RESUMEN
A healthy and balanced diet is an important factor to assure a good functioning of the central and peripheral nervous system. Retinoid X receptor (RXR)-mediated signaling was identified as an important mechanism of transmitting major diet-dependent physiological and nutritional signaling such as the control of myelination and dopamine signalling. Recently, vitamin A5/X, mainly present in vegetables as provitamin A5/X, was identified as a new concept of a vitamin which functions as the nutritional precursor for enabling RXR-mediated signaling. The active form of vitamin A5/X, 9-cis-13,14-dehydroretinoic acid (9CDHRA), induces RXR-activation, thereby acting as the central switch for enabling various heterodimer-RXR-signaling cascades involving various partner heterodimers like the fatty acid and eicosanoid receptors/peroxisome proliferator-activated receptors (PPARs), the cholesterol receptors/liver X receptors (LXRs), the vitamin D receptor (VDR), and the vitamin A(1) receptors/retinoic acid receptors (RARs). Thus, nutritional supply of vitamin A5/X might be a general nutritional-dependent switch for enabling this large cascade of hormonal signaling pathways and thus appears important to guarantee an overall organism homeostasis. RXR-mediated signaling was shown to be dependent on vitamin A5/X with direct effects for beneficial physiological and neuro-protective functions mediated systemically or directly in the brain. In summary, through control of dopamine signaling, amyloid ß-clearance, neuro-protection and neuro-inflammation, the vitamin A5/X - RXR - RAR - vitamin A(1)-signaling might be "one of" or even "the" critical factor(s) necessary for good mental health, healthy brain aging, as well as for preventing drug addiction and prevention of a large array of nervous system diseases. Likewise, vitamin A5/X - RXR - non-RAR-dependent signaling relevant for myelination/re-myelination and phagocytosis/brain cleanup will contribute to such regulations too. In this review we discuss the basic scientific background, logical connections and nutritional/pharmacological expert recommendations for the nervous system especially considering the ageing brain.
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Receptores X Retinoide , Humanos , Receptores X Retinoide/metabolismo , Dieta , Transducción de Señal , Salud Mental , AnimalesRESUMEN
Bladder cancer is a common malignancy associated with high recurrence rates and potential progression to invasive forms. Sorafenib, a multi-targeted tyrosine kinase inhibitor, has shown promise in anti-cancer therapy, but its cytotoxicity to normal cells and aggregation in solution limits its clinical application. To address these challenges, we investigated the formation of supramolecular aggregates of sorafenib with Congo red (CR), a bis-azo dye known for its supramolecular interaction. We analyzed different mole ratios of CR-sorafenib aggregates and evaluated their effects on bladder cancer cells of varying levels of malignancy. In addition, we also evaluated the effect of the test compounds on normal uroepithelial cells. Our results demonstrated that sorafenib inhibits the proliferation of bladder cancer cells and induces apoptosis in a dose-dependent manner. However, high concentrations of sorafenib also showed cytotoxicity to normal uroepithelial cells. In contrast, the CR-BAY aggregates exhibited reduced cytotoxicity to normal cells while maintaining anti-cancer activity. The aggregates inhibited cancer cell migration and invasion, suggesting their potential for metastasis prevention. Dynamic light scattering and UV-VIS measurements confirmed the formation of stable co-aggregates with distinctive spectral properties. These CR-sorafenib aggregates may provide a promising approach to targeted therapy with reduced cytotoxicity and improved stability for drug delivery in bladder cancer treatment. This work shows that the drug-excipient aggregates proposed and described so far, as Congo red-sorafenib, can be a real step forward in anti-cancer therapies.
