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Pyoderma gangrenosum (PG) is a rare ulcerative neutrophilic dermatosis that is occasionally associated with primary immunodeficiency. Though contributions from dysregulation of the innate immune system, neutrophil dysfunction and genetic predisposition have been postulated, the precise pathogenesis of PG has not yet been elucidated. This article reviews reported cases of coexisting PG and primary immunodeficiency in order to gain insight into the complex pathophysiology of PG. Our findings suggest that variations in genes such as RAG1, ITGB2, IRF2BP2 and NFκB1 might play a role in genetically predisposing patients to develop PG. These studies support the feasibility of the role of somatic gene variation in the pathogenesis of PG which warrants further exploration to guide targeted therapeutics.
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Dermatite , Pioderma Gangrenoso , Humanos , Pioderma Gangrenoso/genética , Predisposição Genética para DoençaRESUMO
IL-23 is an inflammatory cytokine that plays an essential role in Th17 immunity by enhancing Th17 cell proliferation and survival, and Th17 cytokine production. IL-23 has pathogenic roles in the development of Th17-mediated inflammatory diseases including psoriasis. Despite successful treatment of psoriasis by blocking IL-23, the regulation of IL-23 expression in psoriasis patients is largely unknown. Dendritic cells are generally considered to be the primary source of IL-23 in psoriasis. While high levels of IL-23 are found in psoriatic epidermis, IL-23 expression in psoriatic keratinoctyes remains a controversial issue. In this study, we demonstrated that IL-23 production is induced by a combination of TNFα and IL-17A in human keratinocytes. Additionally, this IL-23 induction by TNFα and IL-17A is further increased in psoriatic keratinocytes and is enhanced by EGFR signaling. Although IL-23 is also robustly induced by toll-like receptor agonists in dendritic cells and macrophages, IL-23 expression in these cell types is not regulated by TNFα, IL-17A, and EGFR signaling. Given that IL-23 is essential for maintaining Th17 activation, IL-23 induction by TNFα, IL-17A, and EGF in keratinocytes could play an important pathological role in psoriasis pathogenesis as well as the cutaneous rash associated with EGFR inhibition therapy.
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Fator de Crescimento Epidérmico/biossíntese , Regulação da Expressão Gênica , Interleucina-17/biossíntese , Subunidade p19 da Interleucina-23/biossíntese , Queratinócitos/metabolismo , Fator de Necrose Tumoral alfa/biossíntese , Biópsia , Proliferação de Células , Citocinas/metabolismo , Células Dendríticas/metabolismo , Epiderme/metabolismo , Humanos , Interleucina-1/metabolismo , Monócitos/metabolismo , Psoríase/metabolismo , Transdução de Sinais , Pele/patologia , Células THP-1/metabolismo , Células Th17/imunologiaRESUMO
Patient experience surveys (PES) are collected by healthcare systems as a surrogate marker of quality and published unedited online for the purpose of transparency, but these surveys may reflect gender biases directed toward healthcare providers. This retrospective study evaluated PES at a single university hospital between July 2016 and June 2018. Surveys were stratified by overall provider rating and self-identified provider gender. Adjectives from free-text survey comments were extracted using natural language processing techniques and applied to a statistical machine learning model to identify descriptors predictive of provider gender. 109,994 surveys were collected, 17,395 contained free-text comments describing 687 unique providers. The mean overall rating between male (8.84, n = 8558) and female (8.80, n = 8837) providers did not differ (p = 0.149). However, highly-rated male providers were more often described for their agentic qualities using adjectives such as "informative," "forthright," "superior," and "utmost" (OR 1.48, p < 0.01)-whereas highly-rated female providers were more often described by their communal qualities through adjectives such as "empathetic," "sweet," "warm," "attentive," and "approachable" (OR 2.11, p < 0.0001). PES may contain gender stereotypes, raising questions about their impact on physicians and their validity as a quality metric which must be balanced with the need for unedited transparency. Future prospective studies are needed to further characterize this trend across geographically and racially diverse healthcare providers.
