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Abnormal oxidative stress is an established feature of Alzheimer's disease, but clinical trials aiming to reduce oxidative stress have not yet proven an effective therapy for dementia patients. The purpose of this review is to systematically analyze available data describing markers of oxidative stress and antioxidants in blood from subjects with Alzheimer's disease or those with mild cognitive impairment to highlight potential interactions between peripheral redox changes and central nervous system pathology and contribute to the design of future clinical study. PubMed, SCOPUS and Web of Science were systematically queried to collect studies which have evaluated markers of oxidative stress, levels of antioxidants, copper, transferrin and ceruloplasmin levels in blood from subjects with Alzheimer's disease and matched controls. After application of quality measures, results were aggregated in a random effects analysis. We found that markers of lipid peroxidation are elevated in blood in Alzheimer's disease and in mild cognitive impairment, copper metabolism is dysregulated and total antioxidant capacity is decreased. While surprisingly none of the major antioxidative enzymes are significantly decreased, non-enzymatic antioxidants in blood (particularly uric acid, vitamins A, E and C, α- and β-carotene) are significantly decreased. There is significant oxidative damage in peripheral blood early in the process of neurodegeneration. We propose that clinical studies assessing cognitive outcomes after antioxidant therapy tailor interventions to individual patients' deficiencies and confirm an improvement in an appropriate serological marker of oxidative stress. This strategy may be most effectively applied in a clinical trial of primary prevention.

The ever-evolving procedures of the practice of in vitro production (IVP) of embryos has well outpaced the ability of governments and institutions to create standardized rules and regulations around the global trade of these reproductive products. There are several challenges related to identifying and quantifying disease transmission risk in IVP embryos, not the least of which is a lack of published information. The International Embryo Technology Society (IETS) Health and Safety Advisory Committee (HASAC) has identified and addressed several of the challenges related to the potential for disease transmission via IVP embryos. This review will outline the current sanitation practices recommended by the IETS for in vivo derived (IVD) embryos, as well as the current practices at most in vitro fertilization (IVF) labs and will present the case that IVP embryos are not only just as safe as IVD embryos from a disease transmission risk standpoint, but perhaps may even be safer than IVD embryos, as the oocyte, zygote, and embryo in the in vitro production system has no contact with the downstream reproductive anatomy (fimbria, isthmus, oviduct, or uterus) of the donor female., 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 Inc. All rights reserved.)

MicroRNAs (miRNAs) are involved in the regulation of various cellular processes including pathological conditions. MiRNA networks have been extensively researched in age-related degenerative diseases, such as cancer, Alzheimer's disease (AD), and heart failure. Thus, miRNA has been studied from different approaches, in vivo, in vitro, and in silico including miRNA networks. Networks linking diverse biomedical entities unveil information not readily observable by other means. This work focuses on biological networks related to Breast cancer susceptibility 1 (BRCA1) in AD and breast cancer (BC). Using various bioinformatics approaches, we identified subnetworks common to AD and BC that suggest they are linked. According to our results, miR-107 was identified as a potentially good candidate for both AD and BC treatment (targeting BRCA1/2 and PTEN in both diseases), accompanied by miR-146a and miR-17. The analysis also confirmed the involvement of the miR-17-92 cluster, and miR-124-3p, and highlighted the importance of poorly researched miRNAs such as mir-6785 mir-6127, mir-6870, or miR-8485. After filtering the in silico analysis results, we found 49 miRNA molecules that modulate the expression of at least five genes common to both BC and AD. Those 49 miRNAs regulate the expression of 122 genes in AD and 93 genes in BC, from which 26 genes are common genes for AD and BC involved in neuron differentiation and genesis, cell differentiation and migration, regulation of cell cycle, and cancer development. Additionally, the highly enriched pathway was associated with diabetic complications, pointing out possible interplay among molecules underlying BC, AD, and diabetes pathology., 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. Declaration of Competing Interest The authors have no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The strategic goals of the United Nations and the Aichi Targets for biodiversity conservation have not been met. Instead, biodiversity has continued to rapidly decrease, especially in developing countries. Setting a new global biodiversity framework requires clarifying future priorities and strategies to bridge challenges and provide representative solutions. Hyper-arid, arid, and semi-arid lands (herein, arid lands) form about one third of the Earth's terrestrial surface. Arid lands contain unique biological and cultural diversity, and biodiversity loss in arid lands can have a disproportionate impact on these ecosystems due to low redundancy and a high risk of trophic cascades. They contain unique biological and cultural diversity and host many endemic species, including wild relatives of key crop plants. Yet extensive agriculture, unsustainable use, and global climate change are causing an irrecoverable damage to arid lands, with far-reaching consequences to the species, ground-water resources, ecosystem productivity, and ultimately the communities' dependant on these systems. However, adequate research and effective policies to protect arid land biodiversity and sustainability are lacking because a large proportion of arid areas are in developing countries, and the unique diversity in these systems is frequently overlooked. Developing new priorities for global arid lands and mechanisms to prevent unsustainable development must become part of public discourse and form the basis for conservation efforts. The current situation demands the combined efforts of researchers, practitioners, policymakers, and local communities to adopt a socio-ecological approach for achieving sustainable development (SDGs) in arid lands. Applying these initiatives globally is imperative to conserve arid lands biodiversity and the critical ecological services they provide for future generations. This perspective provides a framework for conserving biodiversity in arid lands for all stakeholders that will have a tangible impact on sustainable development, nature, and human well-being., 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.)

