RESUMEN
Metronomic chemotherapy with cyclophosphamide (Cpp) has shown promising results in cancer protocols. These lower and prolonged doses have antiangiogenic, pro-cytotoxic, and moderate secondary effects. Molecular iodine (I2) reduces the viability of cancer cells and, with chemotherapeutic agents, activates the antitumoral immune response and diminishes side effects. The present work evaluates the adjuvant of oral I2 with Cpp using a murine model of mammary cancer. Female Sprague Dawley rats with 7,12-dimethylbenzantracene-induced tumors received Cpp intraperitoneal (50 and 70 mg/kg two times/week, iCpp50 and iCpp70) and oral (0.03%; 50 mg/Kg; oCpp50) doses. I2 (0.05%, 50 mg/100 mL) and oCpp50 were offered in drinking water for three weeks. iCpp70 was the most efficient antitumoral dose but generated severe body weight loss and hemorrhagic cystitis (HC). I2 prevented body weight loss, exhibited adjuvant actions with Cpp, decreasing tumor growth, and canceled HC mechanisms, including decreases in vascular endothelial growth factor (VEGF) and Survivin expression. oCpp50 + I2 diminished angiogenic signals (CD34, vessel-length, and VEGF content) and proinflammatory cytokines (interleukin-10 and tumor necrosis factor-alpha) and increased cytotoxic (lymphocytic infiltration, CD8+ cells, Tbet, and interferon-gamma) and antioxidant markers (nuclear erythroid factor-2 and glutathione peroxidase). I2 enhances the effectiveness of oCpp, making it a compelling candidate for a clinical protocol.
Asunto(s)
Administración Metronómica , Ciclofosfamida , Yodo , Ratas Sprague-Dawley , Animales , Ciclofosfamida/farmacología , Ciclofosfamida/efectos adversos , Ciclofosfamida/administración & dosificación , Femenino , Ratas , Yodo/administración & dosificación , Yodo/farmacología , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/patología , Neoplasias Mamarias Experimentales/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Progresión de la Enfermedad , Antineoplásicos Alquilantes/efectos adversos , Antineoplásicos Alquilantes/administración & dosificación , Antineoplásicos Alquilantes/farmacologíaRESUMEN
Pancreatic alterations such as inflammation and insulin resistance accompany hypothyroidism. Molecular iodine (I2) exerts antioxidant and differentiation actions in several tissues, and the pancreas is an iodine-uptake tissue. We analyzed the effect of two oral I2 doses on pancreatic disorders in a model of hypothyroidism for 30 days. Adult female rabbits were divided into the following groups: control, moderate oral dose of I2 (0.2 mg/kg, M-I2), high oral dose of I2 (2.0 mg/kg, H-I2), oral dose of methimazole (MMI; 10 mg/kg), MMI + M-I2,, and MMI + H-I2. Moderate or high I2 supplementation did not modify circulating metabolites or pancreatic morphology. The MMI group showed reductions of circulating thyroxine (T4) and triiodothyronine (T3), moderate glucose increments, and significant increases in cholesterol and low-density lipoproteins. Acinar fibrosis, high insulin content, lipoperoxidation, and overexpression of GLUT4 were observed in the pancreas of this group. M-I2 supplementation normalized the T4 and cholesterol, but T3 remained low. Pancreatic alterations were prevented, and nuclear factor erythroid-2-related factor-2 (Nrf2), antioxidant enzymes, and peroxisome proliferator-activated receptor gamma (PPARG) maintained their basal values. In MMI + H-I2, hypothyroidism was avoided, but pancreatic alterations and low PPARG expression remained. In conclusion, M-I2 supplementation reestablishes thyronine synthesis and diminishes pancreatic alterations, possibly related to Nrf2 and PPARG activation.
Asunto(s)
Hipotiroidismo , Yodo , Animales , Conejos , Femenino , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Factor 2 Relacionado con NF-E2 , PPAR gamma , Hipotiroidismo/tratamiento farmacológico , Hipotiroidismo/metabolismo , Triyodotironina/metabolismo , Tiroxina/metabolismo , ColesterolRESUMEN
Pancreatitis has been implicated in the development and progression of type 2 diabetes and cancer. The pancreas uptakes molecular iodine (I2), which has anti-inflammatory and antioxidant effects. The present work analyzes whether oral I2 supplementation prevents the pancreatic alterations promoted by low doses of streptozotocin (STZ). CD1 mice (12 weeks old) were divided into the following groups: control; STZ (20 mg/kg/day, i.p. for five days); I2 (0.2 mg/Kg/day in drinking water for 15 days); and combined (STZ + I2). Inflammation (Masson's trichrome and periodic acid-Schiff stain), hyperglycemia, decreased ß-cells and increased α-cells in pancreas were observed in male and female animals with STZ. These animals also showed pancreatic increases in immune cells and inflammation markers as tumor necrosis factor-alpha, transforming growth factor-beta and inducible nitric oxide synthase with a higher amount of activated pancreatic stellate cells (PSCs). The I2 supplement prevented the harmful effect of STZ, maintaining normal pancreatic morphometry and functions. The elevation of the nuclear factor erythroid-2 (Nrf2) and peroxisome proliferator-activated receptor type gamma (PPARγ) contents was associated with the preservation of normal glycemia and lipoperoxidation. In conclusion, a moderated supplement of I2 prevents the deleterious effects of STZ in the pancreas, possibly through antioxidant and antifibrotic mechanisms including Nrf2 and PPARγ activation.
Asunto(s)
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Yodo , Animales , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Experimental/prevención & control , Diabetes Mellitus Tipo 2/prevención & control , Suplementos Dietéticos , Femenino , Yodo/farmacología , Masculino , Ratones , Páncreas , EstreptozocinaRESUMEN
Individual differences in coping with stress may determine either a vulnerable or resilient phenotype. Therefore, it is important to better understand the biology underlying the behavioral phenotype. We assessed whether individual behavioral phenotype to acute stress is related with the hippocampal expression of glucocorticoid receptor (GR), Nurr1, interleukin-1 beta (IL-1ß) or brain-derived neurotrophic factor (BDNF). Wistar male rats were exposed to forced swimming for 15 min and sacrificed at different times. Behavioral response was analyzed, and it was compared with the gene and protein expression of GR, Nurr1, IL-1ß and BDNF in the hippocampus for each time point. Behavioral phenotyping showed a group with high immobility (vulnerable) while another had low immobility (resilient). No significant differences were found in the Nurr1, IL-1ß and BDNF mRNA levels between resilient and vulnerable rats at different recovery times except for Nr3c1 (gene for GR). However, exposure to stress caused significantly higher levels of GR, Nurr1 and IL-1ß proteins of vulnerable compared to resilient rats. This variability of behavioral phenotypes is associated with a differential molecular response to stress that involves GR, Nurr1, and IL-1ß as mediators in coping with stress. This contributes to identifying biomarkers of susceptibility to stress.
Asunto(s)
Conducta Animal/fisiología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Hipocampo/metabolismo , Interleucina-1beta/metabolismo , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismo , Receptores de Glucocorticoides/metabolismo , Estrés Psicológico , Natación , Adaptación Psicológica , Animales , Factor Neurotrófico Derivado del Encéfalo/genética , Modelos Animales de Enfermedad , Femenino , Interleucina-1beta/genética , Masculino , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/genética , Fenotipo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Receptores de Glucocorticoides/genéticaRESUMEN
Molecular iodine (I2) induces apoptotic, antiangiogenic, and antiproliferative effects in breast cancer cells. Little is known about its effects on the tumor immune microenvironment. We studied the effect of oral (5 mg/day) I2 supplementation alone (I2) or together with conventional chemotherapy (Cht+I2) on the immune component of breast cancer tumors from a previously published pilot study conducted in Mexico. RNA-seq, I2 and Cht+I2 samples showed significant increases in the expression of Th1 and Th17 pathways. Tumor immune composition determined by deconvolution analysis revealed significant increases in M0 macrophages and B lymphocytes in both I2 groups. Real-time RT-PCR showed that I2 tumors overexpress T-BET (p = 0.019) and interferon-gamma (IFNγ; p = 0.020) and silence tumor growth factor-beta (TGFß; p = 0.049), whereas in Cht+I2 tumors, GATA3 is silenced (p = 0.014). Preliminary methylation analysis shows that I2 activates IFNγ gene promoter (by increasing its unmethylated form) and silences TGFß in Cht+I2. In conclusion, our data showed that I2 supplements induce the activation of the immune response and that when combined with Cht, the Th1 pathways are stimulated. The molecular mechanisms involved in these responses are being analyzed, but preliminary data suggest that methylation/demethylation mechanisms could also participate.
Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Factor de Transcripción GATA3/genética , Interferón gamma/genética , Yodo/administración & dosificación , Factor de Crecimiento Transformador beta1/genética , