A Bayesian network for estimating hypertension risk due to occupational aluminum exposure.

Background: The correlation between metals and hypertension, such as sodium, zinc, potassium, and magnesium, has been confirmed, while the relationship between aluminum and hypertension is not very clear. This study aimed to evaluate the correlation between plasma aluminum and hypertension in electrolytic aluminum workers by the Bayesian networks (BN). Methods: In 2019, 476 male workers in an aluminum factory were investigated. The plasma aluminum concentration of workers was measured by inductively coupled plasma mass spectrometry. The influencing factors on the prevalence of hypertension were analyzed by the BN. Results: The prevalence of hypertension was 23.9% in 476 male workers. The risk of hypertension from plasma aluminum in the Q2, Q3, and Q4 groups was 5.20 (1.90-14.25), 6.92 (2.51-19.08), and 7.33 (2.69-20.01), respectively, compared with that in the Q1 group. The risk of hypertension from the duration of exposure to aluminum of >10 years was 2.23 (1.09-4.57), compared without aluminum exposure. Area under the curve was 0.80 of plasma aluminum and the duration of exposure to aluminum was based on covariates, indicating that aluminum exposure had important predictive value in the prevalence of hypertension in the occupational population. The results of the study using the BN model showed that if the plasma aluminum of all participants was higher than Q4 (≥47.86 µg/L) and the participants were drinking, smoking, diabetes, central obesity, dyslipidemia, and aged >50 years, the proportion of hypertension was 71.2%. Conclusions: The prevalence of hypertension increased significantly with the increase of plasma aluminum level.

The mechanism of miR-665 targeting GNB3 in aluminum-induced neuronal apoptosis.

BACKGROUND: Aluminum exerts neurotoxic effects through various mechanisms, mainly manifested as impaired learning and memory function. METHODS: Forty SD rats were divided into 0, 10, 20, and 40 mM maltol aluminum [Al(mal)3] groups. Cell experiments are divided into 0, 100, 200, and 400 µM Al(mal)3 dose group and control, Al(mal)3, Al(mal)3+inhibitor NC, Al(mal)3+miR-665 inhibitor intervention group. Water maze was used to detect the learning and memory function of rats, HE staining was used to observe the morphology and number of neurons in the CA1 area of the rat hippocampus, Flow cytometry was used to detect the apoptosis of PC12 cells, PCR and Western blotting were used to detect the expression of Caspase3, miR-665 and GNB3/PI3K/AKT proteins. The target binding relationship between miR-665 and GNB3 was verified by double luciferase reporter gene experiment. RESULTS: In vivo experimental results showed that with the increase of Al(mal)3 concentration, the escape latency of rats was prolonged, the target quadrant dwell time was shortened, and the number of crossing platform was reduced. Moreover, the arrangement of neurons was loose and the number decreased; the expression of Caspase3 and miR-665 increased, while the expression of GNB3/PI3K/AKT proteins decreased. In vitro experiments, with the increase of Al(mal)3 concentration, apoptosis rate of PC12 cells increased, the expression of Caspase3, miR-665 and GNB3/PI3K/AKT proteins were consistent with rat results. After inhibiting miR-665 in the intervention group experiment, apoptosis rate of PC12 cells in the aluminum exposure group decreased, the expression of Caspase3 and miR-665 decreased, and the expression of GNB3/PI3K/AKT proteins increased. CONCLUSION: MiR-665 plays an important role in aluminum induced neuronal apoptosis by targeting GNB3 and regulating the PI3K/AKT pathway.

Erratum: Whole-transcriptome analysis of aluminum-exposed rat hippocampus and identification of ceRNA networks to investigate neurotoxicity of Al.

[This corrects the article DOI: 10.1016/j.omtn.2021.11.010.].

Decoupling of gray and white matter functional networks in cognitive impairment induced by occupational aluminum exposure.

