PFAS soil concentrations surrounding a hazardous waste incinerator in East Liverpool, Ohio, an environmental justice community.

Per- and polyfluoroalkyl substances (PFAS) are a class of synthetic compounds widely used in industrial and consumer products. While PFAS provide product durability, these chemicals are ubiquitous, persistent, bioaccumulative, and toxic. These characteristics make the ultimate disposal of PFAS a challenge.

Direct injection analysis of per and polyfluoroalkyl substances in surface and drinking water by sample filtration and liquid chromatography-tandem mass spectrometry.

We developed and validated a method for direct determination of per- and polyfluoroalkylated substances (PFASs) in environmental water samples without prior sample concentration. Samples are centrifuged and supernatants passed through an Acrodisc Filter (GXF/GHP 0.2  um, 25  mm diameter).

Upregulation of PSMB8 and cathepsins in the human brains of dementia with Lewy bodies.

Proteasome and lysosome are responsible for the homeostasis of proteins, lipids and carbohydrates in cells. Numerous reports indicate the proteolytic pathways have altered functions during neurodegeneration and aging. Dementia with Lewy bodies (DLB) is one of the leading forms of dementia, and the proteolytic alteration in DLB has not yet been fully investigated.

Lower expression level of two RAGE alternative splicing isoforms in Alzheimer's disease.

Alternative splicing (AS) is a common phenomenon in gene expression of eukaryotic organisms, especially in mammals, producing multiple gene isoforms from a single gene that involve in physiological and pathological processes. Receptor for advanced glycation end products (RAGE) has multiple AS isoforms with significant tissue and organism specificity. RAGE signaling has been reported involved in the onset and development of Alzheimer's disease (AD) and the roles of RAGE AS isoforms have not yet been fully illustrated in AD pathogenesis.

Increased 5S rRNA oxidation in Alzheimer's disease.

It is widely accepted that oxidative stress is involved in neurodegenerative disorders such as Alzheimer's disease (AD). Ribosomal RNA (rRNA) is one of the most abundant molecules in most cells and is affected by oxidative stress in the human brain. Previous data have indicated that total rRNA levels were decreased in the brains of subjects with AD and mild cognitive impairment concomitant with an increase in rRNA oxidation.

Clioquinol and other hydroxyquinoline derivatives inhibit Abeta(1-42) oligomer assembly.

Soluble oligomeric amyloid-beta (Abeta) species are toxic to many cell types and are a putative etiological factor in Alzheimer's disease. The NINDS-Custom Collection of 1040 drugs and biologically active compounds was robotically screened for inhibitors of Abeta oligomer formation with a single-site biotinylated Abeta(1-42) oligomer assembly assay. Several quinoline-like compounds were identified with IC(50)'s <10 microM, including the antiprotozoal clioquinol that has been reported to have effects on metal ion metabolism.

Cell-specific actions of HIV-Tat and morphine on opioid receptor expression in glia.

HIV-1 patients who abuse opiate-based drugs, including heroin and morphine, are at a higher risk of developing HIV dementia. The effects of opiates are mediated predominantly through opioid receptors, which are expressed on glial cells. As HIV-1 infection in the CNS is restricted to glial cells, experiments were designed to measure the cell-specific effects of HIV Tat and morphine exposure on opioid receptor expression in both astrocytes and microglia.

Oxidative stress alters neuronal RNA- and protein-synthesis: Implications for neural viability.

Recent studies have demonstrated that impaired protein synthesis occurs in several neurodegenerative conditions associated with oxidative stress. Studies have also demonstrated that administration of oxidative stressors is sufficient to impair different and discrete regulatory aspects of protein synthesis in neural cells, with the majority of these studies focused on the effects of oxidative stressors towards initiation factors. Currently, little is known with regards to oxidative stress effects on the rates of RNA- and protein-synthesis, or the relationship between oxidant-induced impairments in RNA-/protein-synthesis to subsequent neuron death.

Abeta solubility and deposition during AD progression and in APPxPS-1 knock-in mice.

Amnestic mild cognitive impairment (MCI) appears to be a very early stage of Alzheimer's disease (AD). The amyloid-beta peptide (Abeta) is believed to be a possible substrate for AD, but little is currently known about Abeta alterations in MCI and how these changes compare to later stages of disease. In the present study Abeta was differentially extracted from the brains of age-matched control, MCI, and AD cases and compared with plaque counts.

Oxidative inactivation of the proteasome in Alzheimer's disease.

In the present study we isolated proteasome complexes from control, mild cognitive impairment (MCI), and Alzheimer's disease (AD) subjects. No significant difference in the amount of proteasomes was detected across the different groups, although impairments in chymotrypsin-like proteasome activity was observed in AD subjects. Large impairments in proteasome- mediated degradation of an oxidized protein substrate was observed in MCI and AD subjects.

Oxidative damage, protein synthesis, and protein degradation in Alzheimer's disease.

A large number of studies has firmly established that increases in oxidative damage occurs in Alzheimer's disease (AD). Such studies have demonstrated that increased in oxidative damage selectively occurs within the brain regions involved in regulating cognitive performance. Studies from our laboratory and others have provided experimental evidence that increased levels of oxidative damage occur in subjects with Mild Cognitive Impairment (MCI), which is believed to be one of the earliest stages of AD, and is a condition which is devoid of dementia or the extensive neurofibrillary pathology and neuritic plaque deposition observed in AD.

Interplay between protein synthesis and degradation in the CNS: physiological and pathological implications.

Compromise of the ubiquitin-proteasome system (UPS) is a potential basis for multiple physiological abnormalities and pathologies in the CNS. This could be because reduced protein turnover leads to bulk intracellular protein accumulation. However, conditions associated with compromised UPS function are also associated with impairments in protein synthesis, and impairment of UPS function is sufficient to inhibit protein synthesis.

Age-related alterations of Apolipoprotein E and interleukin-1beta in the aging brain.

With normal aging, the brain undergoes several alterations including reduced neuronal functioning and alterations in glia homeostasis. An increase in inflammatory signaling has also been reported in some studies of the aging brain, with inflammation potentially mediating age-related changes in the brain. Apolipoprotein E (ApoE) is produced in the brain and has been shown to possess anti-inflammatory properties in a variety of paradigms.

Decreased RNA, and increased RNA oxidation, in ribosomes from early Alzheimer's disease.

All cells rely on efficient protein synthesis in order to maintain cellular homeostasis. Recent studies from our laboratory indicate that declines in protein synthesis and ribosome function occur in the earliest stage of Alzheimer's disease (AD). Additional studies indicate a potential role for ribosomal RNA oxidation as a potential mediator of decreased protein synthesis in AD.

Proteasome inhibition induces reversible impairments in protein synthesis.

Proteasome inhibition occurs during normal aging and in a variety of age-related diseases, with inhibition of proteasome function sufficient to induce physiological and pathological alterations observed in each of these conditions. It is presumed that proteasome inhibition induces cellular alterations by promoting rapid protein accumulation, as the direct result of impairments in protein removal, which assumes protein synthesis remains relatively unchanged during proteasome inhibition. We conducted experimentation using established proteasome inhibitors and primary rat neuron cultures in order to elucidate whether proteasome inhibition had any effect on neuronal protein synthesis.

Proteasome regulation of oxidative stress in aging and age-related diseases of the CNS.

Proteasome-mediated protein degradation is responsible for a large percentage of bulk protein turnover, particularly the degradation of short-lived and oxidized proteins. Increasing evidence suggests that proteasome inhibition occurs during the aging of the central nervous system (CNS), and in a variety of age-related disorders of the CNS. The focus of this review is to discuss the role of the proteasome as a regulator of oxidative stress, with preservation of proteasome function playing an important role in preventing oxidative stress, and proteasome inhibition playing an important role as a mediator of oxidative stress.

LMP2 knock-out mice have reduced proteasome activities and increased levels of oxidatively damaged proteins.

The proteasome is a large intracellular protease, composed of multiple subunits, that is present in all eukaryotic cells. Proteasome inhibition is known to occur during normal aging, and is believed to contribute towards an age-related increase in oxidative stress, although at present the mechanisms responsible for mediating age-related changes in proteasome activity have not been elucidated. At present the relationship between proteasome subunit expression, proteasome activity, and protein oxidation during normal aging has not been elucidated.

Evaluation of rage isoforms, ligands, and signaling in the brain.

Since the identification of the receptor for advanced glycosylation end products (RAGE) in 1992, there have been tremendous strides made in our understanding of the role RAGE receptors play in a variety of physiological and pathological processes. Despite such progress, several fundamental aspects of RAGE expression and RAGE function remain largely unanswered. In particular, while multiple forms of the RAGE receptor are known to exist, little is known with regards to how these different isoforms of the RAGE receptor work together to mediate RAGE signaling.

Ribosome dysfunction is an early event in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive and devastating disorder that is often preceded by mild cognitive impairment (MCI). In the present study, we report that in multiple cortical areas of MCI and AD subjects, there is a significant impairment in ribosome function that is not observed in the cerebellum of the same subjects. The impairment in ribosome function is associated with a decreased rate and capacity for protein synthesis, decreased ribosomal RNA and tRNA levels, and increased RNA oxidation.

Modulation of apolipoprotein E and interleukin-1beta in the aging liver.

With aging there is a decline in liver function that includes reductions in hepatic blood flow, metabolite clearance, and impaired tissue repair following injury. An increase in inflammatory signaling is often observed during aging, with inflammation potentially mediating age-related changes in the liver. Apolipoprotein E (ApoE) is primarily produced by the liver and has been shown to possess anti-inflammatory properties in a variety of paradigms and experimental settings.

The stationary phase model of aging in yeast for the study of oxidative stress and age-related neurodegeneration.

Understanding the biochemical and genetic alterations that occur during the aging of post-mitotic cells is critical for understanding the etiology of abnormalities observed during the aging of the central nervous system (CNS). While many theories for cellular aging exist, the free radical theory of aging has proved useful in explaining multiple aspects of post-mitotic cell aging, including the aging of neuronal cells. It is well established that Saccharomyces cerevisiae are an invaluable model system for exploring the regulation of aging in actively dividing cells, but increasing evidence suggests that the chronological lifespan or stationary phase model of aging in S.

RNA interference toward UMP1 induces proteasome inhibition in Saccharomyces cerevisiae: evidence for protein oxidation and autophagic cell death.

The proteasome is a large intracellular protease that is responsible for a large portion of intracellular proteolysis, in particular the degradation of a majority of short-lived and oxidized proteins. Inhibition of proteasome function occurs in response to multiple stressors, with proteasome inhibition sufficient for the induction of a wide range of cytotoxic processes. Although considerable advances have been made in the understanding of the proteasome, and the effects of proteasome inhibition, our understanding of these topics in Saccharomyces cerevisiae has been slowed by the inability of proteasome inhibitors to penetrate and/or be retained in S.

Proteasome inhibition increases DNA and RNA oxidation in astrocyte and neuron cultures.

Increased levels of nucleic acid oxidation have been described as part of normal brain aging and have been demonstrated to occur in multiple neurological disorders. The basis for increased nucleic acid oxidation in each of these conditions is presently unknown. Proteasome inhibition occurs in a host of neurodegenerative conditions and likely contributes to increased levels of oxidative damage and neurotoxicity.

Splice variants of the receptor for advanced glycosylation end products (RAGE) in human brain.

Previous studies indicate that the receptor for advanced glycosylation end products (RAGE) plays an important role in multiple pathological processes, including Alzheimer's disease. Currently there are three established isoforms of the RAGE receptor, with each isoform generated as the result of alternative splicing. It is presently unclear which of the RAGE isoforms are normally expressed in the human brain, nor has it been determined if additional RAGE isoforms exist in the human brain.