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1.
J Med Chem ; 66(16): 11447-11463, 2023 08 24.
Artículo en Inglés | MEDLINE | ID: mdl-37535861

RESUMEN

The design and synthesis of a series of 2,7-diazaspiro[4.4]nonane derivatives as potent sigma receptor (SR) ligands, associated with analgesic activity, are the focus of this work. In this study, affinities at S1R and S2R were measured, and molecular modeling studies were performed to investigate the binding pose characteristics. The most promising compounds were subjected to in vitro toxicity testing and subsequently screened for in vivo analgesic properties. Compound 9d (AD258) exhibited negligible in vitro cellular toxicity and a high binding affinity to both SRs (KiS1R = 3.5 nM, KiS2R = 2.6 nM), but not for other pain-related targets, and exerted high potency in a model of capsaicin-induced allodynia, reaching the maximum antiallodynic effect at very low doses (0.6-1.25 mg/kg). Functional activity experiments showed that S1R antagonism is needed for the effects of 9d and that it did not induce motor impairment. In addition, 9d exhibited a favorable pharmacokinetic profile.


Asunto(s)
Receptores sigma , Humanos , Ligandos , Receptores sigma/metabolismo , Unión Proteica , Dolor , Analgésicos/farmacología , Analgésicos/uso terapéutico
2.
Ocul Surf ; 27: 30-37, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36513277

RESUMEN

PURPOSE: To determine the efficacy of Histatin-5 (Hst5) peptide treatment in ameliorating dry eye disease (DED) phenotype in an in-vivo mouse model of scopolamine and desiccating stress (SDS) dry eye. METHODS: SDS was induced in female C57BL/6 mice by subcutaneous injections of scopolamine hydrobromide and exposure to low relative humidity and forced air draft for five days. Mouse eyes were topically treated with synthetic Hst5 peptide or balanced salt solution (BSS) twice a day for four days. Control mice were not exposed to SDS induction and did not receive any treatments. Oregon green dextran (OGD) staining was used to evaluate corneal permeability. Histologically, staining with periodic acid schiff (PAS), immunohistochemistry (IHC) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), were used to quantify the number of goblet cells (GC), CD45+ immune cells and apoptotic cells respectively in formalin fixed paraffin embedded (FFPE) mouse whole eye sections. RESULTS: Compared to treatment with BSS, Hst5 treatment significantly lowered corneal epithelial permeability, prevented conjunctival epithelial GC loss, decreased conjunctival CD45+ immune cell infiltration and reduced conjunctival epithelial cell apoptosis. CONCLUSIONS: Hst5 peptide topical treatment significantly improves the clinical parameters observed in SDS experimental model of DED. This is the first report of the efficacy of Hst5 treatment of dry eye phenotype, and potential novel treatment for DED in the clinic. Hst5 represents a new class of efficacious therapeutic agents, demonstrating pro-epithelial and anti-inflammatory activities at the ocular surface.


Asunto(s)
Síndromes de Ojo Seco , Histatinas , Femenino , Animales , Ratones , Histatinas/metabolismo , Histatinas/uso terapéutico , Modelos Animales de Enfermedad , Desecación , Ratones Endogámicos C57BL , Síndromes de Ojo Seco/metabolismo , Conjuntiva/patología
3.
Int J Mol Sci ; 22(15)2021 Jul 23.
Artículo en Inglés | MEDLINE | ID: mdl-34360629

RESUMEN

Macrophages play a critical role in the inflammatory response to environmental triggers, such as lipopolysaccharide (LPS). Inflammatory signaling through macrophages and the innate immune system are increasingly recognized as important contributors to multiple acute and chronic disease processes. Nitric oxide (NO) is a free radical that plays an important role in immune and inflammatory responses as an important intercellular messenger. In addition, NO has an important role in inflammatory responses in mucosal environments such as the ocular surface. Histatin peptides are well-established antimicrobial and wound healing agents. These peptides are important in multiple biological systems, playing roles in responses to the environment and immunomodulation. Given the importance of macrophages in responses to environmental triggers and pathogens, we investigated the effect of histatin-1 (Hst1) on LPS-induced inflammatory responses and the underlying molecular mechanisms in RAW264.7 (RAW) macrophages. LPS-induced inflammatory signaling, NO production and cytokine production in macrophages were tested in response to treatment with Hst1. Hst1 application significantly reduced LPS-induced NO production, inflammatory cytokine production, and inflammatory signaling through the JNK and NF-kB pathways in RAW cells. These results demonstrate that Hst1 can inhibit LPS-induced inflammatory mediator production and MAPK signaling pathways in macrophages.


