Protective effect of a hydromethanolic extract from Fraxinus excelsior L. bark against a rat model of aluminum chloride-induced Alzheimer's disease: Relevance to its anti-inflammatory and antioxidant effects.

ETHNOPHARMACOLOGICAL RELEVANCE: Fraxinus excelsior L. (FE), commonly known as the ash, belongs to the Oleaceae family and has shown several pharmacological and biological properties, such as antioxidant, immunomodulatory, neuroprotective, and anti-inflammatory effects. It has also attracted the most attention toward neuroinflammation. Moreover, FE bark and leaves have been used to treat neurological disorders, aging, neuropathic pain, urinary complaints, and articular pain in traditional and ethnomedicine. Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder resulting from the involvement of amyloid-beta, metal-induced oxidative stress, and neuroinflammation. AIM OF THE STUDY: The objective of the current study was to assess the neuroprotective effects of hydromethanolic extract from FE bark in an AlCl3-induced rat model of AD. MATERIALS AND METHODS: The maceration process was utilized to prepare the hydromethanolic extract of FE bark, and characterized by LC-MS/MS. To assess the anti-AD effects of the FE extract, rats were categorized into five different groups, AlCl3; normal control; FE-treated groups at 50, 100, and 200 mg/kg. Passive avoidance learning test, Y-maze, open field, and elevated plus maze behavioral tests were evaluated on days 7 and 14 to analyze the cognitive impairments. Zymography analysis, biochemical tests, and histopathological changes were also followed in different groups. RESULTS: LC-MS/MS analysis indicated the presence of coumarins, including isofraxidin7-O-diglucoside in the methanolic extract of FE as a new isofraxidin derivative in this genus. FE significantly improved memory and cognitive function, maintained weight, prevented neuronal damages, and preserved the hippocampus's histological features, as demonstrated by behavioral tests and histopathological analysis. FE increased anti-inflammatory MMP-2 activity, whereas it decreased that of inflammatory MMP-9. Moreover, FE increased plasma antioxidant capacity by enhancing CAT and GSH while decreasing nitrite levels in the serum of treated groups. In comparison between the treated groups, the rats that received high doses of the FE extract (200 mg/kg) showed the highest therapeutic effect. CONCLUSION: FE rich in coumarins could be an effective anti-AD adjunct agent, passing through antioxidant and anti-inflammatory pathways. These results encourage further studies for the development of this extract as a promising agent in preventing, managing, or treating AD and related diseases.

New bithiophene derivative attenuated Alzheimer's disease induced by aluminum in a rat model via antioxidant activity and restoration of neuronal and synaptic transmission.

BACKGROUND: One of the hypotheses that leads to an increased incidence of Alzheimer's disease (AD) is the accumulation of aluminum in the brain's frontal cortex. The present study aimed to evaluate the therapeutic role of a novel bithiophene derivative at two doses against AlCl3-induced AD in a rat model. METHODOLOGY: Adult male rats were divided into six groups, 18 rats each. Group 1: naïve animals, group 2: animals received a daily oral administration of bithiophene dissolved in DMSO (1 mg/kg) for 30 days every other day, groups 3-6: animals received a daily oral administration of AlCl3 (100 mg/kg/day) for 45 consecutive days. Groups 4 and 5 received an oral administration of low or high dose of the bithiophene (0.5 or 1 mg/kg, respectively). Group 6; Animals were treated with a daily oral dose of memantine (20 mg/kg) for 30 consecutive days. MAIN FINDINGS: Al disturbed the antioxidant milieu, elevated the lipid peroxidation, and depleted the antioxidants. It also disturbed the synaptic neurotransmission by elevating the activities of acetylcholine esterase and monoamine oxidase resulting in the depletion of dopamine and serotonin and accumulation of glutamate and norepinephrine. Al also deteriorated the expression of genes involved in apoptosis and the production of amyloid-ß plaques as well as phosphorylation of tau. The new bithiophene at the low dose reversed most of the previous deleterious effects of aluminum in the cerebral cortex and was in many instances superior to the reference drug; memantine. CONCLUSION: Taking together, the bithiophene modulated the AD etiology through antioxidant activity, prevention of neuronal and synaptic loss, and probably mitigating the formation of amyloid-ß plaques and phosphorylation of tau.

Vitamin K2 protects against aluminium chloride-mediated neurodegeneration.

