Zinc Status Alters Alzheimer's Disease Progression through NLRP3-Dependent Inflammation

Alzheimer''s disease is a devastating neurodegenerative disease with a dramatically increasing prevalence and no disease-modifying treatment. Inflammatory lifestyle factors increase the risk of developing Alzheimer''s disease. Zinc deficiency is the most prevalent malnutrition in the world and may be a risk factor for Alzheimer''s disease potentially through enhanced inflammation, although evidence for this is limited. Here we provide epidemiological evidence suggesting that zinc supplementation was associated with reduced risk and slower cognitive decline, in people with Alzheimer''s disease and mild cognitive impairment. Using the APP/PS1 mouse model of Alzheimer''s disease fed a control (35 mg/kg zinc) or diet deficient in zinc (3 mg/kg zinc), we determined that zinc deficiency accelerated Alzheimer''s-like memory deficits without modifying amyloid β plaque burden in the brains of male mice. The NLRP3-inflammasome complex is one of the most important regulators of inflammation, and we show here that zinc deficiency in immune cells, including microglia, potentiated NLRP3 responses to inflammatory stimuli in vitro, including amyloid oligomers, while zinc supplementation inhibited NLRP3 activation. APP/PS1 mice deficient in NLRP3 were protected against the accelerated cognitive decline with zinc deficiency. Collectively, this research suggests that zinc status is linked to inflammatory reactivity and may be modified in people to reduce the risk and slow the progression of Alzheimer''s disease.SIGNIFICANCE STATEMENT Alzheimer''s disease is a common condition mostly affecting the elderly. Zinc deficiency is also a global problem, especially in the elderly and also in people with Alzheimer''s disease. Zinc deficiency contributes to many clinical disorders, including immune dysfunction. Inflammation is known to contribute to the risk and progression of Alzheimer''s disease; thus, we hypothesized that zinc status would affect Alzheimer''s disease progression. Here we show that zinc supplementation reduced the prevalence and symptomatic decline in people with Alzheimer''s disease. In an animal model of Alzheimer''s disease, zinc deficiency worsened cognitive decline because of an enhancement in NLRP3-driven inflammation. Overall, our data suggest that zinc status affects Alzheimer''s disease progression, and that zinc supplementation could slow the rate of cognitive decline.     

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骨代谢过程中,锌是不可缺少的重要微量元素之一,适量的锌对成骨细胞增殖、分化、凋亡等生理过程有重要的作用。本文就锌对成骨细胞生物学作用方面的影响、作用机制及研究现状做一综述。     

Long-term potentiation inhibition by low-level N-methyl-D-aspartate receptor activation involves calcineurin, nitric oxide, and p38 mitogen-activated protein kinase

Low-level activation of N-methyl-d-aspartate receptors (NMDARs) results in a decrease in the ability of tetanic stimulation to induce long-term potentiation (LTP). This NMDAR-mediated LTP inhibition is observed with low micromolar concentrations of NMDA or chelation of ambient extracellular zinc. In rat hippocampal slices, we examined whether LTP inhibition by 1 muM NMDA and zinc chelation share common mechanisms. We found that both forms of LTP inhibition involve nitric oxide (NO) synthase (NOS) and calcineurin. Furthermore, both forms of LTP inhibition are overcome by block of p38 mitogen-activated protein kinase (MAPK), but not by inhibition of extracellular signal-regulated kinase 1/2 or c-Jun-N-terminal kinase. A p38 antagonist also overcame the block of LTP by sodium nitroprusside, an agent that releases NO, suggesting that NO release occurs upstream of MAPK activation. Despite the involvement of p38 MAPK in NMDAR-mediated LTP inhibition, p38 antagonism did not enhance LTP induction in response to weak tetanic stimulation under baseline conditions. These results indicate that p38 MAPK is part of a complex NMDAR-driven signaling pathway involving calcineurin and NO that helps to regulate synaptic plasticity in the CA1 region.     

Zinc enhances long-term potentiation through P2X receptor modulation in the hippocampal CA1 region