Aluminum (Al) is a low-toxic, accumulative substance with neurotoxicity properties that adversely affect human cognitive function. This study aimed to investigate the neurobiological mechanisms underlying cognitive impairment resulting from occupational Al exposure. Resting-state functional magnetic resonance imaging was conducted on 54 individuals with over 10 years of Al exposure. Al levels were measured, and cognitive function was assessed using the Montreal Cognitive Assessment (MoCA). Subsequently, the K-means clustering algorithm was employed to identify functional gray matter (GM) and white matter (WM) networks. Two-sample t-tests were conducted between the cognition impairment group and the control group. Al exhibited a negative correlation with MoCA scores. Participants with cognitive impairment demonstrated reduced functional connectivity (FC) between the middle cingulum network (WM1) and anterior cingulum network (WM2), as well as between the executive control network (WM6) and limbic network (WM10). Notably, decreased FCs were observed between the executive control network (GM5) and WM1, WM4, WM6, and WM10. Additionally, the FC of GM5-GM4 and WM1-WM2 negatively correlated with Trail Making Test Part A (TMT-A) scores. Prolonged Al accumulation detrimentally affects cognition, primarily attributable to executive control and limbic network disruptions.

LNC000152 Mediates Aluminum-Induced Proliferation of Reactive Astrocytes.

Aluminum is a metal element with significant neurotoxicity, and there is a substantial correlation between aluminum exposure and cognitive dysfunction. Glial fibrillary acidic protein (GFAP) is widely used as a marker of reactive astrocyte proliferation in response to pathological injury of the central nervous system. Studies of various neurodegenerative diseases have confirmed that the expression changes in GFAP are associated with nerve injury. We investigated the role of LNC000152 in the aluminum-induced reactive proliferation of astrocytes. By establishing two aluminum-exposed cell models of rat primary astrocytes and CTX-TNA2 cell lines, we examined the expression of LNC000152 and GFAP and detected cell proliferation with EdU and cell cycle changes with flow cytometry. The role of aluminum in promoting glial cell proliferation was verified; the expression levels of LNC000152 and GFAP increased with the concentration of aluminum exposure. Intervention of LNC000152 expression by siRNA technology revealed that LNC000152 affected glial cell responsive proliferation by influencing GFAP expression. These results suggest that LNC000152 plays a role in the reactive proliferation of astrocytes induced by aluminum.

Zinc as a Mediator Through the ROCK1 Pathway of Cognitive Impairment in Aluminum-Exposed Workers: A Clinical and Animal Study.

Aluminum (Al) exposure was implicated in neurodegenerative diseases and cognitive impairment, yet the involvement of zinc (Zn) and its mechanism in Al-induced mild cognitive impairment (MCI) remains poorly understood. The objective is to explore the role of Zn in Al-induced cognitive impairment and its potential mechanisms. Montreal cognitive assessment (MoCA) test scores and serum Al, Zn from Al industry workers were collected. A mediation analysis was performed to evaluate the role of serum Zn among serum Al and MoCA test scores. Subsequently, an Al-exposure study was conducted on a rat model categorized into control, low-, medium-, and high-dose groups. After a Morris Water Maze test and detection of Al, Zn content in the hippocampus, integrated transcriptomic and proteomic analyses between the control group and the high-dose group were performed to identify the differentially expressed genes (DEPs), proteins (DEPs), and pathways. To corroborate these findings, quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting (WB) were selected to identify the gene and protein results. Zn overall mediates the relationship between serum Al and cognitive function (mediation effect 17.82%, effect value = - 0.0351). In the Al-exposed rat model, 734 DEGs, 18 miRNAs, 35 lncRNAs, 64 circRNAs, and 113 DEPs were identified between the high-dose group and the control group. Among them, ROCK1, DMD, and other four DEPs were identified as related to zinc finger proteins (ZNF). Co-enrichment analyses of the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) linked these changes to the RHOA/ROCK1 signaling axis. ZNF-related proteins Rock1, DMD, and DHX57 in the high-dose group were downregulated (p = 0.006, 0.003, 0.04), and the expression of Myl9, Rhoa, miR431, and miR182 was also downregulated (p = 0.003, 0.032, 0.032, and 0.046). These findings also show correlations between Al, Zn levels in the hippocampus, water maze performance, and expressions of Myl9, Rhoa, miR431, miR182, DMD, ROCK1, and DHX57, with both negative and positive associations. Based on the results, we determined that Zn was involved in Al-induced MCI in Al workers and Al-exposed rat models. Al exposure and interaction with Zn could trigger the downregulation of ZNF of ROCK1, DMD, and DHX57. miR431, miR182 regulate RHOA/ROCK1 was one of the Zn-involved pathways in Al-induced cognitive impairment.

