Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 55
Filtrar
1.
Int J Mol Sci ; 25(18)2024 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-39337683

RESUMO

While vitiligo is primarily caused by melanocyte deficiency or dysfunction, recent studies have revealed a notable prevalence of metabolic syndrome (MetS) among patients with vitiligo. This suggests shared pathogenic features between the two conditions. Individuals with vitiligo often exhibit variations in triglyceride levels, cholesterol, and blood pressure, which are also affected in MetS. Given the similarities in their underlying mechanisms, genetic factors, pro-inflammatory signalling pathways, and increased oxidative stress, this study aims to highlight the common traits between vitiligo and metabolic systemic disorders. Serum analyses confirmed increased low-density lipoprotein (LDL) levels in patients with vitiligo, compared to physiological values. In addition, we reported significant decreases in folate and vitamin D (Vit D) levels. Oxidative stress is one of the underlying causes of the development of metabolic syndromes and is related to the advancement of skin diseases. This study found high levels of inflammatory cytokines, such as interleukin-6 (IL-6) and chemokine 10 (CXCL10), which are markers of inflammation and disease progression. The accumulation of insulin growth factor binding proteins 5 (IGFBP5) and advanced glycation end products (AGEs) entailed in atherosclerosis and diabetes onset, respectively, were also disclosed in vitiligo. In addition, the blood-associated activity of the antioxidant enzymes catalase (Cat) and superoxide dismutase (SOD) was impaired. Moreover, the plasma fatty acid (FAs) profile analysis showed an alteration in composition and specific estimated activities of FAs biosynthetic enzymes resembling MetS development, resulting in an imbalance towards pro-inflammatory n6-series FAs. These results revealed a systemic metabolic alteration in vitiligo patients that could be considered a new target for developing a more effective therapeutic approach.


Assuntos
Biomarcadores , Síndrome Metabólica , Estresse Oxidativo , Vitiligo , Vitiligo/sangue , Vitiligo/metabolismo , Humanos , Biomarcadores/sangue , Masculino , Adulto , Feminino , Síndrome Metabólica/metabolismo , Síndrome Metabólica/sangue , Pessoa de Meia-Idade , Vitamina D/sangue , Vitamina D/metabolismo , Lipoproteínas LDL/sangue , Lipoproteínas LDL/metabolismo , Citocinas/sangue , Citocinas/metabolismo , Ácidos Graxos/metabolismo , Ácidos Graxos/sangue , Catalase/sangue , Catalase/metabolismo
2.
Int J Mol Sci ; 24(18)2023 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-37762344

RESUMO

Aging is a natural intrinsic process associated with the loss of fibrous tissue, a slower cell turnover, and a reduction in immune system competence. In the skin, the continuous exposition of environmental factors superimposes extrinsic damage, mainly due to ultraviolet radiation causing photoaging. Although not usually considered a pathogenic event, photoaging affects cutaneous biology, increasing the risk of skin carcinogenesis. At the cellular level, aging is typified by the rise of senescence cells a condition characterized by reduced or absent capacity to proliferate and aberrant hyper-secretory activity. Senescence has a double-edged sword in cancer biology given that senescence prevents the uncontrolled proliferation of damaged cells and favors their clearance by paracrine secretion. Nevertheless, the cumulative insults and the poor clearance of injured cells in the elderly increase cancer incidence. However, there are not conclusive data proving that aged skin represents a permissive milieu for tumor onset. On the other hand, tumor cells are capable of activating resident fibroblasts onto a pro-tumorigenic phenotype resembling those of senescent fibroblasts suggesting that aged fibroblasts might facilitate cancer progression. This review discusses changes that occur during aging that can prime neoplasm or increase the aggressiveness of melanoma and non-melanoma skin cancer.


Assuntos
Envelhecimento da Pele , Neoplasias Cutâneas , Idoso , Humanos , Raios Ultravioleta/efeitos adversos , Neoplasias Cutâneas/etiologia , Envelhecimento , Pele , Carcinogênese
3.
Exp Dermatol ; 31(12): 1837-1852, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35102608

RESUMO

Stem cell-mediated therapies in combination with biomaterial and growth factor-based approaches in regenerative medicine are rapidly evolving with increasing application beyond the dermatologic field. Adipose-derived stem cells (ADSCs) are the more frequently used adult stem cells due to their abundance and easy access. In the case of volumetric defects, adipose tissue can take the shape of defects, restoring the volume and enhancing the regeneration of receiving tissue. When regenerative purposes prevail on volume restoration, the stromal vascular fraction (SVF) rich in staminal cells, purified mesenchymal stem cells (MSCs) or their cell-free derivatives grafting are favoured. The therapeutic efficacy of acellular approaches is explained by the fact that a significant part of the natural propensity of stem cells to repair damaged tissue is ascribable to their secretory activity that combines mitogenic factors, cytokines, chemokines and extracellular matrix components. Therefore, the secretome's ability to modulate multiple targets simultaneously demonstrated preclinical and clinical efficacy in reversing pathological mechanisms of complex conditions such atopic dermatitis (AD), vitiligo, psoriasis, acne and Lichen sclerosus (LS), non-resolving wounds and alopecia. This review analysing both in vivo and in vitro models gives an overview of the clinical relevance of adipose tissue-derivatives such as autologous fat graft, stromal vascular fraction, purified stem cells and secretome for skin disorders application. Finally, we highlighted the major disease-specific limitations and the future perspective in this field.


Assuntos
Dermatologia , Células-Tronco Mesenquimais , Tecido Adiposo , Medicina Regenerativa , Células-Tronco
4.
J Am Acad Dermatol ; 87(1): 56-63, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35240229

RESUMO

BACKGROUND: Recently, several case-control studies demonstrated an association between gliptins and bullous pemphigoid (BP) occurrence. However, data on the clinical and immunologic features of gliptin-associated bullous pemphigoid (GABP) are controversial. OBJECTIVE: This study aimed to clinically and immunologically characterize a large cohort of GABP patients to get an insight into the pathophysiology of this emerging drug-induced variant of BP. METHODS: Seventy-four GABP patients were prospectively enrolled and characterized from 9 different Italian dermatology units between 2013 and 2020. RESULTS: Our findings demonstrated the following in the GABP patients: (1) a noninflammatory phenotype, which is characterized by low amounts of circulating and skin-infiltrating eosinophils, is frequently found; (2) immunoglobulin (Ig)G, IgE, and IgA humoral responses to BP180 and BP230 antigens are reduced in frequency and titers compared with those in patients with idiopathic BP; (3) IgG reactivity targets multiple BP180 epitopes other than noncollagenous region 16A. LIMITATIONS: A limitation of the study is that the control group did not comprise only type 2 diabetes mellitus patients with BP. CONCLUSION: GABP patients show peculiar features of anti-BP180 and -BP230 humoral responses, laying the foundation for diagnostic improvements and getting novel insights into understanding the mechanism of BP onset.


Assuntos
Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Penfigoide Bolhoso , Autoanticorpos , Autoantígenos , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Humanos , Imunoglobulina G , Colágenos não Fibrilares
5.
Int J Mol Sci ; 22(14)2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34298873

RESUMO

Solid tumors are complex systems characterized by dynamic interactions between neoplastic cells, non-tumoral cells, and extracellular components. Among all the stromal cells that populate tumor microenvironment, fibroblasts are the most abundant elements and are critically involved in disease progression. Cancer-associated fibroblasts (CAFs) have pleiotropic functions in tumor growth and extracellular matrix remodeling implicated in local invasion and distant metastasis. CAFs additionally participate in the inflammatory response of the tumor site by releasing a variety of chemokines and cytokines. It is becoming clear that understanding the dynamic, mutual melanoma-fibroblast relationship would enable treatment options to be amplified. To better characterize melanoma-associated fibroblasts, here we analyzed low-passage primary CAFs derived from advanced-stage primary skin melanomas, focusing on the immuno-phenotype. Furthermore, we assessed the expression of several CAF markers and the production of growth factors. To deepen the study of CAF-melanoma cell crosstalk, we employed CAF-derived supernatants and trans-well co-culture systems to evaluate the influences of CAFs on (i) the motogenic ability of melanoma cells, (ii) the chemotherapy-induced cytotoxicity, and (iii) the release of mediators active in modulating tumor growth and spread.