Recent studies have shown that, coupled with other environmental factors, aluminium exposure may lead to neurodegeneration resulting in cognitive impairment resembling Alzheimer's disease. Menaquinone, a form of vitamin K2, aids in maintaining healthy bones and avoids coronary calcification. It also has anti-inflammatory and antioxidant properties. Here, we study the neuroprotective effects of vitamin K2 (MK-7) using the animal model of Alzheimer's disease (AD). Aluminium chloride (AlCl3; 100 mg/kg for 3 weeks orally) was administered to Swiss albino mice to induce neurodegeneration and Vitamin K2 (100 g/kg for 3 weeks orally) was applied as treatment. This was followed by behavioural studies to determine memory changes. The behavioural observations correlated with proinflammatory, oxidative, and brain histopathological changes in AlCl3-treated animals with or without vitamin K2 treatment. AlCl3 administration led to memory decline which was partially restored in Vitamin K2 treated animals. Myeloperoxidase levels in the brain increased due to AlCl3-mediated inflammation, which Vitamin K2 prevented. The acetylcholine esterase and oxidative stress markers induced by AlCl3 were reversed by Vitamin K2. Also, Vitamin K2 helps to restore hippocampal BDNF levels and reduced the amyloid ß accumulation in AlCl3-administered animals. Additionally, Vitamin K2 protected the hippocampal neurons against AlCl3-mediated damage as observed in histopathological studies. We conclude that Vitamin K2 could partially reverse AlCl3-mediated cognitive decline. It increases acetylcholine and BDNF levels while reducing oxidative stress, neuroinflammation, and ß-amyloid deposition, thus protecting the hippocampal neurons from AlCl3-mediated damage.

Efficacy of aluminum chloride in severe regorafenib-associated hand-foot skin reactions: a single-arm trial.

BACKGROUND: Regorafenib, a multikinase inhibitor, causes a high frequency of hand-foot skin reactions (HFSRs). The present study evaluated the efficacy of topical aluminum chloride, a perspiration suppressant, in reducing the severity of hand-foot skin reactions (HFSRs) caused by regorafenib. METHODS: The present single-arm study included patients with metastatic colorectal cancer receiving regorafenib. Aluminum chloride ointment was applied topically one week prior to the start of regorafenib treatment, and the observation period was 12 weeks. The primary endpoint was the incidence of regorafenib-related grade 3 HFSR. Secondary endpoints were the incidence of all grades of HFSR, time to any grade of HFSR, time to improvement from grade 2 or higher to grade 1 or lower, treatment discontinuation rate, treatment interruption rate or dosage reduction due to HFSR, and incidence of adverse effects of aluminum chloride. RESULTS: In total 28 patients were enrolled, and 27 patients were analyzed. The incidence of grade 3 HFSR was 7.4%, meeting the primary endpoint. The incidence of all grades of HFSR was 66.7%, and the median time to the occurrence of any grade of HFSR was 15 days. No patients discontinued or reduced the regorafenib dosage because of HFSR. The most common reason for the interruption of regorafenib therapy was liver dysfunction in nine patients (33%) and HFSR in three patients (11%). No serious adverse events related to aluminum chloride were observed. CONCLUSIONS: Aluminum chloride ointment, a drug commonly used in routine practice to treat hyperhidrosis, is safe to use, has no serious side effects, and may be effective in reducing the occurrence of severe, regorafenib-related HFSR. TRAIL REGISTRATION: ClinicalTrials.gov. identifier: jRCTs031180096, Registered on 25/01/2019.

Resveratrol-Tempeh reduce micronucleus frequencies bone marrow cells and stimulate osteocyte proliferation in aluminum chloride-induced mice.

Aluminum (Al) is widely used for water purification, cooking pots, cosmetic and pharmaceutical preparations, toothpaste tubes, and food processing industries. Although the transport in the digestive tract is very poor but if the load is high, it can be absorbed and accumulated. About 50-70% of Al accumulates in the bones and can have an impact on human health. Resveratrol (RES), isolated from tempeh as an Indonesian food ingredient, can increase cell viability and has promising cytoprotective effects. RES has the capacity to interact with oxidative stress, so it has the potential as a therapy in bone repair. Therefore, this study aimed to evaluate the effect of RES on the number of osteocytes and bone marrow cells in Al-induced mice. Swiss Webster mice were divided into four groups: (1) untreated groups, (2) AlCl3-treated groups, (3) Al+Res5 treated groups, and (4) Al+Res10 treated groups. Al dose 200 mg/kg body weight was administered intraperitoneally. RES was given one hour after administration of Al, with doses of 5 and 10 mg/kg Body Weight. Al and RES administration is carried out for one month. All mice were sacrificed, and mouse bones were isolated for histological preparations and a half for genotoxic assays. Bone marrow cells were collected and stained with My Grunwald. The number of micronuclei polychromatic erythrocytes (MNPCE) was examined in 1,000 PCEs per animal. The number of PCEs is counted by at least 200 erythrocytes (PCE + NCE) per animal. The results showed that the administration of Al significantly increased the number of micronuclei (MN) but after administration of RES at doses of 5 and 10 mg/kg Body Weight significantly reduced the number of MN in bone marrow cells. A dose of RES 10 mg/kg BW stimulates proliferation and increases the number of osteocytes in bone significantly. It can be concluded that Al can cause genotoxicity in bone marrow cells and RES is anti-genotoxic and can stimulate osteocyte proliferation.

