RESUMO
Glucocorticoids (GCs) are commonly used in the treatment of inflammatory skin diseases, although the balance between therapeutic benefits and side effects is still crucial in clinical practice. One of the major and well-known adverse effects of topical GCs is cutaneous atrophy, which seems to be related to the activation of the glucorticoid receptor (GR) genomic pathway. Dissociating anti-inflammatory activity from atrophogenicity represents an important goal to achieve, in order to avoid side effects on keratinocytes and fibroblasts, known target cells of GC action. To this end, we evaluated the biological activity and safety profile of two novel chemical compounds, DE.303 and KL.202, developed as non-transcriptionally acting GR ligands. In primary keratinocytes, both compounds demonstrated anti-inflammatory properties inhibiting NF-κB activity, downregulating inflammatory cytokine release and interfering with pivotal signaling pathways involved in the inflammatory process. Of note, these beneficial actions were not associated with GC-related atrophic effects: treatments of primary keratinocytes and fibroblasts with DE.303 and KL.202 did not induce, contrarily to dexamethasone-a known potent GC-alterations in extracellular matrix components and lipid synthesis, thus confirming their safety profile. These data provide the basis for evaluating these compounds as effective alternatives to the currently used GCs in managing inflammatory skin diseases.
Assuntos
Dermatite , Receptores de Glucocorticoides , Humanos , Pele , Anti-Inflamatórios/efeitos adversos , Queratinócitos , Glucocorticoides/efeitos adversos , Dermatite/tratamento farmacológico , Dermatite/etiologia , AtrofiaRESUMO
The endocannabinoid system regulates physiological processes, and the modulation of endogenous endocannabinoid (eCB) levels is an attractive tool to contrast the development of pathological skin conditions including cancers. Inhibiting FAAH (fatty acid amide hydrolase), the degradation enzyme of the endocannabinoid anandamide (AEA) leads to the increase in AEA levels, thus enhancing its biological effects. Here, we evaluated the anticancer property of the FAAH inhibitor URB597, investigating its potential to counteract epithelial-to-mesenchymal transition (EMT), a process crucially involved in tumor progression. The effects of the compound were determined in primary human keratinocytes, ex vivo skin explants, and the squamous carcinoma cell line A431. Our results demonstrate that URB597 is able to hinder the EMT process by downregulating mesenchymal markers and reducing migratory potential. These effects are associated with the dampening of the AKT/STAT3 signal pathways and reduced release of pro-inflammatory cytokines and tumorigenic lipid species. The ability of URB597 to contrast the EMT process provides insight into effective approaches that may also include the use of FAAH inhibitors for the treatment of skin cancers.
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Endocanabinoides , Neoplasias , Humanos , Endocanabinoides/farmacologia , Endocanabinoides/metabolismo , Alcamidas Poli-Insaturadas/farmacologia , Alcamidas Poli-Insaturadas/metabolismo , Amidoidrolases/metabolismo , Queratinócitos/metabolismoRESUMO
Bovine colostrum, the first milk secreted by the mammary glands of cows shortly after they have given birth, provides a natural source of bioactive substances helpful to promote tissue development and repair, and to maintain a healthy immune system. Owing to its properties, the use of colostrum in the treatment of human diseases is under investigation. We evaluated the biological activity of colostrum on human primary keratinocytes, focusing on its effects with regard to a proliferation/differentiation balance. Using cellular and molecular approaches, we showed that colostrum favors a cell cycle withdrawal by increasing the expression of p21/WAF1 and p27/KIP1. It also promotes the transition of keratinocytes from a proliferating to a differentiating state, as assessed by a decrease in keratin 5 and an increase in keratin 16. We demonstrated the ability of colostrum to induce the expression of early and late differentiation markers (keratin 1, involucrin, and filaggrin) and the synthesis of caspase 14 and bleomycin hydrolase, the two main enzymes involved in filaggrin maturation. Moreover, we showed that bovine colostrum is able to promote keratinocyte stratification and terminal differentiation not only in two-dimensional (2D), but also in a more physiological system of three-dimensional (3D) skin equivalents. Finally, we demonstrated that colostrum stimulates cell differentiation through the PI3K/PLC-γ1/PKCα pathways mainly associated to tyrosine kinase receptors. These results suggest the possibility to benefit from colostrum properties for the treatment of skin diseases characterized by altered differentiation and perturbed barrier function.
Assuntos
Diferenciação Celular , Colostro/metabolismo , Proteínas de Filamentos Intermediários/metabolismo , Queratinócitos/citologia , Pele/citologia , Animais , Bovinos , Células Cultivadas , Feminino , Proteínas Filagrinas , Humanos , Queratinócitos/metabolismo , Gravidez , Pele/metabolismoRESUMO
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 CutâneoRESUMO
BACKGROUND: Infective endocarditis (IE) is associated with high rates of mortality. Prolonged treatments with high-dose intravenous antibiotics often fail to eradicate the infection, frequently leading to high-risk surgical intervention. By providing a mechanism of antibiotic tolerance, which escapes conventional antibiotic susceptibility profiling, microbial biofilm represents a key diagnostic and therapeutic challenge for clinicians. This study aims at assessing a rapid biofilm identification assay and a targeted antimicrobial susceptibility profile of biofilm-growing bacteria in patients with IE, which were unresponsive to antibiotic therapy. RESULTS: Staphylococcus aureus was the most common isolate (50%), followed by Enterococcus faecalis (25%) and Streptococcus gallolyticus (25%). All microbial isolates were found to be capable of producing large, structured biofilms in vitro. As expected, antibiotic treatment either administered on the basis of antibiogram or chosen empirically among those considered first-line antibiotics for IE, including ceftriaxone, daptomycin, tigecycline and vancomycin, was not effective at eradicating biofilm-growing bacteria. Conversely, antimicrobial susceptibility profile of biofilm-growing bacteria indicated that teicoplanin, oxacillin and fusidic acid were most effective against S. aureus biofilm, while ampicillin was the most active against S. gallolyticus and E. faecalis biofilm, respectively. CONCLUSIONS: This study indicates that biofilm-producing bacteria, from surgically treated IE, display a high tolerance to antibiotics, which is undetected by conventional antibiograms. The rapid identification and antimicrobial tolerance profiling of biofilm-growing bacteria in IE can provide key information for both antimicrobial therapy and prevention strategies.
Assuntos
Antibacterianos/farmacologia , Bactérias/classificação , Bactérias/efeitos dos fármacos , Biofilmes/efeitos dos fármacos , Endocardite Bacteriana/diagnóstico , Endocardite/microbiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/uso terapêutico , Bactérias/isolamento & purificação , Farmacorresistência Bacteriana Múltipla , Endocardite/tratamento farmacológico , Endocardite/cirurgia , Endocardite Bacteriana/tratamento farmacológico , Endocardite Bacteriana/cirurgia , Feminino , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Filogenia , Resultado do TratamentoRESUMO
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 , CicatrizaçãoRESUMO
The intracellular serine amidase, fatty acid amide hydrolase (FAAH), degrades a heterogeneous family of lipid-derived bioactive molecules that include amides of long-chain fatty acids with taurine [N-acyl-taurines (NATs)]. The physiological functions of the NATs are unknown. Here we show that genetic or pharmacological disruption of FAAH activity accelerates skin wound healing in mice and stimulates motogenesis of human keratinocytes and differentiation of human fibroblasts in primary cultures. Using untargeted and targeted lipidomics strategies, we identify two long-chain saturated NATs-N-tetracosanoyl-taurine [NAT(24:0)] and N-eicosanoyl-taurine [NAT(20:0)]-as primary substrates for FAAH in mouse skin, and show that the levels of these substances sharply decrease at the margins of a freshly inflicted wound to increase again as healing begins. Additionally, we demonstrate that local administration of synthetic NATs accelerates wound closure in mice and stimulates repair-associated responses in primary cultures of human keratinocytes and fibroblasts, through a mechanism that involves tyrosine phosphorylation of the epidermal growth factor receptor and an increase in intracellular calcium levels, under the permissive control of transient receptor potential vanilloid-1 receptors. The results point to FAAH-regulated NAT signaling as an unprecedented lipid-based mechanism of wound-healing control in mammalian skin, which might be targeted for chronic wound therapy.
Assuntos
Pele/metabolismo , Taurina/metabolismo , Cicatrização , Amidoidrolases/genética , Amidoidrolases/metabolismo , Animais , Células Cultivadas , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Recém-Nascido , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pele/efeitos dos fármacos , Pele/patologia , Especificidade por Substrato , Taurina/química , Taurina/farmacologiaRESUMO
Bioassay-guided fractionation of the methanol extract of the shoots of Myrsine africana led to the isolation of the new compound myricetin 3-O-(2â³,4â³-di-O-acetyl)-α-l-rhamnopyranoside (9) and 11 known compounds. The known compounds quercetin 3-O-(3â³,4â³-di-O-acetyl)-α-l-rhamnopyranoside (8), rutin (10), quercetin 3-O-α-l-rhamnopyranoside (11), and myricetin 3-O-α-l-rhamnopyranoside (12) are reported for the first time from the methanol extract of the shoots of M. africana. Compounds 10 and 12 showed significant inhibition of tyrosinase with 50% inhibition (IC50 values) of the enzyme at 0.13 ± 0.003 and 0.12 ± 0.002 mM, respectively, which was supported by the docking fitness scores obtained through molecular docking analysis. In addition, compounds 1-12 displayed significant antioxidant activity with IC50 values ranging 1.90 to 3.90 µM.
Assuntos
Agaricales/efeitos dos fármacos , Flavonoides/química , Flavonoides/farmacologia , Glicosídeos/química , Glicosídeos/farmacologia , Myrsine/química , Antioxidantes/química , Antioxidantes/farmacologia , Simulação de Acoplamento Molecular/métodos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Quercetina/análogos & derivados , Quercetina/química , Quercetina/farmacologiaRESUMO
Percutaneous coronary intervention (PCI) is a standard of care in the management of coronary artery disease in patients with renal insufficiency (RI). However, outcomes of PCI in these patients remain suboptimal with high cardiovascular morbidity and mortality. The studies comparing target vessel revascularization (TVR) after PCI in patients with mild and moderate RI have shown conflicting results. Hence, a meta-analysis of these studies comparing 30-day and 1-year outcomes after PCI was performed. A systematic review of literature revealed 5 studies involving 16,262 patients. Based on the creatinine clearance (CrCl), patients were divided into 2 groups (mild RI, CrCl > 60 mL/min and moderate RI, CrCl of 30-60 mL/min). End points extracted were all-cause mortality, TVR, myocardial infarction, and major adverse cardiac events at 30-day and 1-year follow-up. Combined relative risks (RR) across all the studies and 95% confidence intervals (CIs) were computed. A 2-sided alpha error of <0.05 was considered statistically significant. Both groups had similar baseline characteristics. Rate of TVR at 30 days was significantly lower in the mild RI group than in the moderate RI group (RR, 1.45; 95% CI, 1.04-2.02; P < 0.05). However, rate of TVR at 1-year follow-up was similar in both groups (RR, 1.02; 95% CI, 0.94-1.11; P, nonsignificant). Incidence of all-cause mortality, TVR, myocardial infarction, and major adverse cardiac events remained higher in the moderate RI group both at 30-day and 1-year follow-up (P < 0.05 for all outcomes). Patients with moderate RI have higher morbidity and mortality at 30 days and 1 year after PCI compared with patients with mild RI. However, there is no difference in the incidence of TVR after PCI at 1 year between the 2 groups.
Assuntos
Doença da Artéria Coronariana/cirurgia , Intervenção Coronária Percutânea/métodos , Insuficiência Renal/fisiopatologia , Seguimentos , Humanos , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do TratamentoRESUMO
Derangement of the epidermal barrier lipids and dysregulated immune responses are key pathogenic features of atopic dermatitis (AD). The Th2-type cytokines interleukin IL-4 and IL-13 play a prominent role in AD by activating the Janus Kinase/Signal Transduction and Activator of Transcription (JAK/STAT) intracellular signaling axis. This study aimed to investigate the role of JAK/STAT in the lipid perturbations induced by Th2 signaling in 3D epidermal equivalents. Tofacitinib, a low-molecular-mass JAK inhibitor, was used to screen for JAK/STAT-mediated deregulation of lipid metabolism. Th2 cytokines decreased the expression of elongases 1, 3, and 4 and serine-palmitoyl-transferase and increased that of sphingolipid delta(4)-desaturase and carbonic anhydrase 2. Th2 cytokines inhibited the synthesis of palmitoleic acid and caused depletion of triglycerides, in association with altered phosphatidylcholine profiles and fatty acid (FA) metabolism. Overall, the ceramide profiles were minimally affected. Except for most sphingolipids and very-long-chain FAs, the effects of Th2 on lipid pathways were reversed by co-treatment with tofacitinib. An increase in the mRNA levels of CPT1A and ACAT1, reduced by tofacitinib, suggests that Th2 cytokines promote FA beta-oxidation. In conclusion, pharmacological inhibition of JAK/STAT activation prevents the lipid disruption caused by the halted homeostasis of FA metabolism.
Assuntos
Citocinas , Janus Quinases , Metabolismo dos Lipídeos , Fatores de Transcrição STAT , Células Th2 , Humanos , Citocinas/metabolismo , Epiderme/metabolismo , Epiderme/efeitos dos fármacos , Ácidos Graxos/metabolismo , Interleucina-4/metabolismo , Inibidores de Janus Quinases/farmacologia , Janus Quinases/antagonistas & inibidores , Janus Quinases/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Piperidinas/farmacologia , Pirimidinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição STAT/antagonistas & inibidores , Fatores de Transcrição STAT/metabolismo , Células Th2/metabolismo , Células Th2/efeitos dos fármacos , Técnicas de Cultura de Células em Três DimensõesRESUMO
Sodium hypochlorite (NaOCl) is widely recognized for its broad-spectrum antimicrobial efficacy in skin wound care. This study investigates the effectiveness of NaOCl against a range of bacterial and fungal isolates from pressure ulcer (PU) patients. We analyzed 20 bacterial isolates from PU patients, comprising carbapenem-resistant Klebsiella pneumoniae (CRKP), multidrug-resistant Acinetobacter baumannii (MDRAB), methicillin-resistant Staphylococcus aureus (MRSA), methicillin-susceptible Staphylococcus aureus (MSSA), along with 5 Candida albicans isolates. Antibiotic resistance profiles were determined using standard susceptibility testing. Whole-genome sequencing (WGS) was employed to identify antimicrobial resistance genes (ARGs) and disinfectant resistance genes (DRGs). Genetic determinants of biofilm formation were also assessed. The antimicrobial activity of NaOCl was evaluated by determining the minimum inhibitory concentration (MIC) and the minimal biofilm eradication concentration (MBEC) for both planktonic and biofilm-associated cells. CRKP and MDRAB showed resistance to fluoroquinolones and carbapenems, while MRSA exhibited resistance to ß-lactams and levofloxacin. MSSA displayed a comparatively lower resistance profile. WGS identified significant numbers of ARGs in CRKP and MDRAB, with fewer DRGs compared to MRSA and MSSA. All isolates possessed genes associated with fimbriae production and adhesion, correlating with pronounced biofilm biomass production. NaOCl demonstrated substantial antimicrobial activity against both planktonic cells and biofilms. The MIC90 for planktonic bacterial cells was 0.125 mg/mL, and the MBEC90 ranged from 0.225 to 0.5 mg/mL. For planktonic C. albicans, the MIC90 was 0.150 mg/mL, and the MBEC90 was 0.250 mg/mL. These results highlight the challenge in treating biofilm-associated infections and underscore the potential of NaOCl as a robust antimicrobial agent against difficult-to-treat biofilm infections at concentrations lower than those typically found in commercial disinfectants.
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Azelaic acid (AzA) has been used for the treatment for inflammatory skin diseases, such as acne and rosacea. Interestingly, an improvement in skin texture has been observed after long-time treatment with AzA. We previously unrevealed that anti-inflammatory activity of AzA involves a specific activation of PPARγ, a nuclear receptor that plays a relevant role in inflammation and even in ageing processes. As rosacea has been considered as a photo-aggravated disease, we investigated the ability of AzA to counteract stress-induced premature cell senescence (SIPS). We employed a SIPS model based on single exposure of human dermal fibroblasts (HDFs) to UVA and 8-methoxypsoralen (PUVA), previously reported to activate a senescence-like phenotype, including long-term growth arrest, flattened morphology and increased synthesis of matrix metalloproteinases (MMPs) and senescence-associated ß-galactosidase (SA-ß-gal). We found that PUVA-treated HDFs grown in the presence of AzA maintained their morphology and reduced MMP-1 release and SA-ß-galactosidase-positive cells. Moreover, AzA induced a reduction in ROS generation, an up-modulation of antioxidant enzymes and a decrease in cell membrane lipid damages in PUVA-treated HDFs. Further evidences of AzA anti-senescence effect were repression of p53 and p21, increase in type I pro-collagen and abrogation of the enhanced expression of growth factors, such as HGF and SCF. Interestingly, PUVA-SIPS showed a decreased activation of PPARγ and AzA counteracted this effect, suggesting that AzA effect involves PPARγ modulation. All together these data showed that AzA interferes with PUVA-induced senescence-like phenotype and its ability to activate PPAR-γ provides relevant insights into the anti-senescence mechanism.
Assuntos
Senescência Celular/efeitos dos fármacos , Fármacos Dermatológicos/farmacologia , Ácidos Dicarboxílicos/farmacologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , PPAR gama/metabolismo , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Células Cultivadas , Senescência Celular/efeitos da radiação , Colágeno Tipo I/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Fibroblastos/citologia , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Metaloproteinase 1 da Matriz/metabolismo , Metoxaleno/farmacologia , Terapia PUVA , Fenótipo , Fosfolipídeos/metabolismo , Fármacos Fotossensibilizantes/farmacologia , Pró-Colágeno/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fator de Células-Tronco/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Raios Ultravioleta , beta-Galactosidase/metabolismoRESUMO
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/metabolismoRESUMO
Spontaneous coronary artery dissection (SCAD) is a rare but increasingly recognized non-atherosclerotic cause of acute coronary syndrome. Common risk factors for SCAD are coronary atherosclerosis, female gender, peripartum period, systemic inflammatory conditions, and connective tissue disorders. It manifests as myocardial ischemia and infarction, arrhythmia, and sudden cardiac death. We present a case series of two young men and one young female with SCAD who had chest pain and were diagnosed with SCAD-associated ST-elevation myocardial infarction. Its diagnosis requires a high degree of clinical suspicion and its management is guided by the patient's clinical condition and the characteristics of the lesions.
RESUMO
Anomalous origin of the left main coronary trunk from the right coronary sinus is a rare condition and is associated with a significantly increased risk of cardiac events, including sudden cardiac death, and it may pose difficulties in their management using revascularization strategies. We present a case of a 68-year-old man with worsening chest pain. Initial evaluation revealed ST elevation of the inferior wall leads and elevated troponins. He was diagnosed with ST-elevation myocardial infarction (STEMI) and sent for emergency cardiac catheterization. Coronary angiography showed 50% stenosis of the mid-right coronary artery (RCA) that extended as a total occlusion to the distal RCA and an unexpected anomalous origin of the left main coronary artery (LMCA). Our patient's LMCA originated from the right cusp sharing a single ostium with the RCA. Multiple attempts of revascularization with percutaneous coronary intervention (PCI), using multiple wires, catheters, and different-sized balloons, were unsuccessful due to complex anatomy. Our patient was managed with medical therapy and discharged home with close cardiology follow-up.
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Cutaneous squamous cell carcinoma (cSCC) is the most common UV-induced keratinocyte-derived cancer, and its progression is characterized by the epithelial-mesenchymal transition (EMT) process. We previously demonstrated that PPARγ activation by 2,4,6-octatrienoic acid (Octa) prevents cutaneous UV damage. We investigated the possible role of the PPARγ activators Octa and the new compound (2Z,4E,6E)-2-methoxyocta-2,4,6-trienoic acid (A02) in targeting keratinocyte-derived skin cancer. Like Octa, A02 exerted a protective effect against UVB-induced oxidative stress and DNA damage in NHKs. In the squamous cell carcinoma A431 cells, A02 inhibited cell proliferation and increased differentiation markers' expression. Moreover, Octa and even more A02 counteracted the TGF-ß1-dependent increase in mesenchymal markers, intracellular ROS, the activation of EMT-related signal transduction pathways, and cells' migratory capacity. Both compounds, especially A02, counterbalanced the TGF-ß1-induced cell membrane lipid remodeling and the release of bioactive lipids involved in EMT. In vivo experiments on a murine model useful to study cell proliferation in adult animals showed the reduction of areas characterized by active cell proliferation in response to A02 topical treatment. In conclusion, targeting PPARγ may be useful for the prevention and treatment of keratinocyte-derived skin cancer.
Assuntos
Carcinoma de Células Escamosas , Neoplasias Cutâneas , Camundongos , Animais , Carcinoma de Células Escamosas/patologia , Transição Epitelial-Mesenquimal , Fator de Crescimento Transformador beta1/farmacologia , PPAR gama/metabolismo , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/metabolismo , CarcinogêneseRESUMO
BACKGROUND: Drug-eluting stents (DES) are associated with a decreased frequency of repeat revascularization compared with bare metal stents (BMS) in patients with coronary artery disease; however, uncertainty over their long-term safety, especially in high-risk patients, such as those with ST elevation myocardial infarction (STEMI), persists. OBJECTIVE: To evaluate the safety and efficacy of DES compared with BMS in STEMI patients at a follow-up of three years or longer. METHODS: Two independent investigators systematically searched the Medline, CENTRAL, Embase and CardioSource databases for randomized trials comparing DES with BMS in STEMI, and reporting outcomes at three years or longer. Relevant study characteristics and clinical end points were extracted. Random-effect and fixed-effect models were used to calculate ORs for heterogeneous and homogenous outcomes, respectively. RESULTS: Ten randomized trials met the eligibility criteria, resulting in the inclusion of 4330 patients in the DES group and 2662 patients in the BMS group. DES use significantly reduced the odds of target vessel (OR 0.44 [95% CI 0.35 to 0.54]) and target lesion revascularization (OR 0.47 [95% CI 0.36 to 0.61]). Furthermore, patients in the DES group experienced major adverse coronary events less frequently than patients in the BMS group, which was driven mainly by the decreased revascularization rate. Although the incidence of stent thrombosis was similar, DES was associated with a higher risk of very late stent thrombosis (OR 1.69 [95% CI 1.11 to 2.57]). There were no differences between the groups with respect to death, cardiac death and myocardial infarction. CONCLUSION: DES continues to be associated with a lower repeat revascularization rate in patients with STEMI, with a small but significantly increased risk of very late stent thrombosis compared with BMS at a follow-up of three years or longer.
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Autophagy is a vital process for cell survival and it preserves homeostasis by recycling or disassembling unnecessary or dysfunctional cellular constituents. Autophagy ameliorates skin integrity, regulating epidermal differentiation and constitutive pigmentation. It induces melanogenesis and contributes to skin color through melanosome turnover. Autophagy activity is involved in skin phenotypic plasticity and cell function maintenance and, if altered, it concurs to the onset and/or progression of hypopigmentary and hyperpigmentary disorders. Overexpression of autophagy exerts a protective role against the intrinsic metabolic stress occurring in vitiligo skin, while its dysfunction has been linked to the tuberous sclerosis complex hypopigmentation. Again, autophagy impairment reduces melanosome degradation by concurring to pigment accumulation characterizing senile lentigo and melasma. Here we provide an updated review that describes recent findings on the crucial role of autophagy in skin pigmentation, thus revealing the complex interplay among melanocyte biology, skin environment and autophagy. Hence, targeting this process may also represent a promising strategy for treating pigmentary disorders.
Assuntos
Hipopigmentação , Transtornos da Pigmentação , Autofagia , Humanos , Melanócitos/metabolismo , Transtornos da Pigmentação/metabolismo , Transtornos da Pigmentação/terapia , Pigmentação da PeleRESUMO
Inflammation and biofilm-associated infection are common in chronic venous leg ulcers (VU), causing deep pain and delayed healing. Albeit important, clinical markers and laboratory parameters for identifying and monitoring persistent VU infections are limited. This study analyzed 101 patients with infected (IVU) and noninfected VUs (NVU). Clinical data were collected in both groups. The serum homocysteine (Hcys) and inflammatory cytokines from the wound fluid were measured. In addition, microbial identification, antibiotic susceptibility, and biofilm production were examined. IVU were 56 (55.4%) while NVU were 45 (44.5%). IVUs showed a significant increase in the wound's size and depth compared to NVUs. In addition, significantly higher levels of interleukin (IL)-6, IL-10, IL17A, and tumor necrosis factor-alpha (TNF-α) were found in patients with IVUs compared to those with NVUs. Notably, hyperhomocysteinemia (HHcy) was significantly more common in patients with IVUs than NVUs. A total of 89 different pathogens were identified from 56 IVUs. Gram-negative bacteria were 51.7%, while the Gram-positives were 48.3%. At the species level, Staphylococcus aureus was the most common isolate (43.8%), followed by Pseudomonas aeruginosa (18.0%). Multidrug-resistant organisms (MDROs) accounted for 25.8% of the total isolates. Strong biofilm producers (SBPs) (70.8%) were significantly more abundant than weak biofilm producers (WBP) (29.2%) in IVUs. SBPs were present in 97.7% of the IVUs as single or multispecies infections. Specifically, SBPs were 94.9% for S. aureus, 87.5% for P. aeruginosa, and 28.6% for Escherichia coli. In IVU, the tissue microenvironment and biofilm production can support chronic microbial persistence and a most severe clinical outcome even in the presence of an intense immune response, as shown by the high levels of inflammatory molecules. The measurement of local cytokines in combination with systemic homocysteine may offer a novel set of biomarkers for the clinical assessment of IVUs caused by biofilm-producing bacteria.
RESUMO
Vitiligo is an acquired skin depigmentation disease involving multiple pathogenetic mechanisms, which ultimately direct cytotoxic CD8+ cells to destroy melanocytes. Abnormalities have been described in several cells even in pigmented skin as an expression of a functional inherited defect. Keratinocytes regulate skin homeostasis by the assembly of a proper skin barrier and releasing and responding to cytokines and growth factors. Alterations in epidermal proliferation, differentiation, and lipid composition as triggers for immune response activation in vitiligo have not yet been investigated. By applying cellular and lipidomic approaches, we revealed a deregulated keratinocyte differentiation with altered lipid composition, associated with impaired energy metabolism and increased glycolytic enzyme expression. Vitiligo keratinocytes secreted inflammatory mediators, which further increased following mild mechanical stress, thus evidencing immune activation. These findings identify intrinsic alterations of the nonlesional epidermis, which can be the prime instigator of the local inflammatory milieu that stimulates immune responses targeting melanocytes.