RESUMO
Hypoxia-inducible factor-1α (HIF-1α) is the master transcription factor of glycolysis, Th17 cell differentiation and suppression of regulatory T cells. In the skin and serum of patients with psoriasis vulgaris, increased expression of HIF-1α has been reported, whereas HIF-1α expression in the skin and serum of patients with hidradenitis suppurativa (HS) has not yet been studied. The objective of the study is to demonstrate is there a role for HIF-1α in the pathogenesis of hidradenitis suppurativa, and its relation to HS severity. Twenty patients suffering from hidradenitis suppurativa were included in the study. Punch biopsies were taken from lesional skin for the determination of HIF-1α expression by immunohistochemical staining, and HIF-1α gene expression by quantitative reverse transcription real time PCR. Quantification of HIF-1α protein concentration was done by enzyme-linked immunosorbent assay. Twenty socio-demographically cross-matched healthy volunteers served as controls. We found increased serum levels of HIF-1α. Literature-derived evidence indicates that the major clinical triggering factors of HS, obesity, and smoking are associated with hypoxia and enhanced HIF-1α expression. Pro-inflammatory cytokines such as tumor necrosis factor-[Formula: see text] via upregulation of nuclear factor [Formula: see text]B enhance HIF-1α expression. HIF-1α plays an important role for keratinocyte proliferation, especially for keratinocytes of the anagen hair follicle, which requires abundant glycolysis providing sufficient precursors molecules for biosynthetic pathways. Metformin via inhibition of mTORC1 as well as adalimumab attenuate HIF-1α expression, the key mediator between Th17-driven deviated immunity and keratinocyte hyperproliferation. In accordance with psoriasis, our study identifies HS as an HIF-1α-driven inflammatory skin disease and offers a new rationale for the prevention and treatment of HS by targeting HIF-1[Formula: see text] overexpression.
Assuntos
Hidradenite Supurativa , Psoríase , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia , Pele/patologia , Regulação da Expressão GênicaRESUMO
The transcriptomic regulation induced by isotretinoin (13-cis retinoic acid) is still a matter of debate as short-term exposures of immortalized sebocytes with isotretinoin produced conflicting results. Based on translational evidence, it has been hypothesized that oral isotretinoin treatment upregulates the expression of the transcription factor p53. Twenty-five patients suffering from acne vulgaris were treated with isotretinoin (0.6 mg/kg body weight) for 6 weeks. Biopsies from back skin were taken before and after isotretinoin treatment for the determination of p53 expression by immunohistochemical staining, quantification of p53 protein concentration by enzyme-linked immunosorbent assay and TP53 gene expression by quantitative reverse transcription real time PCR. Fifteen socio-demographically cross-matched healthy volunteers served as controls. Isotretinoin treatment significantly increased the nuclear expression of p53 in sebaceous glands of treated patients compared to pre-treatment levels and p53 levels of untreated controls. Furthermore, the p53 protein and gene expression significantly increased in the skin after treatment. The magnitude of p53 expression showed an inverse correlation to acne severity score and body mass index. Under clinical conditions, isotretinoin induced the expression of p53, which controls multiple transcription factors involved in the pathogenesis of acne vulgaris including FoxO1, androgen receptor and critical genes involved in the induction of autophagy and apoptosis. Increased p53-FoxO1 signalling enhanced by systemic isotretinoin treatment explains the underlying transcriptomic changes causing sebum suppression but also the adverse effects associated with systemic isotretinoin therapy.
Assuntos
Acne Vulgar , Isotretinoína , Glândulas Sebáceas , Pele , Humanos , Acne Vulgar/tratamento farmacológico , Acne Vulgar/genética , Acne Vulgar/patologia , Isotretinoína/farmacologia , Isotretinoína/uso terapêutico , Glândulas Sebáceas/efeitos dos fármacos , Glândulas Sebáceas/metabolismo , Pele/efeitos dos fármacos , Pele/patologia , Fatores de Transcrição/metabolismo , Proteína Supressora de Tumor p53/metabolismoRESUMO
Persistent post acne erythema (PAE) is common cosmetically unacceptable and challenging sequelae of acne lesions. Tranexamic acid (TXA) is an antifibrinolytic agent that shows a positive effect on wound healing in several studies, and it showed benefits in treating skin diseases like melasma, rosacea erythema and ultraviolet induced pigmentations. Oxymetazoline (OXZ) is a synthetic, highly selective agonist for alpha 1A-adrenoceptor. It is a potent vasoconstrictor. OXZ hydrochloride 1% cream was approved by the FDA in January 2017 as a topical treatment for persistent facial erythema in rosacea patients. Brimonidine tartrate (BMT) is highly selective α2 adrenergic receptor agonist, results in direct, potent vasoconstriction of small arterioles and veins. In 2013, brimonidine 0.33% gel was the first topical therapy to be FDA approved for the treatment of persistent facial erythema from rosacea. To evaluate the efficacy and safety of topical triple combination (TXA 5% + OXZ 1.5% + BMT 0.33%) in the treatment of PAE planned as split face comparative study. This study was conducted on 40 patients diagnosed with persistent PAE for at least 3 months, the right side of the face was treated with topical triple combination in liposomal base and was compared to the left side to which topical lipocream (placebo) was applied as a control. Our treatment plan lasted for 3 months. According to the investigator's global assessment of photographs and computerized analysis of erythema using image analysis software, topical triple combination applied on the right side of face was significantly effective in diminishing PAE when compared to topical placebo left side. Topical triple combination is a safe and cost-effective treatment for PAE.
Assuntos
Acne Vulgar , Eritema , Acne Vulgar/complicações , Acne Vulgar/tratamento farmacológico , Administração Tópica , Tartarato de Brimonidina/administração & dosagem , Quimioterapia Combinada/efeitos adversos , Eritema/tratamento farmacológico , Eritema/etiologia , Humanos , Oximetazolina/administração & dosagem , Rosácea/tratamento farmacológico , Resultado do TratamentoRESUMO
Isotretinoin (13-cis-retinoic acid), a derivative of vitamin A, is used in the treatment of severe acne resulting in sebum suppression induced by sebocyte apoptosis. Isotretinoin treatment is associated with several adverse effects including teratogenicity, hepatotoxicity, and dyslipidemia. Isotretinoin's effects on endocrine systems and its potential role as an endocrine disruptor are not yet adequately investigated. This review presents clinical, endocrine, and molecular evidence showing that isotretinoin treatment adversely affects the pituitary-ovarian axis and enhances the risk of granulosa cell apoptosis reducing follicular reserve. Isotretinoin is associated with pro-apoptotic signaling in sebaceous glands through upregulated expression of p53, forkhead box O transcription factors (FOXO1, FOXO3), and tumor necrosis factor-related apoptosis inducing ligand (TRAIL). Two literature searches including clinical and experimental studies respectively support the hypothesis that isotretinoin's toxicological mode of action on the pituitary-ovarian axis might be caused by over-expressed p53/FOXO1 signaling resulting in gonadotropin suppression and granulosa cell apoptosis. The reduction of follicular reserve by isotretinoin treatment should be especially considered when this drug will be administered for the treatment of acne in post-adolescent women, in whom fertility may be adversely affected. In contrast, isotretinoin treatment may exert beneficial effects in states of hyperandrogenism, especially in patients with polycystic ovary syndrome.
