Manganese induces podocyte injury through regulating MTDH/ALKBH5/NLRP10 axis: Combined analysis at epidemiology and molecular biology levels.

Manganese (Mn) is an essential micronutrient required for various biological processes but excess exposure to Mn can cause neurotoxicity. However, there are few reports regarding the toxicity effect of Mn on the kidney as well as the underlying molecule mechanism. Herein, in vivo experiments were adopted to assess the toxicity effects associated with Mn, and found that chronic Mn treatment induced the injury of glomerular podocytes but not renal tubule in rats. Genome-wide CRISPR/Cas9 knockout screen was then employed to explore the biotargets of the toxic effect of Mn on podocytes. Through functional analyses of the enriched candidate genes, NLRP10 was found to be significantly up-regulated and mediated Mn-induced podocyte apoptosis. Further mechanism investigation revealed that NLRP10 expression was regulated by demethylase AlkB homolog 5 (ALKBH5) in an m6A-dependent fashion upon Mn treatment. Moreover, Mn could directly bind to Metadherin (MTDH) and promoted its combination with ALKBH5 to promote NLRP10 expression and cell apoptosis. Finally, logistic regressions, restricted cubic spline regressions and uniform cubic B-spline were used to investigate the association between Mn exposure and the risk of chronic kidney disease (CKD). A U-shaped nonlinear relationship between CKD risk and plasma Mn level, and a positive linear relationship between CKD risk and urinary Mn levels was found in our case-control study. To sum up, our findings illustrated that m6A-dependent NLRP10 regulation is indispensable for podocyte apoptosis and nephrotoxicity induced by Mn, providing fresh insight into understanding the health risk of Mn and a novel target for preventing renal injury in Mn-intoxicated patients.

Sex differences in functional connectivity and the predictive role of the connectome-based predictive model in Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by cognitive decline. Sex differences in the progression of AD exist, but the neural mechanisms are not well understood. The purpose of the current study was to explore sex differences in brain functional connectivity (FC) at different stages of AD and their predictive ability on Montreal Cognitive Assessment (MoCA) scores using connectome-based predictive modeling (CPM). Resting-state functional magnetic resonance imaging was collected from 81 AD patients (44 females), 78 amnestic mild cognitive impairment patients (44 females), and 92 healthy controls (50 females). The FC analysis was conducted and the interaction effect between sex and group was investigated using two-factor variance analysis. The CPM was used to predict MoCA scores. There were sex-by-group interaction effects on FC between the left dorsolateral superior frontal gyrus and left middle temporal gyrus, left precuneus and right calcarine fissure surrounding cortex, left precuneus and left middle occipital gyrus, left middle temporal gyrus and left precentral gyrus, and between the left middle temporal gyrus and right cuneus. In the CPM, the positive network predictive model significantly predicted MoCA scores in both males and females. There were significant sex-by-group interaction effects on FC between the left precuneus and left middle occipital gyrus, and between the left middle temporal gyrus and right cuneus could predict MoCA scores in female patients. Our results suggest that there are sex differences in FC at different stages of AD. The sex-specific FC can further predict MoCA scores at individual level.

Periodontitis is associated with altered brain structure and function in normal cognition middle-aged and elderly individuals.

BACKGROUND: Numerous studies have proposed that periodontitis is a potential risk factor for Alzheimer's disease. However, the association between periodontitis and brain normal cognition in aged and elderly individuals (NCs) is unclear. Such a link could provide clues to Alzheimer's disease development and strategies for early prevention. OBJECTIVE: To explore the associations between periodontal condition and metrics of both brain structure and function among NCs with the help of multimodal magnetic resonance imaging (MRI). METHODS: High-resolution T1-weighted structural data, resting-state functional-MRI data, and measures of periodontal condition were collected from 40 NCs. Cortical volume, thickness, and area as well as regional homogeneity were calculated with the aid of DPABISurf software. Correlation analyses were then conducted between each imaging metric and periodontal index. RESULTS: Consistent negative correlations were observed between severity of periodontitis (mild, moderate, severe) and cortical volume, area, and thickness, not only in brain regions that took charge of primary function but also in brain regions associated with advanced cognition behavior. Among participants with mild attachment loss (AL) and a shallow periodontal pocket depth (PPD), periodontal index was positively correlated with most measures of brain structure and function, while among participants with severe AL and deep PPD, periodontal index was negatively correlated with measures of brain structure and function (all p < .005 for each hemisphere). CONCLUSIONS: Our results demonstrate that periodontitis is associated with widespread changes in brain structure and function among middle-aged and elderly adults without signs of cognitive decline, which might be a potential risk factor for brain damage.

Education reduces cognitive dysfunction in Alzheimer's disease by changing regional cerebral perfusion: An in-vivo arterial spin labeling study.