The amyloid hypothesis, that established amyloid-β (Aβ) peptide as the primary cause of Alzheimer's disease (AD) and related dementia, has driven the development of treatments for neurodegeneration for 30 years. During the last decades, more than 200 clinical trials testing more than 30 anti-Aβ immunotherapies have been assessed as potential treatments for AD. A vaccine against Aβ was the first immunotherapy intended to avoid aggregation of Aβ into fibrils and senile plaques, but it dramatically failed. Several other vaccines have been proposed as potential AD treatments, targeting different domains or structural motifs of Aβ aggregates, but without clear clinical benefits or effectiveness. In contrast, anti-Aβ therapeutic antibodies have focused on recognizing and removing Aβ aggregates (oligomers, fibrils, or plaques) by eliciting immune clearance. In 2021, the first anti-Aβ antibody, aducanumab (branded as Aduhelm), received FDA approval under an accelerated approval process. The effectiveness and the overall processes regarding the approval of Aduhelm have been under major criticism and scrutiny, prompting a vote of no confidence by public and private health providers, limiting the coverage only to patients enrolled in clinical trials and not for the general elderly patients. Additionally, another three therapeutic anti-Aβ antibodies are following the same path for potential FDA approval. Here, we present the current status of anti-Aβ immunotherapies under evaluation in preclinical and clinical trials for the treatment of AD and related dementia, with a discussion of the main findings and critical lessons learned from the observations from Phase III, II, and I clinical trials of anti-Aβ vaccines and antibodies., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Alzheimer disease (AD) is a chronic disease characterized by a progressive decline in memory and cognition. AD progression is closely correlated with neuropathologic changes and accumulation of the two main hallmark lesions, senile plaques and neurofibrillary tangles. Nevertheless, deciphering the complex biological aspects of AD requires looking for the neuropathologic changes not only as the cause but also as the collective response to a disease process that is essential to maintaining life during aging but ultimately generates a nonfunctional brain. Chronic conditions, such as AD, represent a new homeostatic balance or disease state, where the organism responds or adapts to maintain life. The pathologic diagnosis of AD still remains the gold standard for precise diagnosis of dementia, commonly in conjunction with cognitive-memory tests and brain image scans. Herein, we present a general overview of the main neuropathologic hallmarks and features of AD and related dementia, revealing the key biological and functional changes as potential drivers of age-dependent brain failure related to AD. The present work reflects some of the main ideas presented during the American Society for Investigative Pathology Rous-Whipple Award Lecture 2021., (Copyright © 2022 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) is the leading cause of dementia in the elderly, characterized clinically by progressive decline in cognitive function and neuropathologically by the presence of senile plaques and neuronal loss in the brain. While current drugs for AD are always employed as symptomatic therapies with variable benefits, there is no treatment to delay its progression or halt neurodegeneration. TAR DNA-binding protein 43 (TDP-43) proteinopathy has increasingly been implicated as a prominent histopathological feature of AD and related dementias. Our recent studies have implicated mitochondria as critical targets of TDP-43 neurotoxicity. Here, we demonstrate that the suppression of mitochondrial-associated TDP-43 protects against neuronal loss and behavioral deficits in 5XFAD transgenic mice recapitulating AD-related phenotypes. In AD patients and 5XFAD mice, the level of TDP-43 is increased in mitochondria, and TDP-43 highly co-localizes with mitochondria in brain neurons exhibiting TDP-43 proteinopathy. Chronic administration of a TDP-43 mitochondrial localization inhibitory peptide, PM1, significantly alleviates TDP-43 proteinopathy, mitochondrial abnormalities, microgliosis and even neuronal loss without effect on amyloid plaque load in 12-month-old 5XFAD mice well after the onset of symptoms. Additionally, PM1 also improves the cognitive and motor function in 12-month-old 5XFAD mice and completely prevents the onset of mild cognitive impairment in 6-month-old 5XFAD mice. These data indicate that mitochondria-associated TDP-43 is likely involved in AD pathogenesis and that the inhibitor of mitochondria-associated TDP-43 may be a valuable drug to treat underlying AD., (Published by Elsevier B.V.)

The main difference between the primary structures of human and mouse tau can be found at the N-terminal end of the protein. Residues 17 to 28 in human tau are not present in the mouse form of the molecule. Here we tested the capacity of these human tau residues to bind to specific proteins. Several proteins were observed to bind to these residues. Among those that showed the greatest binding were three related to energetic processes: enolase, glyceraldehyde 3 phosphate dehydrogenase and creatine kinase B. The latter did not bind to tau from brain extracts taken from patients with Alzheimer's disease (AD). This lack of binding could be due to the modification of CKB by oxidation in AD., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The roles of post-translational modifications (PTMs) in the onset and progression of disease have been extensively studied for decades. More specifically, various PTMs have been the focus of research in Alzheimer's disease (AD). The two most discussed hallmarks of the disease, senile plaques and tau tangles, are the result of PTMs of the amyloidβ protein precursor (AβPP) and the microtubule stabilizing protein: tau. While these modifications have been characterized indirectly by biochemical-based methods, the primary shortcoming to this research can be linked to a lack of a thorough molecular-based means of qualitative and quantitative analysis of many of these modifications within transgenic animal, and human samples. In this review, we discuss the important proteins and their associated PTMs linked to AD and the ways in which mass spectrometry has and will be utilized to analyze them. We also comment on novel ways in which molecular-based mass spectrometry methods should be employed going forward to resolve the interconnections of the PTMs involvement in various stages of AD pathology (preclinical, mild cognitive impairment, advanced-stage AD)., (Copyright © 2018. Published by Elsevier B.V.)

