RESUMEN
BACKGROUND AND PURPOSE: Atopic dermatitis (AD) is a multifactorial skin condition with complex interactions of innate and adaptive immune responses. There are several existing therapies for AD, including topical glucocorticosteroids, emollients, phototherapies, calcineurin inhibitors and immunosuppressants, such as cyclosporine A. Although these therapies reduce inflammation, they also cause serious side effects. Therefore, it is necessary to develop new therapeutic approaches for AD treatment without side effects. There are several studies on natural materials or toxins, such as herbs, ginseng extract and snake venom, for AD treatment. However, treatment of AD with bee venom and its major component, melittin has rarely been studied. EXPERIMENTAL APPROACH: Effects of bee venom and melittin were studied in a model of AD in vivo induced by 1-chloro-2,4-dinitrobenzene (DNCB) in female Balb/c mice and in cultures of human keratinocytes, stimulated by TNF-α/IFN-γ. The potential pharmacological effects of bee venom and melittin on these in vivo and in vitro AD-like skin disease models were studied. KEY RESULTS: Bee venom and melittin exhibited potent anti-atopic activities, shown by decreased AD-like skin lesions, induced by DNCB in mice. In vitro studies using TNF-α/IFN-γ-stimulated human keratinocytes showed that bee venom and melittin inhibited the increased expression of chemokines, such as CCL17 and CCL22, and pro-inflammatory cytokines, including IL-1ß, IL-6 and IFN-γ, through the blockade of the NF-κB and STAT signalling pathways. CONCLUSIONS AND IMPLICATIONS: Our results suggest that bee venom and melittin would be suitable for epicutaneous application, as topical administration is often appropriate for the treatment of AD.
Asunto(s)
Venenos de Abeja/farmacología , Dermatitis Atópica/tratamiento farmacológico , Meliteno/farmacología , Animales , Diferenciación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Dermatitis Atópica/patología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Técnicas In Vitro , Ratones , Ratones Endogámicos BALB C , Relación Estructura-ActividadRESUMEN
Dipeptidyl peptidase 4 (DPP-4) inhibitors are widely used antihyperglycemic agents for type 2 diabetes mellitus. Recently, increasing attention has been focused on the pleiotropic actions of DPP-4 inhibitors. The aim of the present study was to examine whether gemigliptin, a recently developed DPP-4 inhibitor, could ameliorate features of metabolic syndrome. Mice were fed a Western diet (WD) for 12 weeks and were subsequently divided into 2 groups: mice fed a WD diet alone or mice fed a WD diet supplemented with gemigliptin for an additional 4 weeks. Gemigliptin treatment attenuated WD-induced body mass gain, hypercholesterolemia, adipocyte hypertrophy, and macrophage infiltration into adipose tissue, which were accompanied by an increased expression of uncoupling protein 1 in subcutaneous fat. These events contributed to improved insulin sensitivity, as assessed by the homeostasis model assessment of insulin resistance and intraperitoneal insulin tolerance test. Furthermore, gemigliptin reduced WD-induced hepatic triglyceride accumulation via inhibition of de novo lipogenesis and activation of fatty acid oxidation, which was accompanied by AMP-dependent protein kinase activation. Gemigliptin ameliorated WD-induced hepatic inflammation and fibrosis through suppression of oxidative stress. These results suggest that DPP-4 inhibitors may represent promising therapeutic agents for metabolic syndrome beyond their current role as antihyperglycemic agents.
Asunto(s)
Dieta Occidental/efectos adversos , Síndrome Metabólico/tratamiento farmacológico , Síndrome Metabólico/etiología , Piperidonas/farmacología , Piperidonas/uso terapéutico , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Adipocitos/patología , Animales , Hígado Graso/tratamiento farmacológico , Fibrosis/tratamiento farmacológico , Hipercolesterolemia/prevención & control , Hipertrofia/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Resistencia a la Insulina , Hígado/patología , Masculino , Síndrome Metabólico/metabolismo , Síndrome Metabólico/patología , Ratones , Grasa Subcutánea/metabolismo , Proteína Desacopladora 1/biosíntesis , Aumento de Peso/efectos de los fármacosRESUMEN
Propionibacterium acnes (P. acnes) is a major contributing factor to the inflammatory component of acne. The many prescription medications for acne allow for a large number of potential combination treatments. However, several antibiotics, apart from their antibacterial effects, exert sideeffects, such as the suppression of host inflammatory responses. Purified bee venom (BV) is a natural toxin produced by honeybees (Apis mellifera L.). BV has been widely used as a traditional medicine for various diseases. In the present study, to investigate the therapeutic effects of BV against P. acnes-induced inflammatory skin disease, P. acnes was intradermally injected into the ears of mice. After the injection, BV was applied to the skin surface of the right ear. Histological observation revealed that P. acnes induced a considerable increase in the number of infiltrated inflammatory cells. However, treatment with BV markedly reduced these reactions compared with the P. acnes-injected mice not treated with BV. Moreover, the expression levels of tumor necrosis factor (TNF)-α, and interleukin (IL)-1ß were significantly reduced in the BV-treated mice compared with the untreated P. acnes-injected mice. In addition, treatment with BV significantly inhibited Toll-like receptor (TLR)2 and CD14 expression in P. acnes-injected tissue. The binding activity of nuclear factor-κB (NF-κB) and activator protein (AP)-1 was markedly suppressed following treatment with BV. The results from our study, using an animal model, indicate that BV exerts an inhibitory effect on inflammatory skin diseases. In conclusion, our data indicate that BV has potential for use as an anti-acne agent and may be useful in the pharmaceutical and cosmetics industries.