OBJECTIVE: Formal education and other cognitive challenges influence brain structure and improve function. It is believed that cognitive activities create a cognitive reserve (CR) that can slow the decline due to aging and neurodegenerative diseases. This study investigated alterations of regional cerebral blood flow (rCBF) associated with high and low CR in different stages of Alzheimer's disease (AD) and examined whether rCBF alteration mediates the relationship between education and cognitive performance. METHODS: Patients with AD or amnestic mild cognitive impairment (aMCI) and healthy controls were divided into low cognitive reserve (LCR) and high cognitive reserve (HCR) subgroups according to median of education years (≤ 9 vs. > 9 years). The final study population included 89 AD patients (67 LCR, 22 HCR), 74 aMCI patients (44 LCR, 30 HCR), and 66 healthy controls (29 LCR, 37 HCR). All subjects were examined by arterial spin labeling magnetic resonance imaging and a neurocognitive test battery. rCBF was compared among groups by two-way analysis of variance. Mediation analyses were used to explore the relationships among education, rCBF, and cognitive test scores. RESULTS: There were significant interaction effects of disease state (AD, aMCI, HC) and education level (LCR, HCR) on CBF in right hippocampus, posterior cingulate cortex, and right inferior parietal cortex (R_IPC). Education regulated episodic memory score by influencing right hippocampal CBF in HC_HCR and aMCI_HCR subgroups. CONCLUSION: Our results indicate that the protective effect of education against cognitive dysfunction in early-stage AD is mediated at least partially by altered CBF in right hippocampus.

Sex Difference in General Cognition Associated with Coupling of Whole-brain Functional Connectivity Strength to Cerebral Blood Flow Changes During Alzheimer's Disease Progression.

Alzheimer's disease (AD) is a progressive age-related neurodegenerative disorder that results in irreversible cognitive impairments. Nonetheless, there are numerous sex-dependent differences in clinical course. We examined potential contributions of neurovascular coupling deficits to sex differences in AD progression. T1-weighted three-dimensional structural magnetic resonance images, functional blood oxygen level dependent and arterial spin labeling images were acquired from 50 AD patients (28 females), 52 amnesic mild cognitive impairment patients (31 females), and 59 healthy controls (36 females). Short- and long-range functional connectivity strength (FCS) and cerebral blood flow (CBF) values were calculated for all participants. Then, the CBF/FCS coupling ratio, which represented the amount of blood supply per unit of connectivity strength, was calculated for each voxel. Two-way ANOVA was performed to identify group × sex interactions and main effects of group. Correlation analysis was used to assess associations between CBF/FCS ratios and Mini-Mental State Examination (MMSE). There were significant group × sex interaction effects on short-range coupling ratios of right middle temporal gyrus, left angular gyrus, left inferior orbital frontal gyrus, and left superior frontal gyrus as well as on the long-range coupling ratios of right middle temporal gyrus, left precuneus, left posterior cingulate cortex, and left angular gyrus. There were significant negative correlations between MMSE scores and CBF/FCS ratios for all regions with significant group × sex interactions among female patients, while positive correlations were found among male patients. Our results demonstrate significant sex differences in neurovascular coupling mechanisms associated with cognitive function during the course of AD.

Sex-dependent changes in emotional memory associated with cerebral blood flow alterations during Alzheimer's disease progression.

PURPOSE: Sex differences in Alzheimer's disease (AD) progression provide clues to pathogenesis and better patient management. We examined sex differences in emotional memory among AD patients, amnestic mild cognitive impairment (aMCI) patients, and healthy controls (HCs) as well as potential associations with altered regional cerebral blood flow (rCBF). METHODS: The recognition memory task with emotional pictures was applied to evaluate enhancement of emotional memory (EEM) and 3D pseudo-continuous arterial spin labeling MRI was performed to measure the rCBF in 74 AD patients (41 females), 74 aMCI patients (45 females), and 74 HCs (43 females). Group differences in EEM were tested by two-way analysis of covariance (ANCOVA) with repeated measures. The main effects of clinical group and sex as well as group × sex interactions on rCBF were assessed by two-way ANCOVA. Correlation analyses were conducted to investigate associations between EEM and rCBF. RESULTS: With disease progression, EEM gradually disappeared. Among aMCI patients, females exhibited a greater index of recollection (Pr) for positive/high-arousal and negative/low-arousal pictures versus neutral pictures (P = 0.005, P = 0.003), while males exhibited a greater Pr for negative/high-arousal versus neutral pictures (P = 0.001). There were significant sex × group effects on rCBF in left inferior parietal, supramarginal, superior temporal and middle temporal gyri, and rCBF of left inferior parietal gyrus was correlated with Pr for positive/high-arousal pictures among female aMCI patients (r = 0.584, q = 0.005). CONCLUSION: Males and females exhibit distinct changes in EEM associated with altered rCBF, which should be considered in future neuroimaging studies.

Integrated 16s RNA sequencing and network pharmacology to explore the effects of polyphenol-rich raspberry leaf extract on weight control.