Uncover the initial cause(s) underlying Alzheimer's disease (AD) pathology is imperative for the development of new therapeutic interventions to counteract AD-related symptomatology and neuropathology in a timely manner. The early stages of AD are characterized by a brain hypometabolic state as denoted by faulty glucose uptake and utilization and abnormal mitochondrial function and distribution which, ultimately, culminates in synaptic "starvation" and neuronal degeneration. Importantly, it was recently recognized that the post-translational modification β-N-acetylglucosamine (O-GlcNAc) modulates mitochondrial function, motility and distribution being proposed to act as a nutrient sensor that links glucose and the metabolic status to neuronal function. Using post-mortem human brain tissue, brain samples from the triple transgenic mouse model of AD (3xTg-AD) and in vitro models of AD (differentiated SH-SY5Y cells exposed to AD-mimicking conditions), the present study is aimed to clarify whether O-GlcNAcylation, the posttranslational modification of intracellular proteins by O-GlcNAc, contributes to "mitochondrial pathology" in AD and its potential as a therapeutic target. A reduction in global O-GlcNAcylation levels was observed in the brain cortex and hippocampus of AD subjects. Moreover, GlcNAcylation levels are higher in mature mice but the levels of this posttranslational modification are lower in 3xTg-AD mice when compared to control mice. The in vitro models of AD also exhibited a marked reduction in global O-GlcNAcylation levels, which was strongly correlated with hampered mitochondrial bioenergetic function, disruption of the mitochondrial network and loss of cell viability. Conversely, the pharmacological modulation of O-GlcNAcylation levels with Thiamet-G restored O-GlcNAcylation levels and cell viability in the in vitro models of AD. Overall, these results suggest that O-GlcNAcylation is involved in AD pathology functioning as a potential link between mitochondrial energetic crisis and synaptic and neuronal degeneration. This posttranslational modification represents a promising therapeutic target to tackle this devastating neurodegenerative disease., (Copyright © 2018 Elsevier B.V. All rights reserved.)

For its fundamental relevance, transport of water and glycerol across the erythrocyte membrane has long been investigated before and after the discovery of aquaporins (AQPs), the membrane proteins responsible for water and glycerol transport. AQP1 is abundantly expressed in the human erythrocyte for maintaining its hydrohomeostasis where AQP3 is also expressed (at a level ~30-folds lower than AQP1) facilitating glycerol transport. This research is focused on two of the remaining questions: How permeable is AQP3 to water? What is the glycerol-AQP3 affinity under near-physiological conditions? Through atomistic modelling and large-scale simulations, we found that AQP3 is two to three times more permeable to water than AQP1 and that the glycerol-AQP3 affinity is approximately 500/M. Using these computed values along with the data from the latest literature on AQP1 and on erythrocyte proteomics, we estimated the water and glycerol transport rates across the membrane of an entire erythrocyte. We used these rates to predict the time courses of erythrocyte swelling-shrinking in response to inward and outward osmotic gradients. Experimentally, we monitored the time course of human erythrocytes when subject to an osmotic or glycerol gradient with light scattering in a stopped-flow spectrometer. We observed close agreement between the experimentally measured and the computationally predicted time courses of erythrocytes, which corroborated our computational conclusions on the AQP3 water-permeability and the glycerol-AQP3 affinity., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Neonatal dried blood spots (DBS) are routinely utilized in the clinical setting as a diagnostic tool for various genetic disorders and infectious diseases. DBS allow for minimally invasive, small volume blood collection and are stored at room temperature. Neonatal whole blood and serum samples can be important in determining genetic risk factors and predicting infantile disease; however, at the present time, limited methods exist for rapidly analyzing DBS samples for their proteomic profile, years after samples have been collected. A novel method is presented for the extraction and analysis of target proteins and peptides from neonatal DBS using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Extraction parameters were optimized to achieve ideal signal intensity and resolution to obtain protein identifications. Samples were extracted from filter paper with 0.1% TFA in H 2 O for 72 h. The extract was subjected to enzymatic digestion, spotted on an ITO-coated glass slide, and washed in order to remove salts. Analysis of extracted blood spots from ten newborns was completed. Similarities and differences in the proteomic profile of the washed extracts are presented, herein, to verify the viability of this method for analysis of dated DBS samples. This method allows for analysis of DBS samples years after collection and can be utilized to correlate diseases or disorders manifesting later in life with potential risk factors presenting in the proteomic profile of the DBS collected at time of birth., (© 2019 Published by Elsevier B.V. on behalf of The Association for Mass Spectrometry: Applications to the Clinical Lab (MSACL).)

