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Naphthalene (NA), the simplest polycyclic aromatic hydrocarbon (PAH), is persistently present in the environment as a byproduct of combustion of fossil fuels, tobacco products and more. Due to its ubiquitous presence, there is widespread exposure to the general population. Certain occupational groups, such as firefighters, have elevated levels of exposure. Firefighters also have increased incidences of certain types of cancer. NA is currently classified by the International Agency for Research on Cancer (IARC) as a Class 2B Carcinogen. There is direct evidence of tumor formation in mice and rats but no direct evidence of the carcinogenecity of NA in humans yet. The mechanism of carcinogenicity in mice and rats has yet to be elucidated but a combination of cytotoxic and genotoxic mechanisms is currently the leading hypothesis. NA metabolism results in the generation of reactive intermediates such as 1,2-epoxide (NAO) and reactive metabolites such as 1,2-naphthoquinone (NQ). Reactive quinone and epoxide metabolites of similar compounds, such as benzo[a]pyrene, have been shown to enact their carcinogenicity through DNA adduct formation. Published ex vivo and in vitro data have demonstrated that NA metabolites can form adducts with DNA. The objective of this study is to identify and quantify NA-DNA adducts in mouse lung as well as mouse and human blood to enable assessment of potential genotoxicity in firefighters. This project will provide direct evidence for the formation of NA-DNA adducts in vivo, lay the foundation for future studies of the genotoxicity of NA, obtain evidence to support more extensive assessments of the carcinogenic risks of NA to firefighters, and could have direct implications for the general population.

Recent studies have examined the relationship between borderline personality disorder (BPD) and interpersonal problems in a relatively broad sense. Findings from these studies have been inconclusive, confirming that BPD is heterogeneous empirically, such that there is no particular interpersonal problem associated with the disorder. This study aims to determine if breaking up BPD into its main symptom domains (affective instability, identity problems, negative relationships, and self-harm) will reveal specific interpersonal problems yet to be found when BPD is considered a unitary construct. Data from the Personality Assessment Inventory – Borderline Features Scale (PAI-BOR) and the Circumplex Scales of Interpersonal Problems (CSIP) given at a baseline were subjected to the Structural Summary Method (SSM) in order to analyze the relationships each domain had with interpersonal problems on a circumplex. Findings showed that not only was BPD as a unitary construct interpersonally diffuse, but three of the four symptom domains showed similarly diffuse results. These results are interpreted within the context of validity of the measures used, and the theoretical preposition that BPD is a core personality disorder representing a general factor of personality pathology.

Inflammatory chronic liver diseases (CLD), including nonalcoholic steatohepatitis (NASH), alcohol-associated liver disease (ALD), hepatitis C virus (HCV), and a combination of ALD with HCV (ALD/HCV), account for nearly 2 million deaths annually. The global prevalence of CLD is a major public health concern due to its ability to alter the predicted pharmacokinetics of xenobiotics, which may lead to nephrotoxicity. Each of these CLD etiologies can cause a disruption in drug disposition and elimination through hepatic dysfunction, including expression changes in drug metabolizing enzymes and transporters. This altered disposition, specifically by transporters, may lead to an increase in plasma retention, a decrease in biliary excretion, and result in an increase in systemic exposure to nephrotoxic compounds. Additionally, CLD can elicit changes in renal physiology, such as decreased glomerular filtration rate, further influencing the elimination of xenobiotics. However, despite increasing evidence that liver dysfunction impacts renal physiology, there is limited supportive clinical information, due to limited diagnosis of liver disease, complexity in liver disease etiology, and inadequacy of renal function tests. Consequently, human renal transporter alterations in CLD etiologies were unknown until recently. In this study, I collated a unique cohort of renal biopsies were identified through extensive medical and social history examinations from patients with CLD etiologies, including nonalcoholic fatty liver disease (NAFLD), NASH, ALD, HCV, and ALD/HCV. With the aim to overcome diagnostic barriers and improve future study limitations, immune regulators that had altered transcriptional expression in each etiology were identified. Expression changes were validated with quantitative protein expression and demonstrated an increase for complement C1q C chain (C1QC) in NASH, ALD, HCV, and ALD/HCV (42.9± 16.6; 38.8± 18.4; 39.0± 13.5; 40.1± 20.1 pmol/mg protein) relative to co

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD) in the United States and many other countries. DKD occurs through a variety of pathogenic processes that are in part driven by hyperglycemia and glomerular hypertension, leading to gradual loss of kidney function and eventually progressing to ESRD. In type 2 diabetes, chronic hyperglycemia and glomerular hyperfiltration leads to glomerular and proximal tubular dysfunction. Simultaneously, mitochondrial dysfunction occurs in the early stages of hyperglycemia and has been identified as a key event in the development of DKD. Clinical management for DKD relies primarily on blood pressure and glycemic control through the use of numerous therapeutics that slow disease progression. Because mitochondrial function is key for renal health over time, therapeutics that improve mitochondrial function could be of value in different renal diseases. Increasing evidence supports the idea that targeting aspects of mitochondrial dysfunction, such as mitochondrial biogenesis and dynamics, restores mitochondrial function and improves renal function in DKD. We will review mitochondrial function in DKD and the effects of current and experimental therapeutics on mitochondrial biogenesis and homeostasis in DKD over time.

Deciphering the precise pathophysiologic mechanisms underlying migraine has proven to be quite elusive. Cortical spreading depression (CSD) has long been a postulated culprit, yet a cogent mechanistic link remains undiscovered. Pathologies of the blood brain barrier (BBB) have been observed in multiple disease states of the CNS, however a discrete role of BBB pathology in migraine remains uninvestigated. CSD events trigger release of several substances into the cellular microenvironment of the CNS, a major constituent being H+ ions, which acidify the regions they are released and are regulated by the NHE1 Na+/H+ antiporter. Previous studies reported sex hormone divergence in protective abilities of endothelial barriers, and migraine incidence shows a similar trend. Sex hormone modulation of endothelial barrier integrity via NHE1 regulation and control of pH flux was investigated to assess effects of testosterone, estradiol, and progesterone in the context of endothelial barrier integrity. Testosterone was found to tighten the endothelial barrier, while estradiol reduced cell surface NHE1 localization without impacting barrier integrity. Progesterone was found to increase surface expression of NHE1, implicating NHE1 activity in progesterone responsive barrier permeability. Quantitative proteomics demonstrated protein enrichment divergence due to hormone treatment. This suggests sex hormone dependent modulation of pH homeostasis via divergent regulation of NHE1 functional expression and modifications to the endothelial proteome. NHE1 functions as a primary regulator of pH within the CNS. Extracellular K+ flux following CSD events is a known inducer of BBB permeability, and it was hypothesized to act indirectly through change in NHE1 function to induce loss of barrier integrity while also increasing triptan uptake through an NHE1 dependent mechanism. With the use of NHE1 knockdowns and pharmacological inhibition, downregulation of NHE1 mitigated paracellular leak of an