Introduction: Obesity is recognized as a chronic low-grade inflammation associated with intestinal flora imbalance, leading to dyslipidemia and inflammation. Modern research has found that polyphenols have anti-obesity effects. However, the mechanism of action of raspberry leaf extract (RLE) with high polyphenols in regulating obesity is still unknown. This study investigated the improvement effect of supplementing RLE on high-fat diet (HFD) induced obesity in mice. Methods: RLE was used to intervene in HFD induced C57BL/6J male mice during prevention stage (1-16 weeks) and treatment stage (17-20 weeks). Their weight changes and obesity-related biochemical indicators were measured. The changes in intestinal flora were analyzed using 16S rRNA sequencing, and finally the targets and pathways of the 7 typical polyphenols (quercetin-3-O-glucuronide, ellagic acid, kaempferol-3-O-rutinoside, chlorogenic acid, brevifolin carboxylic acid, quercetin-3-O-rutinoside, and quercetin) of RLE in the regulation of obesity were predicted by network pharmacology approach. Results and discussion: The results showed that RLE effectively prevented and treated weight gain in obese mice induced by HFD, alleviated adipocyte hypertrophy, reduced Interleukin-6 and Tumor Necrosis Factor Alpha levels, and improved intestinal flora, especially Muriaculaceae, Alistipes and Alloprevotella, and decreased the Firmicutes/Bacteroidota ratio. Network pharmacology analysis selected 60 common targets for 7 RLE polyphenols and obesity. Combined with protein-protein interaction network, enrichment analysis and experimental results, TNF, IL-6, AKT1, and PPAR were predicted as potential key targets for RLE polyphenols. Conclusion: The potential mechanism by which polyphenol-rich RLE regulates obesity may be attributed to the specific polyphenols of RLE and their synergistic effects, therefore RLE has a great anti-obesity potential and may be used as a means to alleviate obesity and related diseases.

Phytochemicals and anti-tyrosinase activities of Paeonia ostii leaves and roots.

Tree peony (sect. Moutan) is a kind of Traditional Chinese Medicine and ornamental plant, which has been widely cultivated and utilized for thousands of years. To further study the active components of Paeonia ostii (Moutan, Fengdan), six fractions (soluble free (F), soluble esterification, soluble glycosylation, insoluble bound, insoluble esterification and insoluble glycosylation) were extracted from the leaves and roots by alkaline and acid treatment for the first time. Twenty-one typical compounds were identified and quantified by HPLC-MS. The results showed that total phenolic content (TPC) in peony roots (PR) and peony leaves (PL) were as high as 125.48 and 280.38 mg GAE·g-1 dw, which maximizes the extraction efficiency of phenolic compounds, especially leaves, compared with the conventional method. PR-F and PL-F had the highest TPC, antioxidant and anti-tyrosinase activities. Paeoniflorin was the main compounds in PL and PR. It and pentagalloylglucose (PGG) almost reached the anti-tyrosinase level of kojic acid, but they showed different inhibitory mechanisms by molecular docking. On the whole, PR-F, PL-F, PGG and paeoniflorin might be potential for skin whitening products.

Correlation study of periodontitis with cognitive impairment.

OBJECTIVES: This study aimed to determine the association of periodontitis with cognitive impairment by evaluating periodontal conditions in middle-aged and elderly people of normal cognition and cognitive impairment. METHODS: Forty patients with cognitive impairment and thirty-five healthy controls were included in this study. Mini-mental state examination (MMSE) was used to evaluate the level of cognitive function in all patients and controls. Periodontal conditions including severity of periodontitis, number of remaining teeth, percentage of bleeding on probing, probing depth (PD), and attachment level (AL) were examined. Periodontal conditions were compared between patients and controls, and the correlation between periodontal conditions and cognitive-function level was analyzed. Statistical analysis was performed with SPSS 26.0. RESULTS: The distribution of severity of periodontitis significantly differed between patients and controls (χ2=13.309 and P=0.001). The proportion of severe periodontitis in the cognitive-impairment group was significantly higher than that in the healthy controls (P<0.05). The percentage of sites with PD≥6 mm and AL≥5 mm in the cognitive-impairment group was higher than that in the controls, whereas the percentage of sites with PD=1-3 mm and AL=0-2 mm was higher in the controls (P<0.05). No significant difference in percentage of bleeding on probing was found in the two groups (P>0.05). Patients with cognitive impairment had fewer teeth than the controls (P<0.05). The level of cognitive function, assessed by MMSE, was positively correlated with the number of teeth and the percentage of sites with AL=0-2 mm, and it was negatively correlated with the percentage of sites with AL≥5 mm (P<0.05). CONCLUSIONS: A correlation existed between periodontitis and cognitive impairment. Further study is essential to explore the specific relationship and related mechanism between periodontitis and cognitive impairment.

DNA thermotropic liquid crystals controlled by positively charged catanionic bilayer vesicles.

We report DNA thermotropic liquid crystal (TLC) formation by positively charged catanionic surfactant bilayer vesicles. The properties of DNA TLCs were found to be manipulated by both the chemical structures of cationic and anionic surfactants and the DNA amount. Positively charged catanionic bilayer vesicles bond to negative DNA sites resulting in the transition from vesicles to long range ordered lamellar crystals of DNA-catanionic surfactants, as confirmed by cryo- and freeze-fracture (FF) TEM observations and small-angle X-ray scattering (SAXS) measurements.