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Atenção à Saúde , Pessoal de Saúde , Feminino , Humanos , Masculino , Avaliação de Resultados da Assistência ao Paciente , Satisfação do Paciente , Estudos Retrospectivos , Inquéritos e QuestionáriosAssuntos
Colite Ulcerativa , Dermatologia , Pioderma Gangrenoso , Humanos , Pioderma Gangrenoso/diagnóstico , Técnica Delphi , ConsensoAssuntos
Melanoma/diagnóstico , Segunda Neoplasia Primária/diagnóstico , Nevo com Halo/diagnóstico , Neoplasias Cutâneas/diagnóstico , Adolescente , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Adulto JovemRESUMO
Human visual function depends on the biological lens, a biconvex optical element formed by coordinated, synchronous generation of growth shells produced from ordered cells at the lens equator, the distal edge of the epithelium. Growth shells are comprised of straight (St) and S-shaped (SSh) lens fibers organized in highly symmetric, sinusoidal pattern which optimizes both the refractile, transparent structure and the unique microcirculation that regulates hydration and nutrition over the lifetime of an individual. The fiber cells are characterized by diversity in composition and age. All fiber cells remain interconnected in their growth shells throughout the life of the adult lens. As an optical element, cellular differentiation is constrained by the physical properties of light and its special development accounts for its characteristic symmetry, gradient of refractive index (GRIN), short range transparent order (SRO), and functional longevity. The complex sinusoidal structure is the basis for the lens microcirculation required for the establishment and maintenance of image formation.
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INTRODUCTION: A survey was conducted by The Harris Poll on behalf of Arcutis Biotherapeutics in the USA to understand perspectives and burden of patients with psoriasis using prescription topical treatments for their disease. This manuscript presents results from the subset of patients with intertriginous psoriasis. METHODS: The survey was conducted online October 21-November 24, 2021, among 507 US adults aged 18+ years with psoriasis diagnosed by a healthcare provider and currently using prescription topical treatment. Participants with intertriginous psoriasis were patients with plaque psoriasis reporting symptoms in the armpit, groin, under breast, stomach fold, or between the buttocks. RESULTS: Of the 507 respondents, 320 (64%) reported symptoms in intertriginous areas at some point, typically between the buttocks (31%). Most patients with intertriginous psoriasis reported it made them feel embarrassed (80%), anxious (79%), or depressed (69%). In addition, 45% of these patients reported intertriginous psoriasis caused a negative impact on sexual anxiety or distress. Quality of life impact was reported as "very strong negative impact" in 16% of patients with groin involvement vs. 6% in patients with no groin involvement and 15% in women vs. 6% in men. Patients with intertriginous psoriasis reported that itch (61%), scaling (53%), redness (49%), and skin cracking (46%) related to intertriginous psoriasis had the greatest negative impact on quality of life. Most (86%) of these patients said they would be more adherent if a single treatment option could be used to treat all affected areas of their body. CONCLUSION: Psoriasis involvement in intertriginous areas over the course of disease is common and has a negative impact on these patients' quality of life, particularly emotional well-being and sexual health.
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BACKGROUND: Topical treatments are the foundation for patients with psoriasis; however, adherence can be limited by patient preferences and treatment burden. METHODS: The Harris Poll conducted an online survey of US patients with psoriasis who use prescription topical therapy to examine their preferences and perspectives on topical treatments. RESULTS: Among patients with psoriasis who use topical treatment (n = 507), most participants described their psoriasis symptoms as mild (31%) or moderate (59%). The body areas most often reported to be affected by psoriasis were the scalp, elbows, legs, intertriginous areas, arms, and knees. Participants reported psoriasis affecting the scalp (39%), elbows (20%), and legs (excluding knees; 19%) caused the greatest impact on quality of life. Most participants (76%) preferred topical therapies to treat their psoriasis, while 20% preferred pills, and 4% preferred injections. The most common product attributes that participants wanted in a topical psoriasis treatment and that would help them to continue to use the treatment were: improvement in plaques (68%), itch relief (68%), and easy to apply (63%). CONCLUSION: The respondents to this survey reported that they prefer topical treatments to pills or injections (76%) and most (89%) reported they are interested in trying a new topical treatment.
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Fármacos Dermatológicos , Preferência do Paciente , Psoríase , Qualidade de Vida , Humanos , Psoríase/tratamento farmacológico , Masculino , Estados Unidos , Feminino , Adulto , Pessoa de Meia-Idade , Fármacos Dermatológicos/administração & dosagem , Fármacos Dermatológicos/uso terapêutico , Administração Tópica , Inquéritos e Questionários , Efeitos Psicossociais da Doença , Idoso , Adulto Jovem , Índice de Gravidade de Doença , Administração Cutânea , Adesão à Medicação/estatística & dados numéricosRESUMO
INTRODUCTION: Teledermatology, defined as the use of remote imaging technologies to provide dermatologic healthcare services to individuals in a distant setting, has grown considerably in popularity since its widespread implementation during the COVID-19 pandemic. Teledermoscopy employs a smartphone dermatoscope attachment paired with a smartphone camera to visualize colors and microstructures within the epidermis and superficial dermis that cannot be seen with the naked eye ABCD criteria alone. METHODS: Our retrospective observational cohort and case-control study evaluated the utility of loaning a smartphone dermatoscope attachment to patients for remote triage of self-selected lesions of concern for skin cancer. The primary outcome was the number (percentage) of in-person follow-up visits required for patients who submitted lesion images, either with or without accompanying dermoscopic images. A medical record review was conducted on all Oregon Health & Science University Department of Dermatology spot check image submissions utilizing the smartphone dermatoscopes between August 2020 and August 2022. De-identified dermoscopic images of lesions that included corresponding non-dermoscopic clinical images in their submission (n = 70) were independently reviewed by a blinded expert dermoscopist. The expert used standard clinical algorithms (ABCD criteria for clinical images; dermoscopy three-point checklist for dermoscopic images) to determine whether the imaged lesion should be converted to an in-person visit for further evaluation and consideration for biopsy. RESULTS: Of the 70 lesions submitted with corresponding clinical and dermoscopy images, 60 met the criteria for in-person evaluation from clinical (non-dermoscopic) image review compared to 28 meeting the criteria for in-person evaluation from dermoscopic images of the same lesion. Thus, a 53% reduction in conversion to an in-person consultation with the addition of smartphone dermatoscope images in virtual lesion triage was observed (p < 0.001, McNemar's Test). CONCLUSION: Implementing patient-led teledermoscopy may reduce the frequency of in-person visits for benign lesions and consequently improve access to in-person dermatology consultations for patients with concerning and possibly malignant lesions.
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Importance: There is no US Food and Drug Administration-approved treatment for pityriasis rubra pilaris (PRP), and it is common for patients to fail to experience improvement with several systemic options. Involvement of interleukin (IL) 23 suggests a potential therapeutic target. Objective: To determine whether guselkumab, an IL-23p19 inhibitor, provides clinical improvement for participants with PRP and better understand gene and protein dysregulation in PRP. Design, Setting, and Participants: This single-arm, investigator-initiated nonrandomized trial was conducted from October 2019 to August 2022 at a single-center academic university with participants from 8 states in the US. In total, 14 adults with moderate to severe PRP were enrolled; 12 completed the trial. Age-matched and sex-matched healthy controls provided skin and blood for proteomic and transcriptomic studies. The primary outcome was observed at 24 weeks, and additional follow-up occurred at 36 weeks. Intervention: Guselkumab is a fully human immunoglobulin G1 λ monoclonal antibody that selectively binds and inhibits the p19 subunit of IL-23. Subcutaneous injections were given at the US Food and Drug Administration-approved dosing schedule for psoriasis over a 24-week period. Main Outcomes and Measures: The primary outcome was the mean change in the Psoriasis Area Severity Index (PASI) score at week 24. Secondary outcomes included pruritus, Dermatology Life Quality Index score, clinical response at week 36, and association with transcriptomics and proteomics expression. Results: A per-protocol analysis was performed for the cohort of 4 female and 8 male patients who had a mean (SD) age of 56.5 (18.7) years. The mean improvement in PASI score, pruritus, and Dermatology Life Quality Index score was 61.8% (P < .001), 62.3% (P = .001), and 60.2% (P < .001), respectively. Nine participants (75%) achieved a 50% improvement in PASI. Among these clinical responders, at week 36, 8 of 9 achieved PASI75, and 6 of 9 achieved PASI90. No participants had pathogenic CARD14 gene variations. There was 1 serious adverse event that was not associated with the study drug. Proteomics and gene expression profiles identified dysregulation of a predominance of inflammatory pathways (such as T helper 17 and nuclear factor κ B) in participants with PRP who later responded well to treatment with guselkumab and stronger dysregulation of keratinocyte development pathways in individuals who did not respond to guselkumab. Conclusion and Relevance: The results of this nonrandomized trial suggest that guselkumab has efficacy in treating refractory moderate to severe adult PRP. Trial Registration: ClinicalTrials.gov Identifier: NCT03975153.
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Anticorpos Monoclonais Humanizados , Interleucina-17 , Pitiríase Rubra Pilar , Transdução de Sinais , Humanos , Pitiríase Rubra Pilar/tratamento farmacológico , Masculino , Feminino , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/farmacologia , Pessoa de Meia-Idade , Adulto , Interleucina-17/antagonistas & inibidores , Interleucina-17/metabolismo , Transdução de Sinais/efeitos dos fármacos , Índice de Gravidade de Doença , Interleucina-23/antagonistas & inibidores , Resultado do Tratamento , Subunidade p19 da Interleucina-23/antagonistas & inibidores , Idoso , Injeções Subcutâneas , Guanilato Ciclase/metabolismo , Proteínas de Membrana , Proteínas Adaptadoras de Sinalização CARDRESUMO
When prescribing low-dose methotrexate, frequent serological testing is recommended in the dermatologic literature, although much of the supporting data is extrapolated from non-dermatologic conditions. We performed a retrospective cohort study to determine the cumulative incidence and timing of low-dose methotrexate-associated serological abnormalities over the first year of therapy, in a pragmatic cohort of patients with dermatologic compared to non-dermatologic diagnoses. Laboratory values recorded included white blood cell count, hemoglobin, platelet count, estimated glomerular filtration rate, alanine aminotransferase, and aspartate aminotransferase. Among 1376 patients, there were no cases of methotrexate-associated grade 4/very severe lab abnormality or fatality. Baseline risk factors associated with moderate-to-severe lab abnormalities included non-dermatologic diagnoses, low hemoglobin, low estimated glomerular filtration rate, and elevated transaminases. The incidence of moderate-to-severe lab abnormalities was 4.4% among all patients, 3.1% among patients with dermatologic diagnoses, and 2.3% among patients with normal baseline lab values. Lab abnormalities led to discontinuation of therapy in 0.8% of patients. Serious changes did not occur in the first two weeks of therapy. We conclude that the cumulative incidence of low-dose methotrexate-associated lab abnormality was lower in patients with dermatologic diagnoses or normal baseline testing and these factors may be used to adjust monitoring practices.
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Dermatologia , Metotrexato , Aspartato Aminotransferases , Estudos de Coortes , Humanos , Metotrexato/efeitos adversos , Estudos RetrospectivosRESUMO
Cutaneous T-cell lymphoma (CTCL) is a life-debilitating malignancy of lymphocytes homing to the skin. Although CTCL is thought to arise from a combination of genetic, epigenetic, and environmental factors, specific triggers are unclear. The skin is colonized by a unique microbiota and is heavily influenced by its interactions. We hypothesized that adaptive immune responses to skin commensals lead to clonal T-cell proliferation and transformation in the appropriate genetic background. We therefore collected lesional and nonlesional skin microbiota from patients with CTCL to study T cell interactions using skin T cell explants and peripheral, skin-homing CD4+ T cells. By various methods, we identified Bacillus safensis in CTCL lesions, a rare human commensal in healthy skin, and showed that it can induce malignant T cell activation and cytokine secretion. Taken together, our data suggest microbial triggers in the skin microbiota of patients with CTCL as potential instigators of tumorigenesis.
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Importance: Shared decision-making (SDM) can improve the quality of care for patients. The extent to which this tool has been used and the evidence supporting its use in dermatology have not been systematically examined. Objective: To perform a scoping review of the literature regarding SDM in dermatology. Evidence Review: Searches of Ovid MEDLINE, PsycINFO, PsycARTICLES, Sciverse Scopus, and EBM Reviews were conduced on July 11, 2019, and March 6, 2020. There were no limits on date, type of article, language, or subject for the initial search. A total of 1673 titles and abstracts were screened by 2 independent reviewers in the Covidence mixed-methods platform. Forty-one full-text studies were assessed for eligibility. For inclusion, articles needed to include a dermatologic diagnosis as well as discussion of SDM or patient decision aids. Two independent reviewers screened 29 full-text articles for inclusion and extracted qualitative data using a set of 26 predefined codes. Qualitative coding was applied to excerpts to categorize the article, define and describe advantages and disadvantages of SDM, understand patient and physician requests for SDM, and discuss methods of implementation. Findings: Despite a small number of articles on SDM (n = 29) in dermatology, the selected literature provided consistent messages regarding the importance of SDM for dermatology and a number of strategies and tools for implementation. Medical dermatology was the most common subspecialty studied, with melanoma, psoriasis, and connective tissue diseases most examined. Only 5 publications introduced SDM tools specifically for dermatologic conditions; of these, only 2 tools were validated. Barriers to implementation that were cited included time and a lack of training for clinicians, although the literature also provided potential solutions to these issues. All articles emphasized the value of SDM for both patients and physicians. Conclusions and Relevance: The literature regarding SDM in dermatology consistently suggests that it is a useful tool for providing patient-centered care. Established tools have been proposed since 2012. More research is needed to implement better practices, especially in dermatologic subspecialties. However, there are substantial suggestions from the literature for strategies and tools with which to begin a shared decision-making practice.
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Tomada de Decisão Compartilhada , Dermatologia/normas , Qualidade da Assistência à Saúde , Humanos , Assistência Centrada no Paciente/normas , Dermatopatias/terapiaRESUMO
In vivo, high-resolution, time-lapse imaging characterized lens development in the zebrafish from 16 to 96 hr postfertilization (hpf). In zebrafish, the lens placode appeared in the head ectoderm, similar to mammals. Delamination of the surface ectoderm resulted in the formation of the lens mass, which progressed to a solid sphere of cells separating from the developing cornea at approximately 24 hpf. A lens vesicle was not observed and apoptosis was not a major factor in separation of the lens from the future cornea. Differentiation of primary fibers began in the lens mass followed by formation of the anterior epithelium after delamination was complete. Secondary fibers differentiated from elongating epithelial cells near the posterior pole. Quantification characterized three stages of lens growth. The study confirmed the advantages of live-cell imaging for three-dimensional quantitative structural characterization of the mechanism(s) responsible for cell differentiation in formation of a transparent, symmetric, and refractile lens.
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Cristalino/embriologia , Microscopia de Fluorescência por Excitação Multifotônica/métodos , Peixe-Zebra/embriologia , Animais , Regulação da Expressão Gênica no DesenvolvimentoRESUMO
Host-microbiota interactions are fundamental for the development of the immune system. Drastic changes in modern environments and lifestyles have led to an imbalance of this evolutionarily ancient process, coinciding with a steep rise in immune-mediated diseases such as autoimmune, allergic and chronic inflammatory disorders. There is an urgent need to better understand these diseases in the context of mucosal and skin microbiota. This Review discusses the mechanisms of how the microbiota contributes to the predisposition, initiation and perpetuation of immune-mediated diseases in the context of a genetically prone host. It is timely owing to the wealth of new studies that recently contributed to this field, ranging from metagenomic studies in humans and mechanistic studies of host-microorganism interactions in gnotobiotic models and in vitro systems, to molecular mechanisms with broader implications across immune-mediated diseases. We focus on the general principles, such as breaches in immune tolerance and barriers, leading to the promotion of immune-mediated diseases by gut, oral and skin microbiota. Lastly, the therapeutic avenues that either target the microbiota, the barrier surfaces or the host immune system to restore tolerance and homeostasis will be explored.
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Interações entre Hospedeiro e Microrganismos/fisiologia , Sistema Imunitário/imunologia , Microbiota/imunologia , Microbiota/fisiologia , Animais , Interações entre Hospedeiro e Microrganismos/genética , HumanosRESUMO
Importance: Pityriasis rubra pilaris is a rare and disabling cutaneous disease that is frequently recalcitrant to conventional therapies and appears to involve interleukin (IL)-17 overexpression. Objective: To investigate the clinical response and safety of ixekizumab in treating pityriasis rubra pilaris. Design, Setting, and Participants: Single-arm, investigator-initiated trial conducted in adult patients with moderate to severe pityriasis rubra pilaris at a single-center academic university from June 2018 to January 2020. A total of 41 patients were screened, 12 were enrolled, and 11 completed the full duration of therapy. A referred, consecutive sample was used during participant selection. The treatment period and primary outcome occurred over 24 weeks with additional patient follow-up through 36 weeks. Intervention: Subcutaneous administration of ixekizumab, a humanized IgG4 antibody that binds IL-17A, at the US Food and Drug Administration-approved dosing schedule for treatment of psoriasis for 24 weeks. Main Outcomes and Measures: The primary outcome was the mean change in Psoriasis Area and Severity Index at 24 weeks. Secondary outcomes included change in affected body surface area, quality of life, induction of sustained remission, and association of improvement with CARD14 genetic variations and cutaneous cytokine expression. Results: A total of 12 white patients (mean [SD] age, 49.8 [15.1] years; 8 male [67%]) were enrolled between June 2018 and April 2019, with 11 completing the full course of intervention. The mean (SEM) improvements in Psoriasis Area and Severity Index, affected body surface area, and Dermatology Life Quality Index were 15.2 (2.1) (P < .0001), 29.8% (9.3%) (P = .009), and 9.5 (2.5) (P = .004), respectively. The 4 participants with the most improvement in Psoriasis Area and Severity Index at week 24 stayed in remission at week 36 (defined as lack of increase in Psoriasis Area and Severity Index from week 24 through week 36), off therapy. Relative dermal IL-17A expression decreased by a 1.9 log-fold change. No participants had known pathogenic CARD14 variations. There were no serious adverse events. Conclusions and Relevance: In this single-armed trial, ixekizumab was associated with reduced clinical signs and symptoms of pityriasis rubra pilaris in a subset of patients, including those in whom other systemic therapies have failed. Trial Registration: ClinicalTrials.gov Identifier: NCT03485976.
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Anticorpos Monoclonais Humanizados/administração & dosagem , Fármacos Dermatológicos/administração & dosagem , Pitiríase Rubra Pilar/tratamento farmacológico , Adulto , Anticorpos Monoclonais Humanizados/efeitos adversos , Proteínas Adaptadoras de Sinalização CARD/genética , Análise Mutacional de DNA , Fármacos Dermatológicos/efeitos adversos , Feminino , Seguimentos , Mutação com Ganho de Função , Guanilato Ciclase/genética , Humanos , Interleucina-17/análise , Interleucina-17/antagonistas & inibidores , Interleucina-17/metabolismo , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Pitiríase Rubra Pilar/diagnóstico , Pitiríase Rubra Pilar/genética , Pitiríase Rubra Pilar/patologia , Qualidade de Vida , Índice de Gravidade de Doença , Pele/efeitos dos fármacos , Pele/metabolismo , Pele/patologia , Resultado do TratamentoRESUMO
PURPOSE: Changes in lens protein expression during zebrafish development results in a smooth gradient of refractive index necessary for excellent optical function. Age-related changes in crystallin expression have been well documented in mammals but are poorly understood in the zebrafish. METHODS: In the zebrafish lens, a systematic analysis of protein content with age was performed using size exclusion chromatography (SEC) combined with linear trap quadrupole Fourier transform tandem mass spectrometry (LTQ-FT LC-MS/MS; rank-order shotgun) proteomics in lenses of larval, juvenile, and adult zebrafish. RESULTS: alpha-Crystallins, previously shown to have low abundance in the zebrafish lens, were found to increase dramatically with maturation and aging. SEC determined that beta-crystallin was predominant at 4.5 days. With age, the alpha- and gamma-crystallins increased, and a high molecular weight fraction appeared between six weeks and six months to become the dominant component by 2.5 years. Similarly, shotgun proteomics determined that beta-crystallins were the predominant proteins in the young lens. With age, the proportion of alpha- and gamma-crystallins increased dramatically. After crystallins, calpain 3, membrane, and cytoskeletal proteins were most abundant. Five new beta-crystallins and 13 new gamma-crystallins were identified. CONCLUSIONS: As expected, SEC and proteomics demonstrated changing levels of protein expression with age, especially among the crystallins. The results also confirmed the existence of novel crystallins in the zebrafish genome.
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Envelhecimento/metabolismo , Cristalino/metabolismo , Proteoma/metabolismo , Peixe-Zebra/crescimento & desenvolvimento , Peixe-Zebra/metabolismo , Animais , Pareamento de Bases , Cromatografia em Gel , Cromatografia Líquida , Cromossomos/metabolismo , Cristalinas/metabolismo , Espectrometria de Massas , Filogenia , Proteômica , Peixe-Zebra/genéticaRESUMO
SPARC is a matricellular glycoprotein involved in regulation of extracellular matrix, growth factors, adhesion, and migration. SPARC-null mice have altered basement membranes and develop posterior sub-capsular cataracts with cell swelling and equatorial vacuoles. Exchange of fluid, nutrients, and waste products in the avascular lens is driven by a unique circulating ion current. In the absence of SPARC, increased circulation of fluid, ions, and small molecules led to increased fluorescein distribution in vivo, loss of resting membrane polarization, and altered distribution of small molecules. Microarray analysis of SPARC-null lenses showed changes in gene expression of ion channels and receptors, matrix and adhesion genes, cytoskeleton, immune response genes, and cell signaling molecules. Our results confirm the hypothesis that the regulation of SPARC on cell-capsular matrix interactions can increase the circulation of fluid and ions in the lens, and the phenotype in the SPARC-null mouse lens is the result of multiple intersecting functional pathways.