Study on the Digestive Behavior of Chlorogenic Acid in Biomimetic Dietary Fiber and the Antioxidative Synergistic Effect of Polysaccharides and Chlorogenic Acid.

Chlorogenic acid (CA) is often combined with dietary fiber polysaccharides in plant foods, which may affect its digestive behavior and antioxidant activity. This study constructed a biomimetic dietary fiber (BDF) model by combining bacterial cellulose (BC) and pectin with CA and investigated the digestive behavior of CA in BDF. Additionally, the study examined the interaction and synergistic effects of polysaccharides and CA against oxidation. Results showed that BDF and natural dietary fiber had similar microstructures, group properties, and crystallization properties, and polysaccharides in BDF were bound to CA. After simulated gastrointestinal digestion, 41.03% of the CA existed in a conjugated form, and it was possibly influenced by the interaction between polysaccharides and CA. And the release of CA during simulated digestion potentially involved four mechanisms, including the disintegration of polysaccharide-CA complex, the dissolution of pectin, escape from BC-pectin (BCP) network structure, and diffusion release. And polysaccharides and CA may be combined through noncovalent interactions such as hydrogen bonding, van der Waals force, or electrostatic interaction force. Meanwhile, polysaccharides-CA combination had a synergistic antioxidant effect by the results of free-radical scavenging experiments, it was probably related to the interaction between polysaccharides and CA. The completion of this work has a positive significance for the development of dietary intervention strategies for oxidative damage.

miR-128-3p is involved in aluminum-induced cognitive impairment by regulating the Sirt1-Keap1/Nrf2 pathway.

Aluminum (Al) is a common neurotoxicant in the environment, but the molecular mechanism of its toxic effects is still unclear. Studies have shown that aluminum exposure causes an increase in neuronal apoptosis. The aim of this study was to investigate the mechanism and signaling pathway of neuronal apoptosis induced by aluminum exposure. The rat model was established by intraperitoneal injection of maltol aluminum for 90 days. The results showed that the escape latency of the three groups exposed to maltol aluminum was higher than that of the control group on the 3rd, 4th and 5th days of the positioning cruise experiment (P < 0.05). On the 6th day of the space exploration experiment, compared with the control group(6.00 ± 0.71,15.33 ± 1.08) and the low-dose group(5.08 ± 1.69,13.67 ± 1.09), the number of times that the high-dose group crossed the platform(2.25 ± 0.76) and the platform quadrant(7.58 ± 1.43) was significantly reduced (P < 0.01). The relative expression levels of Sirt1 and Nrf2 in hippocampal tissues of all groups decreased gradually with increasing maltol aluminum exposure dose the relative expression levels of Sirt1 and Nrf2 in high-dose group (0.261 ± 0.094,0.325 ± 0.108) were significantly lower than those in control group (1.018 ± 0.222,1.009 ± 0.156)(P < 0.05). The relative expression level of Keap1 increased gradually with increasing maltol aluminum exposure dose (P < 0.05). The relative expression level of miR-128-3p in the high-dose group(1.520 ± 0.280) was significantly higher than that in the control group(1.000 ± 0.420) (P < 0.05). The content of GSH-Px in the hippocampus of rats decreased with increasing dose. ROS levels gradually increased. We speculated that subchronic aluminum exposure may lead to the activation of miR-128-3p in rat hippocampus of rats, thereby inhibiting the Sirt1-Keap1/Nrf2 pathway so that the Sirt1-Keap1/Nrf2 pathway could not be activated to exert antioxidant capacity, resulting in an imbalance in the antioxidant system of rats and the apoptosis of neurons, which caused reduced cognitive impairment in rats.

Role of the RIP3-PGAM5-Drp1 pathway in aluminum-induced PC12 cells necroptosis.

Epidemiological studies from diverse global regions suggest a correlation between the accumulation of aluminum in the brain and the onset of various neurodegenerative diseases, including Alzheimer's disease, of which, neuronal cells death happen. Our previous research has found the potential of aluminum to induce neuronal cell death. A comprehensive exploration of the regulatory pathways influenced by aluminum in neuronal cell death could contribute to the development of strategies aimed at preventing the detrimental impact of aluminum on neuronal cells. This study is dedicated to exploring the impact of aluminum on mitochondrial homeostasis through the RIP3-PGAM5-Drp1 pathway, with a specific focus on its potential role in necroptosis. We observed that the inhibition of RIP3 function and the reduction in PGAM5 protein expression both mitigate aluminum-induced necroptosis in PC12 cells and enhance mitochondrial function. However, the inhibition of PGAM5 protein expression does not exert an impact on the expression of RIP3 and MLKL proteins. In summary, our study posits that aluminum can induce necroptosis in PC12 cells through the RIP3-PGAM5-Drp1 pathway.

Cognitive status and its risk factors in patients with hypertension and diabetes in a low-income rural area of China: A cross-sectional study.

OBJECTIVES: The proportion of older people with dementia in China is gradually increasing with the increase in the aging population over recent years. Hypertension and diabetes are common non-communicable diseases among rural populations in China. However, it remains unclear whether these conditions affect the occurrence and development of cognitive impairment as there is limited research on cognitive status and its risk factors among residents of rural areas. METHODS: A multi-stage stratified cluster random sampling method was used to select 5400 participants from rural permanent residents. A self-designed structured questionnaire was used to investigate demographic data of the participants. Cognitive function was assessed using the Montreal Cognitive Function Assessment Scale (MoCA). The results were analyzed using chi-square test, ANOVA and multiple linear regression analysis. RESULTS: A total of 5028 participants returned the survey, giving a response rate of 93.1%. Higher education (odds ratio (OR) = 3.2, 95% confidence interval (CI) 2.87-3.54, p < 0.001), higher income (OR = 1.61, 95% CI 1.16-2.07, p < 0.001), and dietary control (OR = 0.66, 95%CI 0.34-0.98, p < 0.001) were protective factors. A visual representation of the relationship between annual income and MoCA score showed an inverted U-curve, the group with an annual income of 6000-7999 RMB had a maximum OR of 1.93 (95%CI 0.12-2.74, p < 0.001). While difficulty in maintaining sleep were risk factors for cognitive impairment (OR = -2.28, 95% CI-4.18-0.39, p = 0.018). CONCLUSIONS: Participants with middle incomes had better cognitive status than those with the highest incomes. Higher education, proper diet control and good sleep are beneficial to the cognitive status of residents in rural areas.

Nuclear factor kappa B (NF-κB) participates in the aluminum-induced down-regulation of miR29a/b1.

BACKGROUND: Studies have shown that aluminum (Al) is one of the environmental risk factors leading to Alzheimer's disease (AD), and Al exposure can cause elevated levels of BACE1mRNA, ß-secretase (BACE1), and amyloid beta (Aß) in vivo and in vitro. Previous studies by our research group have shown that this is partly caused by the negative regulation of BACE1 by miRNA29a/b1 (miR29a/b1). Despite the observed the role of nuclear factor kappa B (NF-κB) on many miRNAs, the upstream regulation of NF-κB protein on miR29 remains poorly understood. The purpose of this study was to better define the relationship between NF-κB and miR29a/b1 and the potentially relevant signaling pathways. METHODS: On the one hand, we constructed the animal model of Al exposure by the intraperitoneal injection of aluminum-maltolate (Al(mal)3) in rats. Conversely, NF- κB inhibitors were added to adrenal phaeochromocytoma (PC12) cells exposed to Al(mal)3. RESULTS: We verified that NF-κB shows an increasing trend with Al accumulation in the brain of rats, which is accompanied by a downward trend of miR29a/b1. Notably, the suppression of NF-κB significantly increased miR29a/b1 and affected the expression of BACE1mRNA and downstream proteins. CONCLUSION: Al-induced NF-κB can negatively regulate the expression of miR29a/b1, which then significantly enhances the expression of BACE1 and Aß plaques.

Molecular mechanism of the carboxyl terminus of Hsc70-interacting protein in TAU hyperphosphorylation induced by AlCl3 in N2a cells.

Aluminum (Al) is recognized as a neurotoxin. Studies have confirmed that the neurotoxicity induced by Al may be related to tau hyperphosphorylation. Phosphorylated tau is degraded through the ubiquitin-proteasome pathway (UPP), in which the carboxyl terminus of Hsc70-interacting protein (CHIP) plays an important role. However, whether the CHIP plays a role in regulating tau hyperphosphorylation induced by Al is yet to be determined. The purpose of this study was to explore the molecular mechanism of the CHIP in tau hyperphosphorylation induced by AlCl3 in N2a cells. Mouse neuroblastoma cells (N2a) were exposed to different concentrations of AlCl3 (0, 0.5, 1, and 2 mM) and treated with CHIP/CHIP shRNA/CHIP (ΔU-box)/CHIP (ΔTPR) plasmid transfection. The cell viability was determined by the CCK-8 kit. Protein expression was detected by Western blot. The interaction between CHIP and AlCl3 exposure on the proteins was analyzed by factorial design ANOVA. The results showed that Al can cause tau hyperphosphorylation, mainly affecting the pThr231, pSer262, and pSer396 sites of tau in N2a cells. UPP is involved in the degradation of tau hyperphosphorylation induced by Al in N2a cells, of which CHIP may be the main regulatory target. Both the U-box and TPR domains of CHIP are indispensable and play an important role in the regulation of tau hyperphosphorylation induced by AlCl3 in N2a cells.

Changes in miR-134-3p expression and zDHHC3-AMPARs axis in association with aluminum neurotoxicity.

Aluminum (Al) is a neurotoxic substance associated with cognitive dysfunction and neurodegenerative diseases, such as Alzheimer's disease, but the mechanisms for aluminum neurotoxicity remain to be identified. In this work, we try to investigate a novel potential biomarker of cognitive dysfunction following aluminum exposure and the mechanism involved. Recently, miR-134-3p was reported as a novel regulator of cognitive function. To address this, we investigate the expression level of miR-134-3p in plasma from 280 aluminum factory workers and analyzed the correlation between miRNA-134-3p, blood Al concentration, and Montreal Cognitive Assessment Scale (MoCA scale) score. The results implied that occupational aluminum exposure elevated miR-134-3p expression in the plasma of workers accompanied by cognitive impairment. Our experiment studies using both animal models and PC12 cells validated the upregulation of miR-134-3p caused by aluminum. In addition, we identified that palmitoylation enzyme zDHHC3 was the target of miR-134-3p, and the decreasing AMPAR receptor (AMPAR) trafficking was related to the learning and memory impairment induced by aluminum. More importantly, using transfection and interference approaches in PC12 cells, inhibition of miR-134-3p resulted in a recovery of zDHHC3-AMPARs axis to a certain extent in response to aluminum. In summary, miR-134-3p was found to be involved in aluminum neurotoxicity by targeting zDHHC3-AMPARs axis and could serve as a potential biomarker or helpful target.

Evaluation of the default mode network using nonnegative matrix factorization in patients with cognitive impairment induced by occupational aluminum exposure.

Aluminum (Al) is an important environmental pathogenic factor for neurodegenerative diseases, especially mild cognitive impairment (MCI). The aim of this study was to evaluate the gray matter volume of structural covariance network alterations in patients with Al-induced MCI. Male subjects who had been exposed to Al for >10 years were included in the present study. The plasma Al concentration, Montreal cognitive assessment (MoCA) score, and verbal memory assessed by the Rey auditory verbal learning test (AVLT) score were collected from each participant. Nonnegative matrix factorization was used to identify the structural covariance network. The neural structural basis for patients with Al-induced MCI was investigated using correlation analysis and group comparison. Plasma Al concentration was inversely related to MoCA scores, particularly AVLT scores. In patients with Al-induced MCI, the gray matter volume of the default mode network (DMN) was considerably lower than that in controls. Positive correlations were discovered between the DMN and MoCA scores as well as between the DMN and AVLT scores. In sum, long-term occupational Al exposure has a negative impact on cognition, primarily by affecting delayed recognition. The reduced gray matter volume of the DMN may be the neural mechanism of Al-induced MCI.

The role of Nrf2/HO-1 signal pathway in regulating aluminum-induced apoptosis of PC12 cells.

BACKGROUND: Aluminum has definite neurotoxicity and can lead to apoptosis of nerve cells, but the specific mechanism remains to be further explored. The aim of this study was to investigate the role of Nrf2/HO-1 signaling pathway in neural cell apoptosis induced by aluminum exposure. METHODS: In this study, PC12 cells were used as the research object, aluminum maltol [Al(mal)3] was used as the exposure agent, and tert-butyl hydroquinone (TBHQ), an agonist of Nrf2, was used as the intervention agent to construct an in vitro cell model. Cell viability was detected by CCK-8 method, cell morphology was observed by light microscope, cell apoptosis was measured by flow cytometry, and expression of Bax and Bcl-2 proteins and Nrf2/HO-1 signaling pathway proteins were investigated by western blotting. RESULTS: With the increase of Al(mal)3 concentration, PC12 cell viability decreased, the early apoptosis rate and total apoptosis rate increased, the ratio of Bcl-2 and Bax protein expression decreased, and Nrf2/HO-1 pathway protein expression decreased. The use of TBHQ could activate the Nrf2/HO-1 pathway and reverse the apoptosis of PC12 cells induced by aluminum exposure. CONCLUSION: Nrf2/HO-1 signaling pathway plays a neuroprotective role in the apoptosis of PC12 cells caused by Al(mal)3, which provides a possible target for the intervention of aluminum induced neurotoxicity.

Lnc001209 Participates in aluminium-induced apoptosis of PC12 cells by regulating PI3K-AKT-mTOR signalling pathway.

Aluminium (Al) is a common environmental neurotoxin, but the molecular mechanism underlying its toxic effects remains unclear. Many studies have shown that aluminium exposure leads to increased neuronal apoptosis. This study aimed to investigate the mechanisms and signalling pathways involved in aluminium exposure-induced neuronal apoptosis. The results showed a decrease in the number of PC12 cells and changes in cell morphology in the aluminium maltol exposure group. The viability of PC12 cells decreased gradually with increasing of exposure doses, and the apoptosis rate increased. The expression of Lnc001209 decreased gradually with an increase in the aluminium exposure dose. After transfection of Lnc001209 siRNA in aluminium-exposed PC12 cells, the protein expression levels of p-Akt Ser473, p-Akt Thr308, p-P85 Tyr467, p-mTOR Ser2448 and CD36 were increased. RNA pull-down MS showed that Lnc001209 interacts with the CD36 protein. Expression of the CD36 protein was increased in PC12 cells exposed to aluminium. The results of the CD36 intervention experiment showed that the protein expression levels of p-Akt Ser473, p-Akt Thr308, p-P85 Tyr467, and p-mTOR Ser2448 likely increased after CD36 overexpression. In addition, the phosphorylation level of AKT had the most significant increase. The enhancement of p-Akt activity promotes neuronal apoptosis.

Interaction between aluminum exposure and ApoEε4 gene on cognitive function of in-service workers.

The occurrence and development of cognitive impairment, the early stage of AD, may be affected both by factors of environmental (aluminum exposure) and genetic (ApoEε4 gene). But whether there is an interaction between the two factors on cognitive function is still unknown. To explore the interaction between the two factors on cognitive function of in-service workers. A total of 1121 in-service workers in a large aluminum factory were investigated in Shanxi Province. Cognitive function was assessed by the Mini-mental State Examination (MMSE), the clock-drawing test (CDT), the Digit Span Test (DST, including DSFT and DSBT), the fuld object memory evaluation (FOM), and the verbal fluency task (VFT). The plasma-Al (p-Al) concentrations were measured by inductively coupled plasma-mass spectrometry (ICP-MS) as an internal exposure indicator, and the participants were divided into four Al exposure groups according to the quartile of p-Al concentrations, namely Q1, Q2, Q3, and Q4. ApoE genotype was determined by Ligase Detection Reaction (LDR). The multiplicative model was fitted using non-conditional logistic regression and additive model was fitted using crossover analysis to analyze the interaction between p-Al concentrations and the ApoEε4 gene. Finally, a dose-response relationship between p-Al concentrations and cognitive impairment was observed, with the p-Al concentrations increased, cognitive function performance gradually becomes worse (Ptrend＜0.05), and the risk of cognitive impairment gradually increases (Ptrend＜0.05), mainly in executive/visuospatial impairment, auditory memory impairment (particularly the working memory impairment). And ApoEε4 gene may be a risk factor for cognitive impairment, while no association between the ApoEε2 gene and cognitive impairment is observed. Additionally, an additive but no multiplicative interaction between p-Al concentrations and ApoEε4 gene is observed, and when the two factors work together, the risk of cognitive impairment further increased, of which 44.2% can be attributed to the interaction effect.

Simultaneous effects of aluminum exposure on the homeostasis of essential metal content in rat brain and perturbation of gut microbiota.

The theory of the brain-gut axis has confirmed that gut microbiota and metabolites are involved in the progression of neurodegenerative diseases through multiple pathways. However, few studies have highlighted the role of gut microbiota in cognitive impairment induced by aluminum (Al) exposure and its correlations with the homeostasis of essential metal content in the brain. To explore the relationship between alterations in the content of essential metals in the brain and relative abundance changes in gut microbiota induced by Al exposure, the Al, zinc (Zn), copper (Cu), iron (Fe), chromium (Cr), manganese (Mn), and cobalt (Co) content level in the hippocampus, olfactory bulb, and midbrain tissue were measured by inductively coupled plasma mass spectrometry (ICP-MS) methods after Al maltolate was intraperitoneally injected every other day for exposed groups. Then the unsupervised principal coordinates analysis (PCoA) and linear discriminant analysis effect size (LEfSe) were used to analyze the relative abundance of the gut microbiota community and the structure of the gut microbiome. Finally, the correlations between gut microbiota composition and essential metal content in the different exposure groups were explored by using the Pearson correlation coefficient method. Based on the results, we indicated that the content of Al in the hippocampus, olfactory bulb, and midbrain tissue was increased and then decreased with the increasing exposure duration, with peaks occurring between 14 and 30 days. Concomitantly, Al-exposure decreased the Zn, Fe, and Mn levels in these tissues. 16 S rRNA gene sequencing results indicated that significant differences in the intestinal microbial community structure at the phylum, family, and genus levels were found in the Day 90 exposed group compared with the Day 7 exposed group. Ten enriched species in the exposed group were identified as markers at the three levels. Furthermore, ten bacteria at the genus level were identified to have a significantly strong correlation (r = 0.70-0.90) with Fe, Zn, Mn, and Co.

Diffusion Kurtosis Imaging in Evaluating the Mild Cognitive Impairment of Occupational Aluminum Workers.

RATIONALE AND OBJECTIVES: To investigate whether diffusion kurtosis imaging (DKI) can distinguish mild cognitive impairment (MCI) from normal controls (NC) in aluminum (Al)-exposed workers, and to explore the association of DKI with cognitive performance and plasma Al concentration. MATERIALS AND METHODS: 28 patients with MCI and 25 NC at Al factory were enrolled in this study. All subjects underwent conventional MRI and DKI scans. The mean kurtosis (MK), axial kurtosis (Ka), radial kurtosis (Kr), mean diffusivity (MD) and fractional anisotropy (FA) parameters of the hippocampus, substantia nigra, red nucleus, thalamus, anterior cingulate gyrus, genu and crus of the corpus callosum, frontal, parietal and temporal lobe were measured. To compare the parameters between the two groups, the Mann-Whitney rank sum test was used. The correlation of parameter values with cognitive performance and plasma Al concentration was analyzed using Spearman correlation analysis. The receiver operating characteristic (ROC) curve and the Z-scores were used to evaluate the diagnostic efficacy of each parameter. RESULTS: Compared with the NC group, the MK, Ka, Kr, and FA values in the MCI group were significantly decreased, and the MD values were significantly increased (p<0.05). For the diagnosis of MCI, MK in the right hippocampus showed the largest AUC (0.924). The MK, Kr, MD and FA values were correlated with the Montreal Cognitive Assessment (MoCA) scores, and MK values in the right hippocampus showed the greatest correlation with MoCA scores (r=0.744, p <0.001). Plasma Al in the MCI group was higher than that in the NC group, although there was no significant difference in plasma Al between the two groups (p=0.057). There was no correlation between DKI parameters and plasma Al. CONCLUSION: The DKI method might be a sensitive imaging biomarker to discriminate MCI from NC, and could preliminarily assess the severity of cognitive impairment in Al-exposed workers. MK in the right hippocampus appeared to be the best independent predictor. The mechanism of cognitive decline is an important content of aluminum exposure research. This study indicates that the DKI technique could provide valuable information for the diagnosis of MCI.

Effect of the Reelin-Dab1 signaling pathway on the abnormal metabolism of Aß protein induced by aluminum.

Aluminum (Al) is a common neurotoxic element that can exacerbate intracellular ß-amyloid (Aß) deposition. Reelin is a highly conserved extracellular glycoprotein that is involved in intracellular Aß deposition. However, the action of Reelin on aluminum-induced Aß deposition is not fully understood. Here, we investigated the effects of the Reelin-Dab1 signaling pathway on Aß deposition in aluminum maltol (Al(mal)3) exposure in rat pheochromocytoma-derived cells (PC12). Our results showed that Al(mal)3 exposure decreased activity of PC12, increased expression of Aß42, and decreased expression of Aß40. Moreover, Al(mal)3 exposure in PC12 induced Reelin-Dab1 signaling pathway-associated proteins changed, decreased expression of Reelin and Dab1, and increased expression of pdab1. Moreover, the expression of Reelin, Dab1, and Aß40 was found to be elevated in PC12 exposed to Al(mal)3 and corticosterone compared to those exposed to Al(mal)3. Also, the expression of Reelin, Dab1, and Aß40 was found to be depressed in PC12 exposed to Al(mal)3 and streptozotocin compared with cells exposed to Al(mal)3 alone. These results suggested that Al(mal)3 inhibits the expression of the Reelin-Dab1 signaling pathway, promoting Aß deposition. Thus, our findings provided important evidence to better understand how the Reelin-Dab1 signaling pathway may be a potential mechanism of Aß deposition induced by aluminum.