Emerging role of extracellular vesicles in the respiratory system

Holtzman Joshua,이희두 생화학분자생물학회 2020 Experimental and molecular medicine Vol.52 No.-

Extracellular vesicles (EVs) present numerous biomedical ways of studying disease and pathology. They function as protective packaging for the delivery of controlled concentrations of miRNAs and effector molecules, including cytokines, chemokines, genetic material, and small signaling molecules. Previous studies of EVs have yielded valuable insights into pathways of intercellular communication that affect a variety of biological processes and disease responses. The roles of EVs, specifically microRNA-containing EVs (EV-miRNAs), in either mitigating or exacerbating pulmonary disease symptoms are numerous and show promise in helping us understand pulmonary disease pathology. Because of their well-documented involvement in pulmonary diseases, EVs show promise both as possible diagnostic biomarkers and as therapeutic agents. This review surveys the physiological functions of EVs in the respiratory system and outlines the pulmonary disease states in which EVs are involved in intercellular crosstalk. This review also discusses the potential clinical applications of EV-miRNAs in pulmonary diseases.

Current understanding of the Alzheimer’s disease-associated microbiome and therapeutic strategies

Seo Dong-oh,Holtzman David M. 생화학분자생물학회 2024 Experimental and molecular medicine Vol.56 No.-

Alzheimer’s disease (AD) is a fatal progressive neurodegenerative disease. Despite tremendous research efforts to understand this complex disease, the exact pathophysiology of the disease is not completely clear. Recently, anti-Aβ antibodies have been shown to remove amyloid from the brain and slow the clinical progression of mild dementia by ~30%. However, exploring alternative strategies is crucial to understanding and developing more effective therapeutic interventions. In recent years, the microbiota-gut-brain axis has received significant attention in the AD field. Numerous studies have suggested that alterations in the gut microbiota composition are associated with the progression of AD, and several underlying mechanisms have been proposed. However, studies in this area are still in their infancy, and many aspects of this field are just beginning to be explored and understood. Gaining a deeper understanding of the intricate interactions and signaling pathways involved in the microbiota-AD interaction is crucial for optimizing therapeutic strategies targeting gut microbiota to positively impact AD. In this review, we aim to summarize the current understanding of the microbiota-gut-brain axis in AD. We will discuss the existing evidence regarding the role of gut microbiota in AD pathogenesis, suggested underlying mechanisms, biological factors influencing the microbiome-gut-brain axis in AD, and remaining questions in the field. Last, we will discuss potential therapeutic approaches to recondition the community of gut microbiota to alleviate disease progression. An ongoing exploration of the gut-brain axis and the development of microbiota-based therapies hold the potential for advancing AD management in the future.

Spinal Epidural Abscess: A Review of Presentation, Management, and Medicolegal Implications

Sharfman Zachary Tuvya,Gelfand Yaroslav,Shah Pryiam,Holtzman Ari Jacob,Mendelis Joseph Roy,Kinon Merritt Drew,Krystal Jonathan David,Brook Allan,Yassari Reza,Kramer David Claude 대한척추외과학회 2020 Asian Spine Journal Vol.14 No.5

Spinal epidural abscess (SEA) is a rare condition associated with significant morbidity and mortality. Despite advances in diagnostic medicine, early recognition of SEAs remains elusive. The vague presentation of the disease, coupled with its numerous risk factors, the diagnostic requirement for obtaining advanced imaging, and the necessity of specialized care constitute extraordinary challenges to both diagnosis and treatment of SEA. Once diagnosed, SEAs require urgent or emergent medical and/or surgical management. As SEAs are a relatively rare pathology, high-quality data are limited and there is no consensus on their optimal management. This paper focuses on presenting the treatment modalities that have been successful in the management of SEAs and providing a critical assessment of how specific SEA characteristics may render one infection more amenable to primary surgical or medical interventions. This paper reviews the relevant history, epidemiology, clinical presentation, radiology, microbiology, and treatment of SEAs and concludes by addressing the medicolegal implications of delayed treatment of the disease.

