RESUMEN
Understanding the molecular and cellular processes in skin wound healing can pave the way for devising innovative concepts by turning the identified natural effectors into therapeutic tools. Based on the concept of broadscale engagement of members of the family of galactosidebinding lectins (galectins) in pathophysiological processes, such as cancer or tissue repair/regeneration, the present study investigated the potential of galectins1 (Gal1) and 3 (Gal3) in wound healing. Human dermal fibroblasts, which are key cells involved in skin wound healing, responded to galectin exposure (Gal1 at 300 or Gal3 at 600 ng/ml) with selective changes in gene expression among a panel of 84 woundhealingrelated genes, as well as remodeling of the extracellular matrix. In the case of Gal3, positive expression of Ki67 and cell number increased when using a decellularized matrix produced by Gal3treated fibroblasts as substrate for culture of interfollicular keratinocytes. In vivo wounds were topically treated with 20 ng/ml Gal1 or 3, and collagen score was found to be elevated in excisional wound repair in rats treated with Gal3. The tensile strength measured in incisions was significantly increased from 79.5±17.5 g/mm2 in controls to 103.1±21.4 g/mm2 after 21 days of healing. These data warrant further testing mixtures of galectins and other types of compounds, for example a combination of galectins and TGFß1.
Asunto(s)
Proteínas Sanguíneas/biosíntesis , Colágeno/biosíntesis , Dermis/metabolismo , Fibroblastos/metabolismo , Galectinas/biosíntesis , Regulación de la Expresión Génica , Resistencia a la Tracción , Heridas y Lesiones/metabolismo , Dermis/patología , Fibroblastos/patología , Humanos , Heridas y Lesiones/patologíaRESUMEN
Although it has been shown that oestrogen replacement therapy is able to improve wound healing, several side effects of this replacement therapy have precluded its common use in clinical practice. On the other hand, the phytoestrogen genistein (the selective oestrogen receptor modulator belonging to the group of isoflavones) has been introduced into several clinical trials to improve cancer treatment efficiency and experiments suggest its positive effect on wound healing. The main mechanisms of action, which have been elucidated so far, include induction of apoptosis, cell cycle arrest, inhibition of angiogenesis and tyrosine kinase activity as well as cancer chemoprevention and reduction of climacteric symptoms. Unfortunately, all underlying mechanism in the modulation of biological processes involved in wound healing and tumour growth are not yet fully understood. Therefore, the present review summarizes the effects of genistein on biological processes in different wound healing models and selected tumours. Key words: genistein ⢠tissue repair and regeneration ⢠carcinoma ⢠skin.
Asunto(s)
Genisteína/farmacología , Neoplasias/tratamiento farmacológico , Cicatrización de Heridas/efectos de los fármacos , Humanos , Fitoestrógenos/farmacologíaRESUMEN
Selective estrogen receptor modulators (SERMs) have been developed to achieve beneficial effects of estrogens while minimizing their side effects. In this context, we decided to evaluate the protective effect of genistein, a natural SERM, on skin flap viability in rats and in a series of in vitro experiments on endothelial cells (migration, proliferation, antioxidant properties, and gene expression profiling following genistein treatment). Our results showed that administration of genistein increased skin flap viability, but importantly, the difference is only significant when treatment is started 3 days prior the flap surgery. Based on our in vitro experiments, it may be hypothesized that the underlying mechanism may rather by mediated by increasing SOD activity and Bcl-2 expression. The gene expression profiling further revealed 9 up-regulated genes (angiogenesis/inflammation promoting: CTGF, CXCL5, IL-6, ITGB3, MMP-14, and VEGF-A; angiogenesis inhibiting: COL18A1, TIMP-2, and TIMP-3). In conclusion, we observed a protective effect of genistein on skin flap viability which could be potentially applied in plastic surgery to women undergoing a reconstructive and/or plastic intervention. Nevertheless, further research is needed to explain the exact underlying mechanism and to find the optimal treatment protocol.
Asunto(s)
Células Endoteliales/citología , Genisteína/administración & dosificación , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Superóxido Dismutasa/metabolismo , Colgajos Quirúrgicos/fisiología , Animales , Supervivencia Celular , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/efectos de los fármacos , Genisteína/farmacología , Células Endoteliales de la Vena Umbilical Humana , Humanos , Modelos Animales , Ratas , Factores de Tiempo , Regulación hacia ArribaRESUMEN
Estrogen deprivation is considered responsible for many age-related processes, including poor wound healing. Guided by previous observations that estradiol accelerates reepithelialization through estrogen receptor (ER)ß, in the present study, we examined whether selective ER agonists [4,4',4''-(4-propyl [1H] pyrazole-1,3,5-triyl)trisphenol (PPT), ERα agonist; 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN), ERß agonist] affect the expression of basic proliferation and differentiation markers (Ki67, keratin10, 14 and 19, galectin1 and Sox2) of keratinocytes using HaCaT cells. In parallel, ovariectomized rats were treated daily with an ER modulator, and wound tissue was removed 21 days after wounding and routinely processed for basic histological analysis. Our results revealed that the HaCaT keratinocytes expressed both ERα and ß, and thus are well-suited for studying the effects of ER agonists on epidermal regeneration. The activation of ERα produced a protein expression pattern similar to that observed in the control culture, with a moderate expression of Ki67 being observed. However, the activation of ERß led to an increase in cell proliferation and keratin19 expression, as well as a decrease in galectin1 expression. Fittingly, in rat wounds treated with the ERß agonist (DPN), epidermal regeneration was accelerated. In the present study, we provide information on the mechanisms through which estrogens affect the expression patterns of selected markers, thus modulating keratinocyte proliferation and differentiation; in addition, we demonstrate that the pharmacological activation of ER-α and -ß has a direct impact on wound healing.
