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AbstractThis study assessed the antioxidative and protective effects of peptide extracts from selected Euphorbia species on Aluminum Chloride (AlCl3)-induced toxicity in Drosophila melanogaster. Euphorbia humifusa (EHU), Euphorbia hirta (EHI), and Euphorbia graminae (EHG) were screened for bioactive peptides. The crude peptide extract and partially purified peptide fractions of all the plants were subjected to preliminary antioxidants activities through 2, 2-diphenyl-1-picrylhyhdrazyl (DPPH), and nitric oxide (NO) scavenging activities. The most active peptide fraction was subjected to biochemical studies using Drosophila melanogaster. Flies were treated with AlCl3 (100 mg/kg diet), peptide fraction (5 and 10 mg/kg diet), and cotreatment of AlCl3 and the fraction, respectively. After treatment, flies were homogenized for the determination of total thiol and Glutathione (non-protein thiol) content, catalase and Glutathione-S-transferase activities, and nitric oxide (nitrite/nitrate) and hydroperoxide levels. The antioxidant screening revealed that the peptide fraction from Euphorbia humifusa (PEHU) was the most significant compared to the control (ascorbic acid). The PEHU (5 and 10 mg/kg diet) maintained the redox status of the flies in the biochemical study. The PEHU significantly counteracted AlCl3-induced reduction in antioxidants (catalase, GST, GSH and Total thiol), increased nitric oxide levels, and acetylcholinesterase activity and prevented behavioral deficits flies. Hence, the peptide fraction of Euphorbia humifusa may shield against the life-threatening effects of free radicals associated with aluminum chloride toxicity. [ABSTRACT FROM AUTHOR]

Aluminum (Al) may be beneficial to crops, but in excess becomes detrimental to the germination and initial development of seedlings. The main determining indicators are the type of crop and exposure duration. The aim of this study was to examine the influence of Al and of UV-C light on the germination and initial growth of white oats. Seeds were sown on germitest paper in a solution of 100, 200, 300, 400, or 500 mg/L of aluminum chloride and kept in a germination chamber at 20°C for a 12-hr photoperiod. Germination and seedling growth parameters were determined after 5 and 10 days. The seeds were also exposed to two doses of UV-C (0.85 and 3.42 kJ m -2 ) under aluminum chloride stress (200 mg/L). Data demonstrated that treatment with aluminum chloride significantly decrease in germination at 200 mg/L and total seedling length at 100 mg/L. Exposure of seeds to UV-C light under excess Al (200 mg/L) did not show a significant effect on germination and growth compared to control (non-irradiated). Results indicated that exposure to high concentration of Al in the medium adversely altered germination and initial growth of white oat seedlings. Although UV-C light alone was not detrimental to the germination process, treatment with UV-C light also failed to mitigate the toxic effects of Al.

Ethnopharmacological Relevance: Alzheimer's disease is the most common neurodegenerative disease with therapeutic limitations. Insulin resistance plays a role in the progression of Alzheimer's disease. Therapies that modulate insulin secretion and signaling, as well as oxidative stress in the brain are now being investigated for their potential role in the prevention of Alzheimer's disease (AD). Terminalia macroptera (Combretaceae) is a plant that different parts have been used traditionally for the treatment of metabolic and neurological conditions. Previous study has indicated that the crude extract exhibit anti-diabetic property. In addition, the plant is a rich source of tannins, phenolic acids, flavonoids, triterpenes. However, there is no study on its protective effect against biochemical alterations of AD in diabetic rats., Aim of the Study: The present research study investigated the neuroprotective effects of TeMac™ on Alzheimer-like pathology induced by aluminum chloride (AlCl 3 ) in diabetic rats., Methods: A phytochemical analysis of TeMac™ was carried out to quantify tannins. The potential effect of the tannins-enriched fraction (TEF) of TeMac™ to prevent the formation of senile plaques was conducted by its ability to inhibit the activities of β-secretase (EC 3.4.23.46), monoamine oxidase A (EC 1.4.3.4) and the fibrillation of Aβ. A diabetic model was induced from female Wistar rats by a single intraperitoneal injection of streptozotocin (STZ, 35 mg/kg BW). After that, the blood glucose level was measured to confirm the induction of diabetes. Three days after induction, animals received AlCl 3 (75 mg/kg BW) alone (AD control) or concomitantly with 400 mg/kg BW of TEF of TeMac™ or 5 mg/kg BW Daonil by daily gavage for 42 days. At the end of the experiment, rats were sacrificed, blood and brains were collected. The levels of amyloid fibrils, glucose, albumin and the activities of DPP4, β-secretase and phosphatase, and markers of oxidative stress in the brain were assessed., Results: TEF of TeMac™ displays a potential ability to inhibit the activities of β-secretase, monoamine oxidase, and Aβ fibrillation. Treatment with TEF of TeMac™ significantly inhibited DPP4 and BACE1 activities and reduced brain glucose and amyloid fibril levels, and improved cerebral albumin levels and modulated oxidative stress markers., Conclusion: Our findings indicate that TEF of TeMac™ prevents Alzheimer's-type pathology linked to insulin resistance in rats. TEF of TeMac™ may be a potential drug candidate for the treatment of diabetes-associated cognitive impairment., 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 © 2024. Published by Elsevier B.V.)

Ethnopharmacology Relevance: Ganoderma leucocontextum T.H. Li, W. Q. Deng M. Wang & H.P.Hu. is a highland herbal medicine that has been shown to nourish the nervesand prolong life. Nevertheless, there is no evidence to indicate that Ganoderma leucocontextum triterpenoids (GLTs) reduce the damage triggered by Alzheimer's disease (AD)., Aim of the Study: The aim of this investigation was to ascertain the protective effects of GLTs on AD mice models and cells, as well as to look into potential pathways., Materials and Methods: In this study, the phytochemical characterization of GLTs was performed by High Performance Liquid Chromatography (HPLC) and Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS). The AD mouse model was induced by injecting intraperitoneally with D-galactose (120 mg/kg) and administering orally with aluminum chloride (20 mg/kg) daily for 28 days. After that, donepezil (5 mg/kg) and GLTs (0.4, 0.8, and 1.6 g/kg) were administered orally for 35 days. During the treatment period, aluminum chloride (20 mg/kg) and D-galactose (120 mg/kg) were continuously administered. And the behavior of the animals and the molecular changes of the hippocampus were determined after the whole experimental procedure. Furthermore, BV-2 cells were employed to validate GLTs' anti-neuroinflammatory properties., Results: The total triterpenoids content was 443.12 ± 0.21 g/kg and was inferred to contain 19 classes of substances such as organic acids, amino acids, vitamins, flavonoids, and other chemicals in GLTs. Treatment of D-galactose/aluminum chloride-induced mouse with GLTs can ameliorate AD symptoms, counteract cognitive decline, improve Aβ1-42 deposition, reduce the expression level of pro-apoptotic proteins, and attenuate the activation of hippocampal microglia and astrocytes. GLTs significantly increased the expression of antioxidant enzymes and significantly reduced the expression of inflammatory factors. GLTs inhibits nuclear factor kappa B (NF-κB) nuclear translocation and preserves myd88/traf6-mediated mitogen-activated protein kinase (MAPK) phosphorylation. Furthermore, GLTs (2 and 5 mg/mL) inhibited the generation of nitric oxide and protected lipopolysaccharide (1 mg/L)-induced neuroinflammation in BV-2 cells., Conclusions: Taken together, Ganoderma leucocontextum triterpenoids can improve cognitive functions, including learning and memory, by reducing neuroinflammation and oxidative stress, preventing apoptosis, and controlling amyloid genesis., 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 © 2024 Elsevier B.V. All rights reserved.)

To investigate the difference in the development and neurobehavior between aluminum chloride (AlCl 3 ) and nano-alumina (AlNPs) in adult zebrafish and the role of triggering receptor expressed on myeloid cells (TREM2) in this process. Zebrafish embryos were randomly administered with control, negative control, TREM2 knockdown, AlCl 3 , TREM2 knockdown + AlCl 3 , AlNPs, and TREM2 knockdown + AlNPs, wherein AlCl 3 and AlNPs were 50 mg/L and TREM2 knockdown was achieved by microinjecting lentiviral-containing TREM2 inhibitors into the yolk sac. We assessed development, neurobehavior, histopathology, ultrastructural structure, neurotransmitters (AChE, DA), SOD, genes of TREM2 and neurodevelopment (α1-tubulin, syn2a, mbp), and AD-related proteins and genes. AlCl 3 significantly lowered the malformation rate than AlNPs, and further increased rates of malformation and mortality following TREM2 knockdown. The locomotor ability, learning and memory were similar between AlCl 3 and AlNPs. TREM2 deficiency further exacerbated their impairment in panic reflex, microglia decrease, and nerve fibers thickening and tangling. AlCl 3 , rather than AlNPs, significantly elevated AChE activity and p-tau content while decreasing TREM2 and syn2a levels than the control. TREM2 loss further aggravated impairment in the AChE and SOD activity, and psen1 and p-tau levels. Therefore, AlCl 3 induces greater developmental toxicity but equivalent neurobehavior toxicity than AlNPs, while their toxicity was intensified by TREM2 deficiency., 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 © 2024 Elsevier Inc. All rights reserved.)