The complex multifactorial nature of polygenic Alzheimer's disease (AD) presents significant challenges for drug development. AD pathophysiology is progressing in a non-linear dynamic fashion across multiple systems levels - from molecules to organ systems - and through adaptation, to compensation, and decompensation to systems failure. Adaptation and compensation maintain homeostasis: a dynamic equilibrium resulting from the dynamic non-linear interaction between genome, epigenome, and environment. An individual vulnerability to stressors exists on the basis of individual triggers, drivers, and thresholds accounting for the initiation and failure of adaptive and compensatory responses. Consequently, the distinct pattern of AD pathophysiology in space and time must be investigated on the basis of the individual biological makeup. This requires the implementation of systems biology and neurophysiology to facilitate Precision Medicine (PM) and Precision Pharmacology (PP). The regulation of several processes at multiple levels of complexity from gene expression to cellular cycle to tissue repair and system-wide network activation has different time delays (temporal scale) according to the affected systems (spatial scale). The initial failure might originate and occur at every level potentially affecting the whole dynamic interrelated systems within an organism. Unraveling the spatial and temporal dynamics of non-linear pathophysiological mechanisms across the continuum of hierarchical self-organized systems levels and from systems homeostasis to systems failure is key to understand AD. Measuring and, possibly, controlling space- and time-scaled adaptive and compensatory responses occurring during AD will represent a crucial step to achieve the capacity to substantially modify the disease course and progression at the best suitable timepoints, thus counteracting disrupting critical pathophysiological inputs. This approach will provide the conceptual basis for effective disease-modifying pathway-based targeted therapies. PP is based on an exploratory and integrative strategy to complex diseases such as brain proteinopathies including AD, aimed at identifying simultaneous aberrant molecular pathways and predicting their temporal impact on the systems levels. The depiction of pathway-based molecular signatures of complex diseases contributes to the accurate and mechanistic stratification of distinct subcohorts of individuals at the earliest compensatory stage when treatment intervention may reverse, stop, or delay the disease. In addition, individualized drug selection may optimize treatment safety by decreasing risk and amplitude of side effects and adverse reactions. From a methodological point of view, comprehensive "omics"-based biomarkers will guide the exploration of spatio-temporal systems-wide morpho-functional shifts along the continuum of AD pathophysiology, from adaptation to irreversible failure. The Alzheimer Precision Medicine Initiative (APMI) and the APMI cohort program (APMI-CP) have commenced to facilitate a paradigm shift towards effective drug discovery and development in AD., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Glucose transporters (GLUTs), expressed in all types of human cells, are responsible for the uptake of sugars as the primary energy source for the normal functions of good cells and for the abnormal growth of cancer cells. The E. coli xylose permease (XylE), a homologue of human GLUTs, has been investigated more thoroughly than other major facilitator proteins in the current literature. In this paper, we present a molecular dynamics (MD) study of an all-atom model system to elucidate the atomistic details and the free-energy landscape along the path of binding a xylopyranose (XYP) from the extracellular space to the inside of the transporter protein XylE. From the MD simulations, the Gibbs free energy of binding was found to be -4.4kcal/mol in agreement with the experimental value of -4.7kcal/mol. The accuracy of our study is further shown in the computed hydration energy of XYP of -14.6kcal/mol in comparison with the experimental data of -15.0kcal/mol. Along the binding path, the Gibbs free energy of the XYP-XylE complex first rises from zero in the dissociated state to approximately 4 kcal/mol in the transition state (when XylE slightly increases its opening toward the extracellular side to accommodate XYP) before dropping down to -9.0 kcal/mol in the bound state. These quantitative insights indicate the fast equilibration between the bound and the unbound states of XylE and XYP. They also serve as an atomistic-dynamic corroboration of the experimental conclusion that XylE is a high-affinity sugar transporter., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Amyloid-beta (Aβ) peptides, Aβ40 and the more neurotoxic Aβ42, have been the subject of many research efforts for Alzheimer's disease. In two recent independent investigations, the atomistic structure of Aβ42 fibril has been clearly established in the S-shaped conformation consisting of three β-sheets stabilized by salt bridges formed between the Lys28 sidechain and the C-terminus of Ala42. This structure distinctively differs from the long-known structure of Aβ40 in the β-hairpin shaped conformation consisting of two β-sheets. Recent in silico investigations based on all-atom models have reached closer agreement with the in vitro measurements of Aβ40 thermodynamics. In this study, we present an in silico investigation of Aβ42 thermodynamics. Using the established force field parameters in seven sets of all-atom simulations, we examined the stability of small Aβ42 oligomers in physiological saline. We computed the elongation affinity of the S-shaped Aβ42 fibril, reaching agreement with the experimental data. We also estimated the Arrhenius activation barrier along the elongation pathway (from the disordered conformation of a free Aβ42 peptide to its S-shaped conformation on a fibril) that amounts to about 16 kcal/mol, which is consistent with the experimental data. Based on these quantitative agreements, we conclude that aggregation of Aβ42 peptides into fibrils is thermodynamically slow without precipitation by extrinsic factors such as heparan sulfate proteoglycan and highlight the possibility to prevent Aβ42 aggregation by eliminating some precipitation factors or by increasing competitive agents to capture and transport free Aβ42 peptides from the cerebrospinal fluid., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Millions of urban children are chronically exposed to high concentrations of air pollutants, i.e., fine particulate matter (PM2.5) and ozone, associated with increased risk for Alzheimer's disease. Compared with children living with clear air those in Mexico City (MC) exhibit systemic, brain and intrathecal inflammation, low CSF Aβ42, breakdown of the BBB, attention and short-term memory deficits, prefrontal white matter hyperintensities, damage to epithelial and endothelial barriers, tight junction and neural autoantibodies, and Alzheimer and Parkinson's hallmarks. The prefrontal white matter is a target of air pollution. We examined by light and electron microscopy the prefrontal white matter of MC dogs (n: 15, age 3.17±0.74 years), children and teens (n: 34, age: 12.64±4.2 years) versus controls. Major findings in MC residents included leaking capillaries and small arterioles with extravascular lipids and erythrocytes, lipofuscin in pericytes, smooth muscle and endothelial cells (EC), thickening of cerebrovascular basement membranes with small deposits of amyloid, patchy absence of the perivascular glial sheet, enlarged Virchow-Robin spaces and nanosize particles (20-48nm) in EC, basement membranes, axons and dendrites. Tight junctions, a key component of the neurovascular unit (NVU) were abnormal in MC versus control dogs (χ(2)<0.0001), and white matter perivascular damage was significantly worse in MC dogs (p=0.002). The integrity of the NVU, an interactive network of vascular, glial and neuronal cells is compromised in MC young residents. Characterizing the early NVU damage and identifying biomarkers of neurovascular