1000 mg/kg of NAC, E = Aluminum chloride (200 mg/kg) was orally administered daily for 3 weeks and discontinued for one week. Frontal Cortex harvested for histological analysis using Haematoxylin and Eosin stain, Cresyl Fast Violet stain for Nissl granules and Glial fibrillary acidic protein immunohistochemistry specific for astrocytes. Aluminum significantly induced oxidative stress, coupled with marked neurons necrosis, chromatolysis and gliosis in the frontal cortex, upon NAC administration, there was neuro anti-inflammatory response as seen in the significant reduction in astrocytes expression, neuronal cell death and Nissl body aggregation which attenuates neuropathological deficits induced by Al 3+ . It was shown that aluminum is a neurotoxin mediating AD-like oxidative stress, NAC has a therapeutic potential associated with its potent in vivo interaction with astrocytes in response to Al 3+ neuro-inflammation seen in positive expression of Nissl granules and glial cells in addition to possibility of endogenous glutathione neuroprotection after withdrawal of stress mediator in neurodegeneration. Graphical abstract.

Ginsenoside Rg1 is the main active ingredient of Panax ginseng with the activity of neuroprotective, antioxidant and strengthening the immune system. Therefore, we hypothesized that Rg1 may afford anti-aging effects although the mechanism remains to be elucidated. In this study, chemically induced aging mice were established by consecutive administration of D-galactose and AlCl 3 . We found that Rg1 effectively ameliorates spatial learning and memory deficits in aging mice demonstrated by their improved performance in step down avoidance tests and Morris water maze experiments. Rg1 restored aging-induced decline of FGF2 and BDNF, reactivated TrkB/Akt signaling pathways in the hippocampus and prefrontal cortex to inhibit apoptosis, for the expression of anti-apoptotic protein Bcl-2 and apoptosis promoting enzyme cleaved-Caspase3 were antagonistically restored. Therefore, these results established the anti-aging effects of Rg1, and FGF2, BDNF and associated signaling pathways might be promising targets. Our data may provide a new avenue to the pharmacological research and diet therapeutic role of ethnic products such as Rg1 in anti-aging and aging associated diseases., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Aluminium is a ubiquitous element that occurs naturally in the soil making human exposure to it is unavoidable. Tyrosol is present in olive oil and is known to have antioxidant effects. Therefore, the present study explores the toxic effects of aluminium chloride (AlCl 3 ) and evaluates the possible protection by tyrosol in male rats. Testicular injury was induced by the administration of AlCl 3 (34 mg kg -1  day -1 ). Rats were treated with either tyrosol (20 mg kg -1 day -1 ) or AlCl3 (34 mg kg -1 day -1 ). The experiment lasted for 10 weeks. Biochemical, histopathological and protein expression profiles were determined to decipher the role of tyrosol in protecting the cellular damage. Further, histomorphometric analyses of testes showed deranged architecture along with other noted abnormalities. AlCl 3 group rats' testes showed decreased GSH levels, CAT activities, Nrf-2, HO-1, bcl-2 expressions and sperm motility whereas increased caspase-3 expressions, MDA levels, abnormal and dead/live sperm ratio. However, tyrosol treatment attenuated these changes. The present results demonstrate the beneficial role of tyrosol treatment in AlCl 3 induced testicular toxicity alterations of rat., (© 2019 Blackwell Verlag GmbH.)

Currently prescribed medications for the treatment of Alzheimer's disease (AD) that are based on acetylcholinesterase inhibition only offer symptomatic relief but do not provide protection against neurodegeneration. There appear to be an intense need for the development of therapeutic strategies that not only improve brain functions but also prevent neurodegeneration. The oxidative stress is one of the main causative factors of AD. Various antioxidants are being investigated to prevent neurodegeneration in AD. The objective of this study was to investigate the neuroprotective effects of naringenin (NAR) against AlCl3+D-gal induced AD-like symptoms in an animal model. Rats were orally pre-treated with NAR (50 mg/kg) for two weeks and then exposed to AlCl3+D-gal (150 mg/kg + 300 mg/kg) intraperitoneally for one week to develop AD-like symptoms. The standard drug, donepezil (DPZ) was used as a stimulator of cholinergic activity. Our results showed that NAR pre-treatment significantly protected AD-like behavioral disturbances in rats. In DPZ group, rats showed improved cognitive and cholinergic functions but the neuropsychiatric functions were not completely improved and showed marked histopathological alterations. However, NAR not only prevented AlCl3+D-gal induced AD-like symptoms but also significantly prevented neuropsychiatric dysfunctions in rats. Results of present study suggest that NAR may play a role in enhancing neuroprotective and cognition functions and it can potentially be considered as a neuroprotective compound for therapeutic management of AD in the future., Competing Interests: The authors have declared that no competing interests exist.