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Rojo Congo , Neoplasias de la Vejiga Urinaria , Humanos , Sorafenib/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológicoRESUMEN
Dietary intake and tissue levels of carotenoids have been associated with a reduced risk of several chronic diseases, including cardiovascular diseases, type 2 diabetes, obesity, brain-related diseases and some types of cancer. However, intervention trials with isolated carotenoid supplements have mostly failed to confirm the postulated health benefits. It has thereby been speculated that dosing, matrix and synergistic effects, as well as underlying health and the individual nutritional status plus genetic background do play a role. It appears that our knowledge on carotenoid-mediated health benefits may still be incomplete, as the underlying mechanisms of action are poorly understood in relation to human relevance. Antioxidant mechanisms - direct or via transcription factors such as NRF2 and NF-κB - and activation of nuclear hormone receptor pathways such as of RAR, RXR or also PPARs, via carotenoid metabolites, are the basic principles which we try to connect with carotenoid-transmitted health benefits as exemplified with described common diseases including obesity/diabetes and cancer. Depending on the targeted diseases, single or multiple mechanisms of actions may play a role. In this review and position paper, we try to highlight our present knowledge on carotenoid metabolism and mechanisms translatable into health benefits related to several chronic diseases.
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Diabetes Mellitus Tipo 2 , Antioxidantes , Carotenoides , Suplementos Dietéticos , Humanos , Estado NutricionalRESUMEN
The twofold role of autophagy in cancer is often the therapeutic target. Numerous regulatory pathways are shared between autophagy and other molecular processes needed in tumorigenesis, such as translation or survival signaling. Thus, we have assumed that ILK knockdown should promote autophagy, and used together with chloroquine, an autophagy inhibitor, it could generate a better anticancer effect by dysregulation of common signaling pathways. Expression at the protein level was analyzed using Western Blot; siRNA transfection was done for ILK. Analysis of cell signaling pathways was monitored with phospho-specific antibodies. Melanoma cell proliferation was assessed with the crystal violet test, and migration was evaluated by scratch wound healing assays. Autophagy was monitored by the accumulation of its marker, LC3-II. Our data show that ILK knockdown by siRNA suppresses melanoma cell growth by inducing autophagy through AMPK activation, and simultaneously initiates apoptosis. We demonstrated that combinatorial treatment of melanoma cells with CQ and siILK has a stronger antitumor effect than monotherapy with either of these. It generates the synergistic antitumor effects by the decrease of translation of both global and oncogenic proteins synthesis. In our work, we point to the crosstalk between translation and autophagy regulation.
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Autofagia/efectos de los fármacos , Cloroquina/uso terapéutico , Melanoma Experimental/tratamiento farmacológico , Biosíntesis de Proteínas/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Animales , Protocolos de Quimioterapia Combinada Antineoplásica , Homólogo de la Proteína 1 Relacionada con la Autofagia/metabolismo , Línea Celular Tumoral , Cloroquina/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Melanoma Experimental/metabolismo , Ratones , ARN Interferente Pequeño/farmacología , ARN Interferente Pequeño/uso terapéutico , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Prostate cancer (PC) is the second most common tumor in males. The search for appropriate therapeutic options against advanced PC has been in process for several decades. Especially after cessation of the effectiveness of hormonal therapy (i.e., emergence of castration-resistant PC), PC management options have become scarce and the prognosis is poor. To overcome this stage of disease, an array of natural and synthetic substances underwent investigation. An interesting and promising class of compounds constitutes the derivatives of natural retinoids. Synthesized on the basis of the structure of retinoic acid, they present unique and remarkable properties that warrant their investigation as antitumor drugs. However, there is no up-to-date compilation that consecutively summarizes the current state of knowledge about synthetic retinoids with regard to PC. Therefore, in this review, we present the results of the experimental studies on synthetic retinoids conducted within the last decade. Our primary aim is to highlight the molecular targets of these compounds and to identify their potential promise in the treatment of PC.