Zn²⁺ is an essential ion that is stored in and co‐released from glutamatergic synapses and it modulates neurotransmitter receptors involved in long‐term potentiation (LTP). However, the mechanism(s) underlying Zn²⁺‐induced modulation of LTP remain(s) unclear. As the purinergic P2X receptors are relevant targets for Zn²⁺ action, we have studied their role in LTP modulation by Zn²⁺ in the CA1 region of rat hippocampal slices. Induction of LTP in the presence of Zn²⁺ revealed a biphasic effect – 5–50 μm enhanced LTP induction, whereas 100–300 μm Zn²⁺ inhibited LTP. The involvement of a purinergic mechanism is supported by the fact that application of the P2X receptor antagonists 2′,3′‐O‐(2,4,6‐trinitrophenyl) ATP (TNP‐ATP) and periodate‐oxidized ATP fully abolished the facilitatory effect of Zn²⁺. Notably, application of the P2X₇ receptor‐specific antagonist Brilliant Blue G did not modify the Zn²⁺‐dependent facilitation of LTP. Exogenous ATP also produced a biphasic effect – 0.1–1 μm ATP facilitated LTP, whereas 5–10 μm inhibited LTP. The facilitatory effect of ATP was abolished by the application of TNP‐ATP and was modified in the presence of 5 μm Zn²⁺, suggesting that P2X receptors are involved in LTP induction and that Zn²⁺ leads to an increase in the affinity of P2X receptors for ATP. The latter confirms our previous results from heterologous expression systems. Collectively, our results indicate that Zn²⁺ at low concentrations enhances LTP by modulating P2X receptors. Although it is not yet clear which purinergic receptor subtype(s) is responsible for these effects on LTP, the data presented here suggest that P2X₄ but not P2X₇ is involved.     

暂封材料对窝洞充填后微渗漏影响的实验研究

目的：研究暂封材料对复合树脂充填后微渗漏的影响,探讨减少微渗漏的方法。方法：60颗离体牙备Ⅰ类洞后随机分为三组。A、B组为实验组,用氧化锌丁香油粘固剂暂封1周,超声波清洗去除暂封材料,A组再用气水枪冲洗、B组再用75%酒精擦拭及气水枪冲洗。然后用光固化树脂充填窝洞;C组为对照组,不暂封窝洞而直接进行光固化树脂充填。用染色法制备微渗漏检测标本,测量比较各组充填后的微渗漏情况。结果：A组微渗漏大于B组和C组（P〈0.05）,B组和C组间无统计学差异（P〉0.05）。结论：暂封材料残留有增加充填后微渗漏的可能性;超声波清洗后用75%酒精擦拭洞壁可以有效地减少微渗漏的发生及微渗漏程度。     

Effects of social defeat stress and fluoxetine treatment on neurogenesis and behavior in mice that lack zinc transporter 3 (ZnT3) and vesicular zinc

Depression is a leading cause of disability worldwide, in part because the available treatments are inadequate and do not work for many people. The neurobiology of depression, and the mechanism of action of common antidepressant drugs such as selective serotonin reuptake inhibitors (SSRIs), is not well understood. One mechanism thought to underlie the effects of these drugs is upregulation of adult hippocampal neurogenesis. Evidence indicates that vesicular zinc is required for modulation of adult hippocampal neurogenesis, at least under some circumstances. Vesicular zinc refers to zinc that is stored in the synaptic vesicles of certain neurons, including in the hippocampus, and released in response to neuronal activity. It can be eliminated from the brain by deletion of zinc transporter 3 (ZnT3), as is the case in ZnT3 knockout mice. Here, we examined the effects of repeated social defeat stress and subsequent chronic treatment with the SSRI fluoxetine on behavior and neurogenesis in ZnT3 knockout mice. We hypothesized that fluoxetine treatment would increase neurogenesis and reverse stress‐induced behavioral symptoms in wild type, but not ZnT3 knockout, mice. As anticipated, stress induced persistent depression‐like effects, including social avoidance and anxiety‐like behavior. Fluoxetine decreased social avoidance, though the effect was not specific to the stressed mice, but did not affect anxiety‐like behavior. Surprisingly, stress increased the survival of neurons born 1 day after the last episode of defeat stress. Fluoxetine treatment also increased cell survival, particularly in wild type mice, though it did not affect proliferation. Our results did not support our hypothesis that vesicular zinc is required for the behavioral benefits of fluoxetine treatment. As to whether vesicular zinc is required for the neurogenic effects of fluoxetine, our results were inconclusive, warranting further investigation into the role of vesicular zinc in adult hippocampal neurogenesis.     

Zinc and copper play a role in coaggregation inhibiting action of Porphyromonas gingivalis

Background/aim:  We investigated the mechanisms of adherence of salivary and serum proteins, which mimic gingival crevicular fluid (GCF), to Porphyromonas gingivalis , and the effects of these adhered proteins on coaggregation and hemagglutination properties.
Methods:  The amounts of salivary and serum proteins adhering to P. gingivalis were determined using ³H-labeled and non-labeled proteins. The coaggregation between P. gingivalis and Streptococcus oralis or Streptococcus gordonii was observed. Hemagglutination was evaluated using sheep erythrocytes. Proteins that interacted with zinc or copper in saliva and serum and on P. gingivalis were examined using sodium dodecyl sulfate–polyacrylamide gel electrophoresis.
Results:  The amount of salivary or serum proteins that adhered to the surface of P. gingivalis strains was increased by cations, especially zinc and copper ions. The pretreatment of bacterial cells with salivary or serum proteins before the assay inhibited coaggregation with gram-positive bacteria and hemagglutination. These phenomena were enhanced by the presence of zinc or copper ions during the pretreatment of P. gingivalis with proteins. We detected protein bands that were related to these cations in saliva and serum and on P. gingivalis.
Conclusions:  Our findings suggest that zinc and copper ions markedly enhanced the adhesion and accumulation of salivary and serum proteins on cells of P. gingivalis and inhibited the coaggregation and hemagglutination of P. gingivalis . These cations might be useful for limiting the settlement of P. gingivalis in the gingival sulcus with the goal of preventing periodontal disease.     

Effects of oral zinc administration on long‐term ipsilateral and contralateral testes damage after experimental testis ischaemia–reperfusion

The purpose of this study was to examine potential long‐term post‐torsion changes that can occur in the histopathology, biochemistry and spermatogenesis of both torsioned and nontorsioned opposite testes. The study also determines the effect of zinc (Zn) administration on the testicular torsion/detorsion (T/D) damage on both testes. Forty‐eight male rats, divided equally into eight groups: (SHAM), (SHAM+,Zn+), (T/D+, Zn? 1 month), (T/D+,Zn? 2 months), (T/D+,Zn? 3 months), (T/D+,Zn+ 1 months), (T/D+,Zn+ 2 months), (T/D+,Zn+ 3 months), have been used. Drug administration was carried out by adding 100 μg (0.016 ml/rat) Zn per rat to drinking water in related groups. Testicular damage decreased superoxide dismutase (SOD) and glutathione (GSH) and increased malondialdehyde (MDA) in the testis tissues of rats, while Zn administration increased SOD and GSH and decreased MDA in the testis tissues in comparison with the SHAM group. The beneficial effect of zinc sulphate was more evident on the nonrotated testis than the rotated testis. In the histopathological study, a significant decrease in torsion and detorsion injuries was observed in the treatment groups compared to the torsion and detorsion groups. We found a protective effect of zinc sulphate on oxidative stress as a result of T/D injuries in rats, especially for the nonrotated testis; results were supported histopathologically.     

日常膳食锌摄入水平与绝经后女性骨密度之间的关系：一项基于DRYAD数据库的二次分析

目的明确每日膳食锌摄入量与绝经后女性骨密度之间的相关性。方法采用Empowerstats和R软件对DRYAD数据库数据进行二次分析,通过线性回归探索每日膳食锌摄入量与绝经后女性骨密度之间的线性关系,并采用广义加性模型进行曲线拟合分析二者间的非线性关系。结果该研究共纳入282例绝经后女性。在调整年龄、每日钙摄入量后,每日膳食锌摄入量和绝经后女性髋骨骨密度存在阈值关联。当每日摄入锌超过32.9 mg时,每日锌摄入量每增加1 mg,髋骨骨密度增加4.87 mg/cm2(P0.05)。结论每日膳食锌摄入量与绝经后女性骨密度之间存在阈值效应关系,这将为今后绝经后女性预防骨质疏松的营养支持与补充提供依据和指导。     

多中心完全随机、标准治疗平行对照评价京万红软膏治疗糖尿病足慢性创面的临床研究

目的：：通过多中心完全随机、标准治疗平行对照方法评价京万红软膏治疗糖尿病足慢性创面的疗效。方法：本研究共有11家医院参加,采用多中心完全随机、标准治疗平行对照、前瞻性临床研究设计。131例糖尿病足溃疡患者随机分为京万红软膏组67例和对照组64例,两组创面面积分别为(16.7±6.1)cm2和(15.9±8.3) cm2,创面形成时间(45.7±68.3)d和(52.5±79.6)d 。两组分别用京万红软膏或复方磺胺嘧啶锌凝胶涂于创面,观察疗程均为20周。结果：两组患者年龄、糖尿病病程、血常规、肝功能、肾功能等数据差异无统计学意义。京万红组于2、5、10、15周创面愈合速率明显优于复方磺胺嘧啶锌凝胶组,以第5周、10周最为明显(P<0.01)。京万红组创面达到完全上皮化平均时间为(46.5±15.6)d,复方磺胺嘧啶锌凝胶组为(67.9±17.9)d,差异显著(P<0.05)。结论：京万红软膏与复方磺胺嘧啶锌凝胶均有促进糖尿病足创面愈合的作用,京万红软膏作用更优。