Objective: The present study aims to investigate the neuroprotective effect of caffeine against aluminum chloride (AlCl 3 )-induced neurotoxicity in rats. Methods: Twenty-one male albino rats were divided into 3 groups: control, AlCl 3 -intoxicated group that received daily oral administration of AlCl 3 (100 mg/kg for 30 days) and protected group injected daily with caffeine (20 mg/kg intraperitoneally) one hour before oral administration of AlCl 3 for 30 days. Levels of lipid peroxidation, reduced glutathione, and nitric oxide and the activities of acetylcholinesterase (AchE) and Na + /K + -ATPase were measured spectrophotometrically. Tumor necrosis factor-α (TNF-α) was evaluated by ELISA kit. Results: The data revealed evidence of oxidative and nitrosative stress in the cerebral cortex, hippocampus, and striatum of AlCl 3 -intoxicated rats. This was indicated from the increased levels of lipid peroxidation and nitric oxide together with the decreased level of reduced glutathione. Moreover, the daily AlCl 3 administration increased AchE and Na + /K + -ATPase activities and the level of TNF-α in the selected brain regions. Protection with caffeine ameliorated the oxidative stress induced by AlCl 3 in the cerebral cortex, hippocampus, and striatum. In addition, caffeine restored the elevated level of TNF-α in the hippocampus and striatum. This was accompanied by an improvement in the activities of AchE and Na + /K + -ATPase in the studied brain regions. Discussion and conclusions: The present findings clearly indicate that caffeine provides a significant neuroprotection against AlCl 3 -induced neurotoxicity mediated by its antioxidant, anti-inflammatory, and anticholinesterase properties.

The present study was designed to evaluate the effect of cranberry extract (CRAN) and/or losartan (LOS) against aluminium chloride (AlCl 3 ) induced hepatorenal damage associated cardiomyopathy in rats. To induce hepatorenal and cardiotoxicity, animals were received (AlCl 3 ; 70 mg/kg i.p.) for 8 weeks day after day and treated with CRAN (100 mg/kg b.wt.) orally daily for 4 weeks started after 4 weeks from AlCl 3 injection accompanied with an administration of LOS (5 mg/kg i.p.) three times weekly for 4 weeks. Our data revealed that, compared to AlCl 3 , administration of CRAN extract and LOS produced a significant improvement which was evidenced by a significant amelioration in myocardial and vascular indices, kidney and liver markers, lipid profile and oxidative stress indices. Furthermore, histopathological and immunohistochemical examination reinforced the previous results. It could be concluded that combination of CRAN extract and LOS hindered AlCl 3 induced hepatorenal damage complicated cardiomyopathy in rats.

Aluminum (Al) can be ingested from food and released from packaging and can reach key organs involved in human metabolism, including the liver via systemic distribution. Recent studies discuss the occurrence of chemically distinct Al-species and their interconversion by contact with biological fluids. These Al species can vary with regard to their intestinal uptake, systemic transport, and therefore could have species-specific effects on different organs and tissues. This work aims to assess the in vitro hepatotoxic hazard potential of three different relevant Al species: soluble AlCl 3 and two nanoparticulate Al species were applied, representing for the first time an investigation of metallic nanoparticles besides to mineral bound γ-Al 2 O 3 on hepatic cell lines. To investigate the uptake and toxicological properties of the Al species, we used two different human hepatic cell lines: HepG2 and differentiated HepaRG cells. Cellular uptake was determined by different methods including light microscopy, transmission electron microscopy, side-scatter analysis, and elemental analysis. Oxidative stress, mitochondrial dysfunction, cell death mechanisms, and DNA damage were monitored as cellular parameters. While cellular uptake into hepatic cell lines occurred predominantly in the particle form, only ionic AlCl 3 caused cellular effects. Since it is known, that Al species can convert one into another, and mechanisms including 'trojan-horse'-like uptake can lead to an Al accumulation in the cells. This could result in the slow release of Al ions, for which reason further hazard cannot be excluded. Therefore, individual investigation of the different Al species is necessary to assess the toxicological potential of Al particles.

