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1.
Cancers (Basel) ; 13(22)2021 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-34831015

RESUMO

Activating mutations in the Hh pathway underlies the development of sporadic and familial skin BCC. For these oncogenic proliferations displaying ligand-independent activation of the intracellular pathway, two molecules have been approved for therapeutic purposes: vismodegib and sonidegib. Improper Hh signalling occurs in many human tumours also via a paracrine mechanism (ligand-dependent) in which the secretion of Hh ligands by stromal cells support tumour growth. On the other hand, the mobilization of neoplastic stroma by cancer cells is sustained by the activation of Hh signalling in surrounding fibroblasts suggesting a central role of this bidirectional crosstalk in carcinogenesis. Additionally, loss-of-function mutations in the PTCH1 gene in the context of NBCCS, an autosomal dominant disorder predisposing to multiple BCCs, determine tumour permissive phenotypes in dermal fibroblasts. Here, profiling syndromic and BCC-associated fibroblasts unveiled an extraordinary similarity characterized by overexpression of several Hh target genes and a marked pro-inflammatory outline. Both cell types exposed to Hh inhibitors displayed reversion of the tumour-prone phenotype. Under vismodegib and sonidegib treatment, the Wnt/ß-catenin pathway, frequently over-active in tumour stroma, resulted down-regulated by pAKT-GSK3ß axis and consequent increase of ß-catenin turnover. Overall, this study demonstrated that vismodegib and sonidegib impacting on fibroblast tumour supportive functions might be considered in therapy for BCC independently to the mutation status of Hh components in neoplastic cells.

3.
Sci Rep ; 11(1): 16591, 2021 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-34400712

RESUMO

Lipidomics is advantageous in the study of sebum perturbations occurring in acne. An extended evaluation of the sebum lipid profiles in acne-prone sebaceous areas is lacking in dark skin. Yet, there is a void space in understanding how the building blocks of sebum lipids, i.e. individual fatty acids (FAs), are intertwined with acne-prone skin. We aimed to determine the sebum lipidome in facial areas of adolescents with and without acne in Nigeria. A cross-sectional analytical study was conducted in 60 adolescents/young adults divided in 30 acne patients (15F, 15M) and 30 age and sex-matched controls. Sebum samples obtained from foreheads and cheeks were analysed separately by gas chromatography-mass spectrometry (GCMS) and thin layer chromatography (HPTLC). Distributions of sebum components were investigated with multivariate ANOVA-simultaneous component analysis (ASCA). Sebum incretion in acne was paralleled by significantly higher abundance of triglycerides, wax esters, and squalene together with monounsaturated FAs (MUFAs), and straight chain saturated FAs (SFAs), especially those with odd-carbon chain, i.e. C13:0, C15:0, and C17:0. Profiling weight/weight percentage of individual components revealed that, in acne, the free FAs (FFAs) array was shifted towards higher relative abundance of the SFAs C15:0, C16:0, and C17:0 and lower percentage of the anteiso-branched FFAs with 12, 14, 16, and 18 carbons. In acne patients, MUFAs and PUFAs were quantitatively increased and decreased on foreheads and cheeks, respectively. Relative abundance of fatty alcohols was decreased in acne independent on the site. The results indicated that acne associates with site-specific derangement of the pathways regulating the balance among odd straight-chain and branched-chain SFAs, MUFAs, which included sapienate (C16:1n-10), PUFAs, and squalene.


Assuntos
Acne Vulgar/metabolismo , Face , Lipidômica , Lipídeos/análise , Sebo/química , Adolescente , Grupo com Ancestrais do Continente Africano , Bochecha , Estudos Transversais , Ácidos Graxos/análise , Álcoois Graxos/análise , Feminino , Testa , Humanos , Masculino , Nigéria , Índice de Gravidade de Doença , Pigmentação da Pele , Adulto Jovem
4.
Cancer Res ; 80(19): 4087-4102, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32718996

