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  1. Article ; Online: A novel anti-inflammatory treatment for bradykinin-induced sore throat or pharyngitis.

    Leyva-Grado, Victor / Pugach, Pavel / Sadeghi-Latefi, Nazlie

    Immunity, inflammation and disease

    2021  Volume 9, Issue 4, Page(s) 1321–1335

    Abstract: Background: Often thought of as a minor health concern, sore throat or pharyngitis is an important public health issue. It is one of the most common symptoms of upper respiratory diseases including COVID-19 and is a leading cause of physician visits and ...

    Abstract Background: Often thought of as a minor health concern, sore throat or pharyngitis is an important public health issue. It is one of the most common symptoms of upper respiratory diseases including COVID-19 and is a leading cause of physician visits and antibiotic prescriptions. However, few over-the-counter medications are proven to heal sore throat inflammation.
    Methods: Adenocarcinomic human alveolar basal epithelial cells (A549 cells) and three dimensional organotypic human respiratory tissues were used to study inflammation and various treatment effects on respiratory epithelia. The cells and tissues were studied both in the presence and absence of bradykinin, one of the first inflammatory mediators of pharyngitis. Inflammation was measured by analyzing the levels of prostaglandin E2 (PGE2), interleukin 8 (IL-8), and leukotriene B4 (LTB4), transepithelial electrical resistance (TEER), and lactate dehydrogenase (LDH) release. Tissue morphology was analyzed by immunohistochemistry.
    Results: In studying pharyngitis using organotypic human respiratory tissue stimulated with bradykinin, we saw an increase in PGE2 and interleukin-8 (IL-8) in response to bradykinin. Acetyl salicylic acid (ASA), a nonspecific COX inhibitor, was able to mitigate a bradykinin-induced increase in PGE2 in our studies. However, ASA was inflammatory above its therapeutic window, increasing the levels of PGE2 and IL-8 above those seen with bradykinin stimulation alone. We describe a novel, scientifically validated treatment for sore throat, that contains a low dose of ASA and other anti-inflammatory ingredients.
    Conclusion: This study elucidates the complex mechanisms involved in healing pharyngitis, an inflammatory condition of the upper respiratory epithelia. An ASA-based formula (Biovanta) mitigated bradykinin-induced inflammation more strongly than ASA alone in organotypic human respiratory tissues. Surprisingly, we found that many of the most common over the counter sore throat therapies exacerbate inflammation and IL-8 in organotypic human respiratory tissues, suggesting these common treatments may increase the likelihood of further respiratory complications.
    MeSH term(s) Anti-Inflammatory Agents/therapeutic use ; Bradykinin/pharmacology ; Bradykinin/therapeutic use ; COVID-19 ; Humans ; Pharyngitis/drug therapy ; SARS-CoV-2
    Chemical Substances Anti-Inflammatory Agents ; Bradykinin (S8TIM42R2W)
    Language English
    Publishing date 2021-06-21
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 2050-4527
    ISSN (online) 2050-4527
    DOI 10.1002/iid3.479
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Pooled trials drowning in conflict-of-interest oversights.

    Latefi, Nazlie

    Nature medicine

    2011  Volume 17, Issue 4, Page(s) 400–401

    MeSH term(s) Clinical Trials as Topic/ethics ; Conflict of Interest ; Guidelines as Topic ; Humans ; Meta-Analysis as Topic
    Language English
    Publishing date 2011-04-07
    Publishing country United States
    Document type News
    ZDB-ID 1220066-9
    ISSN 1546-170X ; 1078-8956
    ISSN (online) 1546-170X
    ISSN 1078-8956
    DOI 10.1038/nm0411-400b
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Rational drug design for sore throat—An aspirin-based treatment that addresses bradykinin-induced inflammation

    Leyva-Grado, Victor / Pugach, Pavel / Latefi, Nazlie

    bioRxiv

    Abstract: Often thought of as a minor health concern, sore throat or pharyngitis is an important public health issue. It is one of the most common symptoms of upper respiratory diseases including COVID-19 and is a leading cause of physician visits and antibiotic ... ...

    Abstract Often thought of as a minor health concern, sore throat or pharyngitis is an important public health issue. It is one of the most common symptoms of upper respiratory diseases including COVID-19 and is a leading cause of physician visits and antibiotic prescriptions. Despite being on the market for decades, few over the counter sore throat medications are proven to heal sore throat. In studying pharyngitis using organotypic human respiratory tissue stimulated with bradykinin, we saw an increase in prostaglandin E2 (PGE2) and interleukin-8 (IL-8) in response to bradykinin. Bradykinin is one of the first inflammatory signals for pharyngitis and it increases PGE2 in human subjects. If left unregulated, PGE2 may further increase inflammation via the COX pathway and via IL-8, a proinflammatory chemokine responsible for neutrophil infiltration and possibly thus, a cytokine storm. Acetyl salicylic acid (ASA), a non-specific COX inhibitor, was able to mitigate a bradykinin-induced increase in PGE2 in our studies. However, ASA was inflammatory above its small therapeutic window, greatly increasing levels of PGE2 and IL-8 above those seen with bradykinin stimulation alone. Similar to other systems, the respiratory epithelia maintains a delicate balance of pro-inflammatory and anti-inflammatory signals in order to keep the respiratory barrier intact. To our knowledge, this is the first study to try and elucidate the complex mechanisms involved in healing pharyngitis, an inflammatory condition of the respiratory epithelia. Biovanta™, a formula containing ASA mitigated bradykinin-induced inflammation more strongly than ASA alone in organotypic human respiratory tissues. Surprisingly, we found that many of the most common over the counter sore throat therapies exacerbate inflammation and IL-8 in organotypic human respiratory tissues, suggesting these common treatments may possibly increase the likelihood of further respiratory complications in people.
    Keywords covid19
    Publisher BioRxiv
    Document type Article ; Online
    DOI 10.1101/2020.11.06.370395
    Database COVID19

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  4. Article: The CNS synapse revisited: gaps, adhesive welds, and borders.

    Latefi, Nazlie S / Colman, David R

    Neurochemical research

    2007  Volume 32, Issue 2, Page(s) 303–310

    Abstract: Although processes leading up to the point of synapse formation are fairly well understood, the precise sequence of events in which the membranes of two separate cells "lock in" to form a mature synaptic junctional complex is poorly understood. A careful ...

    Abstract Although processes leading up to the point of synapse formation are fairly well understood, the precise sequence of events in which the membranes of two separate cells "lock in" to form a mature synaptic junctional complex is poorly understood. A careful study of the molecules operating at the synapse indicates that their roles are more multifarious than once imagined. In this review we posit that the synapse is a functional organelle with poorly defined boundaries and a complex biochemistry. The role of adhesion molecules, including the integration of their signaling and adhesive properties in the context of synaptic activity is discussed.
    MeSH term(s) Animals ; Cell Adhesion Molecules/physiology ; Neuroglia/physiology ; Neuronal Plasticity/physiology ; Neurons/physiology ; Signal Transduction/physiology ; Synapses/physiology ; Synapses/ultrastructure
    Chemical Substances Cell Adhesion Molecules
    Language English
    Publishing date 2007-02
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 199335-5
    ISSN 1573-6903 ; 0364-3190
    ISSN (online) 1573-6903
    ISSN 0364-3190
    DOI 10.1007/s11064-006-9181-0
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: N-cadherin prodomain cleavage regulates synapse formation in vivo.

    Latefi, Nazlie S / Pedraza, Liliana / Schohl, Anne / Li, Ziwei / Ruthazer, Edward S

    Developmental neurobiology

    2009  Volume 69, Issue 8, Page(s) 518–529

    Abstract: Cadherins are initially synthesized bearing a prodomain that is thought to limit adhesion during early stages of biosynthesis. Functional cadherins lack this prodomain, raising the intriguing possibility that cells may utilize prodomain cleavage as a ... ...

    Abstract Cadherins are initially synthesized bearing a prodomain that is thought to limit adhesion during early stages of biosynthesis. Functional cadherins lack this prodomain, raising the intriguing possibility that cells may utilize prodomain cleavage as a means to temporally or spatially regulate adhesion after delivery of cadherin to the cell surface. In support of this idea, immunostaining for the prodomain of zebrafish N-cadherin revealed enriched labeling at neuronal surfaces at the soma and along axonal processes. To determine whether post-translational cleavage of the prodomain affects synapse formation, we imaged Rohon-Beard cells in zebrafish embryos expressing GFP-tagged wild-type N-cadherin (NCAD-GFP) or a GFP-tagged N-cadherin mutant expressing an uncleavable prodomain (PRON-GFP) rendering it nonadhesive. NCAD-GFP accumulated at synaptic microdomains in a developmentally regulated manner, and its overexpression transiently accelerated synapse formation. PRON-GFP was much more diffusely distributed along the axon and its overexpression delayed synapse formation. Our results support the notion that N-cadherin serves to stabilize pre- to postsynaptic contacts early in synapse development and suggests that regulated cleavage of the N-cadherin prodomain may be a mechanism by which the kinetics of synaptogenesis are regulated.
    MeSH term(s) Animals ; Axons/metabolism ; Axons/ultrastructure ; Brain/cytology ; Brain/embryology ; Brain/metabolism ; Cadherins/chemistry ; Cadherins/genetics ; Cadherins/metabolism ; Cell Differentiation/physiology ; Cells, Cultured ; Green Fluorescent Proteins/genetics ; Green Fluorescent Proteins/metabolism ; Kinetics ; Mutation/genetics ; Neural Pathways/embryology ; Neural Pathways/metabolism ; Neural Pathways/ultrastructure ; Protein Structure, Tertiary/physiology ; Recombinant Fusion Proteins/genetics ; Recombinant Fusion Proteins/metabolism ; Synapses/metabolism ; Synapses/ultrastructure ; Synaptic Membranes/metabolism ; Synaptic Membranes/ultrastructure ; Zebrafish/anatomy & histology ; Zebrafish/embryology ; Zebrafish/metabolism ; Zebrafish Proteins/chemistry ; Zebrafish Proteins/genetics ; Zebrafish Proteins/metabolism
    Chemical Substances Cadherins ; N-cadherin, zebrafish ; Recombinant Fusion Proteins ; Zebrafish Proteins ; Green Fluorescent Proteins (147336-22-9)
    Language English
    Publishing date 2009-04-14
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2256184-5
    ISSN 1097-4695 ; 1932-8451 ; 0022-3034
    ISSN (online) 1097-4695
    ISSN 1932-8451 ; 0022-3034
    DOI 10.1002/dneu.20718
    Database MEDical Literature Analysis and Retrieval System OnLINE

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