Assuntos
Fibroblastos Associados a Câncer/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Melanoma/genética , Neoplasias Cutâneas/genética , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Técnicas de Cocultura , Citocinas/genética , Matriz Extracelular/genética , Perfilação da Expressão Gênica/métodos , Humanos , Inflamação/genética , Células Estromais/metabolismo , Melanoma Maligno Cutâneo
6.
Dermatol Ther ; 33(6): e14277, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32888384

RESUMO

Lichen sclerosus (LS) is a chronic relapsing, inflammatory skin disorder usually involving the anogenital region of both sexes lacking a resolutive therapy. This study compared adipose tissue derived-stromal vascular fraction (AD-SVF) and AD-SVF-enriched platelet-rich plasma (PRP) therapy in the management of genital LS patients. Additionally, in vitro evaluation of cells and growth factors contained in the injected SVF has been evaluated as possible predictive factors for treatment outcome. The study population was 40 patients diagnosed with LS who were symptomatic despite medical treatment. Patients (age 43-78 years) randomized into two groups using a 1:1 allocation ratio, were evaluated clinically and assessing dermatology life quality index (DLQI) before and 6 months after treatment. Both procedures demonstrated a strong safety profile with no complications linked to the therapy. After 6 months, both treatments allowed for a significant improvement respect to baseline. Combinatory therapy demonstrated decreased efficacy in late stage patients. No correlations have been found between clinical and biological findings. AD-SVF and AD-SVF plus PRP are safe and effective regenerative approaches for genital LS patients. Clinical results support the preferential use of combinatory therapy for early stage patients confirming a synergic effect of AD-SVF and PRP. In contrast, AD-SVF plus PRP is discouraged for late stage patients.


Assuntos
Líquen Escleroso e Atrófico , Tecido Adiposo , Adulto , Idoso , Feminino , Genitália , Humanos , Líquen Escleroso e Atrófico/diagnóstico , Líquen Escleroso e Atrófico/terapia , Masculino , Pessoa de Meia-Idade , Plasma Rico em Plaquetas , Pele
7.
Int J Mol Sci ; 21(3)2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31979112

RESUMO

Nevoid basal cell carcinoma syndrome (NBCCS), also named Gorlin syndrome, is a rare multisystem genetic disorder characterized by marked predisposition to basal cell carcinomas (BCCs), childhood medulloblastomas, maxillary keratocysts, celebral calcifications, in addition to various skeletal and soft tissue developmental abnormalities. Mutations in the tumor suppressor gene PATCHED1 (PTCH1) have been found to be associated in the majority of NBCCS cases. PATCH1 somatic mutations and loss of heterozygosity are also very frequent in sporadic BCCs. Unlike non-syndromic patients, NBCCS patients develop multiple BCCs in sun-protected skin area starting from early adulthood. Recent studies suggest that dermo/epidermal interaction could be implicated in BCC predisposition. According to this idea, NBCCS fibroblasts, sharing with keratinocytes the same PTCH1 germline mutation and consequent constitutive activation of the Hh pathway, display features of carcinoma-associated fibroblasts (CAF). This phenotypic traits include the overexpression of growth factors, specific microRNAs profile, modification of extracellular matrix and basement membrane composition, increased cytokines and pro-angiogenic factors secretion, and a complex alteration of the Wnt/-catenin pathway. Here, we review studies about the involvement of dermal fibroblasts in BCC predisposition of Gorlin syndrome patients. Further, we matched the emerged NBCCS fibroblast profile to those of CAF to compare the impact of cell autonomous "pre-activated state" due to PTCH1 mutations to those of skin tumor stroma.


Assuntos
Síndrome do Nevo Basocelular/patologia , Carcinoma Basocelular/patologia , Fibroblastos/patologia , Neoplasias Cutâneas/patologia , Animais , Síndrome do Nevo Basocelular/metabolismo , Carcinoma Basocelular/metabolismo , Fibroblastos/metabolismo , Humanos , Receptor Patched-1/metabolismo , Transdução de Sinais/fisiologia , Neoplasias Cutâneas/metabolismo
8.
Exp Dermatol ; 28(6): 695-703, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31066942