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Antineoplásicos , Diferenciación Celular/efectos de los fármacos , Proteínas de Neoplasias/metabolismo , Neoplasias de la Próstata , Receptores de Ácido Retinoico/metabolismo , Retinoides , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Humanos , Masculino , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Retinoides/síntesis química , Retinoides/química , Retinoides/uso terapéuticoRESUMEN
The reciprocal interactions between cancer cells and the quiescent fibroblasts leading to the activation of cancer-associated fibroblasts (CAFs) serve an important role in cancer progression. Here, we investigated the activation of transcription factors (TFs) in prostate fibroblasts (WPMY cell line) co-cultured with normal prostate or tumorous cells (RWPE1 and RWPE2 cell lines, respectively). After indirect co-cultures, we performed mRNA-seq and predicted TF activity using mRNA expression profiles with the Systems EPigenomics Inference of Regulatory Activity (SEPIRA) package and the GTEx and mRNA-seq data of 483 cultured fibroblasts. The initial differential expression analysis between time points and experimental conditions showed that co-culture with normal epithelial cells mainly promotes an inflammatory response in fibroblasts, whereas with the cancerous epithelial, it stimulates transformation by changing the expression of the genes associated with microfilaments. TF activity analysis revealed only one positively regulated TF in the RWPE1 co-culture alone, while we observed dysregulation of 45 TFs (7 decreased activity and 38 increased activity) uniquely in co-culture with RWPE2. Pathway analysis showed that these 45 dysregulated TFs in fibroblasts co-cultured with RWPE2 cells may be associated with the RUNX1 and PTEN pathways. Moreover, we showed that observed dysregulation could be associated with FER1L4 expression. We conclude that phenotypic changes in fibroblast responses to co-culturing with cancer epithelium result from orchestrated dysregulation of signaling pathways that favor their transformation and motility rather than proinflammatory status. This dysregulation can be observed both at the TF and transcriptome levels.
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Fibroblastos Asociados al Cáncer/metabolismo , Transformación Celular Neoplásica/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Regulación Neoplásica de la Expresión Génica , Fosfohidrolasa PTEN/genética , Factores de Transcripción/genética , Fibroblastos Asociados al Cáncer/patología , Comunicación Celular , Línea Celular , Línea Celular Tumoral , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Técnicas de Cocultivo , Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Células Epiteliales/metabolismo , Células Epiteliales/patología , Fibroblastos/citología , Fibroblastos/metabolismo , Perfilación de la Expresión Génica , Ontología de Genes , Humanos , Masculino , Anotación de Secuencia Molecular , Fosfohidrolasa PTEN/metabolismo , Próstata/metabolismo , Próstata/patología , Transducción de Señal , Factores de Transcripción/clasificación , Factores de Transcripción/metabolismo , TranscriptomaRESUMEN
Cadherin switch is specific of epithelial-mesenchymal transition (EMT) and is closely related to tumor cell invasion. However, the molecular mechanism that promotes the phenotypic changes remains unclear and elusive. We found that integrin-linked kinase (ILK) is a key factor involved in cadherin switch. The expression and activity of ILK are elevated in a variety of cancers but its mechanisms are not exactly understood. In this report, we studied the role and mechanism of ILK in EMT of human bladder cancer. We showed that silencing of ILK expression by small interfering RNA (siRNA) significantly abolished the nuclear translocation or the presence of markers associated with EMT like Snail, Twist, Zeb, and beta-catenin. ILK knockdown by siRNA suppressed N-cadherin expression and increased re-expression of E-cadherin in bladder cancer cells. We suggest that ILK is a major signaling factor involved in EMT. It is essential to understand the molecular mechanism of EMT in aim to possibly use it in search for new therapeutic targets.
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Antígenos CD/metabolismo , Cadherinas/metabolismo , Regulación Neoplásica de la Expresión Génica , Proteínas Serina-Treonina Quinasas/metabolismo , Neoplasias de la Vejiga Urinaria/metabolismo , Neoplasias de la Vejiga Urinaria/patología , Antígenos CD/genética , Western Blotting , Cadherinas/antagonistas & inhibidores , Cadherinas/genética , Membrana Celular/metabolismo , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Transición Epitelial-Mesenquimal , Humanos , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/genética , ARN Mensajero/genética , ARN Interferente Pequeño/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal , Células Tumorales Cultivadas , Neoplasias de la Vejiga Urinaria/genéticaRESUMEN
The high rate of glucose breakdown is the fingerprint of cancer. Increased glycolysis allows tumour cells to fulfil their high energetic and biosynthetic demands. Interestingly, however, rather than metabolizing glucose in the oxidative phosphorylation pathway, cancer cells generally use glucose for aerobic glycolysis. This phenomenon is known as the Warburg effect and is considered as one of the most fundamental forms of metabolic reprogramming during cancerogenesis. Changes in the rate of glycolytic activity of cancer cells are caused mainly by the increased expression of glycolytic enzymes as a consequence of activation of oncogenes or loss of tumour suppressors. In addition, the hypoxic tumour environment also triggers upregulation of a series of genes involved in glucose metabolism. Among the metabolic enzymes that are modulated by these factors in cancer cells are the 6-phosphofructo 2-kinase/fructose 2,6-bisphosphatases (PFKFBs), a family of bifunctional enzymes that control the levels of fructose 2,6-bisphosphate (Fru-2,6-P2), an essential activator of the glycolytic flux. Fru-2,6-P2 strongly activates glucose breakdown in glycolysis through allosteric modulation of the rate-limiting enzyme of glycolysis, phosphofructokinase-1 (PFK-1). Thus far, many studies have reported a correlation between aberrant PFKFB expression level and the grade of tumour aggressiveness, which directly indicates that these enzymes may play a crucial role in cancerogenesis. The objective of this review is to highlight the recent studies on aberrant expression of PFKFBs and its influence on cancer progression.
RESUMEN
Prostate cancer is one of the most common malignancies in men and is predicted to be the second leading cause of cancer-related deaths. After 6-18 months, hormone ablation treatment results in androgen-independent growth of cancer cells, metastasis and progression. The mechanism of androgen-independent growth of prostatic carcinoma cells is still unknown. Identification of factors that facilitate the transition from androgen-dependent to independent states is crucial in designing future diagnostics and medication strategies. To understand the biochemical meaning of hormone dependency deprivation, glycoproteins enriched profiles were compared between DU145 (hormone non-responding) and LNCaP (hormone responding) prostate cancer cells. These results allow for anticipation on the important role of glycosylation in malignant transformation. Both Tn antigen and complex antennary N-oligosaccharides were recognized. Their occurrence might be involved in the development and progression of tumor, and failure of hormone ablation therapy. Among identified proteins in androgen-sensitive cells nucleolin (P19338) was found that is widely described as apoptosis inhibitor, and also transporter of molecules from the membrane to the cytoplasm or nucleus. In addition, 14-3-3 protein family (P27348, P31946, P61981, P63104, P62258, Q04917, and P31947) was investigated across available databases as it forms stable complexes with glycoproteins. Our studies indicate that isoforms: sigma and eta were found in androgen-dependent prostate cancer cells, while other isoforms were present in androgen non-responding cells. 14-3-3 binding partners are involved in cancer pathogenesis. These findings may contribute to a better understanding of prostate cancer tumorigenesis and to a more efficient prognosis and individual therapy in a future. However, it still remains to be revealed how important those changes are for androgen dependency loss in prostate cancer patients carried out on clinically relevant populations.
Asunto(s)
Andrógenos/fisiología , Glicopéptidos/metabolismo , Neoplasias Hormono-Dependientes/fisiopatología , Proteoma , Western Blotting , Línea Celular Tumoral , Transformación Celular Neoplásica , Cromatografía de Afinidad/métodos , Electroforesis en Gel de Poliacrilamida , Humanos , Masculino , Neoplasias Hormono-Dependientes/metabolismo , Espectrometría de Masas en TándemRESUMEN
Melanoma is relatively resistant to chemotherapy, and no targeted therapies are fully effective. The most common mutations in melanoma result in hyperactivation of the mitogen-activated protein kinase (MAPK) and PI3K/AKT/ mTOR pathways responsible for initiating and controlling oncogenic protein translation. This makes both the signaling pathways potentially important therapeutic targets in melanoma. Our studies were carried out on human melanoma cell lines WM793 and 1205 LU with similar genomic alteration (BRAFV600E and PTEN loss). We used a highly specific PI3K/mTOR inhibitor, dactolisib (NVP-BEZ235), and Mnk inhibitor - CGP57380 alone and in combination. Here, we explore the mechanism of action of these drugs alone and in combination, as well as their effect on the viability and invasiveness of melanoma cells. Although when used independently, both drugs suppressed cell proliferation and migration, their combination has additional antitumor effects. We demonstrate that simultaneous inhibition of both pathways may prevent possible drug resistance.
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Antineoplásicos , Melanoma , Quinolinas , Humanos , Inhibidores mTOR , Fosfatidilinositol 3-Quinasas/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Factor 4E Eucariótico de Iniciación/metabolismo , Línea Celular Tumoral , Serina-Treonina Quinasas TOR/metabolismo , Melanoma/tratamiento farmacológico , Melanoma/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Quinolinas/farmacología , Proliferación CelularRESUMEN
Breast cancer (BC) and prostate cancer (PC) are at the top of the list when it comes to the most common types of cancers worldwide. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway is important, in that it strongly influences the development and progression of these tumors. Previous studies have emphasized the key role of inhibitors of the PIK3/AKT/mTOR signaling pathway in the treatment of BC and PC, and it remains to be a crucial method of treatment. In this review, the inhibitors of these signaling pathways are compared, as well as their effectiveness in therapy and potential as therapeutic agents. The use of these inhibitors as polytherapy is evaluated, especially with the use of hormonal therapy, which has shown promising results.
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Neoplasias de la Mama , Neoplasias de la Próstata , Humanos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Hormonas , Inhibidores mTOR , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Neoplasias de la Próstata/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-akt/metabolismo , Sirolimus/uso terapéutico , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Currently, cancer diagnosis relies mostly on morphological examination of exfoliated, aspirated cells or surgically removed tissue. As long as standard diagnosis is concerned, this classical approach seems to be satisfactory. In the recent years, cancer progression has been shown to be accompanied by alterations in mechanical properties of cells. This offers the detection of otherwise unnoticed cancer cell disregarded by histological analysis due to insignificant manifestations. One of techniques, sensitive to changes in mechanical properties, is the atomic force microscopy, which detects cancer cells through their elastic properties. Such measurements were applied to tissue sections collected from patients suffering from various cancers. Despite of heterogeneity and complexity of cancer cell sections, the use of the Young's modulus as an indicator of cell elasticity allow for detection of cancer cells in tissue slices.
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Neoplasias de la Mama/patología , Microscopía de Fuerza Atómica/métodos , Línea Celular Tumoral , Elasticidad , Femenino , HumanosRESUMEN
The aim of this research was to find out whether the passage number effect may influence on the PC-3 cells (the human prostate cancer line derived from bone metastases) response to proton radiation. 2 MeV horizontally focused proton microbeam was used as a radiation source. The cells were treated with a counted number of H(+) ions (50-8000) corresponding to doses of 1.3-209 Gy/cell. For comparison, cell death was also induced by UVC radiation. All cells were stained with Hoechst 33342 and propidium iodide and visualized under a fluorescence microscope. Necrosis was observed at: a) 8000 protons per cell (corresponding to â¼209 Gy/cell) after 2-4 passages, b) 3200 protons per cell (corresponding to â¼84 Gy/cell) for cells after 11-14 passages and c) only 800 protons per cell (corresponding to â¼2 Gy/cell ) after 47-50 passages. Apoptosis was efficiently induced, by protons, only in cells after 50 passages. The results showed that the laboratory conditions affected cellular response of PC-3 cell line to the proton irradiation. The cellular response to the radiation treatment strongly depends on number of passages.
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Apoptosis/efectos de la radiación , Neoplasias Óseas/patología , Neoplasias Óseas/secundario , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/fisiopatología , Protones , Neoplasias Óseas/radioterapia , Línea Celular Tumoral , Supervivencia Celular/efectos de la radiación , Humanos , Masculino , Neoplasias de la Próstata/radioterapiaRESUMEN
UNLABELLED: The aim of this paper is the evaluation of colposcopy and mRNA E6/E7 HPV detection--as the marker of persistent human papilloma virus (HPV) infection in the triage of abnormal Pap smears and in the assessment of cervical intraepithelial neoplasia progression risk. The clinical material consisted of 85 women, participating the national cervical cancer screening in the period of April 2010, and October 2010, reffered to the Outpatient Clinic of Gynecologic Oncology and Female Genital Tract Neoplasms Prophylaxy of the Jagiellonian University Medical College in Krakow, Poland. All subjects were offered gynecological evaluation, Pap smear, colposcopy, DNA HPV (Hybrid Capture2, Qiagen) and mRNA E6/E7 testing (NulciSens, Biomerieux). In case of positive tests colposcopically directed cervical biopsy with histopathologic evaluation were performed. RESULTS: The presence of mRNA E6/E7 HPV transcripts correlated with high grade squamous intraepithelial lesions, statistically significantly. There was statistically difference between colposcopic, histologic concordance comparing to mRNA E6/E7 HPV colposcopic histologic concordance (p < 0.001). CONCLUSIONS: The presence of mRNA E6/E7 HR HPV may be assumed as specific marker of high grade cervical lesions. The combination of mRNA E6/E7 HR HPV ewith colposcopic evaluation increases the colposcopy concordanece with final histologic findings.
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Biomarcadores de Tumor/análisis , Carcinoma de Células Escamosas/virología , Detección Precoz del Cáncer/métodos , Infecciones por Papillomavirus/virología , ARN Viral/análisis , Displasia del Cuello del Útero/virología , Neoplasias del Cuello Uterino/virología , Adulto , Anciano , Anciano de 80 o más Años , Alphapapillomavirus/aislamiento & purificación , Biopsia , Carcinoma de Células Escamosas/patología , Colposcopía , Progresión de la Enfermedad , Femenino , Humanos , Persona de Mediana Edad , Prueba de Papanicolaou , Infecciones por Papillomavirus/patología , ARN Mensajero/análisis , Factores de Riesgo , Neoplasias del Cuello Uterino/patología , Frotis Vaginal , Adulto Joven , Displasia del Cuello del Útero/patologíaRESUMEN
The role of cyclins in hormone-dependent neoplasms is crucial in the development of the disease that is resistant to first-line therapy, as the example of breast cancer shows. However, in prostate cancer, cyclins are studied to a lesser extent. There are some well-described molecular pathways, including cyclins A1 and D1 signaling, however the role of other cyclins, e.g., D2, D3, E, and H, still requires further investigation. Recent studies indicate that cyclins regulate various cellular processes, not only the cell cycle. Furthermore, they remain in cross-talk with many other signaling pathways, e.g., MAPK/ERK, PI3K/Akt, and Notch. The androgen signaling axis, which is pivotal in prostate cancer progression, interferes with cyclin pathways at many levels. This article summarizes current knowledge on the influence of cyclins on prostate cancer progression by describing interactions between the androgen receptor and cyclins, as well as mechanisms underlying the development of resistance to currently used therapies.
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Ciclinas , Neoplasias de la Próstata , Masculino , Humanos , Ciclinas/metabolismo , Receptores Androgénicos/metabolismo , Andrógenos , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismoRESUMEN
A new drug delivery system consisting of clindamycin phosphate entrapped in acid-etched halloysite nanotubes was successfully prepared and characterized. It was then used as an antibacterial component of the multicomponent hydrogel designed as a material for bone regeneration. First, halloysite (HNT) was etched and clindamycin phosphate (CP) was entrapped in both raw and modified nanotubes, resulting in HNT-CP and EHNT-CP systems. They were characterized using SEM, TEM, TGA and FTIR; the entrapment efficiency and release of CP from both systems were also studied. EHNT-CP was then used as an antibacterial component of the two hydrogels composed of alginate, collagen and ß-TCP. The hydrogels were prepared using different crosslinking procedures but had the same composition. The morphology, porosity, degradation rate, CP release profile, cytocompatibility, antibacterial activity and ability to induce biomineralization were studied for both materials. The hydrogel obtained by a chemical crosslinking with EDC followed by the physical crosslinking with calcium ions had better properties and was shown to have potential as a bone repair material.
RESUMEN
Kinetin riboside (KR) is a N6-substituted derivative of adenosine. It is a natural compound which occurs in the milk of coconuts on the nanomole level. KR was initially shown to selectively inhibit proliferation of cancer cells and induce their apoptosis. We observed that KR inhibited growth (20-80%) of not only human cancer, but also normal cells and that this effect strongly depended on the type of cells. The anti-apoptotic Bcl-2 protein was downregulated, while proapoptotic Bax was upregulated in normal as well as in cancer cell lines, upon exposure to KR. Cytochrome c level increased in the cytosol upon treatment of cells with KR. The activity of caspases (ApoFluor®Green Caspase Activity Assay), as well as caspase-3 (caspase-3 activation assay) were increased mainly in cancer cells. The expression of procaspase 9 and its active form in the nucleus as well as in cytosol of KR-treated cells was elevated. In contrast, no effect of KR on caspase 8 expression was noted. The results indicated that non-malignant cells were less sensitive to KR then their cancer analogs and that KR most likely stimulated apoptosis mechanism of cancer cells through the intrinsic pathway.
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Adenosina/farmacología , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Cinetina/farmacología , Neoplasias/metabolismo , Caspasa 3/biosíntesis , Caspasa 8/biosíntesis , Línea Celular Tumoral , Citocromos c/metabolismo , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Proteína X Asociada a bcl-2/metabolismoRESUMEN
OBJECTIVE: The aim of this study was to compare the immunohistochemical expression of vascular endothelial growth factors VEGF-C and D, as well as the expression of VEGFR-3 in VIN and vulvar invasive cancer and to compare the density of lymphatic marker D2-40 antibody in both groups, and to compare them with different clinicopathologic features. MATERIALS & METHODS: The study was performed using tissue material and clinical data from 100 women diagnosed with VIN and 100 women diagnosed with invasive vulvar cancer. RESULTS: No significant differences were found in the expression of VEGF-C and -D or VEGFR-3 between those patients with VIN and those with invasive vulvar cancers. Weak expression of VEGF-C was confirmed only in two cases of the analyzed series; in all cases, expression of VEGF-D and VEGFR-3 was observed. The strongest expression of VEGF-D and VEGFR-3 was observed in the group of invasive cancers. The highest density of lymphatic vessels per 2 mm was observed in VIN. In the cancer group, small lymphatic vessels with a narrow oval lumen were observed. Moreover, in two cases of vulvar cancer, the presence of intratumoral lymphatic vessels was observed. CONCLUSIONS: These results suggest that lymphangiogenesis begins at the preinvasive stage of vulvar carcinogenesis and suggests the important role of VEGF-C, VEGF-D, VEGFR-3 and LV (D2-40) as prognostic factors in the process of carcinogenesis in the vulvar area.
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Carcinoma in Situ/metabolismo , Factor C de Crecimiento Endotelial Vascular/metabolismo , Factor D de Crecimiento Endotelial Vascular/metabolismo , Receptor 3 de Factores de Crecimiento Endotelial Vascular/metabolismo , Neoplasias de la Vulva/metabolismo , Adulto , Anciano , Anticuerpos/farmacología , Biomarcadores de Tumor/metabolismo , Biopsia , Carcinoma in Situ/patología , Carcinoma in Situ/cirugía , Supervivencia sin Enfermedad , Femenino , Humanos , Vasos Linfáticos/inmunología , Vasos Linfáticos/metabolismo , Vasos Linfáticos/patología , Persona de Mediana Edad , Invasividad Neoplásica , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Valor Predictivo de las Pruebas , Pronóstico , Neoplasias de la Vulva/patología , Neoplasias de la Vulva/cirugíaRESUMEN
Beta carotene (BC) is a nutritional compound widespread in foods which can influence vital cellular functions--differentiation, proliferation and apoptosis of normal and cancer cells. However its role in the carcinogenesis remains controversial. We performed a microarray expression analysis in three human acute leukemia cell lines (HL-60, U937 and TF-1) exposed to 10mM BC and found that BC stimulated the apoptosis in all studied cell lines. This effect was most evident in the HL-60 cell line and correlated with increased expression of proapoptotic BAX and CAPN2 genes. The micro-array findings were replicated by the quantitative BAX and CAPN2 expression analysis using real-time PCR and by Western Blot on protein level. The biological tests (TUNEL method) for apoptosis showed consistent proapoptotic effects in all studied cell lines. In this paper the stimulatory effect of BC on apoptosis (enhanced expression of proapoptotic genes and proteins) in human acute myeloid leukemia cells was confirmed. The most potent activation of apoptosis in the HL-60 cells is in line with other investigators observations suggesting distinct molecular mechanism of apoptosis stimulation by BC in different human acute myeloid leukemia cells.