Asunto(s)
Histatinas/farmacología , Activación de Macrófagos/efectos de los fármacos , Macrófagos/efectos de los fármacos , Animales , Citocinas/metabolismo , Evaluación Preclínica de Medicamentos , Lipopolisacáridos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Macrófagos/metabolismo , Ratones , FN-kappa B/metabolismo , Óxido Nítrico/metabolismo , Células RAW 264.7
4.
FEBS J ; 288(23): 6815-6827, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34233061

RESUMEN

The Sigma-2 receptor (S2R) (a.k.a TMEM97) is an important endoplasmic reticular protein involved in cancer, cholesterol processing, cell migration, and neurodegenerative diseases, including Niemann-Pick Type C. While several S2R pharmacologic agents have been discovered, its recent (2017) cloning has limited biological investigation, and no endogenous ligands of the S2R are known. Histatins are a family of endogenous antimicrobial peptides that have numerous important effects in multiple biological systems, including antifungal, antibacterial, cancer pathogenesis, immunomodulation, and wound healing. Histatin-1 (Hst1) has important roles in epithelial wound healing and cell migration, and is the primary wound healing agent in saliva. Little is understood about the downstream machinery that underpins the effects of histatins, and no mammalian receptor is known to date. In this study, we show, using biophysical methods and functional assays, that Hst1 is an endogenous ligand for S2R and that S2R is a mammalian receptor for Hst1.


Asunto(s)
Membrana Celular/metabolismo , Histatinas/metabolismo , Ensayo de Unión Radioligante/métodos , Receptores sigma/metabolismo , Secuencia de Aminoácidos , Movimiento Celular , Células Cultivadas , Células Epiteliales/metabolismo , Epitelio Corneal/citología , Células HEK293 , Células HeLa , Histatinas/genética , Humanos , Ligandos , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Microscopía Confocal , Unión Proteica , Receptores sigma/genética
5.
Int J Mol Sci ; 22(2)2021 Jan 13.
Artículo en Inglés | MEDLINE | ID: mdl-33450870

RESUMEN

The ocular surface has the challenging responsibility of maintaining a clear moist refractive surface while protecting the eye from exogenous pathogens and the environment. Homeostasis of the ocular surface, including its innate immune components, is altered in ocular surface disease states. In this review, we focus on antimicrobial peptides and the role they play in the immune response of the ocular surface during healthy states and dry eye diseases. Antimicrobial peptides are of special interest to the study of the ocular surface because of their various roles that include microbial threat neutralization, wound healing, and immune modulation. This review explores current literature on antimicrobial peptides in ocular surface diseases and discusses their therapeutic potential in ocular surface diseases and dry eye.


Asunto(s)
Córnea/inmunología , Córnea/metabolismo , Síndromes de Ojo Seco/etiología , Síndromes de Ojo Seco/metabolismo , Inmunidad Innata , Inmunomodulación , Proteínas Citotóxicas Formadoras de Poros/metabolismo , Animales , Biomarcadores , Vías Biosintéticas , Defensinas/genética , Defensinas/metabolismo , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Síndromes de Ojo Seco/patología , Síndromes de Ojo Seco/terapia , Expresión Génica , Humanos , Proteínas Citotóxicas Formadoras de Poros/genética , Transporte de Proteínas , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismo
6.
Orbit ; 40(6): 470-480, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-32990145

RESUMEN

PURPOSE: The reconstruction of large (>50%) upper eyelid margin defects can be technically challenging, with multiple approaches described in the literature. We sought to review the recent literature for new techniques or modifications to existing techniques. METHODS: We conducted a Pubmed search for technique papers on the reconstruction of large upper eyelid defects published within the past ten years with a minimum of four patients. RESULTS: We identified ten articles, and divided them into techniques that use a bridging flap from the lower eyelid and those that do not. The number of upper eyelids repaired in each article ranged from 4 to 17. Most techniques could be considered either a modification of the Cutler-Beard technique or a novel anterior lamella flap laid over a graft for the posterior lamella. Postoperative complications included upper or lower eyelid cicatricial retraction, trichiasis, entropion, and lagophthalmos. CONCLUSIONS: Surgeons continue to innovate for this challenging reconstructive surgery. Overall, the trend was to use a graft, most commonly tarsoconjunctiva from the contralateral upper lid, to replace the posterior lamella, and a skin flap, from the lower eyelid or from the adjacent periorbital area, to replace the anterior lamella. Bridging techniques utilized the skin; the skin, orbicularis, and conjunctiva; or a tarsoconjunctival flap from the lower eyelid. Non-bridging techniques generally used a tarsoconjunctival or substitute graft for the posterior lamella, and a skin flap for the anterior lamella.


Asunto(s)
Entropión , Enfermedades de los Párpados , Neoplasias de los Párpados , Procedimientos de Cirugía Plástica , Enfermedades de los Párpados/cirugía , Neoplasias de los Párpados/cirugía , Párpados/cirugía , Humanos , Trasplante de Piel , Colgajos Quirúrgicos
7.
Methods Mol Biol ; 2193: 175-181, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-32808269

RESUMEN

A murine model of corneal epithelial wounding can be performed using simple injury and imaging methods. Here, we describe the creation of a central corneal epithelial defect using mechanical debridement under ophthalmic microscopic visualization. Subsequent monitoring with vital dye application and slit-lamp bio microscopy (slit-lamp) is described in detail.


Asunto(s)
Lesiones de la Cornea/patología , Modelos Animales de Enfermedad , Animales , Lesiones de la Cornea/etiología , Desbridamiento/instrumentación , Desbridamiento/métodos , Epitelio Corneal/patología , Epitelio Corneal/fisiología , Ratones , Ratones Endogámicos C57BL , Procedimientos Quirúrgicos Oftalmológicos/instrumentación , Procedimientos Quirúrgicos Oftalmológicos/métodos , Cicatrización de Heridas
8.
Mol Ther Methods Clin Dev ; 17: 709-716, 2020 Jun 12.
Artículo en Inglés | MEDLINE | ID: mdl-32346548

RESUMEN

Histatin peptides are endogenous anti-microbial peptides that were originally discovered in the saliva. Aside from their broad anti-microbial properties, these peptides play an important role in multiple biological systems. Different members of this family are thought to have relative specializations, with histatin-5 originally being thought to have mostly anti-fungal properties, and histatin-1 having strong wound healing properties. In this report, we describe the robust wound healing properties of histatin-5 and elucidate a functional domain, which is necessary and sufficient for promoting wound healing. We demonstrate these findings in multiple different cell types in vitro and with a standardized murine corneal wound healing model. Discovery of this wound healing domain and description of this functional role of histatin-5 will support developing therapies.

9.
Ocul Surf ; 18(2): 221-230, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-31770600

RESUMEN

PURPOSE: To evaluate the prophylactic antiviral efficacy, corneal tolerance and toxicity of topically dosed BX795, a non-nucleoside small-molecule inhibitor of herpes simplex virus type-1 (HSV-1). METHODS: Prophylactic treatment with BX795 was performed both in-vitro on human corneal epithelial cells and in-vivo on mice prior to HSV-1 challenge. Viral burden was evaluated using a standard plaque assay. In a separate experiment, mice were treated topically 3-times daily for 4-weeks with BX795 to evaluate corneal tolerance and toxicity. Phenol-red thread measurements, fluorescein staining and optical coherence tomography (OCT) were used to evaluate tear production, dryness and corneal structural changes. Corneal sensitivity and intraocular pressure were measured using esthesiometery and tonometery respectively. RESULTS: Both in-vitro and in-vivo results showed a robust suppression of HSV-1 infection when treated prophylactically with BX795. The fluorescein stain and phenol-red results for the BX795-treated eyes did not show signs of corneal surface dryness when compared to trifluridine (TFT), an FDA-approved topical antiviral. The OCT measurements showed no signs of structural changes to the cornea suggesting that BX795 treatment was well tolerated without any apparent signs of toxicity or inflammation. The corneal sensitivity of BX795-treated eyes was not significantly different from TFT-treated eyes. No significant increase in the intraocular pressure of BX795-treated mice was observed. CONCLUSIONS: Prophylactic treatment with BX795 protects corneal cells from HSV-1 infection. The antiviral is well-tolerated on murine corneas without any detectable toxicity.


Asunto(s)
Herpes Simple , Queratitis Herpética , Animales , Córnea , Queratitis Herpética/tratamiento farmacológico , Queratitis Herpética/prevención & control , Ratones , Fosforilación , Proteínas Proto-Oncogénicas c-akt , Pirimidinas , Tiofenos
10.
Sci Rep ; 9(1): 10304, 2019 07 16.
Artículo en Inglés | MEDLINE | ID: mdl-31311993

RESUMEN

The aims of this study were to determine if histatin-1 (H1) is present in normal human tears and whether tear levels of H1 varied between normal patients and those with aqueous deficient dry eye disease (ADDE). Patient samples were obtained from 11 normal patients and 11 severe ADDE patients. Relevant patient characteristics, including age, sex, and dry eye disease (DED) diagnostic parameters were collected. Multiple qualitative and quantitative methods were used to compare the concentration of H1 between patient groups. Mixed linear modeling was used to compare H1 levels between groups, and diagnostic performance was assessed using the receiver-operator-characteristic (ROC). ADDE patients had significantly lower H1 concentrations (85.9 ± 63.7 ng/ml) than the normal group (891.6 ± 196.5 ng/ml) (p < 0.001), while controlling for age and sex. ROC analysis indicated that H1 concentration is potentially a biomarker for ADDE (area under curve = 0.96). Reclassification of patients by DED parameters including, Ocular Surface Disease Index (OSDI) (≤13, >13) and Schirmer I (without anesthesia) (<10 mm, ≥10 mm) showed significant differences in H1 level (OSDI, p = 0.004) and Schirmer I ((p = 0.010). In conclusion, this is the first preliminary report of the presence of H1 in human tears. H1 concentrations are lower in ADDE patients and H1 may have diagnostic potential in evaluation ADDE patients.


Asunto(s)
Regulación hacia Abajo , Síndromes de Ojo Seco/diagnóstico , Histatinas/metabolismo , Lágrimas/metabolismo , Adulto , Biomarcadores/metabolismo , Estudios de Casos y Controles , Síndromes de Ojo Seco/metabolismo , Femenino , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Curva ROC
11.
PLoS One ; 12(5): e0178030, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28542418

RESUMEN

PURPOSE: Ocular surface and corneal epithelial wounds are common and potentially debilitating problems. Ideal treatments for these injuries would promote epithelial healing without inflammation, infection and scarring. In addition the best treatments would be cost-efficient, effective, non-toxic and easily applied. Histatin-1 peptides have been shown to be safe and effective enhancers of epithelial wound healing in other model systems. We sought to determine whether histatin-1 peptides could enhance human corneal epithelial wound healing in vitro. METHODS: Histatin-1 peptides were applied to human corneal epithelial cells and compared over useful dose ranges in scratch assays using time-lapse microscopy. In addition, path finding analysis, cell spreading assays, toxicity and proliferation assays were performed to further characterize the effects of histatin-1 peptide on human corneal limbal epithelial (HCLE). RESULTS: Histatin-1 enhanced human corneal epithelial wound healing in typical wound healing models. There was minimal toxicity and no significant enhancement of proliferation of corneal epithelium in response to histatin-1 application. Corneal epithelial spreading and pathfinding appeared to be enhanced by the application of histatin-1 peptides. CONCLUSIONS: Histatin -1 peptide may enhance migration of HCLE cells and wound healing in vitro. These peptides may have benefit in corneal epithelial wounds and need to be investigated further.


Asunto(s)
Lesiones de la Cornea/tratamiento farmacológico , Epitelio Corneal/efectos de los fármacos , Histatinas/farmacología , Sustancias Protectoras/farmacología , Repitelización/efectos de los fármacos , Análisis de Varianza , Bromodesoxiuridina , Movimiento Celular/efectos de los fármacos , Movimiento Celular/fisiología , Proliferación Celular/efectos de los fármacos , Proliferación Celular/fisiología , Células Cultivadas , Lesiones de la Cornea/metabolismo , Lesiones de la Cornea/patología , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Epitelio Corneal/metabolismo , Epitelio Corneal/patología , Técnica del Anticuerpo Fluorescente , Histatinas/síntesis química , Histatinas/toxicidad , Humanos , Sustancias Protectoras/síntesis química , Sustancias Protectoras/toxicidad , Repitelización/fisiología
12.
PLoS One ; 12(1): e0169346, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28081151

RESUMEN

BACKGROUND: The study of human lacrimal gland biology and development is limited. Lacrimal gland tissue is damaged or poorly functional in a number of disease states including dry eye disease. Development of cell based therapies for lacrimal gland diseases requires a better understanding of the gene expression and signaling pathways in lacrimal gland. Differential gene expression analysis between lacrimal gland and other embryologically similar tissues may be helpful in furthering our understanding of lacrimal gland development. METHODS: We performed global gene expression analysis of human lacrimal gland tissue using Affymetrix ® gene expression arrays. Primary data from our laboratory was compared with datasets available in the NLM GEO database for other surface ectodermal tissues including salivary gland, skin, conjunctiva and corneal epithelium. RESULTS: The analysis revealed statistically significant difference in the gene expression of lacrimal gland tissue compared to other ectodermal tissues. The lacrimal gland specific, cell surface secretory protein encoding genes and critical signaling pathways which distinguish lacrimal gland from other ectodermal tissues are described. CONCLUSIONS: Differential gene expression in human lacrimal gland compared with other ectodermal tissue types revealed interesting patterns which may serve as the basis for future studies in directed differentiation among other areas.


Asunto(s)
Bases de Datos Genéticas , Síndromes de Ojo Seco/metabolismo , Proteínas del Ojo/biosíntesis , Regulación de la Expresión Génica , Aparato Lagrimal/metabolismo , Síndromes de Ojo Seco/patología , Femenino , Humanos , Aparato Lagrimal/patología , Masculino
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