RESUMO

Vitiligo is a common, disfiguring autoimmune disease that negatively affects patients' self-esteem and quality of life. Current treatments are moderately effective in reversing disease and promoting melanocyte regeneration. Thus, therapeutic advanced strategies are emerging from regenerative medicine. It has recently emerged that adipose tissue secretome may be used as a cell-free therapy in skin regeneration since paracrine functions of adipose-derived stem cells alone are responsible for most of the therapeutic effect of stem cells in several animal disease models. In this study, we tested the effect of adipose tissue extracellular fraction (AT-Ex) isolated from lipoaspirates on dermal and epidermal vitiligo cells in vitro. Using this experimental model, we demonstrated that molecules secreted by adipose tissue ameliorate the capability to counteract oxidative stress by a physiological stimulation of intracellular antioxidant enzymes and positively impact on cell proliferation. Due to the presence of Wnt-secreted factors, AT-Ex treatment promotes glycogen synthase kinase 3ß inactivation and consequently Wnt/ß-catenin pathway activation. Collectively, our findings show that AT-Ex could be useful as a natural approach to improve treatment of vitiligo.


Assuntos
Tecido Adiposo/fisiologia , Medicina Regenerativa/métodos , Vitiligo/terapia , Adolescente , Adulto , Idoso , Antioxidantes/metabolismo , Proliferação de Células , Feminino , Fibroblastos/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Masculino , Melanócitos/citologia , Pessoa de Meia-Idade , Estresse Oxidativo , Qualidade de Vida , Espécies Reativas de Oxigênio/metabolismo , Regeneração , Pele/patologia , Proteínas Wnt/metabolismo , Adulto Jovem
9.
Exp Dermatol ; 28(6): 667-673, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30582762

RESUMO

Despite melanocytes are the key players in vitiligo, a continuous cross-talk between epidermal and dermal cells may strictly affect their functionality, in both lesional skin and non-lesional skin. Focusing on this interplay, we have reviewed existing literature supporting evidence on cellular and functional alterations of surrounding epidermal keratinocytes, extracellular matrix (ECM) proteins and fibroblasts in the underlying dermal compartment that may contribute to melanocyte disappearance in vitiligo. We have also examined some clinical and therapeutic aspects of the disease to sustain the non-exclusive involvement of melanocytes within vitiligo. As a result, a different and more complex scenario has appeared that may enable to provide better understanding about origins and progress of vitiligo and that should be considered in the evaluation of new treatment approaches.


Assuntos
Melanócitos/citologia , Pele/citologia , Vitiligo/patologia , Vitiligo/terapia , Animais , Derme/citologia , Epiderme/metabolismo , Matriz Extracelular/metabolismo , Fibroblastos/citologia , Humanos , Hipopigmentação/metabolismo , Queratinócitos/citologia , Pigmentação , Cicatrização
10.
Hum Mol Genet ; 23(15): 3907-22, 2014 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-24599399

RESUMO

Recessive dystrophic epidermolysis bullosa (RDEB) is a genodermatosis characterized by fragile skin forming blisters that heal invariably with scars. It is due to mutations in the COL7A1 gene encoding type VII collagen, the major component of anchoring fibrils connecting the cutaneous basement membrane to the dermis. Identical COL7A1 mutations often result in inter- and intra-familial disease variability, suggesting that additional modifiers contribute to RDEB course. Here, we studied a monozygotic twin pair with RDEB presenting markedly different phenotypic manifestations, while expressing similar amounts of collagen VII. Genome-wide expression analysis in twins' fibroblasts showed differential expression of genes associated with TGF-ß pathway inhibition. In particular, decorin, a skin matrix component with anti-fibrotic properties, was found to be more expressed in the less affected twin. Accordingly, fibroblasts from the more affected sibling manifested a profibrotic and contractile phenotype characterized by enhanced α-smooth muscle actin and plasminogen activator inhibitor 1 expression, collagen I release and collagen lattice contraction. These cells also produced increased amounts of proinflammatory cytokines interleukin 6 and monocyte chemoattractant protein-1. Both TGF-ß canonical (Smads) and non-canonical (MAPKs) pathways were basally more activated in the fibroblasts of the more affected twin. The profibrotic behaviour of these fibroblasts was suppressed by decorin delivery to cells. Our data show that the amount of type VII collagen is not the only determinant of RDEB clinical severity, and indicate an involvement of TGF-ß pathways in modulating disease variability. Moreover, our findings identify decorin as a possible anti-fibrotic/inflammatory agent for RDEB therapeutic intervention.


Assuntos
Epidermólise Bolhosa Distrófica/genética , Fibroblastos/metabolismo , Genótipo , Fenótipo , Pele/metabolismo , Fator de Crescimento Transformador beta/genética , Gêmeos Monozigóticos/genética , Actinas/genética , Actinas/metabolismo , Adulto , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Colágeno Tipo VII/genética , Colágeno Tipo VII/metabolismo , Epidermólise Bolhosa Distrófica/metabolismo , Epidermólise Bolhosa Distrófica/patologia , Fibroblastos/patologia , Regulação da Expressão Gênica , Genes Recessivos , Heterogeneidade Genética , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Inibidor 1 de Ativador de Plasminogênio/genética , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Índice de Gravidade de Doença , Transdução de Sinais , Pele/patologia , Proteínas Smad/genética , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta/metabolismo
11.
Mol Carcinog ; 55(12): 2304-2312, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-26599548

RESUMO

Melanoma, the most lethal form of skin cancer, is frequently associated with alterations in several genes, among which the Bcl-2 oncogene plays an important role in progression, chemosensitivity and angiogenesis. Also microRNA (miRNA) are emerging as modulators of melanoma development and progression, and among them, miR-211, located within the melastatin-1/TRPM1 (transient receptor potential cation channel, subfamily M, member 1 protein) gene, is prevalently expressed in the melanocyte lineage and acts as oncosuppressor. Using several human melanoma cell lines and their Bcl-2 stably overexpressing derivatives, we evaluated whether there was a correlation between expression of Bcl-2 and miR-211. Western blot analysis and quantitative real-time polymerase chain reaction demonstrated reduced expression of pri-miR-211, miR-211, TRPM1, and MLANA levels, after Bcl-2 overexpression, associated with increased expression of well-known miR-211 target genes. Overexpression of mature miR-211 in Bcl-2 overexpressing cells rescued Bcl-2 ability to increase cell migration. A decreased nuclear localization of microphthalmia-associated transcription factor (MITF), a co-regulator of both miR-211 and TRPM1, and a reduced MITF recruitment at the TRPM1 and MLANA promoters were also evidenced in Bcl-2 overexpressing cells by immunofluorescence and chromatin immunoprecipitation experiments, respectively. Reduction of Bcl-2 expression by small interference RNA confirmed the ability of Bcl-2 to modulate miR-211 and TRPM1 expression. © 2015 Wiley Periodicals, Inc.


Assuntos
Regulação Neoplásica da Expressão Gênica , Melanoma/genética , MicroRNAs/genética , Fator de Transcrição Associado à Microftalmia/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Neoplasias Cutâneas/genética , Linhagem Celular Tumoral , Movimento Celular , Humanos , Melanoma/metabolismo , Melanoma/patologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Pele/metabolismo , Pele/patologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia
12.
Cancers (Basel) ; 16(5)2024 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-38473275

RESUMO

Melanoma progression is a multistep evolution from a common melanocytic nevus through a radial superficial growth phase, the invasive vertical growth phase finally leading to metastatic dissemination into distant organs. Melanoma aggressiveness largely depends on the propensity to metastasize, which means the capacity to escape from the physiological microenvironment since tissue damage due to primary melanoma lesions is generally modest. Physiologically, epidermal melanocytes are attached to the basement membrane, and their adhesion/migration is under the control of surrounding keratinocytes. Thus, the epidermal compartment represents the first microenvironment responsible for melanoma spread. This complex process involves cell-cell contact and a broad range of secreted bioactive molecules. Invasion, or at the beginning of the microinvasion, implies the breakdown of the dermo-epidermal basement membrane followed by the migration of neoplastic melanocytic cells in the superficial papillary dermis. Correspondingly, several experimental evidences documented the structural and functional rearrangement of the entire tissue surrounding neoplasm that in some way reflects the atypia of tumor cells. Lastly, the microenvironment must support the proliferation and survival of melanocytes outside the normal epidermal-melanin units. This task presumably is mostly delegated to fibroblasts and ultimately to the self-autonomous capacity of melanoma cells. This review will discuss remodeling that occurs in the epidermis during melanoma formation as well as skin changes that occur independently of melanocytic hyperproliferation having possible pro-tumoral features.

13.
Front Immunol ; 15: 1416473, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39267741

RESUMO

Bullous pemphigoid (BP) is the most common autoimmune bullous disease: it most commonly affects individuals over 70 years old and impacts severely on their quality of life. BP represents a paradigm for an organ-specific autoimmune disease and is characterized by circulating IgG autoantibodies to hemidesmosomal components: BP180 and BP230. While the crucial role of these autoantibodies in triggering BP inflammatory cascade is fully acknowledged, many ancillary etiological mechanisms need to be elucidated yet. Cutaneous melanoma is due to a malignant transformation of skin melanocytes, that produce and distribute pigments to surrounding keratinocytes. Melanoma is the most fatal skin cancer because of its increasing incidence and its propensity to metastasize. Several data such as: i) reported cases of concomitant melanoma and BP; ii) results from association studies; iii) BP onset following immune check-point inhibitors therapy; iv) expression of BP antigens in transformed melanocytes; and vi) circulating autoantibodies to BP antigens in melanoma patients suggest an intriguing, although unproven, possible association between melanoma and BP. However, a possible causative link is still debated and the putative pathogenetic mechanism underlying this association is unclear. This review aims to describe and discuss the possible relationship between BP and melanoma and give an overview of the speculations for or against this association. Of note, if demonstrated, this association could unwrap considerations of clinical relevance that represent new research frontiers.


Assuntos
Autoanticorpos , Autoantígenos , Melanoma , Penfigoide Bolhoso , Humanos , Penfigoide Bolhoso/imunologia , Penfigoide Bolhoso/etiologia , Melanoma/imunologia , Melanoma/etiologia , Autoanticorpos/imunologia , Autoanticorpos/sangue , Autoantígenos/imunologia , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/etiologia , Colágeno Tipo XVII , Colágenos não Fibrilares/imunologia , Melanócitos/imunologia , Melanócitos/patologia , Animais , Relevância Clínica
14.
Cells ; 13(5)2024 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-38474338

RESUMO

BACKGROUND: Cutaneous melanoma arises from skin melanocytes and has a high risk of metastatic spread. Despite better prevention, earlier detection, and the development of innovative therapies, melanoma incidence and mortality increase annually. Major clinical risk factors for melanoma include fair skin, an increased number of nevi, the presence of dysplastic nevi, and a family history of melanoma. However, several external inducers seem to be associated with melanoma susceptibility such as environmental exposure, primarily unprotected sun experience, alcohol consumption, and heavy metals. In recent years, epidemiological studies have highlighted a potential risk of ß-hexachlorocyclohexane (ß-HCH), the most studied organochlorine pesticide, causing cancer induction including melanoma. METHODS: We evaluated in vitro the impact of this pollutant on epidermal and dermal cells, attempting to describe mechanisms that could render cutaneous cells more prone to oncogenic transformation. RESULTS: We demonstrated that ß-HCH impacts melanocyte biology with a highly cell-type specific signature that involves perturbation of AKT/mTOR and Wnt/ß-catenin signaling, and AMPK activation, resulting in lowering energy reserve, cell proliferation, and pigment production. CONCLUSIONS: In conclusion, long-term exposure to persistent organic pollutants damages melanocyte metabolism in its function of melanin production with a consequent reduction of melanogenesis indicating a potential augmented skin cancer risk.


Assuntos
Melanoma , Neoplasias Cutâneas , Humanos , Melanoma/patologia , Neoplasias Cutâneas/patologia , Melanócitos/metabolismo , Hexaclorocicloexano/metabolismo
15.
HLA ; 104(2): e15616, 2024 08.
Artigo em Inglês | MEDLINE | ID: mdl-39091267

RESUMO

Bullous pemphigoid (BP), although a rare disease, is the most frequent subepidermal autoimmune disorder. Treatment with gliptins, used for type 2 diabetes, was reported as associated with BP onset. To identify HLA alleles that may reflect a higher susceptibility to BP in the Italian population, we analysed 30 patients affected by idiopathic bullous pemphigoid (IBP) and 86 gliptin-associated BP (GABP) patients. A significant association between HLA-DQB1*03:01 allele and IBP and GABP patients was found. Of note, both IBP and GABP were significantly associated with one of the following haplotypes: DRB1*11:01, DRB3*02:02, DQA1*05:05, DQB1*03:01 or DRB1*11:04, DRB3*02:02, DQA1*05:05 and DQB1*03:01. These data identify, for the first time, potential markers of susceptibility to BP in the Italian population, especially when associated with gliptin intake.


Assuntos
Alelos , Predisposição Genética para Doença , Haplótipos , Penfigoide Bolhoso , Humanos , Penfigoide Bolhoso/genética , Penfigoide Bolhoso/induzido quimicamente , Itália , Feminino , Masculino , Idoso , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/tratamento farmacológico , Cadeias beta de HLA-DQ/genética , Pessoa de Meia-Idade , Frequência do Gene , Idoso de 80 Anos ou mais
16.
Cell Death Dis ; 15(3): 208, 2024 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-38472212

RESUMO

Therapy of melanoma has improved dramatically over the last years thanks to the development of targeted therapies (MAPKi) and immunotherapies. However, drug resistance continues to limit the efficacy of these therapies. Our research group has provided robust evidence as to the involvement of a set of microRNAs in the development of resistance to target therapy in BRAF-mutated melanomas. Among them, a pivotal role is played by the oncosuppressor miR-579-3p. Here we show that miR-579-3p and the microphthalmia-associated transcription factor (MITF) influence reciprocally their expression through positive feedback regulatory loops. In particular we show that miR-579-3p is specifically deregulated in BRAF-mutant melanomas and that its expression levels mirror those of MITF. Luciferase and ChIP studies show that MITF is a positive regulator of miR-579-3p, which is located in the intron 11 of the human gene ZFR (Zink-finger recombinase) and is co-transcribed with its host gene. Moreover, miR-579-3p, by targeting BRAF, is able to stabilize MITF protein thus inducing its own transcription. From biological points of view, early exposure to MAPKi or, alternatively miR-579-3p transfection, induce block of proliferation and trigger senescence programs in BRAF-mutant melanoma cells. Finally, the long-term development of resistance to MAPKi is able to select cells characterized by the loss of both miR-579-3p and MITF and the same down-regulation is also present in patients relapsing after treatments. Altogether these findings suggest that miR-579-3p/MITF interplay potentially governs the balance between proliferation, senescence and resistance to therapies in BRAF-mutant melanomas.


Assuntos
Melanoma , MicroRNAs , Humanos , Melanoma/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Fator de Transcrição Associado à Microftalmia/genética , Recidiva Local de Neoplasia/genética , MicroRNAs/genética , Inibidores de Proteínas Quinases/farmacologia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica
17.
Front Physiol ; 14: 1284410, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38046945

RESUMO

Aging of human skin is a complex process leading to a decline in homeostasis and regenerative potential of this tissue. Mitochondria are important cell organelles that have a crucial role in several cellular mechanisms such as energy production and free radical maintenance. However, mitochondrial metabolism as well as processes of mitochondrial dynamics, biogenesis, and degradation varies considerably among the different types of cells that populate the skin. Disturbed mitochondrial function is known to promote aging and inflammation of the skin, leading to impairment of physiological skin function and the onset of skin pathologies. In this review, we discuss the essential role of mitochondria in different skin cell types and how impairment of mitochondrial morphology, physiology, and metabolism in each of these cellular compartments of the skin contributes to the process of skin aging.

18.
Cells ; 12(7)2023 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-37048170

RESUMO

Stimulation of melanocytes and murine melanoma cells with αMSH plus the PI3K inhibitor LY294002 resulted in ROS increase, oxidative DNA damage, and pigment retention. We performed cellular and molecular biology assays (Western blot, FACS, immunofluorescence analysis, scratch assay) on murine and human melanoma cells. Treatment with αMSH plus LY294002 altered cortical actin architecture. Given that cytoskeleton integrity requires energy, we next evaluated ATP levels and we observed a drop in ATP after exposure to αMSH plus LY294002. To evaluate if the αMSH-activated PI3K pathway could modulate energy metabolism, we focused on glucose uptake by analyzing the expression of the Glut-1 glucose translocator. Compared with cells treated with αMSH alone, those exposed to combined treatment showed a reduction of Glut-1 on the plasma membrane. This metabolic alteration was associated with changes in mitochondrial mass. A significant decrease of the cell migratory potential was also observed. We demonstrated that the αMSH-dependent PI3K pathway acts as a regulator of energy metabolism via glucose uptake, influencing the actin cytoskeleton, which is involved in melanosome release and cell motility. Hence, these results could constitute the basis for innovative therapeutical strategies.