Effects of Phoenix dactylifera against Streptozotocin-Aluminium Chloride Induced Alzheimer's Rats and Their In Silico Study.

Phoenix dactylifera is known for medicinal importance due to its antioxidant, antidiabetic, antidepressant, and anti-inflammatory properties. This study is aimed at evaluating the effect of P. dactylifera seeds to cure Alzheimer's disease (AD). AD was induced in the rats with streptozotocin + aluminium chloride followed by treatment of methanolic extract of P. dactylifera seeds. The blood glucose levels were determined at regular intervals, which showed a prominent decrease in the extracts treated group. Behavior tests, including the Elevated Plus Maze (EPM) test and Morris Water Maze (MWM) test, were used to evaluate memory patterns in rats. The results indicated that extract-treated rats significantly improved memory behavior compared to the diseased group. After dissection, the serum electrolytes, antioxidant enzymes, and choline esterase enzymes were measured in different organs. The serum parameters creatinine, urea, and bilirubin increased after extract treatment. Similarly, the level of antioxidant enzymes like peroxidases (POD), glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), and thiobarbituric acid reactive substance (TBARS) in the extract-treated group showed improved results that were close to the normal control group. The enzyme (lipase, insulin, amylase, and acetylcholine) levels were found enhanced in extract groups as compared to diseased rats. High-performance liquid chromatography (HPLC) was used to determine the level of dopamine and serotonin neurotransmitters, which were increased significantly for P. dactylifera seeds with values of 0.18 µg/mg tissue and 0.56 µg/mg tissue, respectively. Overall, results showed that P. dactylifera seeds proved to be quite efficient in improving the memory and behavior of treated rats. The antioxidants and enzymes were also increased; therefore, it may be a potential candidate for treating AD.

Selenium Nanoparticles-Enriched Lactobacillus casei ATCC 393 Prevents Cognitive Dysfunction in Mice Through Modulating Microbiota-Gut-Brain Axis.

Purpose: The bidirectional communication between the gut and the central nervous system mediated by gut microbiota is closely related to the occurrence and development of neurodegenerative diseases, including Alzheimer's disease (AD). Selenium (Se) has been identified as playing a role against AD. Probiotics have beneficial effects on host brain function and behavior by modulating the microbiota-gut-brain axis. Herein, we evaluated the protective effects of Lactobacillus casei ATCC 393 (L. casei ATCC 393) and selenium nanoparticles-enriched L. casei ATCC 393 (L. casei ATCC 393-SeNPs) against D-galactose/aluminum chloride-induced AD model mice. Methods: The Morris Water Maze (MWM) test was used to assess cognitive function of mice. The morphology and histopathological changes, antioxidant capacity and immune responses in the brain and ileum were evaluated. The alterations in intestinal permeability of the mice were determined using FITC-dextran. Gut microbiota composition was assessed using 16s rRNA sequencing. Results: Thirteen weeks intervention with L. casei ATCC 393 or L. casei ATCC 393-SeNPs significantly improved cognitive dysfunction, and minimized amyloid beta (Aß) aggregation, hyperphosphorylation of TAU protein, and prevented neuronal death by modulating Akt/cAMP-response element binding protein (CREB)/brain-derived neurotrophic factor (BDNF) signaling pathway. Moreover, compared with L. casei ATCC 393, L. casei ATCC 393-SeNPs further effectively mitigated intestinal barrier dysfunction by improving antioxidant capacity, regulating immune response, restoring gut microbiota balance, and increasing the level of short-chain fatty acids and neurotransmitters, thereby inhibiting the activation of microglia and protecting brain neurons from neurotoxicity such as oxidative stress and neuroinflammation. Conclusion: These findings indicated that targeting the microbiota-gut-brain axis with L. casei ATCC 393-SeNPs may have therapeutic potential for the deficits of cognitive function in the AD model mice. Thus, we anticipate that L. casei ATCC 393-SeNPs may be a promising and safe Se nutritional supplement for use as a food additive to prevent the neurodegenerative disease.

The Effect of Thymoquinone on Oxidative Stress Parameters and Apolipoprotein E in Alzheimer Model in Rats.

INTRODUCTION: In this study, it was aimed to investigate the effect of thymoquinone (TQ) on oxidative stress and apolipoprotein E (ApoE) in an experimental Alzheimer's model created with AlCl3 and D-galactose in rats. METHODS: Thirty-six Wistar Albino male rats saline group (Group 1), aluminum chloride (AlCl3) + D-galactose (D-Gal) group (Group 2), AlCl3 + D-Gal + TQ group (Group 3) were divided into 3 groups. The study was completed with 33 rats. Group 1 was given saline intraperitoneally (i.p) for 28 days. 2nd group; D-Gal at a dose of 60 mg/kg/day and AlCl3 at a dose of 40 mg/kg/day were given i.p. daily for 28 days. 3rd group; D-Gal at a dose of 60 mg/kg/day and AlCl3 at a dose of 40 mg/kg/day were given i.p. daily for 28 days. Group 3 rats were given 20 mg/kg/day TQ in corn oil by gavage for 14 days. Malonyl dialdehyde (MDA), superoxide dismutase (SOD), total antioxidant capacity (TAS), total oxidant capacity (TOS), glutathione peroxidase (GsH-Px), and ApoE levels were determined in the blood and brain tissues of rats in all three groups. One-way ANOVA test was used in the statistical analysis of the data. RESULTS: Means of TAS, TOS, GSH-Px, SOD, MDA, and ApoE in blood and brain tissue of all three groups (excluding ApoE in brain tissue) were different from each other and this difference was statistically significant (p < 0.05). CONCLUSION: In this study, TQ, it was determined that all oxidative stress parameters examined had positively affected and decreased blood tissue ApoE levels. TQ can be used as an antioxidant and curative in Alzheimer's disease.

Nanocurcumin, Promising Potential Protective Agent Against Histopathological Damage in the Cerebral Cortex of Mice Induced by Aluminum Chloride.

<b>Background and Objective:</b> Aluminum (Al) is widely used in many aspects of daily life, such as food packaging, cooking utensil components, food additives, cosmetics and water distillation. This study aimed to evaluate the protective role of nanocurcumin on the cerebral cortex of one and two-month-old mice exposed to 200 mg kg¹ b.wt., aluminium. <b>Materials and Methods:</b> The Swiss Webster mice were used in this study. The control group only received sterile distilled water, the Al group was administered 200 mg kg¹ b.wt., of AlCl₃ solution and the Al+Na Cur group was administered 200 mg kg¹ b.wt., AlCl₃+200 mg kg¹ nanocurcumin by intraperitoneal injection. The nanocurcumin was administered one hour after AlCl₃exposure and then on days 0, 3, 6, 9, 12, 15, 18, 21, 24, 27 and 30. All the mice were anaesthetized and their brains were collected and fixed in a neutral formalin buffer solution for histological analysis. The paraffin method was used in this study. <b>Results:</b> The death of granular neuron cells and karyolysis cells and the vacuolation of the pyramid cell layer of the cerebral cortex could be prevented by the intraperitoneal administration of nanocurcumin. The effect of nanocurcumin administration on the Al group at two months of age was more effective than on the Al group at one month of age. <b>Conclusion:</b> Nanocurcumin can be a promising candidate protective agent against cerebral cortex changes after aluminium administration.

Fluoride mitigates aluminum-toxicity in barley: morpho-physiological responses and biochemical mechanisms.

BACKGROUND: To our knowledge, the role of exogenous fluoride (F-) on aluminum (Al)-stress mitigation in plants has not been investigated yet. In this experiment, barley (Hordeum vulgaris) seedlings were exposed to excessive Al3+ concentrations (aluminum chloride, 0.5, 1.0, 2.0, 3.0, and 4.0 mM) with and without fluoride (0.025% sodium fluoride) to explore the possible roles of fluoride on the alleviation of Al-toxicity. RESULTS: Overall, Al-stress caused inhibition of growth and the production of photosynthetic pigments. Principal component analysis showed that the growth inhibitory effects were driven by increased oxidative stress and the interruption of water balance in barley under Al-stress. Fluoride priming, on the other hand, enhanced growth traits, chlorophyll a and b content, as well as invigorated the protection against oxidative damage by enhancing overall antioxidant capacity. Fluoride also improved osmotic balance by protecting the plasma membrane. Fluoride reduced endogenous Al3+ content, restored Al-induced inhibition of glutathione-S-transferase, and increased  the contents of phytochelatins and metallothioneins, suggesting that fluoride reduced Al3+ uptake and improved chelation of Al3+. CONCLUSIONS: Aluminum chloride-induced harmful effects are abridged by sodium fluoride on barely via enhancing antioxidative responses, the chelation mechanism causing reduction of Al uptake and accumulation of barely tissues. Advanced investigations are necessary to uncover the putative mechanisms underpinning fluoride-induced Al-stress tolerance in barley and other economically significant crops, where our results might serve as a solid reference.

Protective Effect of L-Arginine in an Animal Model of Alzheimer's Disease Induced by Intra-Hippocampal Injection of AlCl3.

Background and Objective: Aluminum chloride (AlCl3) can impair spatial memory recovery. We investigated the protective effect of L-arginine, a precursor of nitric oxide (NO), on memory retrieval in an Alzheimer's animal model induced by AlCl3 at intra-hippocampal CA1 using a seeking behavior practice. Materials and Methods: Wistar rats were deeply anesthetized and cannulated at CA1 (AP: -3.8 mm, L: ±2.2 mm, V: 3 mm), and received once AlCl3 (1-200 µg/rat, intra-CA1), on day of cannulation under stereotaxic device. After a week of recovery, they experienced the novelty task with a three-stage paradigm and injected L-arginine (0.05-25 µg/rat) intra-CA1, pretesting. L-NAME, the neuronal NO synthase inhibitor was administered before L-arginine effective doses in the test stage. Also, a reference group exclusively received beta-amyloid 2 µg/rat. Control group solely received saline. Finally, after euthanasia of rat, the hippocampal sample was collected on ice and evaluated by immunohistochemical marking and specific staining. Results: AlCl3 caused novelty-seeking behavior without meaningful change in animal locomotor activity. ßA (2 µg/rat, intra-CA1) affected the rat's grooming, causing it to stop further in the new side. Pretest injection of L-arginine restored behavior in AlCl3-treated rats; however, this effect was stopped by L-NAME pretreatment, indicating NO involvement. CA1 did not show necrotic change due to AlCl3 exposure; however, neurofibrillary tangles were accumulated in the region. Conclusions: Prophylaxis with L-arginine probably due to NO has a protective role against the dangerous effect of AlCl3 on the function of neurons in the cortical hippocampus.

Pharmacological evaluation of bromelain in mouse model of Alzheimer's disease.

The current study elucidates pharmacological evaluation of bromelain as a bioactive compound obtain from pineapple stem belongs to family Bromeliaceae in AlCl3 and D - galactose induced mice. In mice, co-administration of AlCl3 at dose 5 mg/kg b.w., via the oral route, and D - galactose at dose 60 mg/kg b.w., via intraperitoneal route for 90 days resulted in cognitive impairment, spatial learning, and memory deficits, as well as neurotoxicity. However, 30 consecutive days, treatments via an intraperitoneal route with bromelain low dose (Brm L) at dose 10 mg/kg b.w., bromelain high dose (Brm H) at dose 20 mg/kg b.w., donepezil (Dnpz) at dose 2 mg/kg b.w., and Brm L + Dnpz at doses 10, 2 mg/kg b.w. were considerably reversed the effect of AlCl3 and D - galactose induced AD mice. Consequences of behavioral parameters (Morris water maze, elevated plus maze and locomotor), biochemical estimation (MDA, GSH, SOD, CAT, Nitrite and AChE), and ELISA tests (mouse BACE, Aß1 - 42, TNF-α, IL-6, and BDNF) confirmed significant (p < 0.05) neuroprotective effect of treatments in AlCl3 and D - galactose induced mice. Additionally, hematoxylin and eosin staining of the cerebral cortex and the hippocampus exposed eosinophilic lesions and hyperchromatic nuclei in AD mice, but these neurodegenerative effects were eliminated by Brm L, Brm H, Dnpz, and Brm L + Dnpz treatments. Thus, bromelain alone and in combination with donepezil prevent AlCl3 and D - galactose induced spatial learning and memory deficits, as well as cognitive impairment, by increasing cholinergic activity and synaptic plasticity, as well as reducing oxidative damage, neuroinflammation, Aß 1-42 aggregations, and histopathological damage, according to our findings. The present study consequences indicate that bromelain alone and in combination with donepezil appears to have neuroprotective properties. Henceforward, this may be a promising treatment option for Alzheimer's disease.

Centella asiatica Alleviates AlCl3-induced Cognitive Impairment, Oxidative Stress, and Neurodegeneration by Modulating Cholinergic Activity and Oxidative Burden in Rat Brain.

Aluminum (Al) is linked to the development of many neurological disorders such as Alzheimer's disease (AD), Parkinson's disease, and autism. Centella asiatica (CA) is a regenerating herb traditionally used to stimulate memory. This study was designed to assess the neuroprotective role of ethanolic extract of CA (CAE) in AlCl3-induced neurological conditions in rats. Adult rats were chronically treated with AlCl3 (100 mg/kg b.w./day) for 60 days to establish the dementia model, and co-administration of CAE was evaluated for its ability to attenuate the toxic effect of AlCl3. CAE was given orally at a dose of 150 and 300 mg/kg b.w./day, for 60 days. The behavioral performances of rats were tested through Y-maze and open field tests. Lipid peroxidation, superoxide dismutase, and catalase activity were evaluated to measure oxidative stress; and acetylcholinesterase (AChE) activity was assessed to evaluate cholinergic dysfunction in the rat brain. H&E staining was used to assess structural abnormalities in the cortex and hippocampus. The result showed that AlCl3 induces cognitive dysfunction (impaired learning and memory, anxiety, diminished locomotor activity), oxidative stress, cholinergic impairment, and histopathological alteration in the rat brain. Co-administration of CAE with AlCl3 markedly protects the brain from AlCl3-induced cognitive dysfunction, oxidative stress, AChE activity, and cytoarchitectural alterations. Furthermore, 15 days CAE treatment after 45 days AlCl3 administration markedly ameliorates the AlCl3-induced neurotoxicity indicating its potential for therapeutic use.

Aluminum Chloride-Induced Reproductive Toxicity in Rats: the Protective Role of Zinc Oxide Nanoparticles.

Reproductive toxicity is a major challenge associated with aluminum (Al) exposure. Therefore, this study aimed to investigate the effects of zinc oxide nanoparticle (ZnONP) treatment on Al-induced reproductive toxicity in rats. Thirty-two adult male albino rats were allocated into four equal groups as follows: control, AlCl3 orally administered group (100 mg/kg bwt), ZnONPs injected intraperitoneally (i.p.) group (4 mg/kg bwt), and ZnONPs + AlCl3-treated group. The treatment was daily extended for 42 consecutive days. Oral administration of AlCl3 showed an oxidative damage confirmed by an increase in malondialdehyde and nitric oxide levels and superoxide dismutase activity and accompanied by a decrease in glutathione content and catalase activity. Also, AlCl3 administration increased the pro-inflammatory mediator tumor necrosis factor-alpha. Furthermore, significant declines in the levels of serum male reproductive hormones testosterone, luteinizing hormone, and follicle-stimulating hormone in AlCl3-intoxicated rats were noticed. In parallel, severe histopathological alterations were observed in testis tissues. Additionally, the immunohistochemical analysis showed that AlCl3 administration potentiates cell death in the testicular tissue by elevating the immunostaining intensity signal for the pro-apoptotic protein, cysteinyl aspartate specific protease-3 (caspase-3) and a marked depletion in the cell proliferation expression marker, Ki-67, in germinal cells of AlCl3-treated group. On the other hand, the daily i.p. injection to rats with ZnONPs before AlCl3 was found to ameliorate the reproductive toxicity induced by Al administration through reducing the testicular oxidative stress and improving the inflammatory, apoptotic, and reproductive markers as well as histopathological alterations in the testis. These results suggest that ZnONPs could be used as an alternative agent to minimize the reproductive toxicity associated with Al exposure through its antioxidant, anti-inflammatory, anti-apoptotic, and reproductive modulatory activities.

Chemical Elicitors-Induced Variation in Cellular Biomass, Biosynthesis of Secondary Cell Products, and Antioxidant System in Callus Cultures of Fagonia indica.

Fagonia indica is a rich source of pharmacologically active compounds. The variation in the metabolites of interest is one of the major issues in wild plants due to different environmental factors. The addition of chemical elicitors is one of the effective strategies to trigger the biosynthetic pathways for the release of a higher quantity of bioactive compounds. Therefore, this study was designed to investigate the effects of chemical elicitors, aluminum chloride (AlCl3) and cadmium chloride (CdCl2), on the biosynthesis of secondary metabolites, biomass, and the antioxidant system in callus cultures of F. indica. Among various treatments applied, AlCl3 (0.1 mM concentration) improved the highest in biomass accumulation (fresh weight (FW): 404.72 g/L) as compared to the control (FW: 269.85 g/L). The exposure of cultures to AlCl3 (0.01 mM) enhanced the accumulation of secondary metabolites, and the total phenolic contents (TPCs: 7.74 mg/g DW) and total flavonoid contents (TFCs: 1.07 mg/g DW) were higher than those of cultures exposed to CdCl2 (0.01 mM) with content levels (TPC: 5.60 and TFC: 0.97 mg/g) as compared to the control (TPC: 4.16 and TFC: 0.42 mg/g DW). Likewise, AlCl3 and CdCl2 also promoted the free radical scavenging activity (FRSA; 89.4% and 90%, respectively) at a concentration of 0.01 mM, as compared to the control (65.48%). For instance, the quantification of metabolites via high-performance liquid chromatography (HPLC) revealed an optimum production of myricetin (1.20 mg/g), apigenin (0.83 mg/g), isorhamnetin (0.70 mg/g), and kaempferol (0.64 mg/g). Cultures grown in the presence of AlCl3 triggered higher quantities of secondary metabolites than those grown in the presence of CdCl2 (0.79, 0.74, 0.57, and 0.67 mg/g). Moreover, AlCl3 at 0.1 mM enhanced the biosynthesis of superoxide dismutase (SOD: 0.08 nM/min/mg-FW) and peroxidase enzymes (POD: 2.37 nM/min/mg-FW), while CdCl2 resulted in an SOD activity up to 0.06 nM/min/mg-FW and POD: 2.72 nM/min/mg-FW. From these results, it is clear that AlCl3 is a better elicitor in terms of a higher and uniform productivity of biomass, secondary cell products, and antioxidant enzymes compared to CdCl2 and the control. It is possible to scale the current strategy to a bioreactor for a higher productivity of metabolites of interest for various pharmaceutical industries.

Synergistic effect of photobiomodulation and phthalocyanine photosensitizer on fibroblast signaling responses in an in vitro three-dimensional microenvironment.

Photobiomodulation (PBM) is a promising medical treatment modality in the area of photodynamic therapy (PDT). In this study, we investigated the effect of combined therapy in a 3D microenvironment using aluminum chloride phthalocyanines (AlClPc) as the photosensitizing agent. Normal human fibroblast-containing collagen biomatrix was prepared and treated with an oil-in-water (o/a) AlClPc-loaded nanoemulsion (from 0.5 to 3.0 µM) and irradiated at a range of fluences (from 0.1 to 3.0 J/cm2) using a continuous-wave light-emitting diode (LED) irradiation system (660 nm). PBM at 1.2 J/cm2 and AlClPc/NE at 0.5 µM modified the fibroblast signaling response under 3D conditions, promoting collagen synthesis, ROS production, MMP-9 secretion, proliferation of the actin network, and facile myofibroblastic differentiation. PBM alone (at 1.2 J/cm2 and 0.3 J/cm2) had no significant effect on any of these parameters. The combined therapy affected myofibroblastic differentiation, inflammatory response, and extracellular matrix pliability, and should thus be examined further in subsequent studies considering that no side effects of PBM have been reported. Even though significant progress has been made in the field of phototherapy in recent years, it is necessary to further elucidate the detailed mechanisms underlying its effects already shown in 2D conditions to increase the acceptance of this beneficial and non-invasive therapeutic approach.

Biological Effects of Aqueous Extract of Laurus noboilis L. Leaves on Some Histological and Immunological Parameters in Male Rat Liver Affected by Aluminum Chloride.

The present current study aimed to assess the protective effect of the aqueous extract of Laurus noboilis L. leaves against the toxic effects of aluminum chloride on liver tissue. A number of 36 male albino rats (Wistar) were randomly assigned to six groups (n=6) and treated for 30 days: Group 1 was regarded as the control group, Group 2 received Aluminum Chloride 90 mg/kg body weight orally by gavage, Group3: normal rats received aqueous extracts of Lurus Nobilis L. leaf 150 mg/kg body weight, Group 4: normal rats received aqueous extracts of Lurus Nobilis L. leaf 200 mg/kg body weight, Group 5: normal rats received aqueous extracts of Lurus Nobilis L. leaf 150 mg/kg body weight after a period of 4 h following treatment by Aluminum Chloride 90 mg/kg body weight, Group 6: normal rats received aqueous extracts of Laurus nobilis L. 200 mg /kg after a period of 4 h following treatment by Aluminum chloride with 90 mg/kg body weight. All the experimental animals were sacrificed, and sections of their liver were stained with Hematoxylin-Eosin for histological evaluations. Moreover, the liver enzymes and immune cytokines, such as Alkaline phosphatase (ALP), Alanine aminotransferase (ALT), and Aspartate aminotransferase (AST), tumor necrosis factor-alpha (TNF-alpha), and interleukin-10 (IL-10) were measured. As evidenced by the results of the current study, treatment with aqueous extract of Lurus Nobilis L. leaves at a dose of 150 and 200 mg/kg body weight orally contributed to the mitigation of the toxic effects of Aluminum Chloride in albino rats by reducing the damage and inflammation in the hepatocytes. The study suggested that the aqueous extract of Lurus Nobilis L. enhances the protective effect against liver toxicity.