African Americans May Have to Consume More Than 12 Grams a Day of Resistant Starch to Lower Their Risk for Type 2 Diabetes

Michelle Penn-Marshall,Gold I. Holtzman,William E. Barbeau 한국식품영양과학회 2010 Journal of medicinal food Vol.13 No.4

African Americans have a high prevalence rate of type 2 diabetes mellitus (DM). High-maize™ 260 (National Starch and Chemical Co., Bridgewater, NJ, USA) resistant starch (RS) is a promising food ingredient to reduce risk factors for type 2 DM. A 14-week, double-blind, crossover design study was conducted with African American male (n=8) and female (n=7) subjects at risk for type 2 DM. All subjects consumed bread containing 12g of added RS or control bread (no added RS) for 6 weeks, separated by a 2-week washout period. There were no significant differences in the subjects' fasting plasma glucose levels due to the consumption of the RS bread versus the control bread. Fructosamine levels were significantly lower after consumption of both RS and control bread than at baseline. However, we found no significant difference in fructosamine levels due to treatment effects, i.e., RS bread intake versus the control bread. There were no significant differences in insulin or C-reactive protein levels due to treatment, gender, or sequence effects. Mean homeostasis model assessment of insulin resistance decreased to normal values (>2.5) at the end of the 14-week study, although there were no significant treatment effects. The results of this study suggest that African Americans may need to consume more than 12g/day of RS to lower their risk for type 2 DM.

Sleep, circadian rhythms, and the pathogenesis of Alzheimer Disease

Erik S Musiek,David D Xiong,David M Holtzman 생화학분자생물학회 2015 Experimental and molecular medicine Vol.47 No.-

Disturbances in the sleep–wake cycle and circadian rhythms are common symptoms of Alzheimer Disease (AD), and they have generally been considered as late consequences of the neurodegenerative processes. Recent evidence demonstrates that sleep–wake and circadian disruption often occur early in the course of the disease and may even precede the development of cognitive symptoms. Furthermore, the sleep–wake cycle appears to regulate levels of the pathogenic amyloid-beta peptide in the brain, and manipulating sleep can influence AD-related pathology in mouse models via multiple mechanisms. Finally, the circadian clock system, which controls the sleep–wake cycle and other diurnal oscillations in mice and humans, may also have a role in the neurodegenerative process. In this review, we examine the current literature related to the mechanisms by which sleep and circadian rhythms might impact AD pathogenesis, and we discuss potential therapeutic strategies targeting these systems for the prevention of AD.

Novel allele-dependent role for APOE in controlling the rate of synapse pruning by astrocytes

Chung, Won-Suk,Verghese, Philip B.,Chakraborty, Chandrani,Joung, Julia,Hyman, Bradley T.,Ulrich, Jason D.,Holtzman, David M.,Barres, Ben A. National Academy of Sciences 2016 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.113 No.36

<P>The strongest genetic risk factor influencing susceptibility to lateonset Alzheimer's disease (AD) is apolipoprotein E (APOE) genotype. APOE has three common isoforms in humans, E2, E3, and E4. The presence of two copies of the E4 allele increases risk by similar to 12-fold whereas E2 allele is associated with an similar to twofold decreased risk for AD. These data put APOE central to AD pathophysiology, but it is not yet clear how APOE alleles modify AD risk. Recently we found that astrocytes, a major central nervous system cell type that produces APOE, are highly phagocytic and participate in normal synapse pruning and turnover. Here, we report a novel role for APOE in controlling the phagocytic capacity of astrocytes that is highly dependent on APOE isoform. APOE2 enhances the rate of phagocytosis of synapses by astrocytes, whereas APO4 decreases it. We also found that the amount of C1q protein accumulation in hippocampus, which may represent the accumulation of senescent synapses with enhanced vulnerability to complement-mediated degeneration, is highly dependent on APOE alleles: C1q accumulation was significantly reduced in APOE2 knock-in (KI) animals and was significantly increased in APOE4 KI animals compared with APOE3 KI animals. These studies reveal a novel allele-dependent role for APOE in regulating the rate of synapse pruning by astrocytes. They also suggest the hypothesis that AD susceptibility of APOE4 may originate in part from defective phagocytic capacity of astrocytes which accelerates the rate of accumulation of C1q-coated senescent synapses, enhancing synaptic vulnerability to classical-complement-cascade mediated neurodegeneration.</P>

The Induction of Pattern-Recognition Receptor Expression against Influenza A Virus through Duox2-Derived Reactive Oxygen Species in Nasal Mucosa

Kim, Hyun Jik,Kim, Chang-Hoon,Kim, Min-Ji,Ryu, Ji-Hwan,Seong, Sang Yeop,Kim, Sujin,Lim, Su Jin,Holtzman, Michael J.,Yoon, Joo-Heon American Thoracic Society 2015 AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR Vol.53 No.4

Potential role of orexin and sleep modulation in the pathogenesis of Alzheimer’s disease

Roh, Jee Hoon,Jiang, Hong,Finn, Mary Beth,Stewart, Floy R.,Mahan, Thomas E.,Cirrito, John R.,Heda, Ashish,Snider, B. Joy,Li, Mingjie,Yanagisawa, Masashi,de Lecea, Luis,Holtzman, David M. The Rockefeller University Press 2014 The Journal of experimental medicine Vol.211 No.13

<P>Age-related aggregation of amyloid-β (Aβ) is an upstream pathological event in Alzheimer’s disease (AD) pathogenesis, and it disrupts the sleep–wake cycle. The amount of sleep declines with aging and to a greater extent in AD. Poor sleep quality and insufficient amounts of sleep have been noted in humans with preclinical evidence of AD. However, how the amount and quality of sleep affects Aβ aggregation is not yet well understood. Orexins (hypocretins) initiate and maintain wakefulness, and loss of orexin-producing neurons causes narcolepsy. We tried to determine whether orexin release or secondary changes in sleep via orexin modulation affect Aβ pathology. Amyloid precursor protein (APP)/Presenilin 1 (PS1) transgenic mice, in which the orexin gene is knocked out, showed a marked decrease in the amount of Aβ pathology in the brain with an increase in sleep time. Focal overexpression of orexin in the hippocampus in APP/PS1 mice did not alter the total amount of sleep/wakefulness and the amount of Aβ pathology. In contrast, sleep deprivation or increasing wakefulness by rescue of orexinergic neurons in APP/PS1 mice lacking orexin increased the amount of Aβ pathology in the brain. Collectively, modulation of orexin and its effects on sleep appear to modulate Aβ pathology in the brain.</P>

THE APOKASC CATALOG: AN ASTEROSEISMIC AND SPECTROSCOPIC JOINT SURVEY OF TARGETS IN THE <i>KEPLER</i> FIELDS

Pinsonneault, Marc H.,Elsworth, Yvonne,Epstein, Courtney,Hekker, Saskia,Mé,szá,ros, Sz.,Chaplin, William J.,Johnson, Jennifer A.,Garcí,a, Rafael A.,Holtzman, Jon,Mathur, Savita,Garc& IOP Publishing 2014 The Astrophysical journal Supplement series Vol.215 No.2

<P>We present the first APOKASC catalog of spectroscopic and asteroseismic properties of 1916 red giants observed in the Kepler fields. The spectroscopic parameters provided from the Apache Point Observatory Galactic Evolution Experiment project are complemented with asteroseismic surface gravities, masses, radii, and mean densities determined by members of the Kepler Asteroseismology Science Consortium. We assess both random and systematic sources of error and include a discussion of sample selection for giants in the Kepler fields. Total uncertainties in the main catalog properties are of the order of 80 K in Teff, 0.06 dex in [M/ H], 0.014 dex in log g, and 12% and 5% in mass and radius, respectively; these reflect a combination of systematic and random errors. Asteroseismic surface gravities are substantially more precise and accurate than spectroscopic ones, and we find good agreement between their mean values and the calibrated spectroscopic surface gravities. There are, however, systematic underlying trends with Teff and log g. Our effective temperature scale is between 0 and 200 K cooler than that expected from the infrared flux method, depending on the adopted extinction map, which provides evidence for a lower value on average than that inferred for the Kepler Input Catalog (KIC). We find a reasonable correspondence between the photometric KIC and spectroscopic APOKASC metallicity scales, with increased dispersion in KIC metallicities as the absolute metal abundance decreases, and offsets in T-eff and log g consistent with those derived in the literature. We present mean fitting relations between APOKASC and KIC observables and discuss future prospects, strengths, and limitations of the catalog data.</P>