RESUMEN
Hernias are generally repaired using synthetic prostheses. Infection may already be present or develop during implantation. Based on the increasing resistance to antibiotics, and the well-known antimicrobial properties of silver (Ag), the possibility of coating hernia prostheses with a nanostructured layer containing Ag was explored. Prostheses (Clear Mesh Composite [CMC]) made up of two polypropylene layers (macroporous light mesh and thin transparent film) were tested with human mesothelial cells from omentum biopsies. Mesotheliocytes modulate abdominal wall healing producing cytokines, growth factors, and adhesion molecules. Evaluating the growth of these cells on CMC or film alone showed that cell numbers on CMC increased over time, and were higher than those on film alone. Vimentin immunostaining confirmed the cells to be mesotheliocytes. Subsequently, the biocompatibility of mesh layer, coated or not with a thin layer of Ag/SiO2 -nanoclusters, was analyzed, showing no difference in absence or presence of Ag/SiO2 . Differently, TGF-ß2 production, involved in tissue repair and fibrosis, increased in the presence of Ag/SiO2 . Moreover, Ag/SiO2 -coated mesh showed antibacterial properties. In conclusion, the mesh layer coated with Ag/SiO2 afforded cell growth, and showed antibacterial activity. Coating only the mesh layer did not decrease film transparency, and did not favor the formation of adhesions on the visceral side. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1586-1593, 2017.
Asunto(s)
Materiales Biocompatibles Revestidos , Hernia , Herniorrafia , Implantes Experimentales , Ensayo de Materiales , Peritoneo/metabolismo , Polipropilenos , Dióxido de Silicio , Plata , Mallas Quirúrgicas , Células Cultivadas , Materiales Biocompatibles Revestidos/química , Materiales Biocompatibles Revestidos/farmacología , Epitelio/metabolismo , Femenino , Humanos , Masculino , Peritoneo/citología , Polipropilenos/química , Polipropilenos/farmacología , Dióxido de Silicio/química , Dióxido de Silicio/farmacología , Plata/química , Plata/farmacologíaRESUMEN
OBJECTIVES: The intravenous injection of bisphosphonates, currently used as treatment for osteoporosis, bone Paget's disease, multiple myeloma, or bone metastases, can cause jaw bone necrosis especially in consequence of trauma. The present research aimed to clarify the mechanisms underlying bone necrosis, exploring involvement of the oral mucosa "in vivo." PATIENTS AND METHODS: Specimens of oral mucosa were removed from bisphosphonate-treated patients with or without jaw bone necrosis. In mucosa specimens, expression was evaluated of: cytokines involved in the inflammatory process, factors involved in osteoclast activity, i.e., receptor activator of nuclear factor kappa-B ligand (RANKL) and osteoprotegerin, a factor involved in cell proliferation, namely hydroxymethylglutaryl coenzyme A reductase, and a factor involved in angiogenesis, namely vascular endothelial growth factor (VEGF). RESULTS: Interleukin (IL)-6 and the RANK/osteoprotegerin ratio were significantly elevated in mucosa from patients with versus without jaw necrosis, whereas hydroxymethylglutaryl coenzyme A reductase and VEGF were significantly decreased. CONCLUSIONS: Our results suggest that mucosa, stimulated by bisphosphonate released from the bone, can contribute to the development of jaw necrosis, reducing VEGF, and producing IL-6 in consequence of hydroxymethylglutaryl coenzyme A reductase reduction. In turn, IL-6 stimulates osteoclast activity, as shown by the increased RANKL/osteoprotegerin ratio. CLINICAL RELEVANCE: The results of this study suggest the importance of evaluating during bisphosphonate treatment the production of IL-6, RANKL, osteoprotegerin, and VEGF, in order to monitor the jaw osteonecrosis onset. To avoid repeated mucosa excisions, the determination of these factors could be carried out in crevicular fluid.
Asunto(s)
Osteonecrosis de los Maxilares Asociada a Difosfonatos/metabolismo , Osteonecrosis de los Maxilares Asociada a Difosfonatos/patología , Conservadores de la Densidad Ósea/efectos adversos , Difosfonatos/efectos adversos , Células Endoteliales/fisiología , Imidazoles/efectos adversos , Mucosa Bucal/metabolismo , Osteoclastos/fisiología , Anciano , Osteonecrosis de los Maxilares Asociada a Difosfonatos/cirugía , Conservadores de la Densidad Ósea/administración & dosificación , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/secundario , Neoplasias de la Mama/tratamiento farmacológico , Estudios de Casos y Controles , Proliferación Celular , Citocinas/metabolismo , Difosfonatos/administración & dosificación , Femenino , Líquido del Surco Gingival/química , Humanos , Hidroximetilglutaril-CoA Reductasas/metabolismo , Imidazoles/administración & dosificación , Inyecciones Intravenosas/efectos adversos , Interleucina-6/metabolismo , Masculino , Persona de Mediana Edad , Mucosa Bucal/patología , Mieloma Múltiple/tratamiento farmacológico , Osteoprotegerina/metabolismo , Ligando RANK/metabolismo , Estadísticas no Paramétricas , Factor A de Crecimiento Endotelial Vascular/metabolismo , Ácido ZoledrónicoRESUMEN
Conjugated linoleic acid (CLA) is thought to have anti-proliferative and anti-inflammatory properties, but its effect on cancer cachexia is unknown. Two effects were here investigated: that of CLA on inflammatory mediator production in human lung cancer cells, and that of reduced mediators on the myogenic differentiation of murine muscle C2C12 cells. The latter cells were grown in medium conditioned by human lung cancer A427 cells, with or without CLA, to mimic only the effect of molecules released from the tumor "in vivo", excluding the effect of host-produced cachectic factors. The results obtained show that CLA was found to reduce the production of tumor necrosis factor-α, interleukin (IL)-1ß and prostaglandin E2 (PGE2), but had no effect on IL-6 production. The mechanisms underlying the effect of CLA on cytokine or PGE2 release in A427 cells are probably mediated by activation of peroxisome proliferator-activated receptor (PPAR)α, which increased at 24 h CLA treatment. In turn, the reduced content of inflammatory mediators in medium conditioned by A427 cells, in the presence of CLA, allowed muscle cells to proliferate, again by inducing PPAR. The involvement of PPARα was demonstrated by treatment with the antagonist MK-886. The findings demonstrate the anti-inflammatory and myogenic action of CLA and point to its possible application as a novel dietary supplement and therapeutic agent in inflammatory disease states, such as cachexia.
Asunto(s)
Anticarcinógenos/farmacología , Mediadores de Inflamación/inmunología , Ácidos Linoleicos Conjugados/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/inmunología , Células Musculares/efectos de los fármacos , Animales , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Medios de Cultivo Condicionados/farmacología , Dinoprostona/inmunología , Caballos , Indoles/farmacología , Interleucina-1/inmunología , Interleucina-6/inmunología , Pulmón/efectos de los fármacos , Pulmón/inmunología , Ratones , Células Musculares/citología , Receptores Activados del Proliferador del Peroxisoma/inmunologíaRESUMEN
PUFA from fish oil appear to have anti-inflammatory and anti-oxidative effects and improve nutritional status in cancer patients. With this as background, the aim of the present study was to investigate the effect of EPA plus DHA on inflammatory condition, and oxidative and nutritional status in patients with lung cancer. In our multicentre, randomised, double-blind trial, thirty-three patients with a diagnosis of advanced inoperable non-small-cell lung cancer and undergoing chemotherapy were divided into two groups, receiving four capsules/d containing 510 mg of EPA and 340 mg of DHA, or 850 mg of placebo, for 66 d. At the start of chemotherapy (T0), after 8 d (T1), 22 d (T2) and 66 d (T3), biochemical (inflammatory and oxidative status parameters) and anthropometric parameters were measured in both groups. A significant increase of body weight in the n-3 group at T3 v. T0 was observed. Concerning inflammation, C-reactive protein and IL-6 levels differed significantly between the n-3 and placebo groups at T3, and progressively decreased during chemotherapy in the n-3 group, evidencing n-3 PUFA anti-inflammatory action. Concerning oxidative status, plasma reactive oxygen species levels increased in the placebo group v. the n-3 group at the later treatment times. Hydroxynonenal levels increased in the placebo group during the study, while they stabilised in the n-3 group. Our data confirm that the continual assumption of EPA plus DHA determined an anti-inflammatory and anti-oxidative action which could be considered a preliminary goal in anti-cachectic therapy.
Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Antioxidantes/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/dietoterapia , Suplementos Dietéticos , Ácidos Grasos Omega-3/uso terapéutico , Neoplasias Pulmonares/dietoterapia , Antiinflamatorios no Esteroideos/efectos adversos , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antioxidantes/efectos adversos , Proteína C-Reactiva/análisis , Carcinoma de Pulmón de Células no Pequeñas/sangre , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Cisplatino/administración & dosificación , Cisplatino/uso terapéutico , Terapia Combinada/efectos adversos , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Suplementos Dietéticos/efectos adversos , Ácidos Docosahexaenoicos/administración & dosificación , Método Doble Ciego , Ácido Eicosapentaenoico/administración & dosificación , Ácidos Grasos Omega-3/efectos adversos , Femenino , Humanos , Interleucina-6/sangre , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/inmunología , Masculino , Estrés Oxidativo , Pacientes Desistentes del Tratamiento , Aumento de Peso , GemcitabinaRESUMEN
Peroxisome proliferator-activated receptors (PPARs) mediate the effects of various ligands, known as peroxisome proliferators, a heterogeneous class of compounds including industrial chemicals, pharmaceuticals, and biomolecules such as fatty acids and eicosanoids. Among peroxisome proliferators, fibrate derivatives are considered specific ligands for PPARα, whereas eicosanoids, such as PGJ2, for PPARγ. The study aimed to clarify the relation between PPARs and apoptosis or proliferation on the same type of cells, using clofibrate as specific ligand of PPARα and PGJ2 as specific ligand of PPARγ. The cells used were human hepatocarcinoma HepG2 cells. The results showed that PPARα protein content increased in HepG2 cells treated with clofibrate, causing apoptosis in a time- and concentration-dependent way, as evidenced by the citofluorimetric assay and determination of BAD, myc and protein phosphatase 2A protein content. It also emerged that PPARγ increased in the same cells when treated with a specific ligand of this PPAR; in this case the increase of PPARγ did not cause an increase of apoptosis, but a time- and concentration-dependent inhibition of cell proliferation, evidenced by decreased cell numbers and increased number of cells in the G0/G1 phase of the cycle. It may be concluded that PPARα is chiefly related to apoptosis and PPARγ to cell proliferation.