Assuntos
Melanoma , Fosfatidilinositol 3-Quinases , Humanos , Animais , Camundongos , Fosfatidilinositol 3-Quinases/metabolismo , alfa-MSH/farmacologia , Melanoma/metabolismo , Metabolismo Energético , Glucose , Trifosfato de Adenosina/metabolismo
19.
Nucl Med Commun ; 44(5): 345-350, 2023 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-36826418

RESUMO

BACKGROUND: Sentinel lymph node (SLN) biopsy in cutaneous melanoma patients evaluates the regional draining basin for occult micrometastatic disease. Occasionally, nonidentification of SLN impairs the acquisition of this important prognostic factor. OBJECTIVES: To investigate the outcomes of melanoma patients with negative lymphoscintigraphic findings and patients who underwent SLN biopsy from 2004 to 2015 ( n = 1200) were retrospectively reviewed for tumor characteristics and clinical outcomes. METHODS: Patients with nonvisualized lymph nodes (NV group) who underwent only preoperative lymphoscintigraphy were separated and compared with a cohort drawn from all melanoma patients who completed the surgical procedure within the same period (V group). RESULTS: A negative lymphoscintigraphic scan was observed in 38 cases (3.2% of all patients). The NV group showed a significantly older age (median 66.0 vs. 48.3 years; P < 0.0001). Head and neck melanomas were more frequent in the NV group compared to the control group (25.1 vs. 7.8%; P = 0.009). Tumor characteristics such as ulceration and Breslow thickness do not influence the lymphoscintigraphy result. No differences were found in overall survival (OS) and disease-free survival (DFS) between the groups. CONCLUSIONS: The nonvisualization of regional lymph nodes by lymphoscintigraphy is more frequent in older patients with head and neck melanomas. From the clinical point of view, no specific recommendation emerged for patients' management because the nonvisualization of the SLN did not show a significant influence on DFS and OS rates. However, lack of knowledge of lymph node status suggests performing a tighter follow-up eventually by ultrasound evaluation of all potential lymph node drainage basins.


Assuntos
Melanoma , Linfonodo Sentinela , Neoplasias Cutâneas , Humanos , Idoso , Melanoma/diagnóstico por imagem , Melanoma/cirurgia , Melanoma/patologia , Neoplasias Cutâneas/diagnóstico por imagem , Neoplasias Cutâneas/patologia , Linfonodo Sentinela/patologia , Estudos Retrospectivos , Linfocintigrafia , Metástase Linfática/patologia , Biópsia de Linfonodo Sentinela , Linfonodos/patologia , Melanoma Maligno Cutâneo
20.
Exp Dermatol ; 21(7): 490-6, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22716243

RESUMO

Understanding the cellular and molecular mechanisms leading to melanocyte loss in vitiligo is a mandatory step in improving the overall management of vitiligo patients. Until now, the study of vitiligo was characterised by a fragmented approach, and it is very hard to share and compare the data obtained by the different teams. The scenario mirrors the pathogenic puzzle, but it delays a true productive focus on the disease. The in vitro research is based on different models, ranging from monolayer cell culture of epidermal and dermal cells or 3D reconstructed skin to histological data, gene expression, computer simulation profile. For each model, several different (biochemical, phenotypic, immunological) aspects have been considered, increasing the mass of data difficult to be merged. Our purpose was to provide a practical synopsis of consolidated and advanced possibilities in the study of vitiligo, showing how data have been poorly shared until now. Following a short overview of the background of the disease, the approaches, ranging from basic cell biology to molecular and 'omics' studies, are summarised. New fluorescent probes and techniques open new possibilities for functional studies. Next, intracellular and superficial markers of the melanocytes, the main involved cells, are listed. Moving the focus from the epidermal level to the systemic and subcellular ones, this review aims to propose innovative multidisciplinary options for the vitiligo understanding. This paper focuses on the major practical and theoretical questions to be solved. It may be the basis for a more coordinated and productive approach to the biological question.


Assuntos
Queratinócitos/patologia , Melanócitos/patologia , Vitiligo/metabolismo , Vitiligo/patologia , Biomarcadores/metabolismo , Técnicas de Cultura de Células , Fluorescência , Perfilação da Expressão Gênica , Humanos , Queratinócitos/metabolismo , Melanócitos/metabolismo , Metabolômica , Vitiligo/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA