378 research outputs found
Interplay among oxidative stress, autophagy, and the endocannabinoid system in neurodegenerative diseases. Role of the Nrf2- p62/SQSTM1 pathway and nutraceutical activation
No full textThe onset of neurodegenerative diseases involves a complex interplay of pathological mechanisms, including protein aggregation, oxidative stress, and impaired autophagy. This review focuses on the intricate connection between oxidative stress and autophagy in neurodegenerative disorders, highlighting autophagy as pivotal in disease pathogenesis. Reactive oxygen species (ROS) play dual roles in cellular homeostasis and autophagy regulation, with disruptions of redox
signaling contributing to neurodegeneration. The activation of the Nrf2 pathway represents a critical antioxidant mechanism, while autophagy maintains cellular homeostasis by degrading altered cell components. The interaction among p62/SQSTM1, Nrf2, and Keap1 forms a regulatory pathway essential for cellular stress response, whose dysregulation leads to impaired autophagy and aggregate accumulation. Targeting the Nrf2‐p62/SQSTM1 pathway holds promise for therapeutic intervention, mitigating oxidative stress and preserving cellular functions. Additionally, this review explores the potential synergy between the endocannabinoid system and Nrf2 signaling for neuroprotection. Further research is needed to elucidate the involved molecular mechanisms and develop effective therapeutic strategies against neurodegeneration
Paraquat increases cyanide-insensitive respiration in murine lung epithelial cells by activating an NAD(P)H:paraquat oxidoreductase: identification of the enzyme as thioredoxin reductase
No full textPulmonary fibrosis is one of the most severe consequences of exposure to paraquat, an herbicide that causes rapid alveolar inflammation and epithelial cell damage. Paraquat is known to induce toxicity in cells by stimulating oxygen utilization via redox cycling and the generation of reactive oxygen intermediates. However, the enzymatic activity mediating this reaction in lung cells is not completely understood. Using self-referencing microsensors, we measured the effects of paraquat on oxygen flux into murine lung epithelial cells. Paraquat (10-100 microm) was found to cause a 2-4-fold increase in cellular oxygen flux. The mitochondrial poisons cyanide, rotenone, and antimycin A prevented mitochondrial- but not paraquat-mediated oxygen flux into cells. In contrast, diphenyleneiodonium (10 microm), an NADPH oxidase inhibitor, blocked the effects of paraquat without altering mitochondrial respiration. NADPH oxidases, enzymes that are highly expressed in lung epithelial cells, utilize molecular oxygen to generate superoxide anion. We discovered that lung epithelial cells possess a distinct cytoplasmic diphenyleneiodonium-sensitive NAD(P)H:paraquat oxidoreductase. This enzyme utilizes oxygen, requires NADH or NADPH, and readily generates the reduced paraquat radical. Purification and sequence analysis identified this enzyme activity as thioredoxin reductase. Purified paraquat reductase from the cells contained thioredoxin reductase activity, and purified rat liver thioredoxin reductase or recombinant enzyme possessed paraquat reductase activity. Reactive oxygen intermediates and subsequent oxidative stress generated from this enzyme are likely to contribute to paraquat-induced lung toxicit
Nutraceuticals as potential therapeutics for vesicant‐induced pulmonary fibrosis
No full textExposure to vesicants, including sulfur mustard and nitrogen mustard, causes damage to the epithelia of the respiratory tract and the lung. With time, this progresses to chronic disease, most notably, pulmonary fibrosis. The pathogenic process involves persistent inflammation and the release of cytotoxic oxidants, cytokines, chemokines, and profibrotic growth factors, which leads to the collapse of lung architecture, with fibrotic involution of the lung parenchyma. At present, there are no effective treatments available to combat this pathological process. Recently, much interest has focused on nutraceuticals, substances derived from plants, herbs, and fruits, that exert pleiotropic effects on inflammatory cells and parenchymal cells that may be useful in reducing fibrogenesis. Some promising results have been obtained with nutraceuticals in experimental animal models of inflammation-driven fibrosis. This review summarizes the current knowledge on the putative preventive/therapeutic efficacy of nutraceuticals in progressive pulmonary fibrosis, with a focus on their activity against inflammatory reactions and profibrotic cell differentiation
Marriage of the written word and visual illustration
No full textThere is no abstract available for this creative project.Thesis (M.A.)A book entitled "Glimpses" (31 pages) written by and illustrated by the author bound in at back.Department of Ar
Minimal amidine structure for inhibition of nitric oxide biosynthesis
No full textPharmacological modulation of nitric oxide synthase activity has been achieved using structural analogs of arginine. In the present studies, we demonstrated that the minimal amidine structure required for enzymatic inhibition is formamidine. We found that the production of nitric oxide by primary cultures of rat hepatocytes and several mouse and human cell lines, including RAW 264.7 macrophages, PAM 212 keratinocytes, G8 myoblasts, S180 sarcoma, CX-1 human colon cells, and GH3 rat pituitary cells, was inhibited in a concentration- and time-dependent manner by formamidine. Formamidine was 2- to 6-fold more effective in inhibiting nitric oxide production in cells expressing inducible nitric oxide synthase (NOS2) than in a cell line expressing calcium-dependent neuronal nitric oxide synthase (NOS1). Whereas formamidine had no effect on gamma-interferon-induced expression of nitric oxide synthase protein, its enzymatic activity was blocked. Kinetic analysis revealed that formamidine acts as a simple competitive inhibitor with respect to arginine (K(i) formamidine approximately 800 microM). Using a polarographic microsensor to measure real-time flux of nitric oxide release from RAW 264.7 macrophages, formamidine was found to require 30-90 min to inhibit enzyme activity, suggesting that cellular uptake of the drug may limit its biological activity. Our data indicate that formamidine is an effective inhibitor of nitric oxide production. Furthermore, its low toxicity may make it useful as a potential therapeutic agent in diseases associated with the increased production of nitric oxid
Macrophages and inflammatory mediators in pulmonary injury induced by mustard vesicants
No full textSulfur mustard (SM) and nitrogen mustard (NM) are cytotoxic alkylating agents that cause severe and progressive
injury to the respiratory tract, resulting in significant morbidity and mortality. Evidence suggests that macrophages
and the inflammatory mediators they release play roles in both acute and long-term pulmonary injuries caused by
mustards. In this article, we review the pathogenic effects of SM and NM on the respiratory tract and potential
inflammatory mechanisms contributing to this activit
Fish research project, Oregon
No full textprepared by: James R. Ruzycki, Lance R. Clarke, Michael W. Flesher, Richard W. Carmichael, Debra L. Eddy.Title from PDF title page (viewed on February 16, 2023)."Lower Snake River Compensation Plan: Oregon evaluation studies"--Cover.This archived document is maintained by the State Library of Oregon as part of the Oregon Documents Depository Program. It is for informational purposes and may not be suitable for legal purposes.Includes bibliographical references (pages 23-24).Financed by the U.S. Fish and Wildlife Service under the Lower Snake River Compensation Plan.Mode of access: Internet from the Oregon Government Publications Collection.Text in English
Multidisciplinary approaches to stimulate wound healing
No full textThe new civil wars and waves of terrorism waves are causing crucial social changes, with
consequences in all fields, including health care. In particular, skin injuries are evolving as an
epidemic issue. From a physiological standpoint, although wound repair takes place more rapidly
in the skin than in other tissues, it is still a complex organ to reconstruct. Genetic and clinical
variables, such as diabetes, smoking, and inflammatory/immunological pathologies, are also
important risk factors limiting the regenerative potential of many therapeutic applications.
Therefore, optimization of current clinical strategies is critical. Here we summarize the current
state of the field by focusing on stem cell therapy applications in wound healing, with an emphasis
on current clinical approaches being developed at Sapienza University. These involve protocols
for the ex vivo expansion of adipose tissue–derived mesenchymal stem cells by means of a
patented GMP-compliant platelet lysate, MesengenTM. A combination of multiple strategies,
including genetic modifications of stem cells, biomimetic scaffolds, or novel vehicles such as
nanoparticles, are also discussed as future approaches
Farnesoid X receptor in mustard lung toxicity; new approaches for assessing lung structure and function
No full textThe overall objective of these studies was to characterize the role of farnesoid X receptor (FXR) in nitrogen mustard (NM)-induced lung injury, assess NM-induced lung injury and fibrosis using imaging techniques (i.e., MRI and CT), and predict alterations in lung functioning using mathematical modeling. We hypothesized that NM exposure results in upregulation of FXR in the lung leading to reduced M1 macrophage activation and increased M2 macrophage activation, increased lipid uptake and foam cell formation, and pulmonary fibrosis. In the first specific aim, we utilized male and female FXR knockout (FXR-/-) mice to test this hypothesis. Interestingly, female WT and FXR-/- mice were less sensitive to NM toxicity; this was assessed by histopathological analysis and bronchoalveolar lavage (BAL) cell number and protein content. Based on these findings, we continued our analysis of lung responsiveness to NM in male WT and FXR-/- mice. We found that FXR regulates inflammatory macrophage activation in the lung following NM exposure. We utilized flow cytometry to assess the phenotype of pro and anti-inflammatory macrophages in BAL in response to NM. Loss of FXR resulted in a significant increase in proinflammatory macrophages at 3 d post NM exposure, as expected. This increase in proinflammatory macrophages correlated with increased expression of COX-2 and ARL11, markers of M1 activation in lung macrophages demonstrating that these proinflammatory macrophages are activated. The miRNAs related to NF-κB pathway activation were analyzed and were found to be also upregulated in FXR-/- mice, which may exacerbate proinflammatory macrophage activity. We also found that gene expression of Nur77, a nuclear receptor associated with anti-inflammatory macrophage activation, was significantly reduced in WT mice treated with NM at 14 d post exposure, suggesting an impairment of M2 macrophage activity. As FXR is a nuclear receptor involved in lipid homeostasis, we also analyzed the expression of genes related to lipid metabolism and transport. Both Apoe and Abca1 mRNA levels were significantly increased in FXR-/- mice at 14 d post NM exposure. Conversely, at 28 d post NM, Abcg1 mRNA levels were significantly reduced, which correlates with accumulation of foamy macrophages in lung tissue.
In the second specific aim, we refined MRI and CT imaging methodology to track the progression of NM-induced lung injury and response to the therapeutic, anti-TNFα antibody in the same animal over time. Rats were imaged prior to exposure and then 1-28 days thereafter. High-signal lung volume present in MR images corresponded to edema, inflammation and tissue remodeling; pathologies that were found to persist for 28 d following NM exposure. CT scans were used to assess structural components of the lung and register alterations in tissue radiodensities. Changes in lung volume relative to pre-exposure lung volumes were reduced in rats exposed to NM at 28 d (-1.3 x 10^⁵ vs. 3.9 x 10^⁵ Hounsfield units); this was mitigated by anti-TNFα antibody. Loss of respiratory area caused by NM was restored by the treatment of rats with anti-TNFα antibody.
Following imaging, at 30 d post exposure, rats were anesthetized, and lung function assessed at a positive end expiratory pressure (PEEP) of 3 cm H₂O using a SciReq flexiVent® small animal ventilator. Structural changes generated from MRI and CT imaging analyses (e.g., % of lung injury, AUC of the air portion of the lung, and AUC of the wet/consolidated portion of the lung) were then used to predict alterations in pulmonary mechanics, which was the focus of the third specific aim. Forward modeling was used to measure (using flexiVent® generated data) and calculate (using imaging derived parameters) respiratory system impedance (Zrs), a sensitive indicator of lung function. Strong correlations (r²≥0.96) were observed between measured and calculated Zrs confirming that the model is highly prognostic. We found that measured and calculated real and imaginary Zrs spectra were increased by 30 d post exposure. Using the real and imaginary components of Zrs, we calculated resistance (RL) and elastance (EL) for measured and calculated data. RL and EL were elevated indicating increased lung stiffness, a finding that is typically associated with mustard exposure. As imaging data were collected for earlier time points (e.g., 1, 3, 7, 14, and 21 d post NM exposure), simulations of real and imaginary Zrs spectra were performed using our model. We observed a shift from reduced to increased real Zrs spectra relative to control animals over time, supporting that pathologies progress and alter lung function following NM exposure.
In conclusion, the current studies suggest that FXR plays a key role in mediating pro and anti-inflammatory macrophage activation and foam cell formation associated with NM-induced lung injury. The refinement of MRI and CT imaging methodologies allowed us to quantify NM-induced pathological alterations over time in the same animal and confirm the ability of anti-TNFα to abrogate lung toxicity. We further implemented the structural data derived from these imaging methods into a mathematical model to predict lung function. Overall, these data provide new insights into mechanisms that promote the pathogenesis of NM lung toxicity and strategies to assess lung injury and response to therapeutics.Ph.D.Includes bibliographical reference
Functional characterization of interstitial macrophages and subpopulations of alveolar macrophages from rat lung
No full textAbstract: The specific function of interstitial macro-phages (IM) in the lung is poorly understood because of difficulties in isolating these cells in high purity or large number. In the present studies, a pure population of en-zymatically isolated IM and lung macrophages obtained mechanically from the lung were compared functionally with alveolar macrophages recovered by lavage (AM). Macrophages isolated mechanically from the tissue and AM displayed similarly high levels of Fc-receptor mcdi-ated phagocytosis. In contrast, IM phagocytized significantly fewer opsonized sheep red blood cells per macrophage than AM. In addition, although some varia-tions in the amounts of nitric oxide and superoxide anion produced by AM and macrophages obtained by mechani-cal tissue disruption were observed, these subpopulations released significantly more of these mediators than IM. These data support the concept that macrophages isolated by mechanical disruption of the tissue represent a sub-population of AM. We also found that, in contrast to AM, IM did not respond synergistically to combinations of IFN-’y and lipopolysaccharide (LPS) or tumor necrosis factor a in terms of nitric oxide production. Furthermore, regulation of superoxide anion release in AM and IM by LPS and/or IFN-’y was distinct. Taken together, these studies demonstrate that IM are functionally different from other macrophage subpopulations which might reflect their unique location within the lung. J. Leukoc
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