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Article ; Online: Enhancement of innate immunity in gingival epithelial cells by vitamin D and HDAC inhibitors.

Figgins, Erika L / Arora, Payal / Gao, Denny / Porcelli, Emily / Ahmed, Rabab / Daep, Carlo Amorin / Keele, Garrett / Ryan, Lisa K / Diamond, Gill

Frontiers in oral health

2024 Volume 5, Page(s) 1378566

Abstract: Introduction: The human host defense peptide LL-37 is a component of the innate immune defense mechanisms of the oral cavity against colonization by microbes associated with periodontal disease. We have previously shown that the active form of vitamin D, ...

Abstract	Introduction: The human host defense peptide LL-37 is a component of the innate immune defense mechanisms of the oral cavity against colonization by microbes associated with periodontal disease. We have previously shown that the active form of vitamin D, 1,25(OH) Methods: We treated 3-dimensional primary cultures of GEC topically with the inactive form of vitamin D, in the presence and absence of selected histone deacetylase (HDAC) inhibitors. LL-37 mRNA levels were quantified by quantitative RT-PCR, and inhibition of invasion of bacteria was measured by fluorescence microscopy. Results: Vitamin D treatment led to an induction of LL-37 mRNA levels, as well as an inhibition of pro-inflammatory cytokine secretion. This effect was further enhanced by HDAC inhibitors, most strongly when the HDAC inhibitor, phenyl butyrate (PBA) was combined with Vitamin D Conclusions: Our results demonstrate that a combination of inactive vitamin D and sodium butyrate could be developed as a safe treatment for periodontal disease.
Language	English
Publishing date	2024-03-14
Publishing country	Switzerland
Document type	Journal Article
ISSN	2673-4842
ISSN (online)	2673-4842
DOI	10.3389/froh.2024.1378566
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Article: Potent Antiviral Activity against HSV-1 and SARS-CoV-2 by Antimicrobial Peptoids.

Diamond, Gill / Molchanova, Natalia / Herlan, Claudine / Fortkort, John A / Lin, Jennifer S / Figgins, Erika / Bopp, Nathen / Ryan, Lisa K / Chung, Donghoon / Adcock, Robert Scott / Sherman, Michael / Barron, Annelise E

Pharmaceuticals (Basel, Switzerland)

2021 Volume 14, Issue 4

Abstract: Viral infections, such as those caused by Herpes Simplex Virus-1 (HSV-1) and SARS-CoV-2, affect millions of people each year. However, there are few antiviral drugs that can effectively treat these infections. The standard approach in the development of ... ...

Abstract	Viral infections, such as those caused by Herpes Simplex Virus-1 (HSV-1) and SARS-CoV-2, affect millions of people each year. However, there are few antiviral drugs that can effectively treat these infections. The standard approach in the development of antiviral drugs involves the identification of a unique viral target, followed by the design of an agent that addresses that target. Antimicrobial peptides (AMPs) represent a novel source of potential antiviral drugs. AMPs have been shown to inactivate numerous different enveloped viruses through the disruption of their viral envelopes. However, the clinical development of AMPs as antimicrobial therapeutics has been hampered by a number of factors, especially their enzymatically labile structure as peptides. We have examined the antiviral potential of peptoid mimics of AMPs (sequence-specific
Language	English
Publishing date	2021-03-31
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2193542-7
ISSN	1424-8247
ISSN	1424-8247
DOI	10.3390/ph14040304
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Article ; Online: Development of a tongue-tie case definition in newborns using a Delphi survey: The NYU-Tongue-Tie Case Definition.

Katz, Ralph V / Dearing, Bianca A / Ryan, James M / Ryan, Lisa K / Zubi, Malik K / Sokhal, Gurpreet K

Oral surgery, oral medicine, oral pathology and oral radiology

2019 Volume 129, Issue 1, Page(s) 21–26

Abstract: Objective: The primary purpose of this study was to develop an operational definition of the oral condition of ankyloglossia (also called tongue-tie) that occurs in newborns (i.e., age birth-6 months) and that could consistently be used in research ... ...

Abstract	Objective: The primary purpose of this study was to develop an operational definition of the oral condition of ankyloglossia (also called tongue-tie) that occurs in newborns (i.e., age birth-6 months) and that could consistently be used in research studies. Study design: This 4-round Delphi survey developed the consensus New York University-Tongue-Tie Case Definition (NYU-TTCD) by using a panel of ankyloglossia treatment experts. Results: This tongue-tie case definition (TTCD) was carefully created in a step-wise manner from the bottom up by expert panelists over 4 rounds of inquiry. As a functioning case definition, it offers the diagnostician 2 separate pathways to identifying a newborn as being tongue tied. One pathway requires but a single pathognomonic anatomic feature, and the other pathway requires a single functional deficit accompanied by at least 2 of 12 other diagnostic items (functional, anatomic, or behavioral). Conclusions: This Delphi survey, as administered to a panel of ankyloglossia treatment experts, produced the first consensus case definition of tongue-tie for newborns (i.e., age birth-6 months) for use in epidemiologic research studies ranging from descriptive prevalence studies to clinical trials. Next-step studies should establish the validity, reliability, and utility of this novel NYU-TTCD case definition for epidemiologic and clinical purposes.
MeSH term(s)	Ankyloglossia ; Humans ; Infant, Newborn ; Lingual Frenum ; New York ; Reproducibility of Results ; Surveys and Questionnaires
Language	English
Publishing date	2019-01-17
Publishing country	United States
Document type	Journal Article
ZDB-ID	2650843-6
ISSN	2212-4411 ; 2212-4403
ISSN (online)	2212-4411
ISSN	2212-4403
DOI	10.1016/j.oooo.2019.01.012
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Article ; Online: A Novel Immunocompetent Mouse Model for Testing Antifungal Drugs Against Invasive

Ryan, Lisa K / Hise, Amy G / Hossain, Chowdhury Mobaswar / Ruddick, William / Parveen, Rezwana / Freeman, Katie B / Weaver, Damian G / Narra, Hema P / Scott, Richard W / Diamond, Gill

Journal of fungi (Basel, Switzerland)

2020 Volume 6, Issue 4

Abstract: Disseminated infection ... ...

Abstract	Disseminated infection by
Language	English
Publishing date	2020-09-30
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2784229-0
ISSN	2309-608X ; 2309-608X
ISSN (online)	2309-608X
ISSN	2309-608X
DOI	10.3390/jof6040197
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Article ; Online: Lipidomic analysis of urinary exosomes from hereditary α-tryptasemia patients and healthy volunteers.

Glover, Sarah C / Nouri, Mohammad-Zaman / Tuna, Kubra M / Mendoza Alvarez, Lybil B / Ryan, Lisa K / Shirley, James F / Tang, Ying / Denslow, Nancy D / Alli, Abdel A

FASEB bioAdvances

2019 Volume 1, Issue 10, Page(s) 624–638

Abstract: Exosomes are nano-sized vesicles that are involved in various biological processes including cell differentiation, proliferation, signaling, and intercellular communication. Urinary exosomes were isolated from a cohort of hereditary α-tryptasemia (HαT) ... ...