Aluminum (Al) is a neurotoxin and is associated with the etiology of neurodegenerative diseases, such as Alzheimer's disease (AD). The Al-free ion (Al 3+ ) is the biologically reactive and toxic form. However, the underlying mechanisms of Al toxicity in the brain remain unclear. Here, we evaluated the effects of Al 3+ (in the chloride form-AlCl 3 ) at different concentrations (0.1-100 µM) on the morphology, proliferation, apoptosis, migration and differentiation of neural progenitor cells (NPCs) isolated from embryonic telencephalons, cultured as neurospheres. Our results reveal that Al 3+ at 100 µM reduced the number and diameter of neurospheres. Cell cycle analysis showed that Al 3+ had a decisive function in proliferation inhibition of NPCs during neural differentiation and induced apoptosis on neurospheres. In addition, 1 µM Al 3+ resulted in deleterious effects on neural phenotype determination. Flow cytometry and immunocytochemistry analysis showed that Al 3+ promoted a decrease in immature neuronal marker β3-tubulin expression and an increase in co-expression of the NPC marker nestin and glial fibrillary acidic protein. Thus, our findings indicate that Al 3+ caused cellular damage and reduced proliferation and migration, resulting in global inhibition of NPC differentiation and neurogenesis.

Background and Objectives: Environmental pollution with the different Aluminum (Al) containing compounds has been increased. Liver and kidney are two vital organs targeted by Al accumulation. The aim of this study was to assess the possible protective and curative effects of Lepidium sativum Linn (LS) against Al-induced impairment of liver and kidney in albino rat and to explore the mechanism behind this effect., Materials and Methods: This experimental animal-based study included fifty albino rats divided into five groups, the control, LS-treated (20 mg/kg), AlCl 3 -treated (10 mg/kg), AlCl 3 then LS, and AlCl 3 plus LS-treated, simultaneously for 8 weeks. At the end of the experiment, hepatic and renal functions as well as the biomarkers of antioxidants activities were assessed in the serum. Both liver and kidney were dissected out and histopathologically examined., Results: This study showed that administration of AlCl 3 caused a significant (p<0.05) reduction in rats body weight. It significantly increased serum AST, ALT, ALP, bilirubin, urea, and creatinine levels and decreased total protein and albumin. AlCl 3 significantly reduced enzymatic (catalase), nonenzymatic (reduced glutathione), and ferric reducing antioxidant power (FRAP) in the serum. Histopathologically, it induced necrosis and degeneration of hepatocytes, glomeruli, and renal tubules. Administration of LS after or along with AlCl 3 significantly restored the serum biomarkers of liver and kidney functions to their near-normal levels and had the ability to overcome Al-induced oxidative stress and preserved, to some extent, the normal hepatic and renal structure. The coadministration of LS had a superior effect in alleviating Al-induced changes., Conclusion: Exposure to AlCl 3 induced a set of functional and structural changes in the liver and kidney of rats evident through both biochemical and histopathological assessment. The antioxidant activity of LS seeds mediated a protective and curative effect of LS against such changes. Further study through a rigorous clinical trial to prove LS activity on human is recommended., Competing Interests: The author declares that they have no conflicts of interest.

The present study aimed to investigate whether melatonin (MT) treatment can attenuate immunotoxicity induced by aluminum chloride (AlCl 3 ) in rat spleen. Forty-eight healthy male Wistar rats were randomly allocated and treated with AlCl 3 and/or MT. Rats were orally administered with AlCl 3 for 90 days, from 61st days, rats were injected intraperitoneally with MT for 30 days. Firstly, we found that MT relieved the AlCl 3 -induced immunosuppression by improving spleen structural damage, CD3 + and CD4 + T lymphocyte subsets, IL-2 and TNF-α mRNA expressions and decreasing CD8 + T lymphocyte subsets. Secondly, MT attenuated the AlCl 3 -induced oxidative stress in rat spleen by decreasing the levels of ROS and MDA, while increasing the activities of SOD and CAT. Thirdly, MT relieved the AlCl 3 -induced apoptosis in rat spleen by increasing the MMP and Bcl-2 mRNA and protein expressions, while decreasing apoptosis rates, activity of Caspase-3 and pro-apoptotic gene expression. Finally, MT increased Nrf2 nuclear translocation, and Nrf2 target genes (HO-1, NQO1, SOD1 and CAT) mRNA expressions in the spleen of AlCl 3 -exposed rat. These results suggest that MT may alleviate AlCl 3 -induced immunotoxicity by inhibiting oxidative stress and apoptosis associated with the activation of Nrf2 signaling pathway, which could lay the foundation for the treatment of AlCl 3 immunotoxicity., (Copyright © 2019. Published by Elsevier Inc.)

