RESUMO
Hailey-Hailey disease is a rare hereditary skin disease caused by mutations in the ATP2C1 gene encoding the secretory pathway Ca2+/Mn2+-ATPase 1 (SPCA1) protein. Extracutaneous manifestations of Hailey-Hailey disease are plausible but still largely unknown. The aim of this study was to explore the association between Hailey-Hailey disease and diabetes. A population-based cohort study of 347 individuals with Hailey-Hailey disease was performed to assess the risks of type 1 diabetes and type 2 diabetes, using Swedish nationwide registries. Pedigrees from 2 Swedish families with Hailey-Hailey disease were also investigated: 1 with concurrent type 1 diabetes and HLA-DQ3, the other with type 2 diabetes. Lastly, a clinical cohort with 23 individuals with Hailey-Hailey disease and matched healthy controls was evaluated regarding diabetes. In the register data males with Hailey-Hailey disease had a 70% elevated risk of type 2 diabetes, whereas no excess risk among women could be confirmed. In both pedigrees an unusually high inheritance for diabetes was observed. In the clinical cohort, individuals with Hailey-Hailey disease displayed a metabolic phenotype indicative of type 2 diabetes. Hailey-Hailey disease seems to act as a synergistic risk factor for diabetes. This study indicates, for the first time, an association between Hailey-Hailey disease and diabetes and represents human evidence that SPCA1 and the Golgi apparatus may be implicated in diabetes pathophysiology.
Assuntos
Diabetes Mellitus Tipo 2 , Pênfigo Familiar Benigno , Masculino , Humanos , Feminino , Pênfigo Familiar Benigno/diagnóstico , Pênfigo Familiar Benigno/epidemiologia , Pênfigo Familiar Benigno/genética , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Linhagem , Estudos de Coortes , ATPases Transportadoras de Cálcio/genética , ATPases Transportadoras de Cálcio/metabolismo , MutaçãoRESUMO
The mucus layer covering the skin of fish has several roles, including protection against pathogens and mechanical damage in which proteins play a key role. While proteins in the skin mucus layer of various common bony fish species have been explored, the proteins of shark skin mucus remain unexplored. In this pilot study, we examine the protein composition of the skin mucus in spiny dogfish sharks and chain catsharks through mass spectrometry (NanoLC-MS/MS). Overall, we identified 206 and 72 proteins in spiny dogfish (Squalus acanthias) and chain catsharks (Scyliorhinus retifer), respectively. Categorization showed that the proteins belonged to diverse biological processes and that most proteins were cellular albeit a significant minority were secreted, indicative of mucosal immune roles. The secreted proteins are reviewed in detail with emphasis on their immune potentials. Moreover, STRING protein-protein association network analysis showed that proteins of closely related shark species were more similar as compared to a more distantly related shark and a bony fish, although there were also significant overlaps. This study contributes to the growing field of molecular shark studies and provides a foundation for further research into the functional roles and potential human biomedical implications of shark skin mucus proteins.
Assuntos
Tubarões , Squalus acanthias , Animais , Projetos Piloto , Squalus acanthias/metabolismo , Espectrometria de Massas em TandemRESUMO
The mucus layer covering the skin of fish has several roles, including protection against pathogens and mechanical damage. While the mucus layers of various bony fish species have been investigated, the composition and glycan profiles of shark skin mucus remain relatively unexplored. In this pilot study, we aimed to explore the structure and composition of shark skin mucus through histological analysis and glycan profiling. Histological examination of skin samples from Atlantic spiny dogfish (Squalus acanthias) sharks and chain catsharks (Scyliorhinus retifer) revealed distinct mucin-producing cells and a mucus layer, indicating the presence of a functional mucus layer similar to bony fish mucus albeit thinner. Glycan profiling using liquid chromatography-electrospray ionization tandem mass spectrometry unveiled a diverse repertoire of mostly O-glycans in the mucus of the two sharks as well as little skate (Leucoraja erinacea). Elasmobranch glycans differ significantly from bony fish, especially in being more sulfated, and some bear resemblance to human glycans, such as gastric mucin O-glycans and H blood group-type glycans. This study contributes to the concept of shark skin having unique properties and provides a foundation for further research into the functional roles and potential biomedical implications of shark skin mucus glycans.
RESUMO
Managing painful hard-to-heal leg ulcers is challenging with current therapeutic options. Wounds are prone to being hypoxic, and the subsequent pain is often related to hypoxia. Hyperbaric oxygen therapy (HBOT) is used to treat hard-to-heal leg wounds by delivering 100% oxygen at a pressure 2-3 times higher than atmospheric pressure. Unfortunately, most patients cannot be offered HBOT because it is costly and needs to be applied at specialised centres. Therefore, topical continuous oxygen therapy (TCOT) is a novel alternative for continuous local oxygen delivery to wounds and is associated with improved wound healing; however, its effect on painful wounds is unknown. This retrospective study was conducted on 20 patients, of whom 17 had painful hard-to-heal leg ulcers. In 13 patients (76%) with painful ulcers, TCOT was associated with rapid and substantial pain alleviation. Also, eight (40%) of the patients' wounds healed entirely with TCOT. This study suggests that TCOT may represent a novel pain management device for hard-to-heal wounds.
Assuntos
Úlcera da Perna , Oxigênio , Humanos , Úlcera da Perna/terapia , Dor/etiologia , Estudos Retrospectivos , CicatrizaçãoRESUMO
Darier disease is a severe, rare autosomal dominant inherited skin condition caused by mutations in the ATP2A2 gene encoding sarcoendoplasmic reticulum Ca2+-ATPase isoform 2 in the endoplasmic reticulum. Since sarcoendoplasmic reticulum Ca2+-ATPase isoform 2 is expressed in most tissues, and intracellular calcium homeostasis is of fundamental importance, it is conceivable that other organs besides the skin may be involved in Darier disease. This review focusses on the association of Darier disease with other organ dysfunctions and diseases, emphasizing their common molecular pathology. In conclusion, Darier disease should be considered a systemic condition that requires systemic and disease mechanism targeted treatments.
Assuntos
Doença de Darier , Doença de Darier/diagnóstico , Doença de Darier/genética , Humanos , Mutação , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética , Pele/metabolismoRESUMO
Darier disease and Hailey-Hailey disease are severe, monogenetic dermatological disorders with mutations affecting all cells, making them liable to exhibit extra-dermal symptoms. The aim of this study is to assess broad cognitive function in individuals with these diseases, using an experimental, case-control set-up comparing cognition in patients with that in healthy controls matched for age, sex and level of education. Cognition was assessed with the Cambridge Neuropsycho-logical Test Automated Battery. Patients with Darier disease (n = 29) performed significantly poorer on 5 of the 10 key cognitive measurements, while patients with Hailey-Hailey disease (n = 25) did not perform differently from controls. The main conclusion is that patients with Darier disease exhibit significant impairment in cognitive function, which reinforces the view that Darier disease should be regarded as a disorder affecting multiple organs, and should therefore be given medical consideration, and possibly treat-ment, as such.
Assuntos
Disfunção Cognitiva , Doença de Darier , Pênfigo Familiar Benigno , Estudos de Casos e Controles , Doença de Darier/diagnóstico , Doença de Darier/genética , Humanos , Mutação , Pênfigo Familiar Benigno/diagnóstico , Pênfigo Familiar Benigno/genéticaRESUMO
During wound healing, cells have a high rate of protein synthesis and many proteins need to be folded post-translationally to function, which occurs in the endoplasmic reticulum (ER). In addition to proliferation, several cellular stress conditions, such as hypoxia, in the wound micro-environment lead to the accumulation of unfolded or misfolded proteins in the ER, causing ER stress. Eukaryotic cells have a signalling system to manage ER stress called the unfolded protein response (UPR). Mild UPR activation has a beneficial homeostatic effect; however, excessive UPR induces cell death. Herein, we examined venous leg ulcer biopsies versus normal acute incisional wounds in age-matched elderly subjects and found a large increase in ER stress markers. To study the underlying mechanism, we established several cell cultures from amputated legs from the elderly that showed inherent ER stress. While both keratinocytes and fibroblasts migration was impaired by ER stress, migration of elderly leg skin keratinocytes was markedly improved after treatment with the chemical chaperone and clinically established drug 4-phenylbutyrate (4-PBA) and demonstrated a reduction in ER stress markers. In a full-thickness human skin wound healing model, 4-PBA improved the reepithelialisation rate, which suggests it as a promising drug repurposing candidate for wound healing.
Assuntos
Estresse do Retículo Endoplasmático , Fenilbutiratos , Cicatrização , Fibroblastos , Humanos , Queratinócitos , Pessoa de Meia-Idade , Fenilbutiratos/uso terapêutico , Resposta a Proteínas não Dobradas , Úlcera VaricosaAssuntos
Doença de Darier , Humanos , Doença de Darier/complicações , Doença de Darier/psicologia , Doença de Darier/epidemiologia , Doença de Darier/diagnóstico , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Transtornos de Ansiedade/epidemiologia , Transtornos de Ansiedade/etiologia , Transtornos de Ansiedade/psicologia , Transtorno Depressivo/epidemiologia , Transtorno Depressivo/etiologia , Transtorno Depressivo/psicologia , Ansiedade/etiologia , Ansiedade/psicologia , Ansiedade/epidemiologia , Depressão/epidemiologia , Depressão/psicologia , Depressão/etiologia , Idoso , Fatores de RiscoRESUMO
AIMS/HYPOTHESIS: We studied the role of protein degradation pathways in the regulation of insulin production and secretion and hypothesised that autophagy regulates proinsulin degradation, thereby modulating beta cell function. METHODS: Proinsulin localisation in autophagosomes was demonstrated by confocal and electron microscopy. Autophagy was inhibited by knockdown of autophagy-related (ATG) proteins and using the H(+)-ATPase inhibitor bafilomycin-A1. Proinsulin and insulin content and secretion were assessed in static incubations by ELISA and RIA. RESULTS: Confocal and electron microscopy showed proinsulin localised in autophagosomes and lysosomes. Beta-Atg7 (-/-) mice had proinsulin-containing sequestosome 1 (p62 [also known as SQSTM1])(+) aggregates in beta cells, indicating proinsulin is regulated by autophagy in vivo. Short-term bafilomycin-A1 treatment and ATG5/7 knockdown increased steady-state proinsulin and hormone precursor chromogranin A content. ATG5/7 knockdown also increased glucose- and non-fuel-stimulated insulin secretion. Finally, mutated forms of proinsulin that are irreparably misfolded and trapped in the endoplasmic reticulum are more resistant to degradation by autophagy. CONCLUSIONS/INTERPRETATION: In the beta cell, transport-competent secretory peptide precursors, including proinsulin, are regulated by autophagy, whereas efficient clearance of transport-incompetent mutated forms of proinsulin by alternative degradative pathways may be necessary to avoid beta cell proteotoxicity. Reduction of autophagic degradation of proinsulin increases its residency in the secretory pathway, followed by enhanced secretion in response to stimuli.
Assuntos
Autofagia/fisiologia , Insulina/metabolismo , Animais , Autofagia/genética , Proteína 7 Relacionada à Autofagia/genética , Proteína 7 Relacionada à Autofagia/metabolismo , Western Blotting , Linhagem Celular , Homeostase/genética , Homeostase/fisiologia , Humanos , Células Secretoras de Insulina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Eletrônica , Consumo de Oxigênio/genética , Consumo de Oxigênio/fisiologia , Interferência de RNA/fisiologiaRESUMO
Darier disease (DD) is a rare monogenetic skin disorder with limited data on its potential association with neurological disorders. This study aimed to investigate the association between DD and neurological disorders, specifically Parkinson's disease, dementias, and epilepsy. Using Swedish national registers in a period spanning between 1977 and 2013, 935 individuals with DD were compared with up to 100 comparison individuals each, randomly selected from the general population based on birth year, sex, and county of residence at the time of the first diagnosis of DD. Individuals with DD had increased risks of being diagnosed with Parkinson's disease (RR 2.1, CI 1.1; 4.4), vascular dementia (RR 2.1, CI 1.0; 4.2), and epilepsy, (RR 2.5, CI 1.8; 3.5). No association of DD with other dementias were detected. This study demonstrates a new association between DD and neurodegenerative disorders and epilepsy, underlining the need for increased awareness, interdisciplinary collaboration, and further research to understand the underlying mechanisms. Early identification and management of neurological complications in DD patients could improve treatment strategies and patient outcomes. The findings also highlight the role of SERCA2 in the pathophysiology of neurological disorders, offering new targets for future research and potentials for novel treatments.
Assuntos
Doença de Darier , Demência , Epilepsia , Doença de Parkinson , Humanos , Doença de Parkinson/epidemiologia , Pele , Demência/epidemiologiaRESUMO
Darier disease (DD) is a rare severe acantholytic skin disease caused by mutations in the ATP2A2 gene that encodes for the sarco/endoplasmic reticulum calcium ATPase isoform 2 (SERCA2). SERCA2 maintains endoplasmic reticulum calcium homeostasis by pumping calcium into the ER, critical for regulating cellular calcium dynamics and cellular function. To date, there is no treatment that specifically targets the disease mechanisms in DD. Dantrolene sodium (Dl) is a ryanodine receptor antagonist that inhibits calcium release from ER to increase ER calcium levels and is currently used for non-dermatological indications. In this study, we first identified dysregulated genes and molecular pathways in DD patient skin, demonstrating downregulation of cell adhesion and calcium homeostasis pathways, as well as upregulation of ER stress and apoptosis. We then show in various in vitro models of DD and SERCA2 inhibition that Dl aided in the retention of ER calcium and promoted cell adhesion. In addition, Dl treatment reduced ER stress and suppressed apoptosis. Our findings suggest that Dl specifically targets pathogenic mechanisms of DD and may be a potential treatment.
RESUMO
Regeneration of insulin-producing ß-cells is an alternative avenue to manage diabetes, and it is crucial to unravel this process in vivo during physiological responses to the lack of ß-cells. Here, we aimed to characterize how hepatocytes can contribute to ß-cell regeneration, either directly or indirectly via secreted proteins or metabolites, in a zebrafish model of ß-cell loss. Using lineage tracing, we show that hepatocytes do not directly convert into ß-cells even under extreme ß-cell ablation conditions. A transcriptomic analysis of isolated hepatocytes after ß-cell ablation displayed altered lipid- and glucose-related processes. Based on the transcriptomics, we performed a genetic screen that uncovers a potential role of the molybdenum cofactor (Moco) biosynthetic pathway in ß-cell regeneration and glucose metabolism in zebrafish. Consistently, molybdenum cofactor synthesis 2 (Mocs2) haploinsufficiency in mice indicated dysregulated glucose metabolism and liver function. Together, our study sheds light on the liver-pancreas crosstalk and suggests that the molybdenum cofactor biosynthesis pathway should be further studied in relation to glucose metabolism and diabetes.
Assuntos
Coenzimas , Glucose , Hepatócitos , Células Secretoras de Insulina , Fígado , Metaloproteínas , Cofatores de Molibdênio , Pteridinas , Peixe-Zebra , Animais , Células Secretoras de Insulina/metabolismo , Pteridinas/metabolismo , Coenzimas/metabolismo , Camundongos , Fígado/metabolismo , Fígado/citologia , Metaloproteínas/metabolismo , Metaloproteínas/genética , Hepatócitos/metabolismo , Glucose/metabolismo , Regeneração/genética , Pâncreas/metabolismo , Pâncreas/citologia , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismoRESUMO
Central for wound healing is the formation of granulation tissue, which largely consists of collagen and whose importance stretches past wound healing, including being implicated in both fibrosis and skin aging. Cyclophilin D (CyD) is a mitochondrial protein that regulates the permeability transition pore, known for its role in apoptosis and ischemia-reperfusion. To date, the role of CyD in human wound healing and collagen generation has been largely unexplored. Here, we show that CyD was upregulated in normal wounds and venous ulcers, likely adaptive as CyD inhibition impaired reepithelialization, granulation tissue formation, and wound closure in both human and pig models. Overexpression of CyD increased keratinocyte migration and fibroblast proliferation, while its inhibition reduced migration. Independent of wound healing, CyD inhibition in fibroblasts reduced collagen secretion and caused endoplasmic reticulum collagen accumulation, while its overexpression increased collagen secretion. This was confirmed in a Ppif-KO mouse model, which showed a reduction in skin collagen. Overall, this study revealed previously unreported roles of CyD in skin, with implications for wound healing and beyond.
Assuntos
Colágeno , Fibroblastos , Camundongos Knockout , Peptidil-Prolil Isomerase F , Pele , Cicatrização , Animais , Feminino , Humanos , Masculino , Camundongos , Movimento Celular , Proliferação de Células , Colágeno/metabolismo , Ciclofilinas/metabolismo , Ciclofilinas/genética , Modelos Animais de Doenças , Fibroblastos/metabolismo , Tecido de Granulação/metabolismo , Tecido de Granulação/patologia , Queratinócitos/metabolismo , Peptidil-Prolil Isomerase F/metabolismo , Peptidil-Prolil Isomerase F/genética , Pele/metabolismo , Pele/patologia , Suínos , Cicatrização/fisiologiaRESUMO
Mitochondria are intracellular organelles that play a critical role in numerous cellular processes including the regulation of metabolism, cellular stress response, and cell fate. Mitochondria themselves are subject to well-orchestrated regulation in order to maintain organelle and cellular homeostasis. Wound healing is a multifactorial process that involves the stringent regulation of several cell types and cellular processes. In the event of dysregulated wound healing, hard-to-heal chronic wounds form and can place a significant burden on healthcare systems. Importantly, treatment options remain limited owing to the multifactorial nature of chronic wound pathogenesis. One area that has received more attention in recent years is the role of mitochondria in wound healing. With regards to this, current literature has demonstrated an important role for mitochondria in several areas of wound healing and chronic wound pathogenesis including metabolism, apoptosis, and redox signalling. Additionally, the influence of mitochondrial dynamics and mitophagy has also been investigated. However, few studies have utilised patient tissue when studying mitochondria in wound healing, instead using various animal models. In this review we dissect the current knowledge of the role of mitochondria in wound healing and discuss how future research can potentially aid in the progression of wound healing research.
RESUMO
Impaired skin wound healing is a significant global health issue, especially among the elderly. Wound healing is a well-orchestrated process involving the sequential phases of inflammation, proliferation, and tissue remodeling. Although wound healing is a highly dynamic and energy-requiring process, the role of metabolism remains largely unexplored. By combining transcriptomics and metabolomics of human skin biopsy samples, we mapped the core bioenergetic and metabolic changes in normal acute as well as chronic wounds in elderly subjects. We found upregulation of glycolysis, the tricarboxylic acid cycle, glutaminolysis, and ß-oxidation in the later stages of acute wound healing and in chronic wounds. To ascertain the role of these metabolic pathways on wound healing, we targeted each pathway in a wound healing assay as well as in a human skin explant model using metabolic inhibitors and stimulants. Enhancement or inhibition of glycolysis and, to a lesser extent, glutaminolysis had a far greater impact on wound healing than similar manipulations of oxidative phosphorylation and fatty acid ß-oxidation. These findings increase the understanding of wound metabolism and identify glycolysis and glutaminolysis as potential targets for therapeutic intervention.
Assuntos
Pele , Cicatrização , Humanos , Idoso , Cicatrização/fisiologia , Pele/patologia , Redes e Vias Metabólicas , Glicólise , MetabolômicaRESUMO
Human data supporting a role for endoplasmic reticulum (ER) stress and calcium dyshomeostasis in heart disease is scarce. Darier disease (DD) is a hereditary skin disease caused by mutations in the ATP2A2 gene encoding the sarcoendoplasmic-reticulum Ca2+ ATPase isoform 2 (SERCA2), which causes calcium dyshomeostasis and ER stress. We hypothesized that DD patients would have an increased risk for common heart disease. We performed a cross-sectional case-control clinical study on 25 DD patients and 25 matched controls; and a population-based cohort study on 935 subjects with DD and matched comparison subjects. Main outcomes and measures were N-terminal pro-brain natriuretic peptide, ECG and heart diagnosis (myocardial infarction, heart failure and arrythmia). DD subjects showed normal clinical heart phenotype including heart failure markers and ECG. The risk for heart failure was 1.59 (1,16-2,19) times elevated in DD subjects, while no major differences were found in myocardial infarcation or arrhythmias. Risk for heart failure when corrected for cardivascular risk factors or alcohol misuse was 1.53 (1.11-2.11) and 1.58 (1,15-2,18) respectively. Notably, heart failure occurred several years earlier in DD patients as compared to controls. We conclude that DD patients show a disease specific increased risk of heart failure which should be taken into account in patient management. The observation also strenghtens the clinical evidence on the important role of SERCA2 in heart failure pathophysiology.
Assuntos
Doença de Darier/complicações , Insuficiência Cardíaca/complicações , Adulto , Idoso , Biomarcadores/metabolismo , Estudos de Casos e Controles , Estudos Transversais , Doença de Darier/diagnóstico por imagem , Doença de Darier/enzimologia , Doença de Darier/fisiopatologia , Eletrocardiografia , Feminino , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/enzimologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Mutação/genética , Fatores de Risco , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismoRESUMO
BACKGROUND: Human data supporting a role for endoplasmic reticulum (ER) stress and calcium dyshomeostasis in diabetes is scarce. Darier disease (DD) is a hereditary skin disease caused by mutations in the ATP2A2 gene encoding the sarcoendoplasmic-reticulum ATPase 2 (SERCA2) calcium pump, which causes calcium dyshomeostasis and ER stress. We hypothesize that DD patients have a diabetes-like metabolic phenotype and the objective of this study was to examine the association between DD with impaired glucose tolerance and diabetes. METHODS: Cross-sectional clinical study on 25 DD patients and 25 matched controls. Metabolic status was assessed primarily by fasting blood glucose, oral glucose tolerance test, HOMA2-%S (insulin resistence) and HOMA2-%B (beta cell function). RESULTS: DD subjects showed normal oral glucose tolerance test and HOMA2-%S, while fasting blood glucose was lower and c-peptide as well as HOMA2-%B was higher. CONCLUSION: Increased HOMA2-%B values are indicative of increased basal insulin secretion which is a type of beta cell dysfunction associated to diabetes development. These results supports a role of ER stress in diabetes pathophysiology and contribute to the understanding of DD as a multi-organ syndrome.