Abstract	Exosomes are nano-sized vesicles that are involved in various biological processes including cell differentiation, proliferation, signaling, and intercellular communication. Urinary exosomes were isolated from a cohort of hereditary α-tryptasemia (HαT) patients and from healthy volunteers. There was a greater number of exosomes isolated from the urine in the HαT group compared to the control volunteers. Here, we investigated the differences in both lipid classes and lipid species within urinary exosomes of the two groups. Lipids were extracted from urinary exosomes and subjected to liquid chromatography mass spectrometry using a targeted approach. Various molecular species of glycerophospholipids, glycerolipids, and sterols were significantly reduced in HαT patients. Out of a possible 1127 lipids, 521 lipid species were detected, and relative quantities were calculated. Sixty-four lipids were significantly reduced in urinary exosomes of HαT patients compared to controls. All significantly reduced sphingolipids and most of the phospholipids were saturated or mono-unsaturated lipids. These results suggest exosome secretion is augmented in HαT patients and the lipids within these exosomes may be involved in various biological processes. The unique lipid composition of urinary exosomes from HαT patients will contribute to our understanding of the biochemistry of this disease.
Language	English
Publishing date	2019-08-24
Publishing country	United States
Document type	Journal Article
ISSN	2573-9832
ISSN (online)	2573-9832
DOI	10.1096/fba.2019-00030
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Article ; Online: Activation of vitamin D in the gingival epithelium and its role in gingival inflammation and alveolar bone loss.

Menzel, Lorenzo P / Ruddick, Willam / Chowdhury, Mobaswar H / Brice, David C / Clance, Ryan / Porcelli, Emily / Ryan, Lisa K / Lee, Jungnam / Yilmaz, Özlem / Kirkwood, Keith L / McMahon, Laura / Tran, Amy / Diamond, Gill

Journal of periodontal research

2019 Volume 54, Issue 4, Page(s) 444–452

Abstract: Background and objective: Both chronic and aggressive periodontal disease are associated with vitamin D deficiency. The active form of vitamin D, 1,25(OH): Materials and methods: Wild-type C57Bl/6 mice were made deficient in vitamin D by dietary ... ...

Abstract	Background and objective: Both chronic and aggressive periodontal disease are associated with vitamin D deficiency. The active form of vitamin D, 1,25(OH) Materials and methods: Wild-type C57Bl/6 mice were made deficient in vitamin D by dietary restriction. Cultured primary and immortalized GEC were stimulated with 1,25(OH) Results: Dietary restriction of vitamin D led to alveolar bone loss and increased inflammation in the gingiva in the mouse model. In primary human GEC and established human cell lines, treatment of GEC with 1,25(OH) Conclusion: Vitamin D deficiency in mice contributes to PD, recapitulating the association seen in humans, and provides a unique model to study the development of PD. Vitamin D increases the activity of GEC against the invasion of periodontal pathogens and inhibits the inflammatory response, both in vitro and in vivo. GEC can convert inactive vitamin D to the active form in situ, supporting the hypothesis that vitamin D can be applied directly to the gingiva to prevent or treat periodontal disease.
MeSH term(s)	Alveolar Bone Loss/immunology ; Alveolar Bone Loss/physiopathology ; Animals ; Calcifediol/pharmacology ; Cells, Cultured ; Gingiva/physiology ; Humans ; Inflammation/immunology ; Inflammation/physiopathology ; Interleukin-1alpha/immunology ; Mice ; Mice, Inbred C57BL ; Porphyromonas gingivalis ; Vitamin D/pharmacology ; Vitamins/pharmacology
Chemical Substances	Interleukin-1alpha ; Vitamins ; Vitamin D (1406-16-2) ; Calcifediol (P6YZ13C99Q)
Language	English
Publishing date	2019-02-25
Publishing country	United States
Document type	Journal Article
ZDB-ID	390953-0
ISSN	1600-0765 ; 0022-3484
ISSN (online)	1600-0765
ISSN	0022-3484
DOI	10.1111/jre.12646
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Article ; Online: Vitamin D-mediated induction of innate immunity in gingival epithelial cells.

McMahon, Laura / Schwartz, Kyell / Yilmaz, Ozlem / Brown, Eleith / Ryan, Lisa K / Diamond, Gill

Infection and immunity

2011 Volume 79, Issue 6, Page(s) 2250–2256

Abstract: Human gingival epithelial cells (GEC) produce peptides, such as β-defensins and the cathelicidin LL-37, that are both antimicrobial and that modulate the innate immune response. In myeloid and airway epithelial cells, the active form of vitamin D(3) [1, ... ...