Aluminium, a ubiquitous environmental toxicant, is distinguished for eliciting a broad range of physiological, biochemical, and behavioural alterations in laboratory animals and humans. The present work was conducted to study the functional and structural changes induced by aluminium in rat liver. Twenty five adult male Wistar rats (150-200 g) were randomly divided into five groups; control group and four Al-treated groups viz: Al 1 (25 mg AlCl 3 /kg b.wt), Al 2 (35 mg AlCl 3 /kg b.wt), Al 3 (45 mg AlCl 3 /kg b.wt), and Al 4 (55 mg AlCl 3 /kg b.wt). Rats in the aluminium-treated groups were administered AlCl 3 for 30 days through oral gavage. Aluminium significantly increased the serum levels of liver function markers (ALT, AST, and ALP), phospholipids, and cholesterol. The activities of hepatocyte membrane (ALP, GGT, and LAP) and carbohydrate metabolic (G6P, F16BP, HK, LDH, MDH, ME, and G6PDH) enzymes were significantly altered by AlCl 3 administration. Prolonged Al exposure induced oxidative stress in the liver, as evident by significant hepatocellular DNA damage, increased lipid peroxidation, and decreased non-enzymatic and enzymatic antioxidants. The toxic effects observed in this study were AlCl 3 dose-dependent. Histopathological examination of liver sections revealed enlargement of sinusoidal spaces, derangement of the hepatic chord, loss of discrete hepatic cell boundaries, congestion of hepatic sinusoids, and degeneration of hepatocytes in Al-intoxicated rats. In conclusion, aluminium causes severe hepatotoxicity by inhibiting the hepatocyte membrane enzymes and disrupting the liver's energy metabolism and antioxidant defence., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ocimum basilicum is an important medicinal plant and culinary herb generally known as sweet basil (SB). These plants are effective radical scavengers, that have been employed in treatment of nervous system disorders, and thus, could be beneficial for the management of neurodegenerative diseases (NDs). Current clinical treatments for NDs present several side effects, therefore, there is need to develop new treatments that can mitigate these deadly diseases. Hence, this study investigated the neuroprotective activities of SB leaf and seed in aluminum chloride (AlCl 3 )-induced toxicity in Drosophila melanogaster . HPLC characterization of the leaves and seeds were carried out. AlCl 3 -diet was used to induce neurodegeneration and treated flies received SB leaf and seed extracts-supplemented diet. Survival and locomotor performance activities/levels of oxidative biomarkers [reactive oxygen species (ROS), thiobarbituric acid reactive species (TBARS), total thiol, catalase, superoxide dismutase (SOD) and glutathione-S-transferase (GST)], enzymes linked with neurodegeneration (acetylcholinesterase (AChE) and monoamine oxidase (MAO)) were investigated. SB leaf had significantly ( p  < 0.05) higher polyphenol contents; gallic acid and P-coumaric acid were the most abundant polyphenol in the leaf and seed respectively. Percentage survival and locomotor rates, level/activities of total thiol, catalase, SOD and GST were significantly ( p  < 0.05) reduced while ROS, TBARS, AChE and MAO activities were significantly ( p  < 0.05) increased in AlCl 3 -diet-fed flies. Treatment with SB leaf and seed diet lessened these observed impairments. However, SB leaf had better neuroprotective activities that could be related to the observed higher phenolic constituents. Hence, SB leaf diet may offer improved therapeutic effect in NDs.

This study aimed to examine whether or not aluminum chloride (AlCl 3 )-induced hepatotoxicity might be mitigated using magnetic water (MW) in rats. This study involved 28 adult male rats randomly assigned into the following 4 groups (7 rats/group): normal control (Cnt), MW, AlCl 3 , and Al Cl 3  + MW. The Cnt group orally received normal saline, the MW group drank MW ad libitum for 2 months, and the AlCl 3 and AlCl 3  + MW groups were orally administered AlCl 3 (40 mg/kg b.w.) alone or in combination with MW for 2 months, respectively. MW reduced AlCl 3 toxicity as proved at functional, molecular, and structural levels. Functionally, MW reduced serum levels of liver enzymes (ALT, AST, ALP, GGT), while increased total proteins, and albumin. MW also restored redox balance in the liver (lower MDA levels, higher activities of CAT and SOD enzymes, and upregulated expression of NrF2, HO-1, and GST genes. Molecularly, MW downregulated hepatic expression of the epigenetic (HDAC3), inflammatory (IL1β, TNFα, NFκβ), and endoplasmic reticulum stress (XBP1, BIP, CHOP) genes. Structurally, MW enhanced liver histology. With these results, we could conclude that MW has the potential to ameliorate the hepatotoxic effects of AlCl 3 through targeting oxidative stress, inflammation, epigenesis, and endoplasmic reticulum stress., (© 2024. The Author(s).)

Cognitive impairments affect millions of people worldwide with an increasing prevalence. Research on their etiology and treatment is developing, nevertheless significant gaps remain. Trientine (TETA), as a copper chelator, has been shown to have beneficial effects in different human chronic diseases such as diabetic cardiomyopathy and neuropathy. Here, we examined the impact of TETA on AlCl3-induced neurocognitive dysfunctions and molecular changes in the hippocampus of rats.Thirty-six male Wistar rats (weighing 200-250 g) were randomly divided into four groups including control, TETA (100 mg/kg/day), AlCl3 (100 mg/kg/day), and AlCl3 (100 mg/kg/day)+TETA (100 mg/kg/day), and received chemicals by gavage for 30 days. At the end of the treatment, the open field maze, elevated plus maze, novel object recognition memory test, and shuttle box test were done. Then after, brain-derived neurotrophic factor (BDNF), glycogen synthase kinase-3 β (GSK-3β), acetylcholinesterase activity, oxidative stress markers, and inflammatory mediators were measured in the hippocampus.AlCl3 increased anxiety-like behaviors and impaired recognition and short-term memory. TETA was able to improve AlCl3-induced anxiety-like behaviors and short-term memory dysfunction. In the AlCl3-treated group, there was a significant increase in GSK-3β, oxidative stress, pro-inflammatory and pro-apoptotic markers, and decreased BDNF in the hippocampus. Co-administration of TETA was able to decrease lipid peroxidation, inflammation, GSK-3β, and acetylcholinesterase activity, and increase BDNF in the hippocampus compared with AlCl3-treated rats.It can be concluded that TETA was able to improve neurobehavioral and neurocognitive functions by alleviating oxidative stress, inflammation, and pro-apoptotic pathways leading to the normalization of BDNF and GSK-3β., Competing Interests: Authors declare that there is no conflict of interest., (Thieme. All rights reserved.)

The present study aimed to investigate the effect of catechin-loaded Chitosan-Alginate nanoparticles (NPs) on cognitive function in an aluminum chloride (AlCl 3 )-induced rat model of Alzheimer's disease (AD). The Catechin-loaded Chitosan-Alginate nanocarriers were synthesized through ionotropic gelation (IG) method. Physio-chemical characterization was conducted with the Zetasizer Nano system, the scanning electron microscope, and the Fourier transform infrared spectroscopy. The experiments were performed over 21 days on six groups of male Wistar rats. The control group, AlCl 3 treated group, Catechin group, nanocarrier group, treatment group 1 (AlCl 3  + Catechin), and treatment group 2 (AlCl 3  + nanocarrier). A behavioral study was done by the Morris water maze (MWM) test. In addition, the level of oxidative indices and acetylcholine esterase (AChE) activity was determined by standard procedures at the end of the study. AlCl 3 induced a significant increase in AChE activity, along with a significant decrease in the level of Catalase (CAT) and total antioxidant capacity (TAC) in the hippocampus. Moreover, the significant effect of AlCl 3 was observed on the behavioral parameters of the MWM test. Both forms of Catechin markedly improved AChE activity, oxidative biomarkers, spatial memory, and learning. The present study indicated that the administration of Catechin-loaded Chitosan-Alginate NPs is a beneficial therapeutic option against behavioral and chemical alteration of AD in male Wistar rats., (© 2024 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Rutin, a phenolic compound, exhibits a diverse range of biological properties, including antioxidant, anti-inflammatory, and antimicrobial effects. In this study, we aimed to investigate the potential of rutin, a naturally occurring plant bioactive molecule, to mitigate the neurotoxic effects induced by aluminum chloride (AlCl 3 ). Over a period of 6 weeks, rats were intraperitoneally injected with AlCl 3 at a weekly dose of 60 mg/kg, while rutin treatment was administered orally via gavage at a daily dose of 30 mg/kg. AlCl 3 exposure resulted in a significant increase lipid peroxidation (LPO) by 316.24%, nitrate levels by 504.14%, and tumor necrosis factor-alpha (TNF-α) levels by 93.82% in brain mitochondria. Additionally, AlCl 3 exposure led to a reduction in glutathione levels and the activity of antioxidant enzymes, including superoxide dismutase (SOD) by 19.74%, glutathione peroxidase (GPx) by 44.76%, and catalase by 50.50%. There was also a significant decline in the activity of mitochondrial complex enzymes. In contrast, rutin treatment significantly enhanced the activity of antioxidant enzymes while concurrently reducing lipid peroxidation levels in rats. Specifically, rutin administration exerted a modulatory effect on the inflammatory response triggered by aluminum exposure, effectively suppressing the excessive production of nitrate and TNF-α. These findings highlight the potential of rutin as an effective therapeutic strategy in mitigating and combating neuro-inflammation and oxidative stress associated with aluminum-induced toxicity, thereby effectively restoring mitochondrial function., Competing Interests: Declaration of competing interest We have no conflict of interest to declare., (Copyright © 2024 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

Aluminum (Al) overexposure damages various organ systems, especially the nervous system. Regularly administered aluminum chloride (AlCl 3 ) to rats causes dementia and pathophysiological alterations linked to Alzheimer's disease (AD). Taxifolin's neuroprotective effects against AlCl 3 -induced neurotoxicity in vitro and in vivo studies were studied. Taxifolin (0.1, 0.3, 1, 3, and 10 μM) was tested against AlCl 3 (5 mM)-induced neurotoxicity in C6 and SH-SY5Y cells using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. Additionally, neural morphology was examined by confocal microscopy. Additionally, taxifolin's mode of binding with the co-receptor of toll-like receptor 4 (TLR4), human myeloid differentiation-2 ( h MD-2) was investigated. AlCl 3 (25 mg/kg/d, i.p. ) was administered to rats for 14 d, and from the eighth day, taxifolin (1, 2, and 5 mg/kg/d, i.p. ) was given along with AlCl 3 . This study assessed memory impairment using the Morris water maze, plus maze, and pole tests. This study also performed measurement of oxidant (malondialdehyde [MDA] and nitrite), antioxidant (reduced glutathione), and inflammatory (myeloperoxidase [MPO] activity, TLR4 expression) parameters in rats' brain in addition to histopathology. The docking score for taxifolin with h MD-2 was found to be -4.38 kcal/mol. Taxifolin treatment reduced the neurotoxicity brought on by AlCl 3 in both C6 and SH-SY5Y cells. Treatment with 10 μM taxifolin restored AlCl 3 -induced altered cell morphology. AlCl 3 administration caused memory loss, oxidative stress, inflammation (increased MPO activity and TLR4 expression), and brain atrophy. Taxifolin treatment significantly improved the AlCl 3 -induced memory impairment. Taxifolin treatment also mitigated the histopathological and neurochemical consequences of repeated AlCl 3 administration in rats. Thus, taxifolin may protect the brain against AD.

Objective: Aluminum is a widely used metal in homes and industries. Xylopia aethiopica is an important medicinal plant with antioxidant properties. The objective of this study is to investigate the ameliorative potential of Xylopia aethiopica on aluminum-induced ovarian toxicity in Wistar rat., Methods: Twenty-five rats were randomized into five groups with five rats per group. Group 1 received only distilled water; Group 2: received 150mg/kg of aluminum chloride; Group 3: received 150mg/kg aluminum chloride with 100/kg Xylopia aethiopica seed extracts; Group 4: received 150mg/kg aluminum chloride with 50 mg/kg Xylopia aethiopica seed extracts, and Group 5: received 150mg/kg aluminum chloride with 50mg/Kg zinc sulphate. For twenty-one days, all administrations were done orally. The rats were then sacrificed following chloroform anesthesia. The ovaries were harvested for histological examination., Results: The data were analyzed on IBM SPSS software version 21 and the differences in mean values were considered significant at p<0.05. Xylopia aethiopica extracts significantly (p<0.05) reversed the detrimental effects of aluminum chloride on luteinizing hormone, follicle stimulating hormone, progesterone and estradiol. The histological analysis of the ovaries showed a significant improvement in rats treated with Xylopia aethiopica extract and zinc sulphate. However, Xylopia aethiopica was more effective in a dose-dependent manner., Conclusions: This study suggests that Xylopia aethiopica has ameliorative potential on aluminum-induced toxicity in the ovaries of adult female Wistar Rats.

Background: Aluminum (Al) is a ubiquitous element with proven nephrotoxicity. Silymarin (SM) is a mixture of polyphenolic components extracted from Silybum marianum and exhibited protective influences. However, SM bioactivity can be enhanced by its incorporation in chitosan (CS) through the use of nanotechnology. This work proposed to assess the protective influence of SM and its loaded chitosan nanoparticles (SM-CS-NPs) on aluminum chloride (AlCl 3 )-induced nephrotoxicity., Methods: Six groups were created randomly from 42 male Wistar rats and each one contains 7 rats (n = 7). Group I, acted as a control and received water. Group II received SM (15 mg/kg/day) and group III administered with SM-CS-NPs (15 mg/kg/day). Group IV received AlCl 3 (34 mg/kg) and groups V and VI were treated with SM and SM-CS-NPs with AlCl 3 respectively for 30 days., Results: AlCl 3 administration significantly elevated TBARS, H 2 O 2 , and kidney function levels besides LDH activity. Whereas GSH, CAT, SOD, GPx, GST, and GR values were all substantially reduced along with protein content, and ALP activity. Additionally, significant alterations in lipid profile, hematological parameters, and renal architecture were observed. Moreover, TNF-α, TGF-β, and MMP9 gene expression were upregulated in kidney tissues. The administration of SM or its nanoparticles followed by AlCl 3 intoxication attenuated renal dysfunction replenished the antioxidant system, and downregulated TNF-α, TGF-β, and MMP9 gene expression in renal tissues compared to the AlCl 3 group., Conclusion: SM-CS-NPs have more pronounced appreciated protective effects than SM and have the proficiency to balance oxidant/antioxidant systems in addition to their anti-inflammatory effect against AlCl 3 toxicity., (© 2024 Wiley Periodicals LLC.)

Aluminum chloride is an inorganic polymeric coagulant commonly found in daily life and various materials. Although male reproductive toxicity has been associated with AlCl 3 exposure, the underlying mechanism remains unclear. This study aimed to examine the impact of AlCl 3 exposure on mitophagy and mitochondrial apoptosis in testicular tissue and mouse spermatocytes. Reactive oxygen species (ROS) and ATP levels were measured in GC-2spd after AlCl 3 exposure using a multifunctional enzyme labeler. The changes in mitochondrial membrane potential (MMP) and TUNEL were observed through confocal laser microscopy, and the expression of proteins associated with mitophagy and apoptosis was analyzed using Western blot. Our results demonstrated that AlCl 3 exposure disrupted mitophagy and increased apoptosis-related protein expression in testicular tissues. In the in vitro experiments, AlCl 3 exposure induced ROS production, suppressed cell viability and ATP production, and caused a decrease in MMP, leading to mitophagy and cell apoptosis in GC-2spd cells. Intervention with N-acetylcysteine (NAC) reduced ROS production and partially restored mitochondrial function, thereby reversing the resulting mitophagy and cell apoptosis. Our findings provide evidence that ROS-mediated mitophagy and cell apoptosis play a crucial role in the toxicity of AlCl 3 exposure in GC-2spd. These results contribute to the understanding of male reproductive toxicity caused by AlCl 3 exposure and offer a foundation for future research in this area., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Alzheimer's disease is a progressive neurodegenerative disease and one of the most common causes of dementia. Despite recent advancements, there exists an unmet need for a suitable therapeutic option. This study aimed to evaluate the protective effects of the combination of resveratrol (20 mg/kg/day p.o.) and tannic acid (50 mg/kg/day p.o.) to reduce aluminium trichloride-induced Alzheimer's disease in rats., Methods: Wistar rats weighing 150-200g were administered with aluminium chloride (100 mg/kg/day p.o.) for 90 days to induce neurodegeneration and Alzheimer's disease. Neurobehavioral changes were assessed using novel object recognition test, elevated plus maze test, and Morris water maze test. Histopathological studies were performed using H&E stain and Congo Red stains to check amyloid deposits. Further oxidative stress was measured in brain tissue., Results: Aluminium trichloride treated negative control group showed cognitive impairment in the Morris water maze test, novel object recognition test, and elevated plus maze test. Further, the negative control group showed significant oxidative stress, increase amyloid deposits, and severe histological changes. Treatment with the combination of resveratrol and tannic acid showed significant attenuation in cognitive impairment. The oxidative stress markers and amyloid plaque levels were significantly attenuated with the treatment., Conclusion: The present study indicates the beneficial effects of resveratrol-tannic acid combination in AlCl 3 induced neurotoxicity in rats.

Aluminum chloride (AlCl 3 ) is a potent neurotoxic substance known to cause memory impairment and oxidative stress-dependent neurodegeneration. Naringenin (NAR) is a dietary flavonoid with potent antioxidant and anti-inflammatory properties which was implemented against AlCl 3 -induced neurotoxicity to ascertain its neuroprotective efficacy. Experimental neurotoxicity in mice was induced by exposure of AlCl 3 (10 mg/kg, p.o.) followed by treatment with NAR (10 mg/kg, p.o.) for a total of 63 days. Assessed the morphometric, learning memory dysfunction (novel object recognition, T- and Y-maze tests), neuronal oxidative stress, and histopathological alteration in different regions of the brain, mainly cortex, hippocampus, thalamus, and cerebellum. AlCl 3 significantly suppressed the spatial learning and memory power which were notably improved by administration of NAR. The levels of oxidative stress parameters nitric oxide, advanced oxidation of protein products, protein carbonylation, lipid peroxidation, superoxide dismutase, catalase, glutathione reductase, reduced glutathione, and the activity of acetylcholine esterase were altered 1.5-3 folds by AlCl 3 significantly. Treatment of NAR remarkably restored the level of oxidative stress parameters and maintained the antioxidant defense system. AlCl 3 suppressed the expression of neuronal proliferation marker NeuN that was restored by NAR treatment which may be a plausible mechanism. NAR showed therapeutic efficacy as a natural supplement against aluminum-intoxicated memory impairments and histopathological alteration through a mechanism involving an antioxidant defense system and neuronal proliferation., (© 2024 Wiley Periodicals LLC.)

The male reproductive system is negatively influenced by Al exposure. Al represented a considerable hazard to men's reproduction capabilities. Amygdalin (AMG) and spirulina platensis (SP) have been considered to have a strong antioxidant and repro-protective activity; also, targeted drug delivery systems called niosomes improve the distribution of water-soluble medications like amygdalin and spirulina. Current study targeted to determine the effectiveness of AMG and SP against negative reproductive impact resulted by aluminum chloride (AlCl 3 ) toxicity. Sixty adult male albino rats were separated into 6 groups, including the control group, which received distilled water; AlCl 3 group, which received AlCl 3 ; AMG+AlCl 3 group, which received AlCl 3 +AMG; AMGLN+AlCl 3 group, which received AlCl 3 +amygdalin-loaded niosomes; SP+AlCl 3 group, which received AlCl 3 +SP; and SPLN+AlCl 3 group, which received AlCl 3 +spirulina-loaded niosomes. All treatments were orally gavaged daily for 5 weeks, and rats were weighed weekly. At the termination of the experiment, some males (three from each group) were used for fertility traits via mating thirty virgin rat females (in a ratio of 1:2 and 2:3 male:female, respectively) followed by recording of birth weights and litter size (number of pups per each female) at birth to assess males' reproductive capability. Other males were euthanized for collection of serum, epididymal semen samples, and tissue samples for biochemical, sperm evaluation, gene expression, and histopathological measurements. There are a considerable number of negative impacts of AlCl 3 on male fertility clarified by declined serum testosterone levels; an increased oxidative stress (MDA, TAC); deteriorated semen quality; down-regulation of CYP11A1, StAR, and HSD-3b gene expressions; and testicular tissue degenerative changes. In addition, litter size (number of pups per each female) and birth weights of pups obtained from mated females were affected. AMG and SP treatments, either in niosomal or conventional form, alleviated the AlCl 3 negative effects by reducing oxidative stress; increasing testosterone levels; improving semen quality; upregulating of CYP11A1, StAR, and HSD-3b gene expressions; and reducing degenerative changes of testicular tissue. Besides, negative reproductive effect was diminished as observed by changes in the litter size (number of pups per each female) and birth weights of pups obtained from mated females. AMG and SP treatments (either in niosomal or conventional form), ameliorated the AlCl 3 negative effects as they possess powerful antioxidant activity, as well as they have the ability to improve the reproductive activity of affected males., (© 2023. The Author(s).)

Alzheimer's disease (AD) is a degenerative neurological disorder with unclear pathogenesis. Single-target drugs have very limited efficacy in treating AD, but synthetic multi-target drugs have poor efficacy and safety. Therefore, finding suitable natural multi-target drugs against AD is of great interest for research studies. We chose two flavonols, myricetin and morin, for the relevant study. In this study, we used microinjection of Aβ 1-42 oligomers into the CA1 region of rat hippocampus, combined with gavage of Aluminum chloride hexahydrate (AlCl 3 ·6H 2 O) solution to establish AD rat models, and myricetin and morin were selected as intervening drugs to explore the protective effects against neurological impairment. Experimental results showed that myricetin or morin could reduce the production of Aβ, Tubulin-associated unit (Tau), and Phosphorylated tubulin-associated unit (p-Tau), down-regulate the expression of relevant inflammatory factors, reduce hippocampal cell apoptosis in rats. There was a significant increase in the activity of adenosine triphosphatase, catalase, total superoxide dismutase, and the content of glutathione in the brain tissue. However, the content of malondialdehyde, inducible nitric oxide synthase, and the activity of acetylcholinesterase were decreased in the brain tissue. These two flavonols can regulate the imbalance of monoamine and amino acid neurotransmitter levels. In conclusion, Myricetin or morin can effectively improve learning and memory dysfunction in AD rats induced by Aβ 1-42 /Al 3+ through anti-oxidative stress and anti-apoptotic features., 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 © 2024 Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by hippocampal, and cortical neuron deterioration, oxidative stress, and severe cognitive dysfunction. Aluminum is a neurotoxin inducer for cognitive impairments associated with AD. The treatment approaches for AD are unsatisfactory. Boswellia papyrifera and Syzygium aromaticum are known for their pharmacological assets, including antioxidant activity. Therefore, the current study explored the possible mitigating effects of a combination of Boswellia papyrifera and Syzygium aromaticum against aluminum chloride (AlCl3) induced AD. The AD model was established using AlCl3 (100 mg/kg), and the rats were orally administrated with Boswellia papyrifera or Syzygium aromaticum or a combination of them daily for 8 weeks. The Y-maze test was used to test cognition in the rats, while acetylcholinesterase (AChE) and oxidative stress markers were estimated in homogenates of the cerebral cortex and hippocampus. Also, the histopathological examination of the cortex and hippocampus were investigated. The results revealed that administration of either B. papyrifera or S. aromaticum extracts significantly improved the cognitive functions of AD rats, enhanced AChE levels, increased oxidative enzymes levels, including SOD and GSH, and reduced MDA levels in homogenates of the cerebral cortex and hippocampus and confirmed by improvement in histological examination. However, using a combination therapy gave better results compared to a single treatment. In conclusion, the present study provided primary evidence for using a combination of B. papyrifera and S. aromaticum to treat cognitive dysfunction associated with AlCl3 Induced AD by improving the AChE levels and modulating oxidative stress in the brain.

Aluminum is a neurotoxic food contaminant. Aluminum trichloride (AlCl 3 ) causes hippocampal mitochondrial damage, leading to hippocampal injury. Damaged mitochondria can release mitochondrial reactive oxygen species (mtROS) and activate nucleotide-binding oligomerization domain-like receptor-containing 3 (NLRP3) inflammasomes and apoptosis. E3 ubiquitin ligase PARK2 (Parkin)-mediated mitophagy can attenuate mitochondrial damage. However, the role of mitophagy in AlCl 3 -induced mice hippocampal damage and its regulatory mechanism remain elusive. First, C57BL/6 N mice were treated with 0, 44.825, 89.65, and 179.3 mg/kg body weight AlCl 3 drinking water for 90 d. Apoptosis, NLRP3-inflammasome activation and mitochondrial damage were increased in AlCl 3 -induced hippocampal damage. In addition, Parkin-mediated mitophagy peaked in the middle-dose group and was slightly attenuated in the high-dose group. Subsequently, we used wild-type and Parkin knockout (Parkin -/- ) mice to investigate the AlCl 3 -induced hippocampal damage. The results showed that Parkin -/- inhibited mitophagy, and aggravated AlCl 3 -induced mitochondrial damage, NLRP3-inflammasome activation, apoptosis and hippocampal damage. Finally, we administered MitoQ (mtROS inhibitor) and MCC950 (NLRP3 inhibitor) to AlCl 3 -treated Parkin -/- mice to investigate the mechanism of Parkin-mediated mitophagy. The results showed that inhibition of mtROS and NLRP3 attenuated hippocampal NLRP3-inflammasome activation, apoptosis, and damage in AlCl 3 -treated Parkin -/- mice. These findings indicate that Parkin-mediated mitophagy protects against AlCl 3 -induced hippocampal apoptosis in mice via the mtROS-NLRP3 pathway., 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 © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Aluminum chloride (AlCl 3 ) exposure is pervasive in our daily lives. Numerous studies have demonstrated that exposure to AlCl 3 can lead to male reproductive toxicity. However, the precise mechanism of action remains unclear. The objective of this study is to investigate the mechanism of aluminum-induced toxicity by analyzing the alterations in the global transcriptome gene profile of mouse spermatocytes (GC-2spd cells) exposed to AlCl 3 . GC-2spd cells were exposed to concentrations of 0, 1, 2, and 4 mM AlCl 3 , and high-throughput mRNA-seq was performed to investigate the changes in the transcriptome after exposure to 4 mM AlCl 3 . Our findings indicate that exposure to AlCl 3 led to an increase in oxidative stress, disrupted glutathione metabolism, reduced cell viability, and altered gene expression in mouse spermatocytes. Gene enrichment analysis revealed that the differentially expressed genes (DEGs) were associated with various biological functions such as mitochondrial inner membrane, response to oxidative stress. Furthermore, these DEGs were found to be enriched in pathways including proteasome, glutathione metabolism, oxidative phosphorylation, and Hif-1 signaling pathway. Real-time PCR and western blot were employed to validate the expression alterations of pivotal genes, and the outcomes exhibited concordance with the mRNA-seq findings. This study provides a theoretical basis for revealing the potential mechanism of male reproductive toxicity caused by aluminum exposure., Competing Interests: Declaration of Competing Interest We have no known competing financial interests or personal relationships that might affect the work reported in this article., (Copyright © 2023. Published by Elsevier Ltd.)

Despite the numerous treatment strategies used for Alzheimer's disease (AD), only a few cholinesterase inhibitor drugs, such as memantine, are effective in symptomatically relieving the hallmarks of AD, providing momentary recovery of memory and cognitive decline. These available drugs do not treat the underlying causes of AD, and their chronic use is associated with serious adverse effects and disease progression. Berberine is an isoquinoline alkaloid that has been reported to possess therapeutic potential against AD. Therefore, its activity was evaluated against an aluminum chloride (AlCl 3 )-induced AD rat model, and a berberine-enriched extract (BEE) was used to determine if its activity is equivalent to pure berberine (PB). The rats were administered 300 mg/kg of oral AlCl 3 to induce AD and were then treated with oral PB at a dosage of 50 mg/kg, BEE at a dosage of 50 mg/kg, and rivastigmine at a dosage of 1 mg/kg as a standard drug for 21 days. In this study, various parameters were assessed to evaluate cognitive functions, such as behavioral analysis, antioxidant enzyme levels, acetylcholinesterase (AChE) activity, proinflammatory cytokine levels, real-time polymerase chain reaction (RT-PCR) analysis of different biomarkers (AChE, IL-1α, IL-1β, BACE-1, TNF-α) linked to AD, and histopathological changes in the rats' brains. After 21 days, the disease control group showed a significant decline in cognitive function, decreased levels of antioxidant enzymes, upregulated activity of the AChE enzyme, increased levels of proinflammatory cytokines, and marked elevation in mRNA expression of AD-associated biomarkers. On the other hand, the treatment groups showed significant improvements in memory deficits, elevated levels of antioxidant enzymes, reduced levels of proinflammatory cytokines, decreased AChE activity, and significant downregulation of the expression of predefined biomarkers. Histological examination of the treatment groups showed less neuroinflammation and fewer amyloid plaques compared to the disease control group. In conclusion, both PB and BEE have comparable neuroprotective potential to mitigate the pathological hallmarks of AD. However, controlled clinical trials are needed to assess their efficacy and safety., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The informal aluminum industry is increasingly widespread in low- and middle-income countries, especially in Indonesia. Aluminum exposure is a serious public health problem, especially among workers in the informal aluminum foundry sector. Research on aluminum (Al) is important to advance our understanding of its impact on physiological systems. Here, we investigated the effect of exposure to aluminum longitudinal histological changes on the liver and kidneys of male mice. Mice were separated into six groups (4/group): group 1, group 2, group 3 received vehicles, and group 4, group 5, group 6 were administered a single dose of Al at 200 mg/kg b.w. by intraperitoneally every 3 days for 4 weeks. Post-sacrifice, kidneys and liver were isolated for examination. While Al did not impact the body weight gain of male mice across all groups, it caused liver damage including sinusoidal dilatation, enlarged central veins, vacuolar degeneration, and pyknotic nuclei in one-month-old mice. Furthermore, atrophied glomeruli, blood-filled spaces, and disintegration of renal tubular epithelium are evident at one-month-age. By contrast, sinusoidal dilatation and enlarged central veins were found in mice two- and three-months-old, including hemorrhage in mice (two-month-old) and atrophy of glomeruli. Lastly, the kidneys of three-month-old mice displayed interstitial fibrosis and increasing mesenchyme in the glomeruli. In summary, we demonstrated that Al provoked histological changes in the liver and kidneys with Al-treated 1-month mice being the most susceptible.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that causes cognitive and memory decline. Neuroinflammation is currently considered as being an important pathology in AD. NLRP3, the nucleotide-binding and oligomerization (NOD) domain-like receptor (NLR) family pyrin domain (PYD)-containing 3 (NLRP3) inflammasome is a critical component of the innate immune response, which plays a key role in the development and progression of AD. Therefore, the NLRP3 inflammasome is one of the target treatments for AD. This study aimed to investigate the effect of festidinol, a flavanol isolated from Dracaena conferta, against NLRP3 inflammasome and blood-brain barrier damage in D-galactose and aluminum chloride-induced mice. The induced mice received D-galactose (150 mg/kg) and aluminum chloride (10 mg/kg) intraperitoneally for 90 days to generate cognitive impairment. Festidinol (30 mg/kg) and donepezil (5 mg/kg) were given by oral gavage for 90 days along with the induction. Then, learning and memory behavior, and molecular and morphological changes in the brain, which related to NLRP3 inflammasome, pyroptosis and the blood-brain barrier were measured. The results indicated that festidinol markedly decreased the escape latency and increased the time in the target quadrant in the Morris water maze test. Furthermore, festidinol significantly decreased the ionized calcium-binding adapter molecule 1 (Iba-1) and glial fibrillary acidic protein (GFAP) expression. Festidinol also markedly decreased the NLRP3 inflammasome pathway, interleukin 1 beta (IL-1β), gasdermin-D, N-terminal (GSDMD-N) and caspase-3. Pertinent to the blood-brain barrier, festidinol only decreased tumor necrosis factor-α and matrix metallopeptidase-9, but did not restore the tight junction components. In conclusion, festidinol can restore learning and memory and provide a protective effect against the NLRP3 inflammasome and pyroptosis., 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 © 2023 Elsevier B.V. All rights reserved.)