This study aimed to verify the chelating, antioxidant and cytoprotective activities of Psidium brownianum Mart. Ex DC against mercury and aluminum. The ethanolic extract, as well as the tannic and flavonoid fractions, were prepared and subjected to liquid chromatography-mass spectrometry analysis. Ferric ion reduction and antioxidant activity measurement using the FRAP method were performed with P. brownianum. After determining the sub-allelopathic doses, germination tests using Lactuca sativa (lettuce) seeds were performed. The main compounds identified in the extract and fractions were: quercetin and its derivatives; myricetin and its derivatives; gallic acid; ellagic acid; quinic acid and gallocatechin. The Minimum Inhibitory Concentration (MIC) for all samples were ≥ 1024 μg/mL. The flavonoid fraction in association with mercury chloride demonstrated cytoprotection (p < 0.001). The sub-allelopathic concentration used was 64 μg/mL. The extract and fractions were cytoprotective for radicles and caulicles when assayed in association with mercury and against aluminum for radicles. This suggests that the P. brownianum extract and its fractions present cytoprotective activity, possibly related to the antioxidant effect of secondary metabolites, especially flavonoids., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Asiatic acid (AA), a triterpenoid present in Centella asiatica, possesses the ability to cross blood brain barrier and received considerable attention for its neuroprotective role. We have reported the benefit of AA against aluminum chloride (AlCl 3 )-induced amyloid pathology, enhanced acetylcholine esterase (AChE) activity, and inflammation in Alzheimer's disease (AD) like model rats. Based on that, to find the exact mechanism of action of AA, the present study was designed to evaluate the oxidative stress, tau pathology, apoptosis, and Akt/GSK3β signaling pathway on AlCl 3 -induced neurotoxicity in Wistar rats. AD-like pathology was induced by oral administration of AlCl 3 (100 mg/kg b.w.) for 6 weeks, which demonstrated a significant reduction in spatial memory performance, anxiety, and motor dysfunction and diminished the expression of cyclin-dependent kinase 5 (CDK 5-enzyme implicated in the phosphorylation of tau proteins), pTau, oxidative stress, and apoptosis, whereas oral ingestion of AA (75 mg/kg b.w.) for 7 weeks attenuated the above-said indices, which could be by activating Akt/GSK3β pathway. Current results suggested that AA could be able to modulate various pathological features of AD and could hold promise in AD treatment.