Assuntos
Isotretinoína/toxicidade , Teratogênicos/toxicidade , Acne Vulgar/induzido quimicamente , Acne Vulgar/tratamento farmacológico , Acne Vulgar/metabolismo , Adolescente , Apoptose/efeitos dos fármacos , Feminino , Humanos , Ovário/efeitos dos fármacos , Hipófise/metabolismo , Síndrome do Ovário Policístico/induzido quimicamente , Transdução de Sinais/efeitos dos fármacos , TeratogêneseRESUMO
BACKGROUND: Palmar hyperhidrosis is a common disorder of excessive sweating due to over-stimulation of cholinergic receptors on eccrine glands. OBJECTIVE: To compare the efficacy of laser-assisted drug delivery of onabotulinum toxin A (BoNTA) and intradermal BoNTA injections in the management of palmar hyperhidrosis. PATIENTS AND METHODS: This intrapatient comparative study was conducted on 30 adult patients with idiopathic palmar hyperhidrosis. The palms of the patients were divided into 2 groups. Group 1 was treated with intradermal injections of 50 units of BoNTA, whereas Group 2 was subjected to laser-assisted transcutaneous BoNTA delivery using fractional CO2 laser at different doses (25, 50, and 75 units). Each treatment modality was evaluated using the iodine starch test, hyperhidrosis disease severity scale, and gravimetric scoring. RESULTS: Delivery of 75 units of BoNTA to the dermis on the right-sided palms assisted by fractional CO2 laser was clinically equivalent to 50 units of injection on the left side. Pain intensity was significantly higher on the injected side than on the other side. CONCLUSION: Laser-assisted drug delivery of botulinum toxin can be considered an effective and safe alternative for treatment of palmar hyperhidrosis with minimal side effects and complications.
Assuntos
Toxinas Botulínicas Tipo A/administração & dosagem , Sistemas de Liberação de Medicamentos , Hiperidrose/tratamento farmacológico , Lasers de Gás , Fármacos Neuromusculares/administração & dosagem , Administração Cutânea , Adulto , Feminino , Mãos , Humanos , Injeções Intradérmicas/efeitos adversos , Lasers de Gás/efeitos adversos , Masculino , Dor/etiologia , Índice de Gravidade de Doença , Adulto JovemRESUMO
Alopecia areata (AA) is an autoimmune form of nonscarring hair loss. The aim of the study was to assess the serum concentration of interferon gamma (IFN-γ) and CD8 cell expression in lesional skin biopsies in correlation with the disease severity, activity, duration, and trichoscopic findings in patients with AA. The study included 30 patients with AA and 15 age- and sex-matched healthy controls. Trichoscopy was performed and photographs were captured for the alopecic areas, and the enzyme-linked immunosorbent assay technique was used for serum level of IFN-γ assessment and immunohistochemistry for CD8 cells. The results obtained indicate that IFN-γ serum level in patients was significantly higher than that of control subjects, and significantly correlated with the activity status and the duration of the disease. CD8+ T cells infiltrate intensity significantly correlated with severity. Yellow dots (YDs), vellus hair, black dot, and exclamation marks were the most common trichoscopic findings. The presence of black dots significantly correlated to the disease activity, duration, serum IFN-γ, and CD8+ infiltrate intensity. The presence of YDs significantly correlated with the mean serum IFN-γ level. Exclamation marks significantly correlated with the disease activity and the degree of CD8+ infiltrate. In conclusion, trichoscopy could be a reliable indicator of the IFN-γ serum level and CD8+ T cell infiltrate intensity in AA patient.
Assuntos
Alopecia em Áreas , Alopecia em Áreas/diagnóstico , Biópsia , Linfócitos T CD8-Positivos , Cabelo , Humanos , Interferon gamaRESUMO
Mycosis Fungoides (MF) is the most common type of cutaneous T-cell lymphomas. Early stage patients are treated with topical therapies and have normal life expectancy whereas patients with advanced disease encounter frequent relapses and have a five-year survival rate that does not exceed 15%. The aim of the present study was to characterize the expression of microRNA-16 (miR-16) and microRNA-93 (miR-93) in early and advanced cases of MF in relation to the clinicopathological parameters. Ten skin biopsies of early and advanced MF were investigated for the expression of miR-16 and miR-93 using RT-PCR. Immunohistochemical expression of apoptosis markers (BCL-2 and Survivin) were also investigated in the studied cases compared to normal skin and eczema biopsies. In the present study, BCL-2 and Survivin showed strong positive expression on neoplastic lymphocytes in all cases of MF regardless of their stage. We have also shown that miR-16 was significantly upregulated in advanced cases of MF compared to cases with early disease (p-value was less than 0.05). However, expression of miR-16 did not show any statistically significant correlation with age, gender, or expression of apoptotic markers. On the other hand, the expression of miR-93 showed significant downregulation in all lymphoma cases irrespective of their stage, compared to normal and eczema cases. Our results suggest that upregulation of miR-16 could be used to predict an aggressive course of the disease. We also suggest that miR-93 downregulation could serve as possible tool for establishing early diagnosis in early challenging cases. Our findings also provide consistent evidence that the anti-apoptotic molecules may play an important role in the pathogenesis of this type of cutaneous lymphomas and promote the idea that their inhibition could be an interesting novel therapeutic strategy in the treatment of MF.