Several pollutants can alter neonatal prostatic development predisposing this gland to diseases. The toxicity and endocrine disrupting potential of aluminum has been reported in many organs, but little is known about its effects on the prostate. This study aimed to evaluate the effects that aluminum neonatal exposure can cause in the male ventral prostate and in the female prostate of adult and senile gerbils. Male and female pups were treated orally with aluminum chloride (10 mg/kg) from the 1st to the 14th day life. After treatment, the animals were aged until they reached 90 days or 1 year of life. The prostate glands were dissected out and submitted to morphological, immunohistochemical and ultrastructural analyses. Ventral prostates of adult males showed moderate hyperplasia and increased epithelial proliferation not associated with androgen receptor (AR) deregulation. On the other hand, senile males showed intense prostatic hyperplasia, and increased cell proliferation and epithelial AR regulation. Additionally, at both ages, there was a reduction in the prostate secretory function. The morphological changes observed in the female prostate were like those found in males. However, in adult females, prostatic hyperplasia was accompanied by a lower regulation of AR and estrogen receptor alpha, while in senile females, intense hyperplastic growth was associated with an increase in estrogen receptor alpha and a reduction in stromal AR. These results demonstrate that aluminum chloride neonatal exposure alters the hormonal regulation of the male and female prostate, inducing tissue damage that occurs in adulthood and intensifies during aging., (© 2023 International Federation for Cell Biology.)

Prodigiosin (PDG) is a bacterial metabolite with numerous biological and pharmaceutical properties. Exposure to aluminium is considered a root etiological factor in the pathological progress of Alzheimer's disease (AD). Here, in this investigation, we explored the neuroprotective potential of PDG against aluminium chloride (AlCl 3 )-mediated AD-like neurological alterations in rats. For this purpose, rats were gavaged either AlCl 3 (100 mg/kg), PDG (300 mg/kg), or both for 42 days. As a result of the analyzes performed on the hippocampal tissue, it was observed that AlCl 3 induced biochemical, molecular, and histopathological changes like those related to AD. PDG pre-treatment significantly decreased acetylcholinesterase activity and restored the levels of brain-derived neurotrophic factor, monoamines (dopamine, norepinephrine, and serotonin), and transmembrane protein (Na + /K + -ATPase). Furthermore, PDG boosted the hippocampal antioxidant capacity, as shown by the increased superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glutathione contents. These findings were accompanied by decreases in malondialdehyde and nitric oxide levels. The antioxidant effect may promote the upregulation of the expression of antioxidant genes (Nrf2 and HO-1). Moreover, PDG exerted notable anti-inflammatory effects via the lessening of interleukin-1 beta, tumor necrosis factor-alpha, cyclooxygenase-2, nuclear factor kappa B, and decreases in the gene expression of inducible nitric oxide synthase. In addition, noteworthy decreases in pro-apoptotic (Bax and caspase-3) levels and increases in anti-apoptotic (Bcl-2) biomarkers suggested an anti-apoptotic effect of PDG. In support, the hippocampal histological examination validated the aforementioned changes. To summarize, the promising neuromodulatory, antioxidative, anti-inflammatory, and anti-apoptotic activities of PDG establish it as a potent therapeutic option for AD., (© 2022 Wiley Periodicals LLC.)

Objective: The objective of this study is to investigate the neuroprotective effects of β- sitosterol using the AlCl3 model of Alzheimer's Disease., Methods: AlCl 3 model was used to study cognition decline and behavioral impairments in C57BL/6 mice. Animals were randomly assigned into 4 groups with the following treatments: Group 1 received normal saline for 21 days, Group 2 received AlCl 3 (10 mg/kg) for 14 days; Group 3 received AlCl3(10 mg/kg) for 14 days + β-sitosterol (25mg/kg) for 21 days; while Group 4 was administered β-sitosterol (25mg/kg) for 21 days. On day 22, we performed the behavioral studies using a Y maze, passive avoidance test, and novel object recognition test for all groups. Then the mice were sacrificed. The corticohippocampal region of the brain was isolated for acetylcholinesterase (AChE), acetylcholine (ACh), and GSH estimation. We conducted histopathological studies using Congo red staining to measure β -amyloid deposition in the cortex and hippocampal region for all animal groups., Results: AlCl 3 successfully induced cognitive decline in mice following a 14-day induction period, as shown by significantly decreased (p < 0.001) in step-through latency, % alterations, and preference index values. These animals also exhibited a substantial decrease in ACh (p <0.001) and GSH (p < 0.001) and a rise in AChE (p < 0.001) compared to the control group. Mice administered with AlCl 3 and β-sitosterol showed significantly higher step-through latency time, % alteration time, and % preference index (p < 0.001) and higher levels of ACh, GSH, and lower levels of AChE in comparison to the AlCl 3 model. AlCl3-administered animals also showed higher β-amyloid deposition, which got significantly reduced in the β-sitosterol treated group., Conclusion: AlCl3 was effectively employed to induce a cognitive deficit in mice, resulting in neurochemical changes and cognitive decline. β -sitosterol treatment mitigated AlCl 3 -mediated cognitive impairment., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The effects of 5-methyltetrahydrofolate (5-MTHF) on a rat model of Alzheimer's disease (AD) induced by D-galactose (D-gal) and aluminum chloride (AlCl 3 ) were investigated. Wistar rats were given an i.p. injection of 60 mg/kg D-gal and 10 mg/kg AlCl 3 to induce AD and three doses of 1 mg/kg, 5 mg/kg or 10 mg/kg 5-MTHF by oral gavage. A positive control group was treated with 1 mg/kg donepezil by gavage. Morris water maze performance showed that 5 and 10 mg/kg 5-MTHF significantly decreased escape latency and increased the number of platform crossings and time spent in the target quadrant for AD rats. The administration of 10 mg/kg 5-MTHF decreased the brain content of amyloid β-protein 1-42 (Aβ 1-42 ) and phosphorylated Tau protein (p-Tau) and decreased acetylcholinesterase and nitric oxide synthase activities. Superoxide dismutase activity, vascular endothelial growth factor level and glutamate concentration were increased, and malondialdehyde, endothelin-1, interleukin-6, tumor necrosis factor-alpha and nitric oxide decreased. The administration of 10 mg/kg 5-MTHF also increased the expression of disintegrin and metallopeptidase domain 10 mRNA and decreased the expression of β-site amyloid precursor protein cleavage enzyme 1 mRNA. In summary, 5-MTHF alleviates memory impairment in a D-gal- and AlCl 3 -exposed rat model of AD. The inhibition of Aβ 1-42 and p-Tau release, reduced oxidative stress, the regulation of amyloid precursor protein processing and the release of excitatory amino acids and cytokines may be responsible.

The risk of aluminium exposure to humans is very high as it may get into the human body through excessive dietary contaminants, inhalation of fine particulate matter, or through parenteral routes as a vaccine adjuvant and so forth. The increased level of aluminium in brain tissue has been shown to be associated with several neurodegenerative and neurotoxic adverse effects, including AD. However, the exact mechanism of aluminium-induced neurotoxicity is still unclear. Therefore, our study aimed to investigate the mechanism of neurotoxic and neurodegenerative effects through in vitro exposure of aluminium in rat glioma C6 cell line. The findings of our study have indicated that aluminium chloride exposure may lead to alteration in acetylcholine levels, increased oxidative imbalance and induction of molecular structural and functional markers of neuronal inflammation. This study also demonstrated that aluminium exposure may lead to the induction of caspase-3 along with apoptotic cell death and a significant increase in amyloid-beta and hyperphosphorylated tau levels in C6 cells. Thus, this study may provide a mechanistic understanding of the regulation of neuroinflammatory and neurodegenerative biomarkers due to aluminium exposure., (© 2022 Wiley Periodicals LLC.)

Hippocampus is the brain area where aluminum (Al) accumulates in abundance and is widely associated with learning and memory. In the present study, we evaluate behavioral, tissue, and proteomic changes in the hippocampus of Wistar rats caused by exposure to doses that mimic human consumption of aluminum chloride (AlCl 3 ) in urban areas. For this, male Wistar rats were divided into two groups: Control (distilled water) and AlCl 3 (8.3 mg/kg/day), both groups were exposed orally for 60 days. After the Al exposure protocol, cognitive functions were assessed by the Water maze test, followed by a collection for analysis of the global proteomic profile of the hippocampus by mass spectrometry. Aside from proteomic analysis, we performed a histological analysis of the hippocampus, to the determination of cell body density by cresyl violet staining in Cornu Ammonis fields (CA) 1 and 3, and hilus regions. Our results indicated that exposure to low doses of aluminum chloride triggered a decreased cognitive performance in learning and memory, being associated with the deregulation of proteins expression, mainly those related to the regulation of the cytoskeleton, cellular metabolism, mitochondrial activity, redox regulation, nervous system regulation, and synaptic signaling, reduced cell body density in CA1, CA3, and hilus.

Aluminum is an environmentally abundant potential neurotoxic agent that may result in oxidative damage to a range of cellular biomarkers. The potential sources of aluminum accumulation in the body include drinking water, food, medicines, vaccines, and aluminum cookware utensils, etc. The accumulation of aluminum in the brain is reported to be associated with cholinergic dysfunction, oxidative stress and neuronal damage, which may ultimately cause Alzheimer's disease. Since chronic exposure to aluminum leads to its accumulation in the brain, so this study was done by a long-term (24 weeks) low dose (20 mg/kg) oral exposure of aluminum chloride in rats. In this chronic model, we have evaluated the major hallmarks of Alzheimer's disease including amyloid-beta (Aβ 1-42 ) and phosphorylated-tau (p231-tau) protein in brain tissue. Furthermore, we evaluated the level of acetyl cholinesterase activity, inflammatory cytokines such as TNF-α, IL-6 and IL-1β, and oxidative stress biomarkers in the rat brain in this model. The neurobehavioral parameters were also assessed in animals by using spontaneous locomotor activity, passive avoidance, rotarod test and novel object recognition test to evaluate alteration in learning, memory and muscle co-ordination. We found that chronic oral exposure to aluminum chloride causes a significant increase in structural hallmarks such as Aβ 1-42 and p231-tau levels along with pro-inflammatory cytokines (TNF-α and IL-6), oxidative stress, and a decrease in antioxidant markers such as GSH and catalase in the brain tissue. These biomarkers significantly affected neurobehavioral parameters in animals. This study provides a mechanistic understanding of chronic aluminum-induced neuronal toxicity in the brain with relevance to Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disease (ND) that represents the principal cause of dementia. Effective treatment is still lacking. Without prevention, Alzheimer's disease (AD) incidence is expected to triple within 30 years. The risk increases in highly polluted areas and is positively linked to chronic aluminum (Al) exposure. Canonical Wingless-Int (Wnt)/β-catenin pathway has been found to play a considerable role in ND pathogenesis. Resins of Boswellia serrata (frankincense) have been used traditionally for their psychoactive activity, in addition to their memory-boosting effects. Boswellic acids (BA) are pentacyclic triterpenes. They have antioxidant, anti-inflammatory, antinociceptive, and immunomodulatory activities. This study aimed to elucidate the role of the Wnt/β-catenin pathway in BA protective activity against aluminum-induced Alzheimer's disease. For 6 weeks, rats were treated daily with AlCl3 (100 mg/kg/i.p.) either alone or with BA (125 or 250 mg/kg PO). Results indicated that BA significantly improved learning and memory impairments induced by AlCl 3 treatment. Moreover, BA treatment significantly decreased acetylcholinesterase levels and reduced amyloid-beta (Aβ) expression. In addition, BA ameliorated the increased expression of tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β), inhibited lipid peroxidation, and increased total antioxidants in the brain. Indeed, BA significantly suppressed AlCl 3 -induced decrease of brain-derived neurotrophic factor, pGSK-3β (Ser 9), and β-catenin. BA (250 mg/kg) showed a significant protective effect compared to a lower dose. The results conclude that BA administration modulated the expression of Wnt/β-catenin pathway-related parameters, contributing to BA's role against Al-induced Alzheimer's disease. Effect of Boswellic acids on AlCl 3 -induced neurodegenerative changes. ChE cholinesterase, Ach acetylcholine, BDNF brain-derived neurotrophic factor, IL-1β interleukin-1β, TNF-α tumor necrosis factor-α., (© 2022. The Author(s).)

Aluminium is a metal known to cause neurotoxicity in the brain, by promoting neurodegeneration and affecting memory and cognitive ability. AlCl 3 has been reported to enhance reactive oxygen species (ROS) and inflammatory markers which are further responsible for the degeneration of neurons. AlCl 3 exposure to zebrafish causes behavioral, biochemical, and neurochemical changes in the brain. In our study, Zebrafish were exposed to AlCl 3 at three different doses (50 µg/L, 100 µg/L, and 200 µg/L) for four consecutive days. On days 1st and 4th, a novel diving test was performed to check anxiety in zebrafish. T - maze and novel object recognition test were used to check the memory on days 3rd and 4th with the help of ANY-maze software. On the last day (4th day), zebrafishes were sacrificed and whole brains were used to perform the biochemical, neurotransmitters, histopathological, and immunohistochemistry analysis. Our study revealed that AlCl 3 exposure significantly decreased the total distance traveled, and the number of entries in the top zone and increased the time spent in the bottom zone, checked through the novel diving test. In the T maze test, AlCl 3 treated zebrafish showed significantly increased transfer latency to the favorable zone and time spent, and the number of entries to the unfavorable zone. The exploration time with the novel object was reduced significantly after AlCl 3 treatment. Moreover, reduced glutathione (GSH) and superoxide dismutase (SOD) levels were significantly reduced in AlCl 3 treated zebrafish whereas malondialdehyde (MDA) level was found to be increased, indicating high oxidative stress. The neurotransmitters level was also disturbed indicated by the significantly decreased GABA, dopamine, noradrenaline, and Serotonin levels and increased glutamate level in the brain of zebrafish treated with AlCl 3 . Moreover, histopathological and immunohistochemistry study shows a markedly increased number of pyknotic neurons and reduced the expression of Nrf2 in the zebrafish brain after AlCl 3 exposure. These findings suggest that AlCl 3 significantly causes behavioral, biochemical, neurotransmitters, morphological, and molecular changes in zebrafish, ultimately causing AD., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Shamsher Singh reports was provided by Indo Soviet Friendship College of Pharmacy. Shamsher Singh reports a relationship with Indo Soviet Friendship College of Pharmacy that includes:. Shamsher Singh has No patent pending., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD) is a slowly progressive brain degenerative disorder which gradually impairs memory, thinking, and ability to perform easy routine tasks. This degenerative disorder mainly targets the elderly people and has imposed an endemic burden on society. Hence, there is a crucial need to investigate the efficacious herbal pharmacotherapies that can effectively mitigate and prevent the pathological hallmarks of AD. The current study aims to explore the potential efficacy of curcuminoid-rich extract (CRE) and its ternary complex (TC). Experimental rodents were administered with AlCl 3 (300 mg/kg) to induce AD and treated with rivastigmine, curcuminoid crude extract, CRE, and TC orally for three consecutive weeks. Neurobehavioral, biochemical, and histopathological studies were performed from the last week of the study period. The mRNA expression of different pathological biomarkers was estimated by RT-qPCR analysis. The results of the study suggested that CRE and TC significantly improved the behavioral, biochemical parameters and acetylcholinesterase inhibitory activity in treatment groups. Histological analysis was also carried out indicating that the neurodegenerative changes and neuronal loss were stabilized by CRE and TC supplementation. CRE and TC supplementation remarkably downregulated the interleukin-1α, tumor necrosis factor-α, interleukin-1β, acetylcholinesterase, and β-secretase pathological gene expression. Hence, it was concluded that CRE and TC may act as promising candidates in the prevention of AD via numerous underlying signaling pathways., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aluminum chloride is a chemical compound widely used in both pharmaceutical and industrial sectors. The present study aimed to assess the effect of aluminum chloride on TNF levels and metallothionein gene expression in rat livers. A total of 16 Wistar rats were used as an experimental model and assigned to four groups (n=4). The treated groups received aluminum chloride (Sigma/USA) at a dose of 25g/kg body weight via a feeding tube as follows: group 1: Non-treated rats as the control group, group 2 were treated with aluminum chloride for 8 weeks, group 3 were treated with aluminum chloride for 12 weeks, and group 4 received aluminum chloride for 16 weeks. The TNF-α was measured in liver tissue using an enzyme-linked immunosorbent assay (ELISA). Immunohistochemistry and real-time polymerase chain reaction (RT-PCR) were used to analyze metallothionein gene expression in rat liver. To estimate TNF levels, the results revealed that levels were considerably higher ( P <0.01) in all experimental groups, especially in group 4 which underwent treatment for 16 weeks (401±22.1 ng/ml), as compared to that in the control group. For the immunohistochemistry assay, a gradient intensity of staining for liver tissue was observed, ranging from zero staining in the control group to moderate, medium, and high staining in the experimental groups after 8, 12, and 16 weeks of aluminum chloride treatment, respectively. The greatest amount of methylothionine expression was observed in the livers of group 4 which received aluminum chloride for 16 weeks (15.5-fold), with a significant difference ( P <0.01) from the other experimental groups. In both immunohistochemical and RT-PCR experiments, aluminum administration had a substantial influence on TNFα levels and metallothionein expression in rat livers., Competing Interests: The authors declare that they have no conflict of interest.

Aluminium (Al) is a potent neurotoxic metal known to cause neurodegeneration. Al exposure causes oxidative stress by accumulation of reactive oxygen species, followed by the activation of neuronal cell death in the brain. Asiatic acid (AA), the major bioactive compound of Centella asiatica (a medicinal plant), act as multifunctional drug as well as an antioxidant. Thus, the present study aimed to investigate the potential neuroprotective effect of AA against Al neurotoxicity. Rats were orally administered aluminium chloride (AlCl 3 ; 100 mg/kg b. wt.) dissolved in distilled water for 8 weeks or AA (75 mg/kg b. wt.) in combination with AlCl 3 . The results showed that AlCl 3 -intoxication causes significant impairment of memory, enhances anxiety-like behavior, acetyl cholinesterase (AChE) activity, malondialdehydes (MDA) level, and concomitant decrease in the activities of superoxide dismutase (SOD) and catalase (CAT) in the cortex and hippocampus regions of rat brain. In addition, AlCl 3 -intoxication enhanced neuronal loss and reactive astrogliosis in both regions. However, co-administration of AA with AlCl 3 significantly attenuated the behavioral alterations, restored SOD and CAT activities, while reduced AChE activity and MDA content. Further, the study demonstrated that AA attenuates neuronal loss and reactive astrogliosis in rat brain. In conclusion, the study suggests that AA protects rat brain from Al neurotoxicity by inhibiting oxidative stress, neuronal loss and reactive astrogliosis., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aluminum (Al), a common light metal, affects the developing nervous system. Developmental exposure to Al chloride (AlCl 3 ) induces aberrant neurogenesis by targeting neural stem cells (NSCs) and/or neural progenitor cells (NPCs) in the dentate gyrus (DG) of rats and mice. To investigate whether hippocampal neurogenesis is similarly affected by AlCl 3 exposure in a general toxicity study, AlCl 3 was orally administered to 5-week-old Sprague Dawley rats at dosages of 0, 4000, or 8000 ppm in drinking water for 28 days. AlCl 3 downregulated Sox2 transcript level in the DG at the highest dosage and produced a dose-dependent decrease of SOX2 + cells without altering numbers of GFAP + or TBR2 + cells in the subgranular zone, suggesting that AlCl 3 decreases Type 2a NPCs. High-dose exposure downregulated Pcna, upregulated Pvalb, and altered expression of genes suggestive of oxidative stress induction (upregulation of Nos2 and downregulation of antioxidant enzyme genes), indicating suppressed proliferation and differentiation of Type 1 NSCs. AlCl 3 doses also increased mature granule cells in the DG. Upregulation of Reln may have contributed to an increase of granule cells to compensate for the decrease of Type 2a NPCs. Moreover, upregulation of Calb2, Gria2, Mapk3, and Tgfb3, as well as increased numbers of activated astrocytes in the DG hilus, may represent ameliorating responses against suppressed neurogenesis. These results suggest that 28-day exposure of young-adult rats to AlCl 3 differentially targeted NPCs and mature granule cells in hippocampal neurogenesis, yielding a different pattern of disrupted neurogenesis from developmental exposure., (© 2022 John Wiley & Sons, Ltd.)

Aluminum chloride (AlCl3) and its accumulation in the brain are associated with neurodegenerative disease. Recent investigations have illustrated that silibinin is known to have neuroprotective properties. The present study investigates the neuroprotective effects of silibinin-loaded nanostructured lipid carriers (Sili-NLCs) against AlCl3-induced neurotoxicity in male mice. Sili-NLCs were prepared using the emulsification-solvent evaporation method and subjected to particle size, zeta potential, and entrapment efficiency (% EE) analysis. Mice were treated with AlCl3 (100 mg/kg/day, p.o.) and with the same concentration of silibinin and Sili-NLCs (50,100, and 200 mg/kg/day, p.o.) for 30 days in different groups. After treating animals, behavioral studies were assessed. Also, the brain tissue samples were collected from all mice to evaluate oxidative damage and histological changes. The particle size, polydispersity index, zeta potential, and entrapment efficiency (% EE) of prepared Sili-NLCs found 239.7 ± 4.04 nm, 0.082 ± 0.003, - 16.33 ± 0.15 mV, and 72.65 ± 2.03 %, respectively. Brain uptake studies showed that Sili-NLCs had a 5.7-fold greater uptake in the mice brain than the free drug. The AlCl3 caused significant cognitive impairment and increased the level of lipid peroxidation accompanied by decreasing antioxidant enzyme activity in the brain tissue. These findings correlated well with the histopathological experiments. Furthermore, treatment with Sili-NLCs significantly improved the AlCl3-induced cognitive impairment, neurochemical anomalies, and histopathological changes. Given these results, silibinin, when delivered using NLCs, is potentially more effective than free silibinin in decreasing AlCl3- induced neurotoxicity., (Copyright © 2022. Published by Elsevier B.V.)

Alzheimer's disease (AD) is an irreversible, progressive cognitive dysfunction. Inflammaging is the greatest common factor between AD and hepatorenal malfunction. This study aimed to use melatonin (MEL) and zinc sulfate (Zn) in addition to physical and mental activities (PMA) to ameliorate AlCl 3 -induced AD as well as investigate their impact on the associated hepatorenal impairment., Methods: Seven groups of rats each received: saline (control group), AlCl 3 (70 mg/kg, i.p.), PMA, either alone or with a combination of Mel (10 mg/kg, p.o) and/or Zn (16 mg/kg, p.o). Neurological deterioration was assessed after 5 weeks using behavioral tests, histopathological examination, and measurements of acetylcholinesterase (ACHE), brain monoamines, oxidative stress, and inflammatory markers, Amyloid precursor protein (APP), amyloid-β (Aβ), tau levels, and brain derived neurotrophic factor (BDNF). Moreover, the GSK-3β-Wnt/β-catenin signaling pathway was assessed. Additionally, oxidative stress and inflammatory markers were determined in liver and kidney tissues with concurrent evaluation of hepatic and renal functions., Results: The histopathological examination revealed a cerebral cortex and hippocampus deterioration in the AD group with a decline in spatial learning and memory, besides a significant increase in AD markers in the brain and disturbance in GSK-3β-Wnt/β-catenin signaling. The AD group showed hepatorenal injuries supported by elevated oxidative stress and inflammatory markers. However, adding Mel and Zn to PMA significantly attenuated the neurodegeneration and enhanced hepatic and renal functions by ameliorating oxidant and inflammatory markers., Conclusions: Combining Mel and Zn supplements with PMA defends against AlCl 3 -induced AD by modulating GSK-3β-Wnt/β-catenin signaling and palliates the associated hepatorenal dysfunction., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Exposure to aluminum chloride (AlCl 3 ) induces progressive multiregional neurodegeneration in animal models by promoting oxidative stress and neuroinflammation. The current study was designed to assess the potential efficacy of the natural antioxidants celastrol and thymoquinone (TQ) for alleviating AlCl 3 -induced psychomotor abnormalities and oxidative-inflammatory burden in male albino rats. Four treatment groups were compared: (i) a vehicle control group, (ii) a AlCL 3 group receiving daily intraperitoneal (i.p.) injection of AlCl 3 (10 mg/kg) for 6 weeks, (iii) a AlCl 3 plus TQ (10 mg/kg, i.p.) cotreatment group, and (iv) a AlCl 3 plus celastrol (1 mg/kg, i.p.) cotreatment group. Open-field, rotarod, and forced swimming tests were conducted to assess locomotor activity, motor coordination, anxiety-like behavior, and depressive-like behavior. Acetylcholine (ACh), dopamine, and serotonin levels were measured in brain homogenates. Malondialdehyde (MDA), total antioxidant capacity (TAC), and catalase activity were measured as oxidative stress markers, while tumor necrosis factor-α (TNF-α) and interlukin-6 (IL-6) expression levels were measured as inflammatory markers. Brain derived neurotrophic factor (BDNF) mRNA was measured as an index for the endogenous neuroprotective response. Daily AlCl 3 injection reduced free ambulation, impaired motor coordination, promoted anxiety- and depression-like behaviors, reduced whole-brain ACh, dopamine, and serotonin concentrations, increased MDA accumulation, reduced TAC, elevated TNF-α and IL-6, and suppressed BDNF mRNA expression. All of these effects were significantly reversed by TQ or celastrol cotreatment. Thus, TQ and celastrol may be promising treatments for AlCl 3 -induced neurotoxicity as well as neurodegenerative diseases involving oxidative stress and neuroinflammation., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The present study investigated the potential adverse effects of aluminum chloride (AlCl 3 ) following a 4-week repeated oral administration in Sprague-Dawley rats. The test article was administered once daily by gavage to male and female rats at dose levels of 0, 100, 300, and 900 mg/kg/day for 4 weeks. After administration of AlCl 3 at 900 mg/kg/day, treatment-related systemic toxicity manifested as significant increases in salivation incidence, neutrophil percentage, reticulocytes, serum triglyceride, adrenal gland and liver weights, and single-hepatocyte necrosis, as well as significant decreases in body weight gain, food intake, hemoglobin, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration (MCHC), lymphocyte percentage, serum total protein and albumin, and thymus weight in male rats; and significant increases in salivation incidence, serum triglyceride, and liver weight, as well as a significant decrease in lymphocyte percentage in female rats. At 300 mg/kg/day, a significant decrease in MCHC was found in male rats, but not in female rats. However, this finding was not toxicologically significant because the reduction was minimal and was not accompanied by changes in any other parameters. No treatment-related effects were observed in the 100 mg/kg/day group of both genders. Under the experimental conditions of this study, the target organs of AlCl 3 were determined to be the blood, liver, and thymus in rats. The no-observed-adverse-effect level was found to be 300 mg/kg/day in rats of both genders.

Prolonged exposure to aluminum through occupational hazards or food/water intake has been linked to the occurrence of Alzheimer's disease (AD). This study aimed at investigating the neuroprotective effects of Gallic Acid (GA) against aluminum-chloride induced AD in adult Wistar rats. Twenty eight (28) adult Wistar rats were divided into four groups ( n  = 7). Group A received normal saline as placebo; Group B received 200 mg/kg bw of AlCl 3 only; Group C received 100 mg/kg bw of GA only and group D received 100 mg/kg bw of GA and 200 mg/kg bw of AlCl 3 . At the end of the 60 days experiment, blood samples were collected to obtain serum for analysis and the brain was harvested. Neurobehavioural tests (Morris Water maze, Y-Maze), neurotransmitter levels, oxidative stress markers, serum electrolytes, antioxidant enzymes and histological assessment were carried out. There was a significant decrease in antioxidant enzymes (CAT, GSH and SOD), serum electrolyte (except K+) and neurotransmitter levels (except norepinephrine) with corresponding increase in stress markers (MDA, H 2 O 2 and NO) among group B compared to control but was restored nearly to normal after GA administration. Neurobehavioral tests showed decreased spatial memory impairment and learning deficit in group B compared to control but was ameliorated with GA administration. Histological observation showed neurofibrillary tangles and amyloid plaques in the external granular layer of group B but protected by GA administration. Nutritional supplementation of GA preserve the morphological and physiological integrity of the hippocampus against environmental neurotoxins (AlCl 3 ) by mopping up free radicals associated with oxidative stress induced AD.