Objectives: The aim of this study was to investigate the antioxidant effect of aqueous Lawsonia inermis leaf extract on aluminum-induced oxidative stress and the histology of the pituitary gland of adult Wistar rats., Methods: Thirty-five adult male Wistar rats weighing between 100-196g and 15 mice of the same weight range were included in the study. Lawsonia inermis extracts and aluminum chloride (AlCl 3 ) were administered for a period of three weeks to five rats per group. The subjects in Group 1 (control) were given pellets and distilled water. Group 2 received 60mg/kg/d of aqueous extract of Lawsonia inermis. Group 3 was given 0.5mg/kg/d of AlCl 3 . Group 4 was administered 0.5mg/kg/d of AlCl 3 and 60mg/kg/d of aqueous Lawsonia inermis extract orally. Group 5 received 0.5mg/kg/d of AlCl 3 and 75mg/kg/d of aqueous Lawsonia inermis extract orally. Group 6 was given 0.5mg/kg/d of AlCl 3 and 100mg/kg/d of aqueous Lawsonia inermis extract orally. Group 7 was administered 0.5mg/k/d of AlCl 3 and 5mg/Kg/d ascorbic acid in distilled water orally. Twenty-four hours after the last administration, the animals were weighed, sedated with chloroform, and had their pituitary glands located, removed, and weighed on an electronic analytical balance., Results: Decreased cell counts were observed in the pituitary gland micrographs of the Wistar rats given 0.5mg of aluminum chloride, whereas the Wistar rats given 0.5mg of aluminum chloride and varying doses of Lawsonia inermis had increased dose-dependent cell counts., Conclusion: Aqeuous Lawsonia Inermis leaf extract increased the cell counts of the pituitary glands of adult male Wistar rats, in addition to alleviating aluminum-induced oxidative stress.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder more prevalent among the elderly population. AD is characterised clinically by a progressive decline in cognitive functions and pathologically by the presence of neurofibrillary tangles (NFTs), deposition of beta-amyloid (Aβ) plaque and synaptic dysfunction in the brain. Centella asiatica (CA) is a valuable herb being used widely in African, Ayurvedic, and Chinese traditional medicine to reverse cognitive impairment and to enhance cognitive functions. This study aimed to evaluate the effectiveness of CA in preventing d-galactose/aluminium chloride (d-gal/AlCl 3 ) induced AD-like pathologies and the underlying mechanisms of action were further investigated for the first time. Results showed that co-administration of CA to d-gal/AlCl 3 induced AD-like rat models significantly increased the levels of protein phosphatase 2 (PP2A) and decreased the levels of glycogen synthase kinase-3 beta (GSK-3β). It was further observed that, CA increased the expression of mRNA of Bcl-2, while there was minimal effect on the expression of caspase 3 mRNA. The results also showed that, CA prevented morphological aberrations in the connus ammonis 3 (CA 3) sub-region of the rat's hippocampus. The results clearly demonstrated for the first time that CA could alleviate d-gal/AlCl 3 induced AD-like pathologies in rats via inhibition of hyperphosphorylated tau (P-tau) bio-synthetic proteins, anti-apoptosis and maintenance of cytoarchitecture.

Normal prostate development is highly dependent of an equilibrated hormonal regulation, so that sensible interferences during this period may predispose the gland to lesions during aging. Industrial activities have increased the exposure of this gland to active elements found in environment, such as aluminum (Al). Al presents toxic effect for living beings, having the potential to disrupt the development and growth of several organs and systems. Therefore, the aim of this study was to evaluate whether the prenatal exposure to Al may alter the development and morphophysiology of the gerbil prostate (Meriones unguiculatus). Pregnant females were orally exposed to aluminum chloride (100 mg/kg/day) from 17th to 21th gestational day. Following the birth, the male and female pups were euthanized with 1 (PN1) and 90-days-old (PN90). The prostates were collected for biometrical, three-dimensional reconstruction, morphometrical, stereological, and immunohistochemical analysis. Results indicated that Al decreases the body weight of PN1 males and females, and also reduce the anogenital distance of PN1 females. Moreover, Al changed the prostate developmental patterns of PN1 animals, causing an increase in proliferative status and decreasing androgen receptor immunostaining. The results suggest that Al-promoted changes were permanent, since low androgen receptor frequency, increased serum testosterone levels and high proliferation index were observed in adult gerbils. This study demonstrated that body and prostatic changes were more pronounced in females than in males, and that Al performed as an endocrine-disrupting chemical in gerbils., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aluminum is widely used in industry and in cooking utensils, especially in countries with low economic and social standards. Fluoride is also used in industry, a major component of toothpaste and is added to the drinking water in many countries to fight teeth decay and cavities. Consequently, the coexistence of aluminum and fluoride is highly probable. Growing evidence indicates that environmental pollutants during the early stages of embryonic development may reprogram the offspring's brain capabilities to encounter oxidative stress during the rest of their postnatal life. This study investigated the impact of sodium fluoride (NaF, 0.15 g/L) and aluminum chloride (AlCl 3 , 500 mg/L) added, individually or in combination, to the deionized drinking water starting from day 6 of gestation until just after weaning, or until the age of 70 days postnatal life. A significant decline was observed in tissue contents of vitamin C, reduced glutathione, GSH/GSSH ratio, and the total protein, as well as in the activities of Na + /K + -ATPase and superoxide dismutase (SOD) in almost all cases. On the contrary, lipid peroxidation and NO, as total nitrate, exhibited a significant increase in comparison with the corresponding control. Based on the present results, administration of Al and NaF, alone or in combination abated the quenching effects of the antioxidant system and induced oxidative stress in most brain regions under investigation. In conclusion, aluminum and fluoride are very noxious environmental pollutants that interfere with the proper functions of the brain neurons and their combination together aggravates their hazard.

Current study evaluated the synergistic potential of propolis and vitamin E against sub-acute toxicity of aluminum chloride on different biochemical parameters and liver histology. Swiss albino mice (n=42) were randomly divided into seven groups. Group I received 0.2 ml of 0.9 % saline solution, Group II received Propolis (50 mg/kg b.w.), Group III received vitamin E (150 mg/kg b.w.), Group IV received AlCl(3) 50 mg/kg b.w., Group V received AlCl(3) + Propolis, Group VI received AlCl(3) + vitamin E and Group VII received AlCl(3) + propolis + vitamin E. Blood and tissue samples were collected after 7 and 21 days. The body weight of the animals significantly increased in all groups except Group IV. The concentration of serum high density lipoprotein significantly decreased in Group IV and increased in Group V, VI and VII. The level of aspartate aminotransferase, alanine transferase, alkaline phosphatase, triglycerides, total cholesterol, and low density lipoprotein significantly increased in AlCl(3) treated group and increased in Group V, VI and VII. Tissue sections were processed and stained by hematoxylin and eosin. Group II showed cellular necrosis. Group V, VI showed decreased number of vacuolization, sinusoidal spacing and macrophage cell infiltration. Group VI showed less degenerative changes in the third week. Vitamin E and propolis in combination with Al provides more protection against AlCl(3) induced toxicity.

Aluminum is implicated in the etiology of different neurodegenerative diseases, diabetes and cancer. The current study was conducted to evaluate the protective effects of glycyrrhizic acid (GAM) and silymarin (SLY) on AlCl 3 -induced neurotoxicity in insulin resistant rats. Insulin resistance (IR) was induced by fructose (10%) in drinking water for 18 weeks. Rats received AlCl 3 (34 mg/kg/day) with or without fructose, GAM (40 mg/kg/day), or SLY (100 mg/kg/day). The administration of GAM or SLY suppressed AlCl 3 -induced memory deficit, oxidative stress, and neuroinflammation in brain tissue of IR rats. Both agents inhibited AlCl 3 -induced activation of TLR4 signaling pathway including the downstream activation of NF-κB. The results show that IR can partly exacerbate AlCl 3 -induced neurotoxicity, particularly memory deficit and neuroinflammation. In addition, GAM and SLY showed promising neuroprotective effect against AlCl 3 -induced brain damage in IR rats. The neuroprotection induced by these natural products might be mediated through their antioxidant and anti-inflammatory effects. The latter effect seems to be mediated via inhibition of TLR4 signaling pathway providing new insights on the mechanisms implicated in AlCl 3 -induced neurotoxicity and the neuroprotection afforded by GAM and SLY.

Aluminum (Al) had well-identified adverse influences on the nervous system mainly through the creation of reactive oxygen species (ROS). Melatonin works as an antioxidant through the inhibition of ROS and attenuating peroxidation of lipids. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a pivotal transcription factor which controls the transcription of antioxidant enzymes. This study was conducted to determine the potential neuroprophylactic impacts of melatonin in aluminum chloride (AlCl 3 )-initiated neurotoxicity including potential mechanism(s) of action and relevant signaling in rats. Thirty-six male rats were distributed into 4 groups: Control; AlCl 3 (50 mg/kg bwt, i.p, 3 times weekly for 3 months); melatonin (5 mg/kg bwt, i.p daily for 2 weeks before AlCl 3 and sustained for the next 3 months); and melatonin with AlCl 3 . Neuronal alterations were histopathologically and biochemically evaluated. The neuronal antioxidant-related genes and relevant Nrf2 protein expression were determined by real-time PCR and Western blotting, respectively. The current data showed a substantial increase in brain damage biomarkers, acetylecholinesterase (AchE) activity, and malondialdehyde (MDA) content while the enzymatic antioxidant expression as glutathione-s-transferase (GST), catalase (CAT), and superoxide dismutase (SOD) were substantially attenuated in the aluminum-treated group, with cleared histopathological changes as inflammatory cell infiltration with neuronal degeneration. Supplementation of melatonin resulted in an obvious amelioration in all previous abnormal alteration observed in AlCl 3 -treated rats rather than increased Al burden and/or altered Fe and Cu homeostasis with upregulating both total and phosphorylated Nrf2 expression. Therefore, the study concluded that melatonin has a potential ability to be neuroprophylactic against Al-induced neurotoxic effect and oxidative damage in the rat brain through upregulating and instigating Nrf2 signaling apart from metal chelation.

Tribulus terrestris (T.T) is enriched with steroidal saponins and flavonoids which have neuroprotective effect. The study was aimed to explore the potential of T.T methanol extract (T.T ME) for anti-Alzheirmer activity along with its safety evaluation. Plant was characterized by physicochemical, phytochemical and GCMS analyses whereas acute oral toxicity (OECD 425) was performed for safety evaluation. AlCl 3 induced Alzheimer's disease rat model was used for anti-Alzheirmer activity. T.T ME was given orally at 100, 300 and 1000 mg/kg doses for 21 days and behavioral parameters were observed on 22nd study day. Physicochemical parameters were in permissible limits. GCMS analysis showed eight different compounds and benzene dicarboxylic acid showed maximum % peak area (64.19). No mortality was noted in acute toxicity study. Behavioral studies showed highly significant (p<0.001) improvement in T.T ME treated groups. Antioxidant enzymes and acetylcholinesterase levels were significantly (p<0.05) improved on treatment with T.T ME. Histopathological analysis indicated that neurofibrillary tangles were significantly improved in T.T ME treated groups. Biochemical and behavioral results suggested that T.T contained lead compounds which are effective in the treatment of Alzheimer disease.

In consideration of its noninvasive administration and endogenous stimulation property, the enhancement of brain-derived neurotrophic factor (BDNF) via low-intensity pulsed ultrasound (LIPUS) could be a novel strategy for aluminum (Al) overload-induced cerebral damage. LIPUS was pre-treated 7 days before concomitantly given with aluminum chloride (AlCl 3 ) daily for a period of 42 days. Morris water maze and elevated plus maze were performed to analyze spatial learning and memory. Western Blot and immunoprecipitation were used to detect BDNF and histone acetylation of histone H3 lysine 9 (H3K9) and histone H4 lysine 12 (H4K12) in the hippocampus. Assay of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), and glutathione peroxidase (GSH-Px) indicated the extent of oxidative damages. Aluminium exposure in rats can cause attenuated spatial learning and memory, followed by up-regulated histone deacetylase 6 (HDAC6) expression, down-regulated H3K9 and H4K12 acetylation at the PIII and PIV promoter of BDNF, all of which will eventually inhibit BDNF expression. LIPUS can recover reduced cognitive function by restoring histone acetylation and BDNF expression, accompanied with increased SOD, GSH, and GSH-Px activity. LIPUS treatment might alleviate aluminium exposure-induced cognitive decline by acetylation regulation of BDNF expression and reducing oxidative stress in the hippocampus., (© 2019 The Author(s).)

Aims: Due to rapid increase in industrialization in the last few years, use of aluminum (Al) and its alloys have been increased in different industrial fields. Ample evidence supports the neurotoxic effects of chronic aluminum chloride (AlCl 3 ) administration in rats but acute Al toxicity has been less described so the present study was aimed to investigate the neurotoxic effects of acute AlCl 3 ., Main Methods: To investigate such effects 12 male albino Wistar rats were randomly divided into control and test rats. AlCl 3 at a dose of 150 mg/kg was intraperitoneally injected to test rats for 7 days. Rats were subjected to behavioral assessments 24 h after last dose and after behavioral assessment rats were sacrificed to collect brain samples for further neurochemical, biochemical and histopathological examinations., Key Findings: In the present study acute administration of AlCl 3 resulted in noticeable behavioral deficits. Cognitive deficits and neuropsychiatric disturbances were evident in AlCl 3 injected rats. Test rats also exhibited marked antioxidant enzymes, cholinergic, serotonergic and dopaminergic dysfunctions and DNA fragmentation. Histopathological alterations were observed in hippocampus and cortex of rats injected with AlCl 3 ., Significance: The observed effects may be due to pro-oxidant nature of Al and its participation in free radical mediated cellular injury. Al by promoting oxidative stress, impairing antioxidant defense system and altering brain neurochemistry may act as a potent neurotoxic agent as evident from observed histopathological alterations in brain of test rats. This investigation may further confirm and shed some more light on deleterious effects of acute Al intoxication on brain., (Copyright © 2018 Elsevier Inc. All rights reserved.)