Asunto(s)
Apoptosis , Proliferación Celular , PPAR alfa/metabolismo , PPAR gamma/metabolismo , Apoptosis/efectos de los fármacos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Clofibrato/farmacología , Células Hep G2 , Humanos , Ligandos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Concentración Osmolar , Prostaglandina D2/análogos & derivados , Prostaglandina D2/farmacología , Proteína Fosfatasa 2/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Transducción de Señal/efectos de los fármacos , Factores de Tiempo , Proteína Letal Asociada a bcl/metabolismoRESUMEN
Conjugated linoleic acid (CLA) is reported to have anti-cancer activity, based on animal and in vitro studies. Since it has been suggested that CLA anti-carcinogenic effect stems from its anti-inflammatory properties, this study investigated whether CLA can prevent cell proliferation induced by TPA in human keratinocytes NCTC 2544 contemporary to inhibition of inflammation. Results obtained showed that CLA prevents increased cell proliferation and production of pro-inflammatory molecules determined by TPA, being this effect due to modulation of PPARs and NFkB activity. The involvement of PPARalpha in CLA effect was demonstrated by adding to the cells an antagonist of PPARalpha.
Asunto(s)
Citocinas/biosíntesis , Queratinocitos/efectos de los fármacos , Ácidos Linoleicos Conjugados/farmacología , Acetato de Tetradecanoilforbol/toxicidad , Proliferación Celular/efectos de los fármacos , Células Cultivadas , ADN/metabolismo , Humanos , FN-kappa B/metabolismo , PPAR alfa/antagonistas & inhibidores , PPAR alfa/fisiología , PPAR-beta/fisiologíaRESUMEN
Among diet components, some fatty acids are known to affect several stages of colon carcinogenesis, whereas others are probably helpful in preventing tumors. In light of this, our aim was to determine the composition of fatty acids and the possible correlation with apoptosis in human colon carcinoma specimens at different Duke's stages and to evaluate the effect of enriching human colon cancer cell line with the possible reduced fatty acid(s). Specimens of carcinoma were compared with the corresponding non-neoplastic mucosa: a significant decrease of arachidonic acid, PPARalpha, Bad, and Bax and a significant increase of COX-2, Bcl-2, and pBad were found. The importance of arachidonic acid in apoptosis was demonstrated by enriching a Caco-2 cell line with this fatty acid. It induced apoptosis in a dose- and time-dependent manner via induction of PPARalpha that, in turn, decreased COX-2. In conclusion, the reduced content of arachidonic acid is likely related to carcinogenic process decreasing the susceptibility of cancer cells to apoptosis.
RESUMEN
Conjugated linoleic acid (CLA), found in dairy products, in beef and lamb has been demonstrated to possess anticancer properties protecting several tissues from developing cancer. Moreover, it has been shown to modulate apoptosis in several cancer cell lines. The aim of this study was to investigate which signaling transduction pathways were modulated in CLA-induced apoptosis in human hepatoma SK-HEP-1 cells. The cells exposed to CLA were evaluated for PPARalpha, PP2A, pro-apoptotic proteins Bak, Bad and caspases, and anti-apoptotic proteins Bcl-2 and Bcl-X(L). Cells were also treated with okadaic acid, a PP2A inhibitor, or with Wy-14643, a specific PPARalpha agonist. The CLA-induced apoptosis was concomitant to the increase of percentage of cells in the S phase, PPARalpha, PP2A and pro-apoptotic proteins; simultaneously, antiapoptotic proteins decreased. Inhibition of PP2A prevented apoptosis, and PPARalpha agonist showed similar effect as CLA. The increased PP2A could be responsible for the dephosphorylation of Bcl-2 and Bad, permitting apoptotic activity of Bax and Bad. The increase of caspase 8 and 9 suggested that both the intrinsic and extrinsic apoptotic pathways were induced. PP2A was probably increased by PPARalpha, since putative PPRE sequences were found in genes encoding its subunits. In conclusion, CLA induces apoptosis in human hepatoma SK-HEP-1 cells, by increasing PPARalpha, PP2A and pro-apoptotic proteins.