Abstract	Human gingival epithelial cells (GEC) produce peptides, such as β-defensins and the cathelicidin LL-37, that are both antimicrobial and that modulate the innate immune response. In myeloid and airway epithelial cells, the active form of vitamin D(3) [1,25(OH)(2)D(3)] increases the expression and antibacterial activity of LL-37. To examine the activity of vitamin D on the innate immune defense of the gingival epithelium, cultured epithelial cells were treated with either 10(-8) M 1,25(OH)(2)D(3) or ethanol for up to 24 h. A time-dependent induction of LL-37 mRNA up to 13-fold at 24 h in both standard monolayer and three-dimensional cultures was observed. Induction of the vitamin D receptor and the 1-α-hydroxylase genes was also observed. The hydroxylase was functional, as LL-37 induction was observed in response to stimulation by 25(OH)D(3). Through microarray analysis of other innate immune genes, CD14 expression increased 4-fold, and triggering receptor expressed on myeloid cells-1 (TREM-1) was upregulated 16-fold after 24 h of treatment with 1,25(OH)(2)D(3). TREM-1 is a pivotal amplifier of the innate immune response in macrophages, leading to increased production by inflammatory response genes. Activation of TREM-1 on the GEC led to an increase in interleukin-8 (IL-8) mRNA levels. Incubation of three-dimensional cultures with 1,25(OH)(2)D(3) led to an increase in antibacterial activity against the periodontal pathogen Aggregatibacter actinomycetemcomitans when the bacteria were added to the apical surface. This study is the first to demonstrate the effect of vitamin D on antibacterial defense of oral epithelial cells, suggesting that vitamin D(3) could be utilized to enhance the innate immune defense in the oral cavity.
MeSH term(s)	Antimicrobial Cationic Peptides/metabolism ; Cells, Cultured ; Epithelial Cells/immunology ; Fluorescent Antibody Technique ; Gene Expression Regulation/immunology ; Gingiva/immunology ; Host-Pathogen Interactions ; Humans ; Immunity, Innate/immunology ; Immunity, Innate/physiology ; Immunoblotting ; Receptors, Calcitriol/immunology ; Reverse Transcriptase Polymerase Chain Reaction ; Vitamin D/physiology
Chemical Substances	Antimicrobial Cationic Peptides ; Receptors, Calcitriol ; Vitamin D (1406-16-2) ; ropocamptide (3DD771JO2H)
Language	English
Publishing date	2011-03-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	218698-6
ISSN	1098-5522 ; 0019-9567
ISSN (online)	1098-5522
ISSN	0019-9567
DOI	10.1128/IAI.00099-11
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Article: Vitamin D-Mediated Induction of Innate Immunity in Gingival Epithelial Cells

McMahon, Laura / Schwartz, Kyell / Yilmaz, Ozlem / Brown, Eleith / Ryan, Lisa K / Diamond, Gill

Infection and immunity. 2011 June, v. 79, no. 6

2011

Abstract	Human gingival epithelial cells (GEC) produce peptides, such as β-defensins and the cathelicidin LL-37, that are both antimicrobial and that modulate the innate immune response. In myeloid and airway epithelial cells, the active form of vitamin D₃ [1,25(OH)₂D₃] increases the expression and antibacterial activity of LL-37. To examine the activity of vitamin D on the innate immune defense of the gingival epithelium, cultured epithelial cells were treated with either 10⁻⁸ M 1,25(OH)₂D₃ or ethanol for up to 24 h. A time-dependent induction of LL-37 mRNA up to 13-fold at 24 h in both standard monolayer and three-dimensional cultures was observed. Induction of the vitamin D receptor and the 1-α-hydroxylase genes was also observed. The hydroxylase was functional, as LL-37 induction was observed in response to stimulation by 25(OH)D₃. Through microarray analysis of other innate immune genes, CD14 expression increased 4-fold, and triggering receptor expressed on myeloid cells-1 (TREM-1) was upregulated 16-fold after 24 h of treatment with 1,25(OH)₂D₃. TREM-1 is a pivotal amplifier of the innate immune response in macrophages, leading to increased production by inflammatory response genes. Activation of TREM-1 on the GEC led to an increase in interleukin-8 (IL-8) mRNA levels. Incubation of three-dimensional cultures with 1,25(OH)₂D₃ led to an increase in antibacterial activity against the periodontal pathogen Aggregatibacter actinomycetemcomitans when the bacteria were added to the apical surface. This study is the first to demonstrate the effect of vitamin D on antibacterial defense of oral epithelial cells, suggesting that vitamin D₃ could be utilized to enhance the innate immune defense in the oral cavity.
Keywords	antibacterial properties ; bacteria ; epithelial cells ; epithelium ; ethanol ; gene expression regulation ; genes ; humans ; inflammation ; innate immunity ; interleukin-8 ; macrophages ; messenger RNA ; microarray technology ; mouth ; pathogens ; peptides ; vitamin D
Language	English
Size	p. 2250-2256.
Publishing place	American Society for Microbiology
Document type	Article
ZDB-ID	218698-6
ISSN	1098-5522 ; 0019-9567
ISSN (online)	1098-5522
ISSN	0019-9567
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Small intestinal immunopathology and GI-associated antibody formation in hereditary alpha-tryptasemia.

The Journal of allergy and clinical immunology

2021 Volume 148, Issue 3, Page(s) 813–821.e7

Abstract: Background: Hereditary alpha-tryptasemia (HαT) is characterized by elevated basal serum tryptase due to increased copies of the TPSAB1 gene. Individuals with HαT frequently present with multisystem complaints, including anaphylaxis and seemingly ... ...

Abstract	Background: Hereditary alpha-tryptasemia (HαT) is characterized by elevated basal serum tryptase due to increased copies of the TPSAB1 gene. Individuals with HαT frequently present with multisystem complaints, including anaphylaxis and seemingly functional gastrointestinal (GI) symptoms. Objective: We sought to determine the prevalence of HαT in an irritable bowel syndrome cohort and associated immunologic characteristics that may distinguish patients with HαT from patients without HαT. Methods: Tryptase genotyping by droplet digital PCR, flow cytometry, cytometry by time-of-flight, immunohistochemistry, and other molecular biology techniques was used. Results: HαT prevalence in a large irritable bowel syndrome cohort was 5% (N = 8/158). Immunophenotyping of HαT PBMCs (N ≥ 27) revealed increased total and class-switched memory B cells. In the small bowel, expansion of tissue mast cells with expression of CD203c, HLA-DR, and FcεRI, higher intestinal epithelial cell pyroptosis, and increased class-switched memory B cells were observed. IgG profiles in sera from individuals with HαT (N = 21) significantly differed from those in individuals with quiescent Crohn disease (N = 20) and non-HαT controls (N = 19), with increased antibodies directed against GI-associated proteins identified in individuals with HαT. Conclusions: Increased mast cell number and intestinal epithelial cell pyroptosis in the small intestine, and class-switched memory B cells in both the gut and peripheral blood associated with IgG reactive to GI-related proteins, distinguish HαT from functional GI disease. These innate and adaptive immunologic findings identified in association with HαT are suggestive of subclinical intestinal inflammation in symptomatic individuals.
MeSH term(s)	Adult ; Epithelial Cells/immunology ; Female ; Gastrointestinal Diseases/blood ; Gastrointestinal Diseases/genetics ; Gastrointestinal Diseases/immunology ; Gastrointestinal Diseases/pathology ; Genetic Diseases, Inborn/blood ; Genetic Diseases, Inborn/genetics ; Genetic Diseases, Inborn/immunology ; Genetic Diseases, Inborn/pathology ; Genotype ; Humans ; Immunoglobulin G/blood ; Immunoglobulin G/immunology ; Intestine, Small/cytology ; Intestine, Small/immunology ; Intestine, Small/pathology ; Male ; Mast Cells/immunology ; Mastocytosis/blood ; Mastocytosis/genetics ; Mastocytosis/immunology ; Mastocytosis/pathology ; Middle Aged ; Pyroptosis ; Tryptases/blood ; Tryptases/genetics ; Young Adult
Chemical Substances	Immunoglobulin G ; TPSAB1 protein, human (EC 3.4.21.59) ; Tryptases (EC 3.4.21.59)
Language	English
Publishing date	2021-04-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
ZDB-ID	121011-7
ISSN	1097-6825 ; 1085-8725 ; 0091-6749
ISSN (online)	1097-6825 ; 1085-8725
ISSN	0091-6749
DOI	10.1016/j.jaci.2021.04.004
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Article ; Online: Potent in vitro and in vivo antifungal activity of a small molecule host defense peptide mimic through a membrane-active mechanism.

Menzel, Lorenzo P / Chowdhury, Hossain Mobaswar / Masso-Silva, Jorge Adrian / Ruddick, William / Falkovsky, Klaudia / Vorona, Rafael / Malsbary, Andrew / Cherabuddi, Kartikeya / Ryan, Lisa K / DiFranco, Kristina M / Brice, David C / Costanzo, Michael J / Weaver, Damian / Freeman, Katie B / Scott, Richard W / Diamond, Gill

Scientific reports

2017 Volume 7, Issue 1, Page(s) 4353

Abstract: Lethal systemic fungal infections of Candida species are increasingly common, especially in immune compromised patients. By in vitro screening of small molecule mimics of naturally occurring host defense peptides (HDP), we have identified several active ... ...

Abstract	Lethal systemic fungal infections of Candida species are increasingly common, especially in immune compromised patients. By in vitro screening of small molecule mimics of naturally occurring host defense peptides (HDP), we have identified several active antifungal molecules, which also exhibited potent activity in two mouse models of oral candidiasis. Here we show that one such compound, C4, exhibits a mechanism of action that is similar to the parent HDP upon which it was designed. Specifically, its initial interaction with the anionic microbial membrane is electrostatic, as its fungicidal activity is inhibited by cations. We observed rapid membrane permeabilization to propidium iodide and ATP efflux in response to C4. Unlike the antifungal peptide histatin 5, it did not require energy-dependent transport across the membrane. Rapid membrane disruption was observed by both fluorescence and electron microscopy. The compound was highly active in vitro against numerous fluconazole-resistant clinical isolates of C. albicans and non-albicans species, and it exhibited potent, dose-dependent activity in a mouse model of invasive candidiasis, reducing kidney burden by three logs after 24 hours, and preventing mortality for up to 17 days. Together the results support the development of this class of antifungal drug to treat invasive candidiasis.
MeSH term(s)	Antifungal Agents/chemistry ; Antifungal Agents/pharmacology ; Candida albicans/drug effects ; Candida albicans/genetics ; Candida albicans/metabolism ; Candida albicans/ultrastructure ; Complement C4/immunology ; Disease Resistance ; Drug Resistance, Fungal ; Host-Derived Cellular Factors/chemistry ; Host-Derived Cellular Factors/pharmacology ; Host-Pathogen Interactions/genetics ; Host-Pathogen Interactions/immunology ; Humans ; Membranes/drug effects ; Microbial Sensitivity Tests ; Peptides/chemistry ; Peptides/pharmacology
Chemical Substances	Antifungal Agents ; Complement C4 ; Host-Derived Cellular Factors ; Peptides
Language	English
Publishing date	2017-06-28
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-017-04462-6
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