Asunto(s)
Receptor alfa de Estrógeno/agonistas , Receptor beta de Estrógeno/agonistas , Queratinocitos/efectos de los fármacos , Nitrilos/farmacología , Fenoles/farmacología , Pirazoles/farmacología , Cicatrización de Heridas/efectos de los fármacos , Animales , Diferenciación Celular/efectos de los fármacos , Línea Celular , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/metabolismo , Femenino , Humanos , Queratinocitos/citología , Queratinocitos/metabolismo , Queratinocitos/patología , Ratas Sprague-Dawley , Piel/efectos de los fármacos , Piel/metabolismo , Piel/patologíaRESUMEN
OBJECTIVES: Although the exact underlying mechanisms are still unknown, Plantago lanceolataâ L. (PL) water extracts are frequently used to stimulate wound healing and to drain abscesses. Therefore, in this experimental study the effect of PL water extract on skin wound healing was studied in Sprague-Dawley rats. METHODS: Two excisional and one incisional skin wounds were performed on the back of each rat. Wounds were treated for three consecutive days with two different concentrations of the aqueous extract of PL. Rats were sacrificed 7, 14, and 21 days after surgery. Samples of wounds were processed for macroscopic (excisions - wound contraction measurement), biomechanical (incisions - wound tensile strength (TS) measurement) and histological examination (excisions). KEY FINDINGS: It was shown that open wounds treated with PL extract contained myofibroblasts and demonstrated significantly higher contraction rates. Furthermore, significantly increased wound TSs were recorded in treated rats as a consequence of increased organization of extracellular matrix proteins, such as the collagen type 1. CONCLUSIONS: We demonstrated that PL aqueous extract improves skin wound healing in rats. However, further research need to be performed to find optimal therapeutic concentration, and exact underlying mechanism prior obtained results may be introduced into the clinical practice.
Asunto(s)
Miofibroblastos/metabolismo , Extractos Vegetales/farmacología , Plantago , Cicatrización de Heridas/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Masculino , Ratas , Ratas Sprague-Dawley , Resistencia a la TracciónRESUMEN
Galectins are representatives of endogenous lectins - molecules specifically recognizing distinct sugar motifs. They play an important role in the processes of cell proliferation, differentiation, migration and extracellular matrix formation. Furthermore, galectins are able to transfer cellular signals and to participate in intercellular interaction. It has been proven that galectins play an important role in the formation of tumor and/or wound healing microenvironment. This review contains an overview of experimental and clinical studies dealing with biological roles of galectins in tissue repair and in its parallel - the tumor growth.
Asunto(s)
Galectinas/fisiología , Neoplasias/fisiopatología , Cicatrización de Heridas/fisiología , Animales , Transformación Celular Neoplásica/patología , Progresión de la Enfermedad , Matriz Extracelular/patología , Matriz Extracelular/fisiología , Humanos , Neoplasias/patologíaRESUMEN
BACKGROUND/AIM: Stromal cells in the tumor microenvironment are primarily considered as sources of promalignant factors. The objective of our study was to define the effect of extracellular matrix (ECM) produced by normal dermal or cancer-associated fibroblasts exposed to adhesion/growth-regulatory lectin galectin-1 on human umbilical vein endothelial cells (HUVECs). MATERIALS AND METHODS: Fibroblasts were cultured for 10 days with lectin, followed by removing cellular constituents after an osmotic shock. Freshly-isolated HUVECs were placed on the ECM. In parallel, HUVECs were seeded on untreated and gelatin-coated surfaces as controls. A positive control for growth of HUVECs culture using medium supplemented with vascular endothelial growth factor completed the test panel. Cells were kept in contact to the substratum for two days and then processed for immunocytochemistry. RESULTS: HUVECs seeded on fibroblast-generated ECM presented a comparatively high degree of proliferation. Furthermore, contact to substratum produced by tumor-associated fibroblasts led to generation of a meshwork especially rich in fibronectin. CONCLUSION: Galectin-1 is apparently capable to trigger ECM production favorable for growth of HUVECs, prompting further work on characterizing structural features of the ECM and in situ correlation of lectin presence, ECM constitution and neoangiogenesis.