Effect of aluminum combined with ApoEε4 on Tau phosphorylation and Aß deposition.

BACKGROUND: Aluminum is an environmental neurotoxin widely exposed to animals and humans. Studies have shown that Alzheimer's disease (AD) is characterized by abnormally phosphorylated tau and Aß deposition, aluminum exposure can lead to abnormal phosphorylated tau and Aß deposition. Numerous epidemiological data and studies have confirmed that ApoEε4 is a risk factor for AD. However, whether there is an interaction effect between aluminum and ApoEε4 has yet to be verified. METHODS: SH-SY5Y cells were exposed with AlCl3 and transfected with ApoEε4 respectively. The experimental groups included the blank control group, the low dose group (200 µM AlCl3), the medium dose group (400 µM AlCl3), the high dose group (800 µM AlCl3), empty plasmid group, ApoEε4 group and 400 µM AlCl3+ApoEε4 group. The cell viability was determined by CCK-8 kit after transfection for 48 h.The contents of total tau proteins, tau-181, tau-231, tau-262, tau-396 and Aß42, were determined by ELISA kit. The interaction between AlCl3 and ApoEε4 was analyzed by factorial design. RESULTS: With the increase of aluminum exposure, SH-SY5Y cell viability decreased, and the expression of the total tau, tau-181, tau-231, tau-262, tau-396 and Aß content increased. The viability of cells transfected with ApoEε4 is significantly lower than control group, and the expressions of total tau, tau-181, tau-231, tau-262, tau-396 and Aß in ApoEε4 transfected cells were significantly higher than control group. The viability of cells treated with AlCl3 plus ApoEε4 was lower than those treated with, either AlCl3, or ApoEε4. The expression of total tau, tau-181, tau-231, tau-262, tau-396 and Aß in the cells treated with AlCl3 plus ApoEε4 were significantly higher than those in other groups (p < 0.05). Moreover, analyzing data based on the factorial design, there was existed an interaction between AlCl3 and ApoEε4 (p < 0.05). CONCLUSION: Al and ApoEε4 gene can cause morphological changes of SH-SY5Y cells, reduce cell activity, and have obvious cytotoxic effects, and increase the phosphorylation levels of tau and the deposition of Aß increases. In the presence of both Al and ApoEε4 genes, the two factors interact with each other and show a synergistic effect.

Physiological, Biochemical, and Transcriptomic Responses of Neolamarckia cadamba to Aluminum Stress.

Aluminum is the most abundant metal of the Earth's crust accounting for 7% of its mass, and release of toxic Al3+ in acid soils restricts plant growth. Neolamarckia cadamba, a fast-growing tree, only grows in tropical regions with acidic soils. In this study, N. cadamba was treated with high concentrations of aluminum under acidic condition (pH 4.5) to study its physiological, biochemical, and molecular response mechanisms against high aluminum stress. High aluminum concentration resulted in significant inhibition of root growth with time in N. cadamba. The concentration of Al3+ ions in the root tip increased significantly and the distribution of absorbed Al3+ was observed in the root tip after Al stress. Meanwhile, the concentration of Ca, Mg, Mn, and Fe was significantly decreased, but P concentration increased. Aluminum stress increased activities of antioxidant enzymes such as superoxide dismutase (SOD), catalase from micrococcus lysodeiktic (CAT), and peroxidase (POD) in the root tip, while the content of MDA was decreased. Transcriptome analysis showed 37,478 differential expression genes (DEGs) and 4096 GOs terms significantly associated with treatments. The expression of genes regulating aluminum transport and abscisic acid synthesis was significantly upregulated; however, the genes involved in auxin synthesis were downregulated. Of note, the transcripts of several key enzymes affecting lignin monomer synthesis in phenylalanine pathway were upregulated. Our results shed light on the physiological and molecular mechanisms of aluminum stress tolerance in N. cadamba.

Aluminum exposure promotes histopathological and pro-oxidant damage to the prostate and gonads of male and female adult gerbils.

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.