Asunto(s)
Acné Vulgar/microbiología , Venenos de Abeja/farmacología , Propionibacterium acnes/efectos de los fármacos , Animales , Antibacterianos/farmacología , Abejas , Modelos Animales de Enfermedad , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Receptores de Lipopolisacáridos/genética , Receptores de Lipopolisacáridos/metabolismo , Ratones , Ratones Endogámicos ICR , FN-kappa B/genética , FN-kappa B/metabolismo , Receptor Toll-Like 2/genética , Receptor Toll-Like 2/metabolismo , Factor de Transcripción AP-1/genética , Factor de Transcripción AP-1/metabolismo , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The tumor microenvironment has many roles involving tumor progression, invasion and metastasis. The tumor cells at the tumor border loose epithelial properties and acquire mesenchymal features. This, epithelial-to-mesenchymal transition (EMT) has been suggested to be an important process for tissue and lymphovascular invasion. Pulmonary tissue samples from 15 patients with primary adenocarcinoma were evaluated with using immunofluorescence multi-staining the EMT-associated markers including E-cadherin and alpha-smooth muscle actin (α-SMA), and transcription factors including E-SNAIL and SLUG, and ZEB1. The data were analyzed in specific area, such as tumor center and tumor border. In this study we show that the invasive adenocarcinoma differentially expressed SNAIL and SLUG, and Zeb1 and it was associated with the loss of epithelial marker (E-cadherin) and gaining of mesenchymal marker (α-SMA) at the invasive border of lung carcinoma. The positive rates of SNAIL and ZEB1 were 26.7% and 0% in the tumor center and 40% and 20% in tumor margin, respectively. In addition, the expression of both SNAIL and ZEB1 at the border of tumor was observed in two cases (2/10). These two cases were associated with lymph node metastasis and advanced stage. The process of EMT has been suggested to be of prime importance for tissue and lymphovascular invasion. The process of EMT may be activated in the tumor border of lung adenocarcinoma. Related transcription factors, such as SNAIL and SLUG, and ZEB1, might be induced by paracrine effects of surrounded inflammatory cells and fibroblasts.
Asunto(s)
Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Biomarcadores de Tumor/análisis , Transición Epitelial-Mesenquimal/fisiología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Actinas/análisis , Actinas/biosíntesis , Adenocarcinoma del Pulmón , Anciano , Anciano de 80 o más Años , Cadherinas/análisis , Cadherinas/biosíntesis , Femenino , Técnica del Anticuerpo Fluorescente , Proteínas de Homeodominio/análisis , Proteínas de Homeodominio/biosíntesis , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Transcripción de la Familia Snail , Factores de Transcripción/análisis , Factores de Transcripción/biosíntesis , Homeobox 1 de Unión a la E-Box con Dedos de ZincRESUMEN
Atherosclerosis is a multifactorial and progressive disease in which the inflammatory reaction and inflammation-related factors play important roles at all stages. Modulation of NF-κB and Sp1 expression may be important targets for the prevention and treatment of atherosclerotic vascular disease. To develop a novel therapeutic approach in atherosclerosis, we examined the simultaneous suppression of the transcription factors NF-κB and Sp1 which regulate inflammation. We employed chimeric decoy oligodeoxynucleotide (ODN) containing the consensus of NF-κB and Sp1-binding sites to suppress these transcription factors simultaneously and to test chimeric decoy for anti-atherogenic effects in an atherogenic diet-induced atherosclerotic mouse model with inflammatory stimulation. C57BL/6 mice were fed with an atherogenic diet (15% fat, 1.25% cholesterol and 0.5% cholic acid) for 12 weeks to induce atherosclerosis; lipopolysaccharide (LPS, 2 mg/kg) was intraperitoneally injected in the first week of study to simulate underlying infectious burden during development of atherosclerosis. Decoy ODNs were injected into tail vein at 2, 4, 6, 8, 10 and 12 weeks after only three LPS injections in mice fed the atherogenic diet. Chimeric decoy ODN alleviated atherosclerotic changes and reduced serum cholesterol and inflammatory cytokines. In accordance with these results, the expressions of atherosclerotic markers were inhibited by chimeric decoy ODN. Chimeric decoy ODN modulates multiple pathogenic aspects of an atherogenic diet-induced atherosclerosis with inflammatory stimulation: hypercholesterolaemia and inflammation. Therefore, this study demonstrates the efficacy of chimeric decoy ODN on atherosclerosis with immunological complication.