RESUMO

Cancer stem-like cells (CSC) induce aggressive tumor phenotypes such as metastasis formation, which is associated with poor prognosis in triple-negative breast cancer (TNBC). Repurposing of FDA-approved drugs that can eradicate the CSC subcompartment in primary tumors may prevent metastatic disease, thus representing an effective strategy to improve the prognosis of TNBC. Here, we investigated spheroid-forming cells in a metastatic TNBC model. This strategy enabled us to specifically study a population of long-lived tumor cells enriched in CSCs, which show stem-like characteristics and induce metastases. To repurpose FDA-approved drugs potentially toxic for CSCs, we focused on pyrvinium pamoate (PP), an anthelmintic drug with documented anticancer activity in preclinical models. PP induced cytotoxic effects in CSCs and prevented metastasis formation. Mechanistically, the cell killing effects of PP were a result of inhibition of lipid anabolism and, more specifically, the impairment of anabolic flux from glucose to cholesterol and fatty acids. CSCs were strongly dependent upon activation of lipid biosynthetic pathways; activation of these pathways exhibited an unfavorable prognostic value in a cohort of breast cancer patients, where it predicted high probability of metastatic dissemination and tumor relapse. Overall, this work describes a new approach to target aggressive CSCs that may substantially improve clinical outcomes for patients with TNBC, who currently lack effective targeted therapeutic options. SIGNIFICANCE: These findings provide preclinical evidence that a drug repurposing approach to prevent metastatic disease in TNBC exploits lipid anabolism as a metabolic vulnerability against CSCs in primary tumors.


Assuntos
Antineoplásicos/farmacologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Compostos de Pirvínio/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Colesterol/metabolismo , Reposicionamento de Medicamentos , Feminino , Glucose/metabolismo , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Camundongos Endogâmicos NOD , Células-Tronco Neoplásicas/patologia , Neoplasias de Mama Triplo Negativas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
5.
J Exp Clin Cancer Res ; 37(1): 318, 2018 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-30558661

RESUMO

BACKGROUND: Combination therapy with BRAF and MEK inhibitors significantly improves survival in BRAF mutated melanoma patients but is unable to prevent disease recurrence due to the emergence of drug resistance. Cancer stem cells (CSCs) have been involved in these long-term treatment failures. We previously reported in lung cancer that CSCs maintenance is due to altered lipid metabolism and dependent upon Stearoyl-CoA-desaturase (SCD1)-mediated upregulation of YAP and TAZ. On this ground, we investigated the role of SCD1 in melanoma CSCs. METHODS: SCD1 gene expression data of melanoma patients were downloaded from TCGA and correlated with disease progression by bioinformatics analysis and confirmed on patient's tissues by qRT-PCR and IHC analyses. The effects of combination of BRAF/MEKi and the SCD1 inhibitor MF-438 were monitored by spheroid-forming and proliferation assays on a panel of BRAF-mutated melanoma cell lines grown in 3D and 2D conditions, respectively. SCD1, YAP/TAZ and stemness markers were evaluated in melanoma cells and tissues by qRT-PCR, WB and Immunofluorescence. RESULTS: We first observed that SCD1 expression increases during melanoma progression. BRAF-mutated melanoma 3D cultures enriched for CSCs overexpressed SCD1 and were more resistant than 2D differentiated cultures to BRAF and MEK inhibitors. We next showed that exposure of BRAF-mutated melanoma cells to MAPK pathway inhibitors enhanced stemness features by upregulating the expression of YAP/TAZ and downstream genes but surprisingly not SCD1. However, SCD1 pharmacological inhibition was able to downregulate YAP/TAZ and to revert at the same time CSC enrichment and resistance to MAPK inhibitors. CONCLUSIONS: Our data underscore the role of SCD1 as prognostic marker in melanoma and promote the use of SCD1 inhibitors in combination with MAPK inhibitors for the control of drug resistance.


Assuntos
MAP Quinase Quinase Quinases/antagonistas & inibidores , Melanoma/enzimologia , Células-Tronco Neoplásicas/enzimologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Estearoil-CoA Dessaturase/antagonistas & inibidores , Linhagem Celular Tumoral , Interações Medicamentosas , Humanos , MAP Quinase Quinase Quinases/genética , MAP Quinase Quinase Quinases/metabolismo , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Estearoil-CoA Dessaturase/biossíntese , Estearoil-CoA Dessaturase/genética , Transfecção
6.
Sci Rep ; 8(1): 11500, 2018 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-30065281

RESUMO

The skin surface lipids (SSL) result from the blending of sebaceous and epidermal lipids, which derive from the sebaceous gland (SG) secretion and the permeability barrier of the stratum corneum (SC), respectively. In humans, the composition of the SSL is distinctive of the anatomical distribution of the SG. Thus, the abundance of sebum biomarkers is consistent with the density of the SG. Limited evidence on the influence that the SG exerts on the SC lipidome is available. We explored the differential amounts of sebaceous and epidermal lipids in areas at different SG density with lipidomics approaches. SC was sampled with adhesive patches from forearm, chest, and forehead of 10 healthy adults (8F, 2M) after mechanical removal of sebum with absorbing paper. Lipid extracts of SC were analysed by HPLC/(-)ESI-TOF-MS. In the untargeted approach, the naïve molecular features extraction algorithm was used to extract meaningful entities. Aligned and normalized data were evaluated by univariate and multivariate statistics. Quantitative analysis of free fatty acids (FFA) and cholesterol sulfate (CHS) was performed by targeted HPLC/(-)ESI-TOF-MS, whereas cholesterol and squalene were quantified by GC-MS. Untargeted approaches demonstrated that the relative abundance of numerous lipid species was distinctive of SC depending upon the different SG density. The discriminating species included FFA, CHS, and ceramides. Targeted analyses confirmed that sebaceous FFA and epidermal FFA were increased and decreased, respectively, in areas at high SG density. CHS and squalene, which are biomarkers of epidermal and sebaceous lipid matrices, respectively, were both significantly higher in areas at elevated SG density. Overall, results indicated that the SG secretion intervenes in shaping the lipid composition of the epidermal permeability barrier.


Assuntos
Lipídeos/fisiologia , Glândulas Sebáceas/metabolismo , Glândulas Sebáceas/fisiologia , Sebo/metabolismo , Sebo/fisiologia , Pele/metabolismo , Pele/fisiopatologia , Adulto , Ceramidas/metabolismo , Colesterol/metabolismo , Ésteres do Colesterol/metabolismo , Ácidos Graxos não Esterificados/metabolismo , Feminino , Humanos , Masculino , Permeabilidade , Esqualeno/metabolismo
7.
Nat Commun ; 9(1): 3425, 2018 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-30143626

RESUMO

Transcription factors ensure skin homeostasis via tight regulation of distinct resident stem cells. Here we report that JunB, a member of the AP-1 transcription factor family, regulates epidermal stem cells and sebaceous glands through balancing proliferation and differentiation of progenitors and by suppressing lineage infidelity. JunB deficiency in basal progenitors results in a dermatitis-like syndrome resembling seborrheic dermatitis harboring structurally and functionally impaired sebaceous glands with a globally altered lipid profile. A fate switch occurs in a subset of JunB deficient epidermal progenitors during wound healing resulting in de novo formation of sebaceous glands. Dysregulated Notch signaling is identified to be causal for this phenotype. In fact, pharmacological inhibition of Notch signaling can efficiently restore the lineage drift, impaired epidermal differentiation and disrupted barrier function in JunB conditional knockout mice. These findings define an unprecedented role for JunB in epidermal-pilosebaceous stem cell homeostasis and its pathology.


Assuntos
Transdução de Sinais/fisiologia , Fatores de Transcrição/metabolismo , Animais , Diferenciação Celular/fisiologia , Epiderme/metabolismo , Camundongos , Camundongos Knockout , Glândulas Sebáceas/citologia , Glândulas Sebáceas/metabolismo , Células-Tronco/citologia , Células-Tronco/metabolismo , Fatores de Transcrição/genética , Cicatrização/genética , Cicatrização/fisiologia
8.
Mech Ageing Dev ; 170: 98-105, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29155056

RESUMO

Skin aging is associated with alterations of surface texture, sebum composition and immune response. Mechanical stress induces repair mechanisms, which may be dependent on the age and quality of the skin. The response to mechanical stress in young and aged individuals, their subjective opinion and the objective effectiveness of skin care products were evaluated by biophysical skin quality parameters (stratum corneum hydration, transepidermal water loss, skin pH, pigmentation and erythema) at baseline, 1, 6, 24h and 7days at the forearms of 2 groups of healthy volunteers, younger than 35 years (n=11) and older than 60 years (n=13). In addition, casual surface lipid composition was studied under the same conditions at the baseline and day 7 after mechanical stress induction. Evaluations were also performed in stressed skin areas treated daily with skin care products and the subjective opinion of the volunteers was additionally documented. The tested groups exhibited age-associated baseline skin functions as well as casual surface lipid composition and different reaction patterns to mechanical stress. Skin care was more effective in normalizing skin reaction to stress in the young than in the aged group. The subjective volunteer opinion correlated with the objective measurements.


