Search

Environmental behaviors of heavy metal in soil are strongly influenced by seasonal freeze-thaw events at the mid-high altitudes. However, the potential impact mechanisms of freeze-thaw cycles on the vertical migration of heavy metal are still poor understood. This study aimed to explore how exogenous cadmium (Cd) migrated and remained in soil during the in-situ seasonal freeze-thaw action using rare earth elements (REEs) as tracers. As a comparison, soil which was incubated in the controlled laboratory (25 °C) was employed. Although there was no statistically significant difference in the Cd levels of different soil depths under different treatments, the original aggregate sources of Cd in the 5-10 cm and 10-15 cm soil layers differed. From the distributions of REEs in soil profile, it can be known that Cd in the subsurface of field incubated soil was mainly from the breakdown of >0.50 mm aggregates, while it was mainly from the <0.106 mm aggregates for the laboratory incubated soil. Furthermore, the dissolved and colloidal Cd concentrations were 0.47 μg L -1 and 0.62 μg L -1 in the leachates from field incubated soil than those from control soil (0.21 μg L -1 and 0.43 μg L -1 ). Additionally, the colloid-associated Cd in the leachate under field condition was mainly from the breakdown of >0.25 mm aggregates and the direct migration of <0.106 mm aggregates, while it was the breakdown of >0.50 mm and the direct migration of <0.106 mm aggregates for the soil under laboratory condition. Our results for the first time provided insights into the fate of exogenous contaminants in seasonal frozen regions using the rare earth element tracing method., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: Tortuous microvessels are characteristic of microvascular remodeling associated with numerous physiological and pathological scenarios. Three-dimensional (3D) hemodynamics in tortuous microvessels influenced by red blood cells (RBCs), however, are largely unknown, and important questions remain. Is blood viscosity influenced by vessel tortuosity? How do RBC dynamics affect wall shear stress (WSS) patterns and the near-wall cell-free layer (CFL) over a range of conditions? The objective of this work was to parameterize hemodynamic characteristics unique to a tortuous microvessel., Methods: RBC-resolved simulations were performed using an immersed boundary method-based 3D fluid dynamics solver. A representative tortuous microvessel was selected from a stimulated angiogenic network obtained from imaging of the rat mesentery and digitally reconstructed for the simulations. The representative microvessel was a venule with a diameter of approximately 20 μm. The model assumes a constant diameter along the vessel length and does not consider variations due to endothelial cell shapes or the endothelial surface layer., Results: Microvessel tortuosity was observed to increase blood apparent viscosity compared to a straight tube by up to 26%. WSS spatial variations in high curvature regions reached 23.6 dyne/cm 2 over the vessel cross-section. The magnitudes of WSS and CFL thickness variations due to tortuosity were strongly influenced by shear rate and negligibly influenced by tube hematocrit levels., Conclusions: New findings from this work reveal unique tortuosity-dependent hemodynamic characteristics over a range of conditions. The results provide new thought-provoking information to better understand the contribution of tortuous vessels in physiological and pathological processes and help improve reduced-order models., (© 2024 John Wiley & Sons Ltd.)

Alzheimer's disease is characterized by a progressive cognitive decline in older individuals accompanied by the deposition of two pathognomonic proteins amyloid-β and tau. It is well documented that synaptotoxic soluble amyloid-β aggregates facilitate synaptic long-term depression, a major form of synaptic weakening that correlates with cognitive status in Alzheimer's disease. Whether synaptotoxic tau, which is also associated strongly with progressive cognitive decline in patients with Alzheimer's disease and other tauopathies, also causes facilitation remains to be clarified. Young male adult and middle-aged rats were employed. Synaptotoxic tau and amyloid-β were obtained from different sources including (i) aqueous brain extracts from patients with Alzheimer's disease and Pick's disease tauopathy; (ii) the secretomes of induced pluripotent stem cell-derived neurons from individuals with trisomy of chromosome 21; and (iii) synthetic amyloid-β. In vivo electrophysiology was performed in urethane anaesthetized animals. Evoked field excitatory postsynaptic potentials were recorded from the stratum radiatum in the CA1 area of the hippocampus with electrical stimulation to the Schaffer collateral-commissural pathway. To study the enhancement of long-term depression, relatively weak low-frequency electrical stimulation was used to trigger peri-threshold long-term depression. Synaptotoxic forms of tau or amyloid-β were administered intracerebroventricularly. The ability of agents that inhibit the cytokine tumour necrosis factor-α or the integrated stress response to prevent the effects of amyloid-β or tau on long-term depression was assessed after local or systemic injection, respectively. We found that diffusible tau from Alzheimer's disease or Pick's disease patients' brain aqueous extracts or the secretomes of trisomy of chromosome 21 induced pluripotent stem cell-derived neurons, like Alzheimer's disease brain-derived amyloid-β and synthetic oligomeric amyloid-β, potently enhanced synaptic long-term depression in live rats. We further demonstrated that long-term depression facilitation by both tau and amyloid-β was age-dependent, being more potent in middle-aged compared with young animals. Finally, at the cellular level, we provide pharmacological evidence that tumour necrosis factor-α and the integrated stress response are downstream mediators of long-term depression facilitation by both synaptotoxic tau and amyloid-β. Overall, these findings reveal the promotion of an age-dependent synaptic weakening by both synaptotoxic tau and amyloid-β. Pharmacologically targeting shared mechanisms of tau and amyloid-β synaptotoxicity, such as tumour necrosis factor-α or the integrated stress response, provides an attractive strategy to treat early Alzheimer's disease., Competing Interests: The authors declare that they have no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

How the two pathognomonic proteins of Alzheimer's disease (AD); amyloid ß (Aß) and tau, cause synaptic failure remains enigmatic. Certain synthetic and recombinant forms of these proteins are known to act concurrently to acutely inhibit long-term potentiation (LTP). Here, we examined the effect of early amyloidosis on the acute disruptive action of synaptotoxic tau prepared from recombinant protein and tau in patient-derived aqueous brain extracts. We also explored the persistence of the inhibition of LTP by different synaptotoxic tau preparations. A single intracerebral injection of aggregates of recombinant human tau that had been prepared by either sonication of fibrils (SτAs) or disulfide bond formation (oTau) rapidly and persistently inhibited LTP in rat hippocampus. The threshold for the acute inhibitory effect of oTau was lowered in amyloid precursor protein (APP)-transgenic rats. A single injection of synaptotoxic tau-containing AD or Pick's disease brain extracts also inhibited LTP, for over two weeks. Remarkably, the persistent disruption of synaptic plasticity by patient-derived brain tau was rapidly reversed by a single intracerebral injection of different anti-tau monoclonal antibodies, including one directed to a specific human tau amino acid sequence. We conclude that patient-derived LTP-disrupting tau species persist in the brain for weeks, maintaining their neuroactivity often in concert with Aß. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.

Objective: Fluid shear stress is thought to be a regulator of endothelial cell behavior during angiogenesis. The link, however, requires an understanding of stress values at the capillary level in angiogenic microvascular networks. Critical questions remain. What are the stresses? Do capillaries experience similar stress magnitudes? Can variations explain vessel-specific behavior? The objective of this study was to estimate segment-specific shear stresses in angiogenic networks., Methods: Images of angiogenic networks characterized by increased vascular density were obtained from rat mesenteric tissues stimulated by compound 48/80-induced mast cell degranulation. Vessels were identified by perfusion of a 40 kDa fixable dextran prior to harvesting and immunolabeling for PECAM. Using a network flow-based segment model with physiologically relevant parameters, stresses were computed per vessel for regions across multiple networks., Results: Stresses ranged from 0.003 to 2328.1 dyne/cm 2 and varied dramatically at the capillary level. For all regions, the maximum segmental shear stresses were for capillary segments. Stresses along proximal capillaries branching from arteriole inlets were increased compared to stresses along capillaries in more distal regions., Conclusions: The results highlight the variability of shear stresses along angiogenic capillaries and motivate new discussions on how endothelial cells may respond in vivo to segment-specific microenvironment during angiogenesis., (© 2023 John Wiley & Sons Ltd.)

Non-invasive sensory stimulation in the range of the brain's gamma rhythm (30-100 Hz) is emerging as a new potential therapeutic strategy for the treatment of Alzheimer's disease (AD). Here, we investigated the effect of repeated combined exposure to 40 Hz synchronized sound and light stimuli on hippocampal long-term potentiation (LTP) in vivo in three rat models of early AD. We employed a very complete model of AD amyloidosis, amyloid precursor protein (APP)-overexpressing transgenic McGill-R-Thy1-APP rats at an early pre-plaque stage, systemic treatment of transgenic APP rats with corticosterone modelling certain environmental AD risk factors and, importantly, intracerebral injection of highly disease-relevant AD patient-derived synaptotoxic beta-amyloid and tau in wild-type animals. We found that daily treatment with 40 Hz sensory stimulation for 2 weeks fully abrogated the inhibition of LTP in all three models. Moreover, there was a negative correlation between the magnitude of LTP and the level of active caspase-1 in the hippocampus of transgenic APP animals, which suggests that the beneficial effect of 40 Hz stimulation was dependent on modulation of pro-inflammatory mechanisms. Our findings support ongoing clinical trials of gamma-patterned sensory stimulation in early AD., (© 2023 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

The wall shear stress (WSS) exerted by blood flowing through microvascular capillaries is an established driver of new blood vessel growth, or angiogenesis. Such adaptations are central to many physiological processes in both health and disease, yet three-dimensional (3D) WSS characteristics in real angiogenic microvascular networks are largely unknown. This marks a major knowledge gap because angiogenesis, naturally, is a 3D process. To advance current understanding, we model 3D red blood cells (RBCs) flowing through rat angiogenic microvascular networks using state-of-the-art simulation. The high-resolution fluid dynamics reveal 3D WSS patterns occurring at sub-endothelial cell (EC) scales that derive from distinct angiogenic morphologies, including microvascular loops and vessel tortuosity. We identify the existence of WSS hot and cold spots caused by angiogenic surface shapes and RBCs, and notably enhancement of low WSS regions by RBCs. Spatiotemporal characteristics further reveal how fluctuations follow timescales of RBC "footprints." Altogether, this work provides a new conceptual framework for understanding how shear stress might regulate EC dynamics in vivo., Competing Interests: The authors declare that they have no competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Physiological Society.)

Amyloid β protein (Aβ) and tau, the two main proteins implicated in causing Alzheimer's disease (AD), are posited to trigger synaptic dysfunction long before significant synaptic loss occurs in vulnerable circuits. Whereas soluble Aβ aggregates from AD brain are well recognized potent synaptotoxins, less is known about the synaptotoxicity of soluble tau from AD or other tauopathy patient brains. Minimally manipulated patient-derived aqueous brain extracts contain the more diffusible native forms of these proteins. Here, we explore how intracerebral injection of Aβ and tau present in such aqueous extracts of patient brain contribute to disruption of synaptic plasticity in the CA1 area of the male rat hippocampus. Aqueous extracts of certain AD brains acutely inhibited long-term potentiation (LTP) of synaptic transmission in a manner that required both Aβ and tau. Tau-containing aqueous extracts of a brain from a patient with Pick's disease (PiD) also impaired LTP, and diffusible tau from either AD or PiD brain lowered the threshold for AD brain Aβ to inhibit LTP. Remarkably, the disruption of LTP persisted for at least 2 weeks after a single injection. These findings support a critical role for diffusible tau in causing rapid onset, persistent synaptic plasticity deficits, and promoting Aβ-mediated synaptic dysfunction. SIGNIFICANCE STATEMENT The microtubule-associated protein tau forms relatively insoluble fibrillar deposits in the brains of people with neurodegenerative diseases including Alzheimer's and Pick's diseases. More soluble aggregates of disease-associated tau may diffuse between cells and could cause damage to synapses in vulnerable circuits. We prepared aqueous extracts of diseased cerebral cortex and tested their ability to interfere with synaptic function in the brains of live rats. Tau in these extracts rapidly and persistently disrupted synaptic plasticity and facilitated impairments caused by amyloid β protein, the other major pathologic protein in Alzheimer's disease. These findings show that certain diffusible forms of tau can mediate synaptic dysfunction and may be a target for therapy., Competing Interests: D.M.W. is an employee of Biogen. M.S.P. and A.B. are employees and shareholders of AstraZeneca. R.W. and J.A.P. are employees of Transpharmation Ireland. All the other authors declare no competing financial interests., (Copyright © 2023 the authors.)

We previously showed that death-associated protein kinase 1 (DAPK1) expression is increased in hippocampal tissue in a mouse model of major depressive disorde and is related to cognitive dysfunction in Alzheimer's disease. In addition, depression is a risk factor for developing Alzheimer's disease, as well as an early clinical manifestation of Alzheimer's disease. Meanwhile, cognitive dysfunction is a distinctive feature of major depressive disorder. Therefore, DAPK1 may be related to cognitive dysfunction in major depressive disorder. In this study, we established a mouse model of major depressive disorder by housing mice individually and exposing them to chronic, mild, unpredictable stressors. We found that DAPK1 and tau protein levels were increased in the hippocampal CA3 area, and tau was hyperphosphorylated at Thr231, Ser262, and Ser396 in these mice. Furthermore, DAPK1 shifted from axonal expression to overexpression on the cell membrane. Exercise and treatment with the antidepressant drug citalopram decreased DAPK1 expression and tau protein phosphorylation in hippocampal tissue and improved both depressive symptoms and cognitive dysfunction. These results indicate that DAPK1 may be a potential reason and therapeutic target of cognitive dysfunction in major depressive disorder., Competing Interests: None

Peri-urban vegetable field plays an essential role in providing vegetables for local residents. Because of its particularity, it is affected by both industrial and agricultural activities which have led to the accumulations of heavy metal in soil. So far, information on heavy metal pollution status, spatial features, and human health risks in peri-urban vegetable areas across China is still scarce. To fill this gap, we systematically compiled soil and vegetable data collected from 123 articles published between 2010 and 2022 at a national level. The pollution status of heavy metals (i.e., cadmium (Cd), mercury (Hg), arsenic (As), lead (Pb), chromium (Cr), copper (Cu), nickel (Ni), and zinc (Zn)) in peri-urban vegetable soils and vegetables were investigated. To evaluate the levels of heavy metal pollution in soil and human health risks, the geoaccumulation index (Igeo) and target hazard quotient (HQ) were calculated. The results showed that mean concentrations of Cd, Hg, As, Pb, Cr, Cu, Ni, and Zn in peri-urban vegetable soils were 0.50, 0.53, 12.03, 41.97, 55.56, 37.69, 28.55, and 75.38 mg kg -1 , respectively. The main pollutants in peri-urban vegetable soil were Cd and Hg, and 85.25% and 92.86% of the soil samples had I geo > 1, respectively. The mean I geo values of this regions followed the order of northwest > central > south > north > east > southwest > northeast for Cd and northeast > northwest > north > southwest > east > central > south for Hg. The mean Cd, Hg, As, Pb, Cr, Cu, Ni, and Zn concentrations in vegetables were 0.30, 0.26, 0.37, 0.54, 1.17, 6.17, 1.96, and 18.56 mg kg -1 , respectively. Approximately 87.01% (Cd), 71.43% (Hg), 20% (As), 65.15% (Pb), 27.08% (Cr) of the vegetable samples exceeded the safety requirement values. The vegetables grown in central, northwest, and northern China accumulated much more heavy metals than those grown in other regions. As the HQ values for adults, 53.25% (Cd), 71.43% (Hg), 84.00% (As), and 58.33% (Cr) of the sampled vegetables were higher than 1. For children, the HQ values were higher than 1 for 66.23% (Cd), 73.81% (Hg), 86.00% (As), and 87.50% (Cr) of the sampled vegetables. The findings of this study demonstrate that the situation of heavy metal pollution in peri-urban vegetable areas across China are not optimistic and residents who consume the vegetables are at high risk of health issues. To ensure soil quality and human health, strategies should be taken to guide vegetable production and remedy soil pollution in peri-urban areas with the rapidly urbanizing China., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Cognitive decline in Alzheimer's disease correlates with the extent of tau pathology, in particular tau hyperphosphorylation that initially appears in the transentorhinal and related regions of the brain including the hippocampus. Recent evidence indicates that tau hyperphosphorylation caused by either amyloid-β or long-term depression, a form of synaptic weakening involved in learning and memory, share similar mechanisms. Studies from our group and others demonstrate that long-term depression-inducing low-frequency stimulation triggers tau phosphorylation at different residues in the hippocampus under different experimental conditions including aging. Conversely, certain forms of long-term depression at hippocampal glutamatergic synapses require endogenous tau, in particular, phosphorylation at residue Ser396. Elucidating the exact mechanisms of interaction between tau and long-term depression may help our understanding of the physiological and pathological functions of tau/tau (hyper)phosphorylation. We first summarize experimental evidence regarding tau-long-term depression interactions, followed by a discussion of possible mechanisms by which this interplay may influence the pathogenesis of Alzheimer's disease. Finally, we conclude with some thoughts and perspectives on future research about these interactions., Competing Interests: None

Freeze-thaw action has the potential to facilitate the mobilization of colloid-associated contaminants in soil. However, the differences in colloid-associated contaminants following autumn freeze-thaw (AFT) events and spring freeze-thaw (SFT) events remain unclear. In this study, the potential influence mechanisms of AFT and SFT on both the generation and migration of colloids and colloid-associated cadmium (Cd) in soil were explored. Higher aggregate stabilities were found in soils after AFT compared with after SFT. After SFT, lower Cd concentrations were found in soil aggregates of 0.25-0.50 mm and <0.106 mm and higher concentrations were found in 0.106-0.25 mm aggregates. Moreover, SFT generated higher amounts of colloidal Cd than AFT, while AFT increased the total Cd concentration in leachates. Additionally, compared with SFT, AFT led to higher Cd concentrations in dissolved and colloid-associated forms in leachates. These findings demonstrate that higher amounts of colloid and fewer loadings of Cd in colloids in Cd contaminated soil can be found after SFT events. Thus, to better understand the environmental risk of contaminants in areas subject to seasonal freeze-thaw cycles, the differences between freeze-thaw processes in spring and autumn should be considered., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Aging behaviors of metals in the field differ from those in a controlled laboratory environment. Whether aging conditions influence the fates of metals in soil remains unclear. In this study, distributions of cadmium (Cd) and phosphatase activity were compared in soil aggregates (i.e., >2, 1-2, 0.25-1, and <0.25 mm) along a profile (0-5, 5-10, and 10-15 cm) at the end of 500-day aging experiments under both controlled laboratory and field conditions. Cd concentration in the 0-5 cm layer was lower and Cd concentration in the 5-10 cm layer was higher in field-aged soil compared to laboratory-aged soil. 25.26-35.62% of soil Cd was loaded in >2 mm aggregates of field-aged soils, and 58.41-66.95% was in laboratory-aged soils. Higher loadings of Cd in 0.25-1 and <0.25 mm aggregates were found in field-aged soil. A higher proportion of exchangeable Cd fraction (20.93% of total soil Cd) was found in the 0-5 cm layer of field-aged soil than in laboratory-aged soil (17.63%), while the opposite tendency was found in deeper soil layers. Soil phosphatase activities in field-aged soils were 1.13-1.26 times higher than in laboratory-aged soils. Phosphatase loadings in the >2 mm aggregates were lower and loadings in both the 1-2 and 0.25-1 mm aggregates were higher in field-aged soils than in laboratory-aged soils. Furthermore, correlation analysis and principal component analysis indicated that available Cd fractions accounted for most of the variations in phosphatase activities. In summary, the fates of the exogenous metal Cd differed between field and controlled laboratory conditions. To better understand the behaviors of heavy metals in soil, especially in a seasonal freeze-thaw area, further field studies are needed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Shear stress is recognized as a regulator of angiogenesis. However, the shear stress experienced by the endothelial cells of capillary sprouts remains unknown. The objective of this study was to estimate shear stress due to local interstitial flow along endothelial tip cells at the end of the capillary sprout lumen. Computational fluid dynamics were used to model flow within a blind-ended vessel, transendothelial flow across the vessel wall, and flow within the surrounding perivascular/interstitial space. Shear stress along the wall of the tip cells was calculated while varying sprout length, perivascular space channel width, and vessel wall hydraulic conductivity. Increasing sprout length, increasing wall hydraulic conductivity, and decreasing perivascular space width increased shear stress magnitude. Wall shear stress magnitude within the lumen ranged from 0.015 to 0.55 dyne/cm 2 at the sprout entrance and linearly decreased to near zero at the base of the tip cells. Tip cell wall shear stress magnitude due to interstitial flow ranged from 0.009 to 4.65 dyne/cm 2 . In 3 out of 8 cases, shear stress magnitude was above 1 dyne/cm 2 and considered physiologically relevant. The results provide a framework for discussing the role of local mechanical cues in regulating endothelial cell dynamics involved in angiogenesis. Mainly, interstitial flows may generate physiologically relevant shear stresses on tip cells in certain scenarios. This source of tip cell shear stress has not been previously considered or modeled., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The gap between in vitro and in vivo assays has inspired biomimetic model development. Tissue engineered models that attempt to mimic the complexity of microvascular networks have emerged as tools for investigating cell-cell and cell-environment interactions that may be not easily viewed in vivo . A key challenge in model development, however, is determining how to recreate the multi-cell/system functional complexity of a real network environment that integrates endothelial cells, smooth muscle cells, vascular pericytes, lymphatics, nerves, fluid flow, extracellular matrix, and inflammatory cells. The objective of this mini-review is to overview the recent evolution of popular biomimetic modeling approaches for investigating microvascular dynamics. A specific focus will highlight the engineering design requirements needed to match physiological function and the potential for top-down tissue culture methods that maintain complexity. Overall, examples of physiological validation, basic science discoveries, and therapeutic evaluation studies will emphasize the value of tissue culture models and biomimetic model development approaches that fill the gap between in vitro and in vivo assays and guide how vascular biologists and physiologists might think about the microcirculation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lampejo, Hu, Lucas, Lomel, Nguyen, Dominguez, Ren, Huang and Murfee.)

Soluble amyloid-β-protein (Aβ) oligomers, a major hallmark of AD, trigger the integrated stress response (ISR) via multiple pathologies including neuronal hyperactivation, microvascular hypoxia, and neuroinflammation. Increasing eIF2α phosphorylation, the core event of ISR, facilitates metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD), and suppressing its phosphorylation has the opposite effect. Having found the facilitation of mGluR5-LTD by Aβ in live rats, we wondered if suppressing eIF2α phosphorylation cascade would protect against the synaptic plasticity and cognitive disrupting effects of Aβ. We demonstrate here that the facilitation of mGluR5-LTD in a delayed rat model by single i.c.v. injection of synthetic Aβ 1-42 . Systemic administration of the small-molecule inhibitor of the ISR called ISRIB (trans-isomer) prevents Aβ-facilitated LTD and abrogates spatial learning and memory deficits in the hippocampus in exogenous synthetic Aβ-injected rats. Moreover, ex vivo evidence indicates that ISRIB normalizes protein synthesis in the hippocampus. Targeting the ISR by suppressing the eIF2α phosphorylation cascade with the eIF2B activator ISRIB may provide protective effects against the synaptic and cognitive disruptive effects of Aβ which likely mediate the early stage of sporadic AD., (© 2022. The Author(s).)

Background: Cognitive decline in Alzheimer's disease (AD) correlates with the extent of tau pathology, in particular tau hyperphosphorylation, which is strongly age-associated. Although elevation of cerebrospinal fluid or blood levels of phosphorylated tau (p-Tau) at residues Thr181 (p-Tau181), Thr217 (p-Tau217), and Thr231 (p-Tau231) are proposed to be particularly sensitive markers of preclinical AD, the generation of p-Tau during brain activity is poorly understood., Objective: To study whether the expression levels of p-Tau181, p-Tau217, and p-Tau231 can be enhanced by physiological synaptic long-term depression (LTD) which has been linked to the enhancement of p-Tau in hippocampus., Methods: In vivo electrophysiology was performed in urethane anesthetized young adult and aged male rats. Low frequency electrical stimulation (LFS) was used to induce LTD at CA3 to CA1 synapses. The expression level of p-Tau and total tau was measured in dorsal hippocampus using immunofluorescent staining and/or western blotting., Results: We found that LFS enhanced p-Tau181 and p-Tau217 in an age-dependent manner in the hippocampus of live rats. In contrast, phosphorylation at residues Thr231, Ser202/Thr205, and Ser396 appeared less sensitive to LFS. Pharmacological antagonism of either N-methyl-D-aspartate or metabotropic glutamate 5 receptors inhibited the elevation of both p-Tau181 and p-Tau217. Targeting the integrated stress response, which increases with aging, using a small molecule inhibitor ISRIB, prevented the enhancement of p-Tau by LFS in aged rats., Conclusion: Together, our data provide a novel in vivo means to uncover brain plasticity-related cellular and molecular processes of tau phosphorylation at key sites in health and aging.

The value-added utilization of tobacco stalk lignin is the key to the development of tobacco stalk resources. However, the serious heterogeneity is the bottleneck for making full use of tobacco stalk lignin. Based on this, lignin was separated from tobacco stalk through hydrothermal assisted dilute alkali pretreatment. Subsequently, the tobacco stalk alkaline lignin was fractionated into five uniform lignin components by sequential solvent fractionation. Advanced spectral technologies (FT-IR, NMR, and GPC) were used to reveal the effects of hydrothermal assisted dilute alkali pretreatment and solvent fractionation on the structural features of tobacco stalk lignin. The lignin fractions extracted with n -butanol and ethanol had low molecular weight and high phenolic hydroxyl content, thus exhibiting superior chemical reactivity and antioxidant capacity. By contrast, the lignin fraction extracted with dioxane had high molecular weight and low reactivity, nevertheless, the high residual carbon rate made it suitable as a precursor for preparing carbon materials. In general, hydrothermal assisted dilute alkali pretreatment was proved to be an efficient method to separate lignin from tobacco stalk, and the application of sequential solvent fractionation to prepare lignin fractions with homogeneous structural features has specific application prospect., Competing Interests: ZL, ZW, SG, YT, XL, NH, QY, and XZ were employed by the companies China Tobacco Hubei Industrial Co., Ltd. and Hubei Xinye Reconstituted Tobacco Development Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Liu, Wang, Gao, Tong, Le, Hu, Yan, Zhou, He and Wang.)

Synaptic dysfunction is a likely proximate cause of subtle cognitive impairment in early Alzheimer's disease. Soluble oligomers are the most synaptotoxic forms of amyloid ß-protein (Aß) and mediate synaptic plasticity disruption in Alzheimer's disease amyloidosis. Because the presence and extent of cortisol excess in prodromal Alzheimer's disease predicts the onset of cognitive symptoms we hypothesised that corticosteroids would exacerbate the inhibition of hippocampal synaptic long-term potentiation in a rat model of Alzheimer's disease amyloidosis. In a longitudinal experimental design using freely behaving pre-plaque McGill-R-Thy1-APP male rats, three injections of corticosterone or the glucocorticoid methylprednisolone profoundly disrupted long-term potentiation induced by strong conditioning stimulation for at least 2 months. The same treatments had a transient or no detectible detrimental effect on synaptic plasticity in wild-type littermates. Moreover, corticosterone-mediated cognitive dysfunction, as assessed in a novel object recognition test, was more persistent in the transgenic animals. Evidence for the involvement of pro-inflammatory mechanisms was provided by the ability of the selective the NOD-leucine rich repeat and pyrin containing protein 3 (NLRP3) inflammasome inhibitor Mcc950 to reverse the synaptic plasticity deficit in corticosterone-treated transgenic animals. The marked prolongation of the synaptic plasticity disrupting effects of brief corticosteroid excess substantiates a causal role for hypothalamic-pituitary-adrenal axis dysregulation in early Alzheimer's disease., (© 2021. The Author(s).)

To date, although there are many studies investigating the toxicity of heavy metal to plant, little research exists in the seasonal freeze-thaw (FT) regions where FT cycles often happen during the plant growing process. To reveal the adaptive mechanisms of plants to the combination stresses of cadmium (Cd) and FT, the Cd accumulation, subcellular distribution, chemical forms, and antioxidant enzyme activity (peroxidase (POD)) were investigated in spinach (Spinacia oleracea L.) growing under different soil Cd levels (i.e., 0.10 mg Cd kg -1 soil (low), 1.21 mg Cd kg -1 soil (medium), and 2.57 mg Cd kg -1 soil (high)). Compared to the non-freeze-thaw (NFT) treatments, higher Cd concentrations in the root and lower translocation factors from root to leaf were found for the plants experiencing FT cycles. FT significantly decreased the Cd concentrations in the leaves under the low- and medium-Cd treatments, while similar values were found for the high-Cd treatments. Generally, FT could decrease the concentrations and proportions of Cd stored in the cell wall and soluble fractions and increase them in the organelle fractions for the medium- and high-Cd treatments, while opposite tendency was found for the low-Cd treatments. Moreover, larger Cd amounts in the inorganic and water-soluble forms were found for the low- and medium-Cd treated plants under FT, while lower values were found for the high-Cd treatments. Additionally, POD, which presented higher activities at the low- and medium-Cd treatments and lower activities at the high-Cd treatments under FT, were also significantly influenced by the Cd × FT interaction. This study indicated that FT could significantly change the accumulations of Cd in plant, and it provided a new insight into the Cd accumulation by plants in the seasonal FT region., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

To date, most studies about the aging of metals in soil were based on the controlled laboratory experiments, and few works have attempted to investigate how aging process influences the distribution and bioavailability of metals in soil under the field condition. The purpose of this study was to compare the aging of cadmium (Cd) in soils under the controlled laboratory and the field by monitoring time-dependent soil Cd speciation changes, Cd release kinetics, and Cd bioavailability to plant through the 438-day aging experiments. During the aging process, the proportions of Cd associated with the most weakly bound fraction tended to decrease, with corresponding increases in the more stable binding fractions. After aging, a higher concentration of available Cd was found in the field aging soil (0.74 mg kg -1 ) than the laboratory aging soil (0.65 mg kg -1 ). The Elovich equation was the best model to describe the soil available Cd aging process. The constant b in the Elovich equation, which was defined as the transformation rate, was in the order of laboratory aging soil > field aging soil. Moreover, higher Cd release amounts were found for the field aging soil (2.74 mg kg -1 ) than the laboratory aging soil (2.57 mg kg -1 ) at the end of aging. Additionally, higher body Cd concentrations were found for the vegetables grown in the field aging soils (1.49 mg kg -1 , fresh weight) than those grown in the laboratory aging soils (1.32 mg kg -1 , fresh weight). Therefore, this study indicated that the metal distribution process and its bioavailability may be overestimated or underestimated if research data from the laboratory experiments are used to derive soil quality criteria or investigate soil metal bioavailability., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Previous publications indicated that genetic predisposition might play important roles in the onset of osteonecrosis of the femoral head (ONFH) in systemic lupus erythematosus (SLE). Some gene loci such as complement C3d receptor 2 ( CR2 ), nitric oxide synthase 3 ( NOS3 ), collagen type II alpha 1 chain ( COL2A1 ), protein tyrosine phosphatase non-receptor type 22 ( PTPN22 ), and transient receptor potential cation channel subfamily V member 4 ( TRPV4 ) were reported to be involved in this process., Aim: To investigate whether the risk of ONFH in SLE is associated with single nucleotide variations (SNVs) in these five genes., Methods: SNVs in the CR2 , NOS3 , COL2A1 , PTPN22 , and TRPV4 genes were examined by using FastTarget and Illumina Miseq sequencing technologies in 49 cases of SLE with ONFH. Burrows-wheeler aligner was used to align the sequencing reads to hg19, and GATK and Varscan programs were used to perform SNV calling. PolyPhen-2, SIFT, and MutationTaster were used to assess the functional effects of non-synonymous SNVs., Results: Six of the 49 patients were confirmed to have low frequency SNVs, including one patient with SNVs in NOS3 (exon 6: c.814G>A: p.E272K and exon 7: c.814G>A: p.E272K.), four in COL2A1 (rs41263847: exon 29: c.1913C>T: p.T638I, exon 28: c.1706C>T: p.T569I, and rs371445823: exon 8: c.580G>A: p.A194T, exon 7: c.373G>A: p.A125T), and one in CR2 (rs45573035: exon 2: c.200C>G: p.T67S)., Conclusion: The onset of ONFH in SLE might be associated with the identified SNVs in NOS3, COL2A1 , and CR2 ., Competing Interests: Conflict-of-interest statement: There are no conflicts of interest to report., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: We report a rare case of secondary acute angle closure attack because of lupus choroidopathy and accompanying polyserositis, as an initial presentation of a novel type of systemic lupus erythematosus in a 44-year-old woman., Case Presentation: The patient complained of eyelid oedema and chemosis with bilateral severe loss of visual acuity. Systemic lupus erythematosus was diagnosed based on malar rash, polyserositis, proteinuria and positive antibody titers for antinuclear antibodies, anti-DNA, antinucleosome antibodies and ribosomal RNP. Subsequently, secondary bilateral acute angle closure caused by choroidal effusions with lupus choroidopathy was diagnosed. A month after steroid and immunosuppressive drug therapy, the patient's intraocular pressure and visual acuity returned to normal. During the subsequent year, the secondary acute angle closure did not recur and polyserositis remained under control., Conclusions: Bilateral, secondary acute angle closure attack due to SLE choroidopathy can be an initial presentation of SLE, which is often accompanied by polyserositis. Prompt and aggressive high doses of steroids and immunosuppressive therapy are strongly recommended.

How endogenously produced soluble amyloid ß-protein (Aß) affects synaptic plasticity in vulnerable circuits should provide insight into early Alzheimer's disease pathophysiology. McGill-R-Thy1-APP transgenic rats, modeling Alzheimer's disease amyloidosis, exhibit an age-dependent soluble Aß-mediated impairment of the induction of long-term potentiation (LTP) by 200 Hz conditioning stimulation at apical CA3-to-CA1 synapses. Here, we investigated if synaptic weakening at these synapses in the form of activity-dependent persistent reversal (depotentiation) of LTP is also altered in pre-plaque rats in vivo . In freely behaving transgenic rats strong, 400 Hz, conditioning stimulation induced stable LTP that was NMDA receptor- and voltage-gated Ca 2+ channel-dependent. Surprisingly, the ability of novelty exploration to induce depotentiation of 400 Hz-induced LTP was impaired in an Aß-dependent manner in the freely behaving transgenic rats. Moreover, at apical synapses, low frequency conditioning stimulation (1 Hz) did not trigger depotentiation in anaesthetized transgenic rats, with an age-dependence similar to the LTP deficit. In contrast, at basal synapses neither LTP, induced by 100 or 200 Hz, nor novelty exploration-induced depotentiation was impaired in the freely behaving transgenic rats. These findings indicate that activity-dependent weakening, as well as strengthening, is impaired in a synapse- and age-dependent manner in this model of early Alzheimer's disease amyloidosis.

Soluble synaptotoxic aggregates of the main pathological proteins of Alzheimer's disease, amyloid β-protein (Aß) and tau, have rapid and potent inhibitory effects on long-term potentiation (LTP). Although the promotion of synaptic weakening mechanisms, including long-term depression (LTD), is posited to mediate LTP inhibition by Aß, little is known regarding the action of exogenous tau on LTD. The present study examined the ability of different assemblies of full-length human tau to affect LTD in the dorsal hippocampus of the anaesthetized rat. Unlike Aß, intracerebroventricular injection of soluble aggregates of tau (SτAs), but not monomers or fibrils, potently increased the threshold for LTD induction in a manner that required cellular prion protein. However, MTEP, an antagonist of the putative prion protein coreceptor metabotropic glutamate receptor 5, did not prevent the disruption of synaptic plasticity by SτAs. In contrast, systemic treatment with Ro 25-6981, a selective antagonist at GluN2B subunit-containing NMDA receptors, reduced SτA-mediated inhibition of LTD, but not LTP. Intriguingly, SτAs completely blocked Aß-facilitated LTD, whereas a subthreshold dose of SτAs facilitated Aß-mediated inhibition of LTP. Overall, these findings support the importance of cellular prion protein in mediating a range of, sometimes opposing, actions of soluble Aß and tau aggregates with different effector mechanisms on synaptic plasticity., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Reactive arthritis (ReA) is sterile arthritis triggered by bacterial gastrointestinal or urogenital infections. Although the pathogenesis of ReA remains unclear, genetic factors seem to play an important role. Different killer cell immunoglobulin-like receptors (KIRs) and their corresponding specific histocompatibility leukocyte antigen-C (HLA-C) ligand genotypes have been implicated in susceptibility and resistance to infections and autoimmune diseases but have, thus far, not been investigated in ReA., Methods: This study was conducted in 138 ReA patients (65 females, 73 males); aged 18-69 years (mean, 37 years) and 151 randomly selected healthy control individuals matched for ethnicity, age and sex. These subjects were genotyped for KIR genes and HLA-C alleles by polymerase chain reaction with sequence-specific primers., Results: The frequencies of inhibitory KIR2DL2 and KIR2DL5 were significantly lower in the ReA patients than in the controls (p = .005 and p = .033, respectively). The presence of more than seven inhibitory KIR genes was protective (p = .016). Moreover, we found that activating KIR2DS1 alone or in combination with the HLA-C1C1 genotype (which indicates the absence of the HLA ligands for their homologous inhibitory receptor KIR2DL1) is associated with susceptibility to ReA (p = .039 and p = .011, respectively), whereas KIR2DL2 in combination with the HLA-C1 ligand is associated with protection against ReA (p = .039)., Conclusion: These observations indicate that high levels of activating and low levels of inhibitory KIR signals may affect the functions of NK cells and T cells. This imbalance enables the innate and adaptive immune responses of the host to be easily triggered by pathogens, resulting in the overproduction of local and systemic cytokines that contribute to the pathogenesis of ReA.

The early stages of Alzheimer's disease are associated with synaptic dysfunction prior to overt loss of neurons. To identify extracellular molecules that impair synaptic plasticity in the brain, we studied the secretomes of human iPSC-derived neuronal models of Alzheimer's disease. When introduced into the rat brain, secretomes from human neurons with either a presenilin-1 mutation, amyloid precursor protein duplication, or trisomy of chromosome 21 all strongly inhibit hippocampal long-term potentiation. Synaptic dysfunction caused by presenilin-1 mutant and amyloid precusor protein duplication secretomes is mediated by Aβ peptides, whereas trisomy of chromosome 21 (trisomy 21) neuronal secretomes induce dysfunction through extracellular tau. In all cases, synaptotoxicity is relieved by antibody blockade of cellular prion protein. These data indicate that human models of Alzheimer's disease generate distinct proteins that converge at the level of cellular prion protein to induce synaptic dysfunction in vivo., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Synaptic long-term depression (LTD) is believed to underlie critical mnemonic processes in the adult hippocampus. The roles of the metabotropic and ionotropic actions of glutamate in the induction of synaptic LTD by electrical low-frequency stimulation (LFS) in the living adult animal is poorly understood. Here we examined the requirement for metabotropic glutamate (mGlu) and NMDA receptors in LTD induction in anaesthetized adult rats. LTD induction was primarily dependent on NMDA receptors and required the involvement of both the ion channel function and GluN2B subunit of the receptor. Endogenous mGlu5 receptor activation necessitated the local application of relatively high doses of either competitive or non-competitive NMDA receptor antagonists to block LTD induction. Moreover, boosting endogenous glutamate activation of mGlu5 receptors with a positive allosteric modulator lowered the threshold for NMDA receptor-dependent LTD induction by weak LFS. The present data provide support in the living animal that NMDA receptor-dependent LTD is boosted by endogenously released glutamate activation of mGlu5 receptors. Given the predominant perisynaptic location of mGlu5 receptors, the present findings emphasize the need to further evaluate the contribution and mechanisms of these receptors in NMDA receptor-dependent synaptic plasticity in the adult hippocampus in vivo.

Promotion of long-term depression (LTD) mechanisms by synaptotoxic soluble oligomers of amyloid-β (Aß) has been proposed to underlie synaptic dysfunction in Alzheimer's disease (AD). Previously, LTD was induced by relatively non-specific electrical stimulation. Exploiting optogenetics, we studied LTD using a more physiologically diffuse spatial pattern of selective pathway activation in the rat hippocampus in vivo. This relatively sparse synaptic LTD requires both the ion channel function and GluN2B subunit of the NMDA receptor but, in contrast to electrically induced LTD, is not facilitated by boosting endogenous muscarinic acetylcholine or metabotropic glutamate 5 receptor activation. Although in the absence of Aß, there is no evidence of hippocampal LTD asymmetry, in the presence of Aß, the induction of LTD is preferentially enhanced in the left hippocampus in an mGluR5-dependent manner. This circuit-selective disruption of synaptic plasticity by Aß provides a route to understanding the development of aberrant brain lateralization in AD., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Bu-Shen-Jian-Pi-Yi-Qi therapy, which refers to reinforcing kidney, regulating qi, and invigorating spleen, is a traditional Chinese medicine, and we investigated its efficacy in treatment of alcohol-induced osteoporosis and its underlying mechanism. Forty adult male Sprague-Dawley rats were randomly assigned into alcohol-supplemented group, JIAN-GU-LING (JGL) group, calcium D3 + alfacalcidol group, and sham-treated group. Bone mineral density (BMD), bone mineral content (BMC), and bone biomechanical properties were assessed. Biochemical analyses of serum and urine specimens were detected. Reverse transcription-polymerase chain reaction was used to detect the mRNA level of vitamin D receptor (VDR). There were markedly lower bone metabolic markers and biomechanical properties in alcohol-supplemented group compared with sham-treated group (all P < 0.05). BMD, BMC, 25(OH)D3, and 1,25(OH)2D3 were elevated in JGL group relative to calcium D3 + alfacalcidol group (all P < 0.05). U-Ca/Cr and U-P/Cr in JGL group were higher than those in the calcium D3 + alfacalcidol group (all P < 0.05). VDR mRNA level in the JGL group was elevated markedly in comparison with alcohol + calcium D3 + alfacalcidol group (P < 0.05). Based on our results, Bu-Shen-Jian-Pi-Yi-Qi therapy inhibits bone loss, promotes bone formation, and effectively improves bone metabolism in rats with experimental alcoholic osteoporosis. The disease reversal is evidenced by increased BMD and BMC, improved biomechanical properties, elevated VDR mRNA level, enhanced response sensitivity of 1, 25(OH)2D3, and reduced S-Ca/P.

NMDA-type glutamate receptors (NMDARs) are currently regarded as paramount in the potent and selective disruption of synaptic plasticity by Alzheimer's disease amyloid β-protein (Aβ). Non-NMDAR mechanisms remain relatively unexplored. Here we describe how Aβ facilitates NMDAR-independent long-term depression of synaptic transmission in the hippocampus in vivo. Synthetic Aβ and Aβ in soluble extracts of Alzheimer's disease brain usurp endogenous acetylcholine muscarinic receptor-dependent long-term depression, to enable long-term depression that required metabotropic glutamate-5 receptors (mGlu5Rs). We also find that mGlu5Rs are essential for Aβ-mediated inhibition of NMDAR-dependent long-term potentiation in vivo. Blocking Aβ binding to cellular prion protein with antibodies prevents the facilitation of long-term depression. Our findings uncover an overarching role for Aβ-PrP(C)-mGlu5R interplay in mediating both LTD facilitation and LTP inhibition, encompassing NMDAR-mediated processes that were previously considered primary.

Both electrically induced synaptic long-term potentiation (LTP) and long-term depression have been extensively studied as models of the cellular basis of learning and memory mechanisms. Recently, considerable interest has been generated by the possibility that the activity-dependent persistent reversal of previously established synaptic LTP (depotentiation) may play a role in the time- and state-dependent erasure of memory. Here, we examined the requirement for glutamate receptor activation in experience-induced reversal of previously established LTP in the CA1 area of the hippocampus of freely behaving rats. Continuous exploration of non-aversive novelty for ~30 min, which was associated with hippocampal activation as measured by increased theta power in the electroencephalogram, triggered a rapid and persistent reversal of high frequency stimulation-induced LTP both at apical and basal synapses. Blockade of metabotropic glutamate (mGlu) receptors with mGlu5 subtype-selective antagonists, or N-methyl-D-aspartate (NMDA) receptors with GluN2B subunit-selective antagonists, prevented novelty-induced depotentiation. These findings strongly indicate that activation of both mGlu5 receptors and GluN2B-containing NMDA receptors is required for experience-triggered induction of depotentiation at CA3-CA1 synapses. The mechanistic concordance of the present and previous studies of experience-induced and electrically induced synaptic depotentiation helps to integrate our understanding of the neurophysiological underpinnings of learning and memory.

Alzheimer's disease (AD) is characterized by episodic memory impairment that often precedes clinical diagnosis by many years. Probing the mechanisms of such impairment may provide much needed means of diagnosis and therapeutic intervention at an early, pre-dementia, stage. Prior to the onset of significant neurodegeneration, the structural and functional integrity of synapses in mnemonic circuitry is severely compromised in the presence of amyloidosis. This review examines recent evidence evaluating the role of amyloid-ß protein (Aβ) in causing rapid disruption of synaptic plasticity and memory impairment. We evaluate the relative importance of different sizes and conformations of Aβ, including monomer, oligomer, protofibril and fibril. We pay particular attention to recent controversies over the relevance to the pathophysiology of AD of different water soluble Aβ aggregates and the importance of cellular prion protein in mediating their effects. Current data are consistent with the view that both low-n oligomers and larger soluble assemblies present in AD brain, some of them via a direct interaction with cellular prion protein, cause synaptic memory failure. At the two extremes of aggregation, monomers and fibrils appear to act in vivo both as sources and sinks of certain metastable conformations of soluble aggregates that powerfully disrupt synaptic plasticity. The same principle appears to apply to other synaptotoxic amyloidogenic proteins including tau, α-synuclein and prion protein.

The cognitive and related symptoms of Alzheimer's disease are mainly attributable to synaptic failure. Here we review recent research on how the Alzheimer's disease amyloid ß-protein (Aß) affects glutamate receptors and fast excitatory synaptic transmission and plasticity of that transmission. l-glutamate, the main excitatory neurotransmitter in the brain, has long been implicated in causing NMDA receptor-mediated excitotoxicity leading to neurodegeneration in the late stages of the disease. However there is now extensive evidence that soluble Aß oligomers disrupt synaptic transmission and especially synaptic plasticity via non-excitotoxic glutamatergic mechanisms. New data highlight the relatively selective involvement of certain glutamate receptor subtypes including GluN2B (NR2B) subunit-containing NMDA receptors and mGlu5 receptors. Aß exerts direct and indirect effects on synaptic plasticity-related glutamate receptor signaling and trafficking between different neuronal compartments. For example, Aß-induced ectopic NMDA and mGlu receptor-mediated signaling coupled with caspase-3 activation may cause inhibition of long-term potentiation and facilitation of long-term depression. Intriguingly, some of the disruptive synaptic actions of Aß have been found to be dependent on endogenous tau located in dendrites or spines. Given the role of glutamatergic transmission in regulating Aß production and release, future therapies targeting glutamate offer the opportunity to remedy both mis-processing of Aß and cellular mechanisms of synaptic failure in early AD., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: T-helper (Th) 22 is involved in the pathogenesis of inflammatory diseases. The roles of Th22 cells in the pathophysiological of ankylosing spondylitis (AS) and rheumatoid arthritis (RA) remain unsettled. So we examined the frequencies of Th22 cells, Th17 cells and Th1 cells in peripheral blood (PB) from patients with AS and patients with RA compared with both healthy controls as well as patients with osteoarthritis., Design and Methods: We studied 32 AS patients, 20 RA patients, 10 OA patients and 20 healthy controls. The expression of IL-22, IL-17 and IFN-γ were examined in AS, RA, OA patients and healthy controls by flow cytometry. Plasma IL-22 and IL-17 levels were examined by enzyme-linked immunosorbent assay., Results: Th22 cells, Th17 cells and interleukin-22 were significantly elevated in AS and RA patients compared with OA patients and healthy controls. Moreover, Th22 cells showed positive correlation with Th17 cells as well as interleukin-22 in AS and RA patients. However, positive correlation between IL-22 and Th17 cells was only found in AS patients not in RA patients. In addition, the percentages of both Th22 cells and Th17 cells correlated positively with disease activity only in RA patients not in AS patients., Conclusions: The frequencies of both Th22 cells and Th17 cells were elevated in PB from patients with AS and patients with RA. These findings suggest that Th22 cells and Th17 cells may be implicated in the pathogenesis of AS and RA, and Th22 cells and Th17 cells may be reasonable cellular targets for therapeutic intervention.

Background: T-helper (Th) 22 and Th17 cells are implicated in the pathogenesis of autoimmune diseases. The roles of Th22 cells in the pathophysiology of rheumatoid arthritis (RA) remain unsettled., Materials and Methods: CD4(+)IFNγ(-)IL17(-)IL-22(+) T cells (Th22 cells), CD4(+)IFNγ(-)IL-22(-)IL17(+) T cells (pure Th17 cells), CD4(+)IL17(+) T cells (Th17 cells), and CD4(+)IFNγ(+) T cells (Th1 cells) in RA, osteoarthritis patients, and healthy controls were examined by flow cytometry. Plasma IL-22 and IL-17 levels were examined by enzyme-linked immunosorbent assay., Results: Th22 cells, pure Th17 cells, Th17 cells, and interleukin-22 were significantly elevated in RA patients compared with osteoarthritis and healthy controls, but there were no significant differences regarding Th1 cells and interleukin-17. Th22 cells showed a positive correlation with interleukin-22 as well as pure Th17 cells or Th17 cells in RA patients. Additionally, the percentages of Th22 cells, pure Th17 cells as well as Th17 cells correlated positively with both C-reactive protein levels and 28-joints disease activity score., Conclusion: Together, our results indicated a possible role of Th22 pure Th17 cells and Th17 cells in RA, and blockade of the interleukin-22 may be a reasonable therapeutic strategy for RA.

Alzheimer's disease (AD) is characterized neuropathologically by the deposition of different forms of amyloid beta-protein (A beta) including variable amounts of soluble species that correlate with severity of dementia. The extent of synaptic loss in the brain provides the best morphological correlate of cognitive impairment in clinical AD. Animal research on the pathophysiology of AD has therefore focussed on how soluble A beta disrupts synaptic mechanisms in vulnerable brain regions such as the hippocampus. Synaptic plasticity in the form of persistent activity-dependent increases or decreases in synaptic strength provide a neurophysiological substrate for hippocampal-dependent learning and memory. Acute treatment with human-derived or chemically prepared soluble A beta that contains certain oligomeric assemblies, potently and selectively disrupts synaptic plasticity causing inhibition of long-term potentiation (LTP) and enhancement of long-term depression (LTD) of glutamatergic transmission. Over time these and related actions of A beta have been implicated in reducing synaptic integrity. This review addresses the involvement of neurotransmitter intercellular signaling in mediating or modulating the synaptic plasticity disrupting actions of soluble A beta, with particular emphasis on the different roles of glutamatergic and cholinergic mechanisms. There is growing evidence to support the view that NMDA and possibly nicotinic receptors are critically involved in mediating the disruptive effect of A beta and that targeting muscarinic receptors can indirectly modulate A beta's actions. Such studies should help inform ongoing and future clinical trials of drugs acting through the glutamatergic and cholinergic systems.

Currently, treatment with the relatively low-affinity NMDA receptor antagonist memantine provides limited benefit in Alzheimer's disease (AD). One probable dose-limiting factor in the use of memantine is the inhibition of NMDA receptor-dependent synaptic plasticity mechanisms believed to underlie certain forms of memory. Moreover, amyloid-beta protein (Abeta) oligomers that are implicated in causing the cognitive deficits of AD potently inhibit this form of plasticity. Here we examined if subtype-preferring NMDA receptor antagonists could preferentially protect against the inhibition of NMDA receptor-dependent plasticity of excitatory synaptic transmission by Abeta in the hippocampus in vivo. Using doses that did not affect control plasticity, antagonists selective for NMDA receptors containing GluN2B but not other GluN2 subunits prevented Abeta(1-42) -mediated inhibition of plasticity. Evidence that the proinflammatory cytokine TNFalpha mediates this deleterious action of Ass was provided by the ability of TNFalpha antagonists to prevent Abeta(1-42) inhibition of plasticity and the abrogation of a similar disruptive effect of TNFalpha using a GluN2B-selective antagonist. Moreover, at nearby synapses that were resistant to the inhibitory effect of TNFalpha, Abeta(1-42) did not significantly affect plasticity. These findings suggest that preferentially targeting GluN2B subunit-containing NMDARs may provide an effective means of preventing cognitive deficits in early Alzheimer's disease.

Long before the onset of clinical Alzheimer's disease non-fibrillar, soluble assembly states of amyloid-beta (Abeta) peptides are believed to cause cognitive problems by disrupting synaptic function in the absence of significant neurodegeneration. Since many of the risk factors for Alzheimer's disease are vascular, impairment of cerebral blood flow by soluble Abeta has been proposed to be critical in triggering these early changes. However, it is not known if soluble Abeta can affect cerebrovascular function at the concentrations required to cause inhibition of synaptic plasticity mechanisms believed to underlie the early cognitive deficits of Alzheimer's disease. Here we developed a new method to simultaneously assess the ability of soluble Abeta to impair plasticity at synapses and to affect resting and activity-dependent local blood flow in the rat hippocampus in vivo. Intracerebroventricular injection of soluble synthetic Abeta(40) dimers rapidly inhibited plasticity of excitatory synaptic transmission at doses (10-42 pmol) comparable to natural Abeta, but failed to affect vascular function measured using laser-Doppler flowmetry (LDF). Like wild-type Abeta(40), the more vasculotropic Abeta produced by people with familial hemorrhagic stroke of the Dutch type (Abeta(40)E22Q), impaired hippocampal plasticity without causing a significant change in local blood flow. Furthermore, neither resting nor activation-evoked hippocampal perfusion was affected by soluble Abeta(42), even at a concentration that markedly (25%) reduced baseline synaptic transmission. These findings demonstrate that the putative synaptotoxic soluble Abeta species of early Alzheimer's disease cause synaptic dysfunction in the absence of detectible changes in local blood flow. This strongly indicates that early cognitive deficits can be caused by soluble Abeta independently of deleterious effects on cerebrovascular dynamics.

There is growing evidence that mild cognitive impairment in early AD (Alzheimer's disease) may be due to synaptic dysfunction caused by the accumulation of non-fibrillar, oligomeric Abeta (amyloid beta-peptide), long before widespread synaptic loss and neurodegeneration occurs. Soluble Abeta oligomers can rapidly disrupt synaptic memory mechanisms at extremely low concentrations via stress-activated kinases and oxidative/nitrosative stress mediators. Here, we summarize experiments that investigated whether certain putative receptors for Abeta, the alphav integrin extracellular cell matrix-binding protein and the cytokine TNFalpha (tumour necrosis factor alpha) type-1 death receptor mediate Abeta oligomer-induced inhibition of LTP (long-term potentiation). Ligands that neutralize TNFalpha or genetic knockout of TNF-R1s (type-1 TNFalpha receptors) prevented Abeta-triggered inhibition of LTP in hippocampal slices. Similarly, antibodies to alphav-containing integrins abrogated LTP block by Abeta. Protection against the synaptic plasticity-disruptive effects of soluble Abeta was also achieved using systemically administered small molecules targeting these mechanisms in vivo. Taken together, this research lends support to therapeutic trials of drugs antagonizing synaptic plasticity-disrupting actions of Abeta oligomers in preclinical AD.

Compelling evidence has shown that in hippocampus tumor necrosis factor alpha (TNF-alpha) at pathological concentration inhibits long-term potentiation (LTP), a synaptic model of learning and memory. In the present work we investigated the role of TNF-alpha in LTP of C-fiber evoked field potentials in spinal dorsal horn, which is relevant to pathological pain. We showed that spinal application of TNF-alpha affected neither basal synaptic transmission mediated by C-fibers nor spinal LTP of C-fiber evoked field potentials induced by tetanic stimulation in intact rats. However, in rats with neuropathic pain, produced by either lumbar 5 ventral root transection (L5 VRT) or spared nerve injury (SNI), spinal application of TNF-alpha induced LTP of C-fiber evoked field potentials. Spinal application of JNK inhibitor (SP600125) or p38 MAPK inhibitor (SB203580) did not affect the spinal LTP induced by tetanic stimulation in intact rats, but completely blocked LTP induced by TNF-alpha in L5 VRT rats. NF-kappa B (NF-kappaB) inhibitor (PDTC) also blocked LTP induced by TNF-alpha. These results suggest that TNF-alpha and its downstream molecules may have no acute effect on spinal synaptic transmission in intact animals and induce LTP in rats with neuropathic pain produced by nerve injury.

Clonidine, a specific alpha2-adrenergic receptor agonist, has been found to be effective for the treatment of neuropathic pain, the mechanism underlying the effect is, however, not well understood. Here, the effect of clonidine on long-term potentiation (LTP) of C-fiber evoked field potentials in spinal dorsal horn, which is a synaptic model of injury-induced hyperalgesia, was investigated. LTP of C-fiber evoked field potentials was recorded in the superficial layers of spinal dorsal horn in anesthetized adult Sprague-Dawley rats. Clonidine and other substances were applied locally at the recording spinal segments before or after LTP induction by tetanic stimulation. We found that (1) Clonidine completely blocked LTP induction, when applied 30 min before tetanic stimulation and depressed spinal LTP, when applied 30 min and 3 h after LTP induction. (2) The inhibitory effect of clonidine on spinal LTP had two phases: a fast phase lasting for about 3.5 h and a slow phase persisting for the rest time of experiments (up to 8 h after drug). (3) Spinal clonidine at low dose (10.7 micro g/100 micro l) depressed spinal LTP but not C-fiber baseline response and at higher dose (107 micro g/100 micro l) depressed both of them. (4) Pretreatment with alpha2-adrenergic receptor antagonist yohimbine completely blocked the inhibitory effect of clonidine. (5) Pretreatment with muscarinic receptor antagonist atropine, nitric oxide synthesis inhibitor l-NNA or cGMP inhibitor ODQ depressed the fast phase inhibition significantly and abolished the slow phase inhibition completely. These results suggest that clonidine may exert analgesic effect by depressing the synaptic plasticity in spinal dorsal horn, via activation of muscarinic receptor-NO-cGMP pathway.

Peripheral nerve injury leads to the establishment of a novel synaptic connection between afferent Abeta-fiber and lamina II neurons in spinal dorsal horn, which is hypothesized to underlie mechanical allodynia. However, how the novel synapses transmit nociceptive information is poorly understood. In the present study, the role of protein tyrosine kinases (PTKs) in Abeta-fiber-evoked excitatory postsynaptic currents (EPSCs) recorded in lamina II neurons in transverse spinal cord slices of rats was investigated using the whole-cell patch-clamp recording technique. In the slices from sciatic nerve transection (SNT) rats, genistein (50 microM), a broad-spectrum PTKs inhibitor, or PP2 (20 microM), a selective Src family tyrosine kinase inhibitor, significantly reduced the amplitude of Abeta-fiber EPSCs. In sham-operated rats, however, Abeta-fiber EPSCs were insensitive to genistein and PP2. The N-methyl-D-aspartate (NMDA) receptor antagonist AP-V (50 microM) suppressed Abeta-fiber EPSCs in slices from SNT rats but not from sham-operated rats. Following nerve injury, the slow inward currents elicited by bath application of NMDA (100 muM) significantly increased at -70 mV. In SNT rats, genistein and PP2 reduced Abeta-fiber-evoked EPSCs mediated by NMDA receptor; however, genistein produced little effect on Abeta-fiber EPSCs mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor. These data suggested that PTKs, especially Src family members, participated in Abeta-fiber-evoked synaptic transmission following sciatic nerve injury via potentiation of NMDA receptor function.

The benzodiazepine diazepam impairs memory and long-term potentiation (LTP) in the hippocampus. Here, we investigate the effect of diazepam on LTP of C-fiber evoked field potentials in spinal dorsal horn, which is relevant to pathological pain. LTP of C-fiber evoked field potentials was recorded in the superficial layers of spinal dorsal horn in urethane-anesthetized Sprague--Dawley rats. Diazepam was applied locally at the recording spinal segments before and after LTP induction by tetanic stimulation. We found (1) Diazepam completely blocked LTP induction. (2) Diazepam and midazolam reversed spinal LTP, when applied at 30 min after LTP induction and depressed but could not reverse spinal LTP, when applied at 3 h after LTP induction. (3) Pretreatment with benzodiazepine receptor antagonist flumazenil or GABA(A) receptor antagonist bicuculline completely blocked the inhibitory effects of diazepam on spinal LTP. In contrast, when the inhibitory effect of diazepam was fully established, neither of these antagonists was capable of reversing the inhibition by diazepam. (4) Spinal application of the GABA(A) receptor agonist 3-amino-1-propanesulfonic acid (3-APSA) at a dose of 50 microg, produced a transient inhibition of spinal LTP. These results suggest that diazepam might prevent and depress spinal plastic change produced by noxious stimulation via activation of the GABA(A) -benzodiazepine receptor complex.

Long-term potentiation (LTP) of C-fiber-evoked field potentials in spinal dorsal horn may be relevant to pathological pain. Our previous work has shown that the late phase of the spinal LTP is protein synthesis-dependent. Considerable evidence has accumulated that dopamine D1/D5 receptors are important for late-phase LTP in hippocampus. In this study, the role of D1/D5 receptors in LTP of C-fiber-evoked field potentials in spinal dorsal horn was evaluated in urethan-anesthetized Sprague-Dawley rats. We found the following. 1) Spinal application of SKF 38393, a D1/D5 receptor agonist, induced a slowly developed LTP of C-fiber-evoked field potentials, lasting for >10 h, and the effect was blocked by the D1/D5 antagonist SCH 23390, whereas a D2 receptor agonist (quinpirole) induced depression of C-fiber responses, lasting for 2 h. 2) The potentiation produced by D1/D5 receptor agonist occluded the late phase but not the early phase of the spinal LTP produced by tetanic stimulation. 3) SCH 23390 selectively depressed the late-phase LTP, when applied 40 min before tetanic stimulation. 4) The D1/D5 agonist-induced potentiation is blocked by the protein synthesis inhibitor anisomycin. 5) Activation of protein kinase A by spinal application of 8-Br-cAMP also induced spinal LTP, and the action occluded the potentiation induced by the D1/D5 receptor agonist. These results suggest that the spinal D1/D5 receptors participate in the protein synthesis-dependent late-phase LTP of C-fiber-evoked field potentials in spinal dorsal horn through the cAMP signaling pathway.

Nerve injury produces a long lasting neuropathic pain, manifested as allodynia, a decrease in pain threshold and hyperalgesia, an increase in response to noxious stimuli. The mechanism underlying the lasting abnormal pain is not well understood. Our previous works have shown that electrical tetanic stimulation of the sciatic nerve induces long-term potentiation (LTP) of C-fiber evoked field potentials in the spinal dorsal horn, which is considered as a synaptic model of pathological pain. In the present study we tested if nerve injury, which is proved to produce neuropathic pain, induced the spinal LTP in intact rats. C-fiber evoked field potentials in spinal dorsal horn produced by electrical stimulation (10-20 V, 0.5 ms, 1/min) of the sciatic nerve were recorded. For induction of LTP of C-fiber evoked field potentials, three types of noxious stimuli were applied. (1) Electrical tetanic stimulation (40 V, 0.5 ms pulses at 100 Hz for 1 s repeated four times at 10 s intervals). (2) Transection of the sciatic nerve at 4-5 mm distal to the stimulation electrode. (3) Crushing the sciatic nerve with a forceps four times at 4-5 mm distal to stimulation electrode (from distal to proximal with 1 mm spacing at 10 s intervals), which simulated electrical tetanic stimulation. Acute nerve injury was made by either transection of the sciatic nerve at the distal to the stimulating electrode or crushing the sciatic nerve. We found that nerve injury by cutting or crushing the sciatic nerve produced LTP of C-fiber evoked field potentials lasting until the end of the experiments (3-9 h), and that pretreatment of the sciatic nerve with lidocaine 10 min prior to the nerve transectoin completely blocked LTP induced by nerve transection. The nerve transection-induced LTP was blocked by NMDA receptor antagonist AP5. LTP produced by nerve transection could not be further potentiated by electrical tetanic stimulation, while LTP induced by single electrical tetanic stimulation could be further potentiated by transection of the sciatic nerve. However, when LTP was saturated by several times of electrical tetanic stimulation, nerve transection did not affect the spinal LTP. We conclude that acute nerve injury induces LTP of C-fiber evoked field potentials in intact animals and that nerve transection is more powerful than electrical tetanic stimulation for induction of the spinal LTP. The results further support the notion that LTP of C-fiber evoked field potentials may underlie neuropathic pain.

By using stereological morphometric techniques, we examined the ultrastructure of synapses in lamine II of the spinal dorsal horn of Sprague Dawley rats 30 min, 3 h and 5 h after long-term potentiation (LTP) induction. We found that the numerical density per unit volume (Nv) of total synapses, the thickness of the postsynaptic density (PSD), width of the synaptic cleft increased significantly after the establishment of LTP. (1) Thirty minutes after the formation of LTP, the thickness of the PSD increased from 0.029 +/-0.0064 microm (control) to 0.036 +/-0.009 microm (P<0.05) and the width of the synaptic cleft increased from 0.0181+/-0.0024 microm (control) to 0.0197+/-0.0029 microm (P< 0.05); the number of synaptic vesicles decreased from 0.122 +/-0.011/microm(2) to 0.085 +/-0.010/microm(2) (P<0.05); (2) 3 h after the formation of LTP, the thickness of PSD and the width of the synaptic cleft had no difference compared with those 30 min after LTP. The number of synaptic vesicles increased from 0.122 +/-0.011/microm(2) to 0.138 +/-0.015/microm(2); the curvature of the synaptic interface increased from 1.153+/-0.195 to 1.386 +/-0.311 (P<0.05, compared with control). Nv of negative synapses increased from 0.0187 +/-0.0056 to 0.0543 +/-0.0152 (P<0.05, compared with control), Nv of perforated synapses also increased from 0.0135 +/-0.0053 to 0.0215 +/-0.0076 (P<0.05, compared with control). These data suggest that the increase in thickness of PSD might be the major morphological change during the induction of LTP, while the increase in curvature of the synaptic interface, and the number of perforated synapses might be responsible for the maintenance of the spinal LTP.

Our previous studies have shown that long-term potentiation (LTP) of C-fiber-evoked field potentials in the spinal dorsal horn is NMDA receptor dependent. It is known that elevation of Ca(2+) in the postsynaptic neurons through NMDA receptor channels during high-frequency stimulation of the afferent fibers is crucial for LTP induction, but how this leads to a prolonged potentiation of synaptic transmission in the spinal dorsal horn is not clear. In the hippocampus, a rise of Ca(2+) activates calcium/calmodulin-dependent protein kinase II (CaMK II) through autophosphorylation. Once this occurs, the kinase remains active, even when Ca(2+) concentration returns to baseline level. Phosphorylated CaMK II potentiates synaptic transmission by enhancement of AMPA receptor channel function via phosphorylation of GluR1 subunit of the receptor and the addition of AMPA receptors to synapses. Up to now, the role of CaMK II in the induction and maintenance of LTP of the C-fiber-evoked field potentials in spinal dorsal horn has not been evaluated. In the present study, we examined the expression of CaMK II and phospho-CaMK II in the lumbar segments (L4-L6) of the rat spinal dorsal horn at 30 min and 3 h after the establishment of LTP induced by tetanic electrical stimulation of the sciatic nerve (40 V, 0.5 ms pulses at 100 Hz for 1 s repeated four times at 10 s intervals) by using Western blot and electrophysiological techniques. To determine the role of the phospho-CaMK II in the induction and maintenance of the spinal LTP, a selective CaMK II inhibitor KN-93 (100 micromol/L) was applied directly onto the spinal cord at the recording segments before and after LTP induction. We found that (1) the protein level of phospho-CaMKII increased at both 30 min and 3 h after LTP induction, while the total protein level of CaMK II increased at 3 h but not at 30 min after LTP induction. (2) Spinal application of KN-93 at 30 min prior to the tetanus blocked both LTP induction and the increase in phospho-CaMK II. (3) 30 min after LTP induction, spinal application of KN-93 depressed LTP and the level of phospho-CaMK II (n=3). (4) Spinal application of KN-93 at 3 h after LTP, however, affected neither the amplitude of the spinal LTP nor the level of phospho-CaMK II in the spinal dorsal horn. These results suggest that activation of CaMK II is probably crucial for the induction and the early-phase maintenance of LTP of C-fiber-evoked field potentials in the spinal dorsal horn.