Background: Mounting evidences indicate that oxidative stress, neuroinflammation, and dysregulation of gut microbiota are related to neurodegenerative disorders (NDs). Butyrolactone I (BTL-I), a marine fungal metabolite, was previously reported as an in vitro neuroprotectant and inflammation inhibitor. However, little is known regarding its in vivo effects, whereas zebrafish (Danio rerio) could be used as a convenient in vivo model of toxicology and central nervous system (CNS) diseases., Methods: Here, we employed in vivo and in silico methods to investigate the anti-NDs potential of BTL-I. Specifically, we established a cognitive deficit model in zebrafish by intraperitoneal (i.p.) injection of aluminum trichloride (AlCl 3 ) (21 μg) and assessed their behaviors in the T-maze test. The proinflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) as well as acetylcholinesterase (AChE) activity or glutathione (GSH) levels were assayed 24 h after AlCl 3 injection. The intestinal flora variation of the zebrafish was investigated by 16S rDNA high-throughput analysis. The marine fungal metabolite, butyrolactone I (BTL-I), was used to modulate zebrafish cognitive deficits evoked by AlCl 3 and evaluated about its effects on the above inflammatory, cholinergic, oxidative stress, and gut floral indicators. Furthermore, the absorption, distribution, metabolism, excretion, and toxicity (ADMET) and drug-likeness properties of BTL-I were studied by the in silico tool ADMETlab., Results: BTL-I dose-dependently ameliorated AlCl 3 -induced cognitive deficits in zebrafish. While AlCl 3 treatment elevated the levels of central and peripheral proinflammatory cytokines, increased AChE activity, and lowered GSH in the brains of zebrafish, these effects, except GSH reduction, were reversed by 25-100 mg/kg BTL-I administration. Besides, 16S rDNA high-throughput sequencing of the intestinal flora of zebrafish showed that AlCl 3 decreased Gram-positive bacteria and increased proinflammatory Gram-negative bacteria, while BTL-I contributed to maintaining the predominance of beneficial Gram-positive bacteria. Moreover, the in silico analysis indicated that BTL-I exhibits acceptable drug-likeness and ADMET profiles., Conclusions: The present findings suggest that BTL-I is a potential therapeutic agent for preventing CNS deficits caused by inflammation, neurotoxicity, and gut flora imbalance., (© 2022. The Author(s).)

Exposure of consumers to aluminum-containing nanomaterials (Al NMs) is an area of concern for public health agencies. As the available data on the genotoxicity of Al 2 O 3 and Al 0 NMs are inconclusive or rare, the present study investigated their in vitro genotoxic potential in intestinal and liver cell models, and compared with the ionic form AlCl 3 . Intestinal Caco-2 and hepatic HepaRG cells were exposed to Al 0 and Al 2 O 3 NMs (0.03 to 80 μg/cm 2 ). Cytotoxicity, oxidative stress and apoptosis were measured using High Content Analysis. Genotoxicity was investigated through γH2AX labelling, the alkaline comet and micronucleus assays. Moreover, oxidative DNA damage and carcinogenic properties were assessed using the Fpg-modified comet assay and the cell transforming assay in Bhas 42 cells respectively. The three forms of Al did not induce chromosomal damage. However, although no production of oxidative stress was detected, Al 2 O 3 NMs induced oxidative DNA damage in Caco-2 cells but not likely related to ion release in the cell media. Considerable DNA damage was observed with Al 0 NMs in both cell lines in the comet assay, likely due to interference with these NMs. No genotoxic effects were observed with AlCl 3 . None of the Al compounds induced cytotoxicity, apoptosis, γH2AX or cell transformation., (Copyright © 2021. Published by Elsevier Ltd.)

Aluminum (Al) is an abundant metal with wide application in our daily lives including medicine, industry, cosmetics, and packaging. After entrance to the body, aluminum binds to transferrin and reaches different tissues. Al is a metalloestrogen that can lead to oxidative stress (OxS) and endocrine disruption. No detailed study can be found addressing the effect of Al on the ovary and granulosa cells (GCs). In this study, the focus is on the treated ovaries and GCs of NMRI mice exposed to low, middle, and high doses of aluminum chloride (AlCl 3 ) via in vitro and in vivo assays. The steroidogenic, proliferative, apoptotic, and autophagic-related genes were examined. Up-regulated expression of steroidogenic and proliferative genes was detected. The observed apoptotic and autophagic genes had variable expression. Interrupted ovarian structure, disrupted folliculogenesis, presence of Call-Exner bodies, overexpression of steroidogenic gene, and unbalanced apoptosis/autophagy and proliferation resembled features of granulosa cell tumor (GCT)., (Copyright © 2021. Published by Elsevier B.V.)

The chemical compositions of essential oils (EOs) prepared from six spices including cinnamon, amomum tsao-ko, cardamom, amomum, black pepper and white pepper were analyzed by gas chromatography-mass spectrometry (GC/MS), which led to identify almost 200 volatile compounds. All EOs of spices showed cholinesterase inhibitory activity. Among them, pepper EO showed most potent acetylcholinesterase (AChE) inhibitory activity with IC 50 values of 8.54 μg/mL (black pepper EO) and 5.02 μg/mL (white pepper EO). Molecular docking and in vitro validation suggested that 3-carene, α-pinene and β-pinene with IC 50 value of 1.73, 2.66, and 14.75 μg/mL, respectively, might be active constituents of spices oil in inhibiting AChE. Furthermore, amomum tsao-ko EO and amomum EO can improve behavioral disorder in dementia zebrafish induced by aluminum trichloride (AlCl 3 )., (© 2021 Wiley-VHCA AG, Zurich, Switzerland.)

Treatment with aluminum chloride (AlCl 3 ) suppresses the growth of osteoblastic cells; however, the molecular mechanisms underlying the impact of AlCl 3 on cell growth have not been fully characterized. In this study, we observed that exposure of hFOB1.19 cells to AlCl 3 arrested cells at G 0 /G 1 phase by inducing p21 expression. Further studies indicated that AlCl 3 upregulated the phosphorylation level of signal transducer and activator of transcription 1 (STAT1) at serine 727 site (Ser727). By chromatin immunoprecipitation and electrophoretic mobility shift assay, we found that AlCl 3 promoted STAT1/DNA binding activity to p21 promoter, thus resulting in the upregulation of p21. Moreover, siRNA-mediated knockdown of STAT1 attenuated p21 level induced by AlCl 3 . Notably, using hFOB1.19 cells stably expressing dominant-negative STAT1 (Ser727Ala), we demonstrated that phosphorylation of STAT1 at Ser727 site is required for p21-mediated cycle arrest induced by AlCl 3 . Mechanism investigation indicated that AlCl 3 stimulated the phosphorylation of JNK, and administration of JNK inhibitor SP600125 prevented AlCl 3 -induced G 0 /G 1 arrest through suppressing the phosphorylation of STAT1. Notably, pretreatment with N-acetyl-cysteine, a reactive oxygen species scavenger, conferred a significantly inhibitory effect on AlCl 3 -mediated activation of JNK/STAT1 signaling pathway. Taken together, our findings provide the molecular mechanism for G 0 /G 1 arrest induced by AlCl 3 in osteoblastic cells.

Patients suffering from Alzheimer's disease (AD) are still increasing worldwide. The development of (AD) is related to oxidative stress and genetic factors. This study investigated the therapeutic effects of ellagic acid (EA) on the entorhinal cortex (ERC), which plays a major role in episodic memory, in the brains of an AD rat model. AD was induced using AlCl 3 (50 mg/kg orally for 4 weeks). Rats were divided into four groups: control, AD model, EA (treated with 50 mg/kg EA orally for 4 weeks), and ADEA (AD rats treated with EA after AlCl 3 was stopped) groups. All rats were investigated for episodic memory using the novel object recognition test (NORT), antioxidant serum biomarkers, lipid peroxidation, histopathology of the ERC, and quantitative PCR for the superoxide dismutase ( SOD ) gene. EA therapy in AD rats significantly increased the discrimination index for NORT and the levels of SOD, glutathione, and total antioxidant capacity. Lipid peroxidation products were decreased, and the neurofibrillary tangles and neuritic plaques in the ERC sections were reduced after EA administration. The decrease in ERC thickness in the AD group, caused by caspase-3-mediated apoptosis and neurotoxicity due to amyloid precursor protein, was modulated by the increased SOD mRNA expression. Adjustment of the ERC antioxidant environment and decreased oxidative stress under EA administration enhanced SOD expression, resulting in the modulation of amyloid precursor protein toxicity and caspase-3-mediated apoptosis, thereby restoring episodic memory.

The number of people with dementia worldwide is estimated at 50 million by 2018 and continues to rise mainly due to increasing aging and population growth. Clinical impact of current interventions remains modest and all efforts aimed at the identification of new therapeutic approaches are therefore critical. Previously, we showed that JM-20, a dihydropyridine-benzodiazepine hybrid molecule, protected memory processes against scopolamine-induced cholinergic dysfunction. In order to gain further insight into the therapeutic potential of JM-20 on cognitive decline and Alzheimer's disease (AD) pathology, here we evaluated its neuroprotective effects after chronic aluminum chloride (AlCl 3 ) administration to rats and assessed possible alterations in several types of episodic memory and associated pathological mechanisms. Oral administration of aluminum to rodents recapitulates several neuropathological alterations and cognitive impairment, being considered a convenient tool for testing the efficacy of new therapies for dementia. We used behavioral tasks to test spatial, emotional- associative and novel object recognition memory, as well as molecular, enzymatic and histological assays to evaluate selected biochemical parameters. Our study revealed that JM-20 prevented memory decline alongside the inhibition of AlCl 3 -induced oxidative stress, increased AChE activity, TNF-α and pro-apoptotic proteins (like Bax, caspase-3, and 8) levels. JM-20 also protected against neuronal damage in the hippocampus and prefrontal cortex. Our findings expanded our understanding of the ability of JM-20 to preserve memory in rats under neurotoxic conditions and confirm its potential capacity to counteract cognitive impairment and etiological factors of AD by breaking the progression of key steps associated with neurodegeneration., (Copyright © 2021 Elsevier B.V. All rights reserved.)