dysfunction may provide a fresh insight into Alzheimer pathogenesis and open opportunities for pediatric neuroprotection., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Millions of Mexico, US and across the world children are overweight and obese. Exposure to fossil-fuel combustion sources increases the risk for obesity and diabetes, while long-term exposure to fine particulate matter (PM2.5) and ozone (O3) above US EPA standards is associated with increased risk of Alzheimer's disease (AD). Mexico City Metropolitan Area children are chronically exposed to PM2.5 and O3 concentrations above the standards and exhibit systemic, brain and intrathecal inflammation, cognitive deficits, and Alzheimer disease neuropathology. We investigated adipokines, food reward hormones, endothelial dysfunction, vitamin D and apolipoprotein E (APOE) relationships in 80 healthy, normal weight 11.1±3.2 year olds matched by age, gender, BMI and SES, low (n: 26) versus high (n:54) PM2.5 exposures. Mexico City children had higher leptin and endothelin-1 (p<0.01 and p<0.000), and decreases in glucagon-like peptide-1 (GLP 1), ghrelin, and glucagon (<0.02) versus controls. BMI and leptin relationships were significantly different in low versus high PM2.5 exposed children. Mexico City APOE 4 versus 3 children had higher glucose (p=0.009). Serum 25-hydroxyvitamin D<30 ng/mL was documented in 87% of Mexico City children. Leptin is strongly positively associated to PM 2.5 cumulative exposures. Residing in a high PM2.5 and O3 environment is associated with 12h fasting hyperleptinemia, altered appetite-regulating peptides, vitamin D deficiency, and increases in ET-1 in clinically healthy children. These changes could signal the future trajectory of urban children towards the development of insulin resistance, obesity, type II diabetes, premature cardiovascular disease, addiction-like behavior, cognitive impairment and Alzheimer's disease. Increased efforts should be made to decrease pediatric PM2.5 exposures, to deliver health interventions prior to the development of obesity and to identify and mitigate environmental factors influencing obesity and Alzheimer disease., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The human pathogen Chlamydia pneumoniae has been implicated in chronic inflammatory diseases including type 2 diabetes. Therefore, we designed a study to evaluate pancreatic beta cells and mast cells during chlamydial infection. Our study revealed that C. pneumoniae infected mast cells significantly (p<0.005) decreased beta cell ATP and insulin production, in contrast to uninfected mast cells co-cultured with beta cells. Infected mast cells exhibited pyknotic nuclei and active caspase-3 and caspase-1 expression. Additionally, ex vivo analyses of tissues collected from C. pneumoniae infected mice showed increased interleukin-1β production in splenocytes and pancreatic tissues as was observed with in vitro mast cell-beta cell co-cultures during C. pneumoniae infection. Notably, infected mast cells promoted beta cell destruction. Our findings reveal the negative effect of C. pneumoniae on mast cells, and the consequential impact on pancreatic beta cell function and viability., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) is a progressive, neurodegenerative brain disorder characterized by extracellular accumulations of amyloid β (Aβ) peptides, intracellular accumulation of abnormal proteins, and early loss of basal forebrain neurons. Recent studies have indicated that the conformation of Aβ is crucial for neuronal toxicity, with intermediate misfolded forms such as oligomers being more toxic than the final fibrillar forms. Our previous work shows that Aβ blocks the potassium (K(+)) currents IM and IA in septal neurons, increasing firing rates, diminishing rhythmicity and firing coherence. Evidence also suggests that oxidative stress (OS) plays a role in AD pathogenesis. Thus we wished to determine the effect of oligomeric and fibrillar forms of Aβ₁₋₄₂ on septohippocampal damage, oxidative damage, and dysfunction in AD. Oligomeric and fibrillar forms of Aβ₁₋₄₂ were injected into the CA1 region of the hippocampus in live rats. The rats were sacrificed 24 hours and 1 month after Aβ or sham injection to additionally evaluate the temporal effects. The expression levels of the K(+) voltage-gated channel, KQT-like subfamily, member 2 (KCNQ₂) and the OS-related genes superoxide dismutase 1, 8-oxoguanine DNA glycosylase, and monamine oxidase A, were analyzed in the hippocampus, medial, and lateral septum. Our results show that both forms of Aβ exhibit time-dependent differential modulation of OS and K(+) channel genes in the analyzed regions. Importantly, we demonstrate that Aβ injected into the hippocampus triggered changes in gene expression in anatomical regions distant from the injection site. Thus the Aβ effect was transmitted to anatomically separate sites, because of the functional coupling of the brain structures., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Although the pathogenesis of sporadic Alzheimer disease (AD) is not clearly understood, it is likely dependent on several age-related factors. Diabetes is a risk factor for AD, and multiple mechanisms connecting the 2 diseases have been proposed. Hyperglycemia enhances the formation of advanced glycation end products (AGEs) that result from the auto-oxidation of glucose and fructose. The interaction of AGEs with their receptor, named RAGE, elicits the formation of reactive oxygen species that are also believed to be an early event in AD pathology. To investigate a functional link between the disorders diabetes and AD, the effect of 2 AGEs, pentosidine and glyceraldehydes-derived pyridinium (GLAP), was studied on BACE1 expression both in vivo, in streptozotocin treated rats, and in vitro in differentiated neuroblastoma cells. We showed that pentosidine and GLAP were able to upregulate BACE1 expression through their binding with RAGE and the consequent activation of NF-κB. In addition, both pentosidine and GLAP were found to be increased in the brain in sporadic AD patients. Our findings demonstrate that activation of the AGEs/RAGE axis, by upregulating the key enzyme for amyloid-β production, provides a pathologic link between diabetes mellitus and AD., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Introduction: Intracanal disinfection is a crucial step in regenerative endodontic procedures. However, this novel endodontic treatment lacks standardization, and numerous treatment protocols have been reported without knowledge of the effect of disinfection protocols on the survival of stem cells. The aim of this study was to test the hypothesis that different root canal irrigation protocols alter survival of stem cells from the apical papilla (SCAP)., Methods: SCAP were isolated from immature human third molars, and a subpopulation of STRO-1 expressing cells was selected and expanded in vitro. Standardized human root segments (n = 5/group) were irrigated with 1 of 4 protocols: (1) 17% ethylenediaminetetraacetic acid (EDTA), (2) 6% NaOCl/17% EDTA/6% NaOCl, (3) 17% EDTA/2% chlorhexidine (CHX), or (4) 6% NaOCl/17% EDTA/6% NaOCl/isopropyl alcohol/2% CHX. Subsequently, STRO-1-enriched SCAP were mixed with platelet-rich-plasma, seeded into the root tips, and cultured for 21 days. Roots were then decalcified, processed for immunohistochemistry, and stained for vimentin and TO-PRO-3. The proportion of viable (vimentin-positive) cells was calculated on the basis of the total cell counts (TO-PRO-3) for each group., Results: Irrigation with 17% EDTA best supported cell survival (89% viability; P < .001 versus all other groups), followed by irrigation with 6% NaOCl/17% EDTA/6% NaOCl (74%; P < .001 versus the 2 groups containing 2% CHX). Conversely, protocols that included 2% CHX lacked any viable cells., Conclusions: Collectively, the results suggest that irrigants alone greatly affect the survivability of STRO-1-enriched SCAP within the root canal environment and that inclusion of EDTA in irrigation protocols might be beneficial in regenerative procedures., (Published by Elsevier Inc.)

Immunophilins are receptors for immunosuppressive drugs such as the macrolides cyclosporin A (CsA) and FK506; correspondingly these immunophilins are referred to as cyclophilins and FK506-binding proteins (FKBPs). In particular, CsA targets cyclophilin D (CypD), which can modulate mitochondrial Ca(2+) dynamics. Since mitochondria have been implicated in the regulation of astrocytic cytosolic Ca(2+) (Ca(cyt)(2+)) dynamics and consequential Ca(2+)-dependent exocytotic release of glutamate, we investigated the role of CypD in this process. Cortical astrocytes isolated from CypD deficient mice Ppif(-/-) displayed reduced mechanically induced Ca(cyt)(2+) increases, even though these cells showed augmented exocytotic release of glutamate, when compared to responses obtained from astrocytes isolated from wild-type mice. Furthermore, acute treatment with CsA to inhibit CypD modulation of mitochondrial Ca(2+) buffering, or with FK506 to inhibit FKBP12 interaction with inositol-trisphosphate receptor of the endoplasmic reticulum, led to similar reductive effects on astrocytic Ca(cyt)(2+) dynamics, but also to an enhanced Ca(2+)-dependent exocytotic release of glutamate in wild-type astrocytes. These findings point to a possible role of immunophilin signal transduction pathways in astrocytic modulation of neuronal activity at the tripartite synapse., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Traditional and molecular methods (PCR) were used to detect, quantify and identify the source of fecal pollution in coastal sites of Puerto Rico and Trinidad. Enterococci and Escherichia coli standard plate counts were used as a general indicator of fecal contamination while the PCR detection of Bifidobacteria adolescentis and human or bovine specific Bacteroidales were used to examine potential sources. Seven of 14 sites in Trinidad including Maracas Bay which is a major public beach contained significant fecal contamination based on enterococci numbers counts exceeding established thresholds for areas of direct contact. Forty six percent of the 27 stations in Puerto Rico were over the established thresholds for enterococci and 49% according to E. coli counts. About 31% of the stations examined in Puerto Rico had evidence of human derived fecal contamination. Human fecal pollution was detected in only one station from Trinidad. Bovine derived contamination was detected only once., (Published by Elsevier Ltd.)

There is considerable interest in the role of metals such as iron, copper, and zinc in amyloid plaque formation in Alzheimer's disease. However to convincingly establish their presence in plaques in vivo, a sensitive technique is required that is both quantitatively accurate and avoids isolation of plaques or staining/fixing brain tissue, since these processes introduce contaminants and redistribute elements within the tissue. Combining the three ion beam techniques of scanning transmission ion microscopy, Rutherford back scattering spectrometry and particle induced X-ray emission in conjunction with a high energy (MeV) proton microprobe we have imaged plaques in freeze-dried unstained brain sections from CRND-8 mice, and simultaneously quantified iron, copper, and zinc. Our results show increased metal concentrations within the amyloid plaques compared with the surrounding tissue: iron (85 ppm compared with 42 ppm), copper (16 ppm compared to 6 ppm), and zinc (87 ppm compared to 34 ppm).

Many different proteins associated with the cell cycle, including cyclins, cyclin-dependent kinases, and proto-oncogenes such as c-MYC (MYC), are increased in degenerating neurons. Consequently, an ectopic activation of the cell cycle machinery in neurons has emerged as a potential pathogenic mechanism of neuronal dysfunction and death in many neurodegenerative diseases, including Alzheimer's disease. However, the exact role of cell cycle re-entry during disease pathogenesis is unclear, primarily because of the lack of relevant research models to study the effects of cell cycle re-entry on mature neurons in vivo. To address this issue, we developed a new transgenic mouse model in which forebrain neurons (CaMKII-MYC) can be induced to enter the cell cycle using the physiologically relevant proto-oncogene MYC to drive cell cycle re-entry. We show that such cell cycle re-entry results in neuronal cell death, gliosis, and cognitive deficits. These findings provide compelling evidence that dysregulation of cell cycle re-entry results in neurodegeneration in vivo. Our current findings, coupled with those of previous reports, strengthen the hypothesis that neurodegeneration in Alzheimer's disease, similar to cellular proliferation in cancer, is a disease that results from inappropriate cell cycle control.

Oxidative stress is known to play a key role in the initiation and promotion of the neurodegeneration that characterizes the pathogenesis of Alzheimer disease (AD). An accumulation of redox active transition metals, including iron and copper, is likely a major generator of reactive oxidative species and other free radicals and is thought to induce a detrimental cycle of oxidative stress, amyloid-beta aggregation, and neurodegeneration. As such, metal chelators may provide an alternative therapeutic approach to sequester redox active metals and prevent the onslaught of oxidative damage. Unfortunately, however, metal chelation approaches are currently limited in their potential, since many cannot readily pass the blood-brain barrier (BBB), due to their hydrophilicity, and many are neurotoxic at high concentrations. To circumvent such issues, here we describe the development of iron chelator-nanoparticle conjugation that allows delivery of target chelator to the brain in the absence of neurotoxicity. Such nanoparticle delivery of iron chelators will likely provide a highly advantageous mode of attack on the oxidative stress that plagues AD as well as other conditions characterized by excess metal accumulation., (Copyright 2009 Elsevier B.V. All rights reserved.)

Alzheimer disease and cerebrovascular dementia are two common causes of dementia and, by present diagnostic criteria, are mutually exclusive using vascular pathology as an arbitrary demarcation in differential diagnosis. However, evidence from epidemiological, neuropathological, clinical, pharmacological, and functional studies suggest considerable overlap in risk factors and pathological changes suggesting shared common pathogenic mechanisms between these two diseases such that vascular factors play a vital role in the pathogenesis of Alzheimer disease. A high energy demand and lack of an endogenous fuel reserve make the brain highly dependent upon a continuous blood supply where disruption of cerebral blood vessels and blood flow can have serious consequences on neural activities. Indeed, many studies implicate metabolic defects in Alzheimer disease, such a reduced brain metabolism is one of the best documented abnormalities in the disease. Notably, since endothelial reactive oxygen species such as nitric oxide act as vasodilators at low concentrations, increased production coupled with elevated reactive oxygen species scavenging of nitric oxide, can lead to reduced bioavailability of nitric oxide and increased oxidative stress that damage sensitive vascular cells. In this respect, we and others have demonstrated that oxidative stress is one of the earliest pathological changes in the brain of Alzheimer disease patients and plays a critical role in the vascular abnormalities underlying metabolic defects in Alzheimer disease. Here, we discuss vascular factors in relation to Alzheimer disease and review hypoperfusion as a potential cause by triggering mitochondrial dysfunction and increased oxidative stress initiating the pathogenic process.

Chronic renal disease is characterized by declining renal function, loss of intrinsic renal cells, and their replacement with fibrotic tissue. This study investigates apoptosis and its regulation in the context of chronic renal disease. RNA was extracted from renal biopsies from patients with various forms of chronic renal disease. Expression of genes of the Bcl-2 family, death receptor pathway, and growth factors were measured by reverse-transcription real-time polymerase chain reaction. Apoptosis was detected by the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling technique. Tubulointerstitial apoptosis was positively associated with tubulointerstitial injury and renal dysfunction and increased 2.3-fold per unit (U) increase in transforming growth factor beta(1) (TGFbeta(1)) mRNA (P<0.05). Conversely, a 1 U increase in epidermal growth factor (EGF) mRNA was associated with a 47% decrease in tubulointerstitial apoptosis (P<0.05). Tubulointerstitial injury was correlated with increased TGFbeta(1) and tumour necrosis factor alpha (TNFalpha) mRNA (P<0.005) and decreased EGF mRNA (P<0.05). Additionally, for a 10 U decrease in the glomerular filtration rate there was an estimated increase of 5 and 10% in TGFbeta(1) and TNFalpha mRNA, respectively (P<0.05), whereas EGF mRNA decreased by an estimated 15% (P<0.005). Therefore dysregulation of cytokine/growth factor expression plays a central role in the progression of chronic renal disease through contribution to renal cell loss, tubulointerstitial injury, and renal dysfunction.

Clusterin/apolipoprotein J is a multifunctional protein up-regulated during various pathophysiological states. Since oxidative stress plays an important role in brain aging, and in many neurodegenerative disorders, to further understand the mechanistic underpinnings of clusterin expression, in this study, we examined clusterin expression in human neuroblastoma cells under conditions of increased production of reactive oxygen species and lipid peroxidation. Specifically, we analyzed clusterin mRNA and protein levels in human neuroblastoma IMR-32 and SH-SY5Y cells following exposure to sub-lethal amounts of iron-ascorbate to induce an increase in reactive oxygen species generation and lipid peroxidation. Under such conditions, we observed a time-dependent up-regulation of clusterin protein and mRNA levels, detected by immunoblot analysis and RT-PCR, respectively. Given the known roles of clusterin, the results of the present study support the notion that an increase in clusterin expression may be a physiological defence mounted to reduce cell damage and maintain cell viability during periods of increased oxidative stress.

The pathogenesis, which is primarily responsible for Alzheimer's disease (AD) and cerebrovascular accidents (CVA), seems to involve chronic hypoperfusion. The role of hypoperfusion, as a key factor for vascular lesions that causes oxidative stress, appears to be widely accepted as an initiator of AD. Specifically, accumulated oxidative stress increases vascular endothelial permeability and promotes leukocyte adhesions, which is coupled with alterations in endothelial signal transduction and redox-regulated transcription factors. Based on these recent findings, we hypothesize that the cellular and molecular mechanisms by which hypoperfusion-induced reactive oxygen species (ROS) accumulation impairs endothelial barrier function and promotes leukocyte adhesion induces alterations in normal vascular function and results in the development of AD. We are theorizing that mitochondria play a key role in the generation of ROS, resulting in oxidative damage to neuronal cell bodies, as well as other cellular compartment in the AD brain. All of these changes have been found to accompany AD pathology. We have studied the ultrastructural features of vascular lesions and mitochondria in brain vascular wall cells from human AD, yeast artificial chromosome (YAC) and C57B6/SJL transgenic positive (Tg+) mice overexpressing amyloid beta precursor protein (AbetaPP). In situ hybridization using mitochondrial DNA (mtDNA) probes for human wild and 5 kb deleted types and mouse types was performed along with immunocytochemistry using antibodies against amyloid precursor protein (APP), 8-hydroxy-2'-guanosine (8-OHG) and cytochrome c oxidase (COX). There was a higher degree of amyloid deposition, overexpression of oxidative stress markers, mitochondria DNA deletion and mitochondrial structural abnormality in the vascular walls of the human AD, YAC and C57B6/SJL Tg (+) mice compared to age-matched controls. Therefore, selective pharmacological intervention, directed for abolishing the chronic hypoperfusion state, would possibly change the natural course of development of dementing neurodegeneration.

Conversion of the cellular prion protein (PrP(C)) into its pathological isoform (PrP(Sc)), the key molecular event in the pathogenesis of prion diseases, is accompanied by a conformational transition of alpha-helix into beta-sheet structures involving alpha-helix 1 (alpha1) domain from residues 144 to 154 of the protein. Reduction and alkylation of PrP(C) have been found to inhibit the conversion of PrP(C) into PrP(Sc) in vitro. Here we report that while antibody affinity of epitopes in the N- and C-terminal domains remained unchanged, reduction and alkylation of the PrP molecule induced complete concealment of an epitope in alpha1 for anti-PrP antibody 6H4 that is able to cure prion infection in the cell model. Mass spectrometric analysis of recombinant PrP showed that the alkylation reaction takes place at reduced cysteines but no modification was observed in this cryptic epitope. Our study suggests that reduction and alkylation result in local or global rearrangement of PrP tertiary structure that is maintained in both liquid and solid phases. The implications in the conversion of PrP(C) into PrP(Sc) and the therapeutics of prion diseases are discussed.