Assuntos
Envelhecimento/metabolismo , Metabolismo dos Lipídeos , Envelhecimento da Pele , Pele/metabolismo , Estresse Mecânico , Adulto , Idoso , Envelhecimento/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pele/patologia , Higiene da Pele
9.
Free Radic Biol Med ; 115: 266-277, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29229551

RESUMO

Pleural mesothelioma is a deadly form of cancer. The prognosis is extremely poor due to the limited treatment modalities. Uptake of asbestos fibres, the leading cause of mesothelioma, lead to the accumulation of reactive-oxygen-species (ROS). Interestingly, increasing ROS production by using ROS-generating drugs may offer a strategy to selectively trigger cell death. Exemestane, an aromatase inhibitor, has previously shown anti-tumor properties in mesothelioma preclinical models suggesting a role of G protein-coupled receptor 30 (GPR30) in the drug response. As exemestane, in addition to blocking estrogen biosynthesis, generates ROS that are able to arrest the growth of breast cancer, we explored the role of ROS, antioxidant defense system, and ROS-induced signalling pathways in mesothelioma cells during exemestane response. Here we report that exemestane treatment reduced cell proliferation with an increase in ROS production and reduction of cyclic adenosine monophosphate (cAMP) levels in MSTO-H211, Ist-Mes1, Ist-Mes2 and MPP89 exemestane-sensitive mesothelioma cell lines, but not in NCI-H2452 exemestane-insensitive mesothelioma cells. Exemestane induced a significant antioxidant response in NCI-H2452 cells, as highlighted by an increase in γ-glutamylcysteine levels, catalase (Cat), superoxide-dismutase and (SOD) and glutathione-peroxidase (GSH-Px) activity and nuclear factor E2-related factor 2 (Nrf2) activation, responsible for drug insensitivity. Conversely, exemestane elevated ROS levels along with increased ERK phosphorylation and a reduction of p-STA3 in exemestane-sensitive mesothelioma cells. ROS generation was the crucial event of exemestane action because ROS inhibitor N-acetyl-L-cysteine (NAC) abrogated p-ERK and p-STAT3 modulation and cellular death. Exemestane also modulates ERK and STAT3 signalling via GPR30. Results indicate an essential role of ROS in the antiproliferative action of exemestane in mesothelioma cells. It is likely that the additional oxidative insults induced by exemestane results in the lethal effects of mesothelioma cells by increasing ROS production. As such, manipulating ROS levels with exemestane seems to be a feasible strategy to selectively kill mesothelioma cells with less toxicity to normal cells by regulating ERK and STAT3 activity.


Assuntos
Androstadienos/farmacologia , Antineoplásicos/farmacologia , Inibidores da Aromatase/farmacologia , Mesotelioma/tratamento farmacológico , Neoplasias Pleurais/tratamento farmacológico , Acetilcisteína/farmacologia , Asbestos/efeitos adversos , Morte Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , AMP Cíclico/metabolismo , Exposição Ambiental/efeitos adversos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Receptores de Estrogênio , Receptores Acoplados a Proteínas G , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Resultado do Tratamento
10.
J Lipid Res ; 57(6): 1051-8, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27127078

RESUMO

Acne is a multifactorial skin disorder frequently observed during adolescence with different grades of severity. Multiple factors centering on sebum secretion are implicated in acne pathogenesis. Despite the recognized role of sebum, its compositional complexity and limited analytical approaches have hampered investigation of alterations specifically associated with acne. To examine the profiles of lipid distribution in acne sebum, 61 adolescents (29 males and 32 females) were enrolled in this study. Seventeen subjects presented no apparent clinical signs of acne. The 44 affected individuals were clinically classified as mild (13 individuals), moderate (19 individuals), and severe (12 individuals) acne. Sebum was sampled from the forehead with Sebutape(TM) adhesive patches. Profiles of neutral lipids were acquired with rapid-resolution reversed-phase/HPLC-TOF/MS in positive ion mode. Univariate and multivariate statistical analyses led to the identification of lipid species with significantly different levels between healthy and acne sebum. The majority of differentiating lipid species were diacylglycerols (DGs), followed by fatty acyls, sterols, and prenols. Overall, the data indicated an association between the clinical grading of acne and sebaceous lipid fingerprints and highlighted DGs as more abundant in sebum from adolescents affected with acne.


Assuntos
Acne Vulgar/metabolismo , Diglicerídeos/isolamento & purificação , Lipídeos/isolamento & purificação , Pele/metabolismo , Esteróis/isolamento & purificação , Acne Vulgar/patologia , Adolescente , Adulto , Cromatografia Líquida de Alta Pressão , Diglicerídeos/metabolismo , Feminino , Hemiterpenos , Humanos , Lipídeos/química , Lipídeos/classificação , Masculino , Pentanóis/química , Pentanóis/isolamento & purificação , Sebo/metabolismo , Índice de Gravidade de Doença , Pele/química , Pele/patologia , Esteróis/metabolismo
11.
Development ; 143(10): 1823-31, 2016 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-26989175

RESUMO

Sebocytes, which are characterized by lipid accumulation that leads to cell disruption, can be found in hair follicle-associated sebaceous glands (SGs) or in free SGs such as the Meibomian glands in the eyelids. Because genetic tools that allow targeting of sebocytes while maintaining intact epidermal lipids are lacking, the relevance of sebaceous lipids in health and disease remains poorly understood. Using Scd3, which is expressed exclusively in mature sebocytes, we established a mouse line with sebocyte-specific expression of Cre recombinase. Both RT-PCR analysis and crossing into Rosa26-lacZ reporter mice and Kras(G12D) mice confirmed Cre activity specifically in SGs, with no activity in other skin compartments. Importantly, loss of SCD3 function did not cause detectable phenotypical alterations, endorsing the usefulness of Scd3-Cre mice for further functional studies. Scd3-Cre-induced, diphtheria chain A toxin-mediated depletion of sebaceous lipids resulted in impaired water repulsion and thermoregulation, increased rates of UVB-induced epidermal apoptosis and caused a severe pathology of the ocular surface resembling Meibomian gland dysfunction. This novel mouse line will be useful for further investigating the roles of sebaceous lipids in skin and eye integrity.


Assuntos
Apoptose/efeitos da radiação , Olho/efeitos da radiação , Lipídeos/química , Glândulas Sebáceas/química , Raios Ultravioleta , Água/química , Animais , Regulação da Temperatura Corporal/efeitos da radiação , Síndromes do Olho Seco/complicações , Síndromes do Olho Seco/patologia , Homozigoto , Humanos , Inflamação/complicações , Inflamação/patologia , Integrases/metabolismo , Glândulas Tarsais/metabolismo , Glândulas Tarsais/efeitos da radiação , Camundongos Endogâmicos C57BL , Tamanho do Órgão , Especificidade de Órgãos/efeitos da radiação , Fenótipo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Sebo/metabolismo
12.
FEBS Lett ; 589(12): 1376-82, 2015 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-25889637

RESUMO

The roles of the epidermal growth factor receptor (EGFR) in sebaceous glands remain poorly explored. We show that human sebocytes express EGFR and lower levels of ERBB2 and ERBB3, all receptors being downregulated after the induction of lipid synthesis. Nile red staining showed that siRNA-mediated downregulation of EGFR or ERBB3 increases lipid accumulation, whereas ERBB2 downregulation has no effect. Spectrometry confirmed induction of triglycerides after EGFR or ERBB3 downregulation and revealed induction of cholesteryl esters after downregulation of EGFR, ERBB2 or ERBB3. Thus, EGFR/ERBB receptors differentially modulate sebaceous lipogenesis, a key feature of sebaceous gland physiology and of several skin diseases.


Assuntos
Receptores ErbB/metabolismo , Regulação Enzimológica da Expressão Gênica , Lipogênese , Receptor ErbB-2/metabolismo , Receptor ErbB-3/metabolismo , Glândulas Sebáceas/metabolismo , Biomarcadores/metabolismo , Linhagem Celular , Ésteres do Colesterol/metabolismo , Regulação para Baixo , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Ácidos Graxos não Esterificados/metabolismo , Humanos , Ligantes , Ácido Linoleico/metabolismo , Interferência de RNA , RNA Interferente Pequeno , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/genética , Receptor ErbB-3/antagonistas & inibidores , Receptor ErbB-3/genética , Glândulas Sebáceas/enzimologia , Triglicerídeos/metabolismo , Regulação para Cima
13.
Exp Dermatol ; 24(4): 245-51, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25644500

RESUMO

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that modulate the expression of multiple different genes involved in the regulation of lipid, glucose and amino acid metabolism. PPARs and cognate ligands also regulate important cellular functions, including cell proliferation and differentiation, as well as inflammatory responses. This includes a role in mediating skin and pilosebaceous unit homoeostasis: PPARs appear to be essential for maintaining skin barrier permeability, inhibit keratinocyte cell growth, promote keratinocyte terminal differentiation and regulate skin inflammation. They also may have protective effects on human hair follicle (HFs) epithelial stem cells, while defects in PPARγ-mediated signalling may promote the death of these stem cells and thus facilitate the development of cicatricial alopecia (lichen planopilaris). Overall, however, selected PPARγ modulators appear to act as hair growth inhibitors that reduce the proliferation and promote apoptosis of hair matrix keratinocytes. The fact that commonly prescribed PPARγ-modulatory drugs of the thiazolidine-2,4-dione class can exhibit a battery of adverse cutaneous effects underscores the importance of distinguishing beneficial from clinically undesired cutaneous activities of PPARγ ligands and to better understand on the molecular level how PPARγ-regulated cutaneous lipid metabolism and PPARγ-mediated signalling impact on human skin physiology and pathology. Surely, the therapeutic potential that endogenous and exogenous PPARγ modulators may possess in selected skin diseases, ranging from chronic inflammatory hyperproliferative dermatoses like psoriasis and atopic dermatitis, via scarring alopecia and acne can only be harnessed if the complexities of PPARγ signalling in human skin and its appendages are systematically dissected.


Assuntos
PPAR gama/fisiologia , Fenômenos Fisiológicos da Pele , Animais , Cabelo/fisiologia , Doenças do Cabelo/etiologia , Doenças do Cabelo/fisiopatologia , Humanos , Mediadores da Inflamação/fisiologia , Ligantes , PPAR gama/agonistas , Transdução de Sinais , Pele/efeitos dos fármacos , Pele/patologia , Envelhecimento da Pele/efeitos dos fármacos , Envelhecimento da Pele/fisiologia , Dermatopatias/tratamento farmacológico , Dermatopatias/fisiopatologia , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/prevenção & controle , Tiazolidinedionas/farmacologia
14.
Exp Dermatol ; 23(10): 759-61, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25039349

RESUMO

Lipid droplets (LD) are dynamic organelles that manage cellular lipid synthesis, storage and retrieval. Although LD-associated proteins, including the perilipin family (PLIN1-PLIN5), are essential for these functions, they have been poorly characterized in sebocytes. Here, we employed siRNAs to downregulate PLIN3 in SZ95 sebaceous gland cells and evaluated the consequences in lipid accumulation by nile red staining and mass spectrometry. Nile red staining revealed that siRNA-mediated downregulation of PLIN3 significantly impaired linoleic acid-induced lipid accumulation in SZ95 sebocytes. Mass spectrometry revealed that PLIN3 was implicated in the metabolism of linoleic acid, a lipid source used in the build-up of triglycerides, among other acyl lipids. Furthermore, the expression of key enzymes of sebaceous lipogenesis was altered in PLIN3-deficient sebocytes, consistent with the changes observed in the neutral lipid abundance, suggesting that PLIN3 functions are intertwined with the lipogenic pathways implicated in sebaceous lipogenesis, such as desaturation and triglyceride synthesis.


Assuntos
Lipogênese , Glândulas Sebáceas/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Linhagem Celular , Regulação para Baixo , Humanos , Ácido Linoleico/metabolismo , Lipogênese/genética , Redes e Vias Metabólicas , Perilipina-3 , RNA Interferente Pequeno/genética , Glândulas Sebáceas/citologia , Triglicerídeos/metabolismo , Proteínas de Transporte Vesicular/antagonistas & inibidores , Proteínas de Transporte Vesicular/genética
15.
J Clin Invest ; 124(9): 3713-24, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25061872

RESUMO

The endocannabinoid system (ECS) regulates multiple physiological processes, including cutaneous cell growth and differentiation. Here, we explored the effects of the major nonpsychotropic phytocannabinoid of Cannabis sativa, (-)-cannabidiol (CBD), on human sebaceous gland function and determined that CBD behaves as a highly effective sebostatic agent. Administration of CBD to cultured human sebocytes and human skin organ culture inhibited the lipogenic actions of various compounds, including arachidonic acid and a combination of linoleic acid and testosterone, and suppressed sebocyte proliferation via the activation of transient receptor potential vanilloid-4 (TRPV4) ion channels. Activation of TRPV4 interfered with the prolipogenic ERK1/2 MAPK pathway and resulted in the downregulation of nuclear receptor interacting protein-1 (NRIP1), which influences glucose and lipid metabolism, thereby inhibiting sebocyte lipogenesis. CBD also exerted complex antiinflammatory actions that were coupled to A2a adenosine receptor-dependent upregulation of tribbles homolog 3 (TRIB3) and inhibition of the NF-κB signaling. Collectively, our findings suggest that, due to the combined lipostatic, antiproliferative, and antiinflammatory effects, CBD has potential as a promising therapeutic agent for the treatment of acne vulgaris.


Assuntos
Anti-Inflamatórios/farmacologia , Canabidiol/farmacologia , Glândulas Sebáceas/efeitos dos fármacos , Acne Vulgar/tratamento farmacológico , Acne Vulgar/etiologia , MAP Quinases Reguladas por Sinal Extracelular/fisiologia , Humanos , Lipogênese/efeitos dos fármacos , Glândulas Sebáceas/citologia , Glândulas Sebáceas/patologia , Sebo/fisiologia , Canais de Cátion TRPV/fisiologia
17.
Front Microbiol ; 5: 74, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24578700

RESUMO

In some filamentous fungi, the pathways related to the oxidative stress and oxylipins production are involved both in the process of host-recognition and in the pathogenic phase. In fact, recent studies have shown that the production of oxylipins in filamentous fungi, yeasts and chromists is also related to the development of the organism itself and to mechanisms of communication with the host at the cellular level. The oxylipins, also produced by the host during defense reactions, are able to induce sporulation and to regulate the biosynthesis of mycotoxins in several pathogenic fungi. In A. flavus, the oxylipins play a crucial role as signals for regulating the biosynthesis of aflatoxins, the conidiogenesis and the formation of sclerotia. To investigate the involvement of an oxylipins based cross-talk into Z. mays and A. flavus interaction, we analyzed the oxylipins profile of the wild type strain and of three mutants of A. flavus that are deleted at the Aflox1 gene level also during maize kernel invasion. A lipidomic approach has been addressed through the use of LC-ToF-MS, followed by a statistical analysis of the principal components (PCA). The results showed the existence of a difference between the oxylipins profile generated by the WT and the mutants onto challenged maize. In relation to this, aflatoxin synthesis which is largely hampered in vitro, is intriguingly restored. These results highlight the important role of maize oxylipin in driving secondary metabolism in A. flavus.

18.
J Invest Dermatol ; 134(4): 1001-1011, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24166135

RESUMO

Peroxisome proliferator-activated receptor γ (PPARγ) antagonizes inflammatory signals by interfering with NF-κB nuclear translocation. Consistently, PPARγ agonists have been proposed in various inflammatory skin disorders, but their wide use has been limited by severe side effects. Classes of compounds with specific PPARγ agonism have been designed to selectively target inflammatory pathways. Among these compounds, GED-0507-34L has been developed and recently used in phase II clinical trials for inflammatory bowel diseases. This study was aimed at assessing the role of GED-0507-34L in preclinical models of inflammatory skin diseases. The compound modulated PPARγ function and suppressed the inflammatory process inhibiting NF-κB nuclear translocation with the consequent reduction of inflammatory cytokines expression, such as IL-6, IL-8, IL-12, IL-21, IL-23, tumor necrosis factor-α (TNF-α), and cyclooxygenase-2 (COX-2) in normal human keratinocytes and lymphocytes treated with lipopolysaccharide (LPS) or TNF-α. Moreover, an altered proliferation and expression of differentiation markers induced by TNF-α were also counteracted. In psoriasis-like skin lesions elicited in mice by IL-21, topical application of GED-0507-34L reduced cellular infiltrate and epidermal hyperplasia, normalizing the differentiation process. The results indicate that GED-0507-34L possesses anti-inflammatory properties useful for the management of patients with inflammatory skin diseases including psoriasis. Phase I trial on patients is ongoing.


Assuntos
Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Compostos de Anilina/uso terapêutico , Inflamação/tratamento farmacológico , PPAR gama/metabolismo , Fenilpropionatos/uso terapêutico , Propionatos/uso terapêutico , Pele/patologia , Compostos de Anilina/química , Animais , Biópsia , Adesão Celular , Proliferação de Células , Células Cultivadas , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Epiderme/metabolismo , Humanos , Queratinócitos/citologia , Lipopolissacarídeos/química , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Fenilpropionatos/química , Propionatos/química , Ligação Proteica , Psoríase/metabolismo , Interferência de RNA , Pele/efeitos dos fármacos
19.
J Invest Dermatol ; 134(4): 910-920, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24129064

RESUMO

The transcriptional basis of sebocyte differentiation and lipid production is mostly unclear. Peroxisome proliferator-activated receptor gamma (PPARγ), a lipid-activated transcription factor, has been implicated in differentiation and lipid metabolism of various cell types. Here, we show that PPARγ is differentially expressed in normal and pathological human sebocytes and appears to have roles in their differentiation and lipid production. We used laser-microdissected normal and pathological human sebaceous glands (SGs) and SZ95 cells (immortalized sebocyte cell line) analyzed by real-time quantitative PCR and immunohistochemistry. Lipids were analyzed by quantitative fluorimetry- and mass spectrometry-based approaches. We have observed that PPARγ and its target genes, ADRP (adipose differentiation-related protein) and PGAR (PPARγ angiopoietin-related protein), are expressed in sebocytes and show association with their level of differentiation. Also, PPARγ is present in normal and hyperplastic SG, whereas its expression levels are decreased in SG adenoma and SG carcinoma cells, reflecting a maturation-linked expression pattern. Furthermore, in SZ95 sebocytes, naturally occurring lipids, including arachidonic acid and arachidonic acid keto-metabolites (e.g., 5-KETE (5-oxo-6E,8Z,11Z,14Z-eicosatetraenoic acid), 12-KETE (12-oxo-5Z,8Z,10E,14Z-eicosatetraenoic acid)), appear to regulate PPARγ signaling pathways, which in turn modulate phospholipid biosynthesis and induce neutral lipid synthesis. Collectively, our findings highlight the importance of endogenous ligand-activated PPARγ signaling in human sebocyte biology and suggest that PPARγ might be a promising candidate for the clinical management of SG disorders.


Assuntos
Ácido Araquidônico/metabolismo , Lipídeos/biossíntese , PPAR gama/metabolismo , Glândulas Sebáceas/citologia , Glândulas Sebáceas/metabolismo , Sebo/citologia , Carcinoma/metabolismo , Diferenciação Celular , Linhagem Celular , Células Cultivadas , Regulação da Expressão Gênica , Humanos , Ligantes , Proteínas de Membrana/metabolismo , Perilipina-2 , Transdução de Sinais
20.
Biochim Biophys Acta ; 1830(10): 4642-9, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23688400

RESUMO

BACKGROUND: Lipid synthesis and storage are accomplished by lipid droplets (LDs). The perilipin family of LD-associated proteins, comprising 5 members (PLIN1-PLIN5), has been well characterized in adipocytes but not in sebocytes, epithelial cells in which LD formation is a key feature of the cellular differentiation. METHODS: Perilipin expression in the sebaceous gland cell line SZ95 and in human sebaceous glands was studied by qRT-PCR, Western blots, and immunohistochemistry. Lipid accumulation was evaluated by Nile red staining and mass spectrometry. RESULTS: PLIN2 and PLIN3 are the most abundant perilipins in undifferentiated sebocytes. Induction of lipogenesis by linoleic acid (LA) resulted in increased transcript levels of all perilipins except for PLIN3 and in a time-dependent increase of PLIN2 protein. Nile red staining revealed that siRNA-mediated downregulation of PLIN2 significantly impaired basal and LA-induced lipid accumulation. Mass spectrometry revealed PLIN2 deficiency to cause a reduction in the amount of several specific lipid fractions, including di- and triacyl-glycerol esters, phosphatidylcholine lipids, and ceramides in sebocytes under basal conditions. In contrast, PLIN2 downregulation exerted a statistically significant inhibitory effect only on the accumulation of specific LA-induced triglycerides. PLIN2-deficient mice showed normal morphology of sebaceous glands. However, their sebaceous glands were significantly reduced in size and showed less cell proliferation. CONCLUSIONS: PLIN2 is the major perilipin regulated during sebocyte differentiation in vitro. PLIN2 is also important for sebaceous lipid accumulation in vitro and regulates sebaceous gland size in vivo. GENERAL SIGNIFICANCE: Our study provides the first systematic analysis of LD-associated proteins in sebocytes.


Assuntos
Diferenciação Celular , Metabolismo dos Lipídeos , Proteínas de Membrana/fisiologia , Glândulas Sebáceas/citologia , Animais , Sequência de Bases , Linhagem Celular , Primers do DNA , Humanos , Proteínas de Membrana/metabolismo , Camundongos , Perilipina-2 , Reação em Cadeia da Polimerase , Glândulas Sebáceas/metabolismo
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