Assuntos
Progressão da Doença , MicroRNAs/genética , Micose Fungoide/diagnóstico , Micose Fungoide/genética , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genética , Apoptose , Egito , Regulação Neoplásica da Expressão Gênica , Humanos , Micose Fungoide/metabolismo , Micose Fungoide/patologia , Prognóstico , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Survivina/metabolismoRESUMO
Oral isotretinoin is the most effective anti-acne drug with the strongest sebum-suppressive effect caused by sebocyte apoptosis. It has been hypothesized that upregulation of nuclear FoxO transcription factors and p53 mediate isotretinoin-induced sebocyte apoptosis in vivo. It is the aim of our study to analyse the distribution of the pro-apoptotic transcription factors FoxO1 and FoxO3 in the nuclear and cytoplasmic compartments of human sebocytes in vivo before and during isotretinoin treatment of acne patients. Immunohistochemical analysis of skin biopsies with antibodies distinguishing phosphorylated and non-phosphorylated human FoxO1 and FoxO3 proteins was performed before isotretinoin treatment, six weeks after initiation of isotretinoin therapy, and in acne-free control patients not treated with isotretinoin. Our in vivo study demonstrates a significant increase in the nucleo-cytoplasmic ratio of non-phosphorylated FoxO1 and FoxO3 during isotretinoin treatment of acne patients. Translational and presented experimental evidence indicates that upregulation of nuclear FoxO1 and FoxO3 proteins is involved in isotretinoin-induced pro-apoptotic signalling in sebocytes confirming the scientific hypothesis of isotretinoin-mediated upregulation of FoxO expression.
Assuntos
Acne Vulgar/metabolismo , Proteína Forkhead Box O1/metabolismo , Proteína Forkhead Box O3/metabolismo , Isotretinoína/administração & dosagem , Glândulas Sebáceas/efeitos dos fármacos , Administração Oral , Adolescente , Adulto , Apoptose , Biópsia , Núcleo Celular/efeitos dos fármacos , Citoplasma/efeitos dos fármacos , Citoplasma/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Fosforilação , Glândulas Sebáceas/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Adulto JovemRESUMO
OBJECTIVE: To evaluate the incidence of benign prostatic hyperplasia (BPH) and metabolic syndrome in patients with androgenetic alopecia (AGA) in comparison with those with no AGA, as several previous studies have reported inconsistent results of an association between metabolic syndrome and BPH with AGA. PATIENTS SUBJECTS AND METHODS: This cross-sectional study included 400 participants, divided into 300 patients diagnosed with AGA, with different grades according to Norwood-Hamilton classification, and 100 control subjects with no AGA. Criteria for diagnosis of metabolic syndrome according to Adult Treatment Panel-III criteria (waist circumference, blood pressure, fasting blood sugar, high-density lipoprotein and triglycerides), as well as criteria for diagnosis of BPH (prostatic volume, urine flow, and prostate-specific antigen) were assessed in all patients and compared with the control subjects. RESULTS: There were significant differences between the AGA and no-AGA groups for the following variables: waist circumference, body mass index, fibrinogen level, fasting blood sugar, cholesterol, C-reactive protein, erythrocyte sedimentation rate, and glycosylated haemoglobin. There was a significant difference in number of patients with AGA manifesting criteria of metabolic syndrome (51% vs 28%), as well as BPH diagnostic criteria (36% vs 6.8%) compared with the control subjects. Both BPH and metabolic syndrome were shown to be significant independent variables associated with AGA. CONCLUSIONS: Dermatologists, urologists, and primary care physicians should monitor patients with early onset AGA for the development of urinary symptoms, to permit an earlier diagnosis of BPH; and for metabolic syndrome symptoms, to permit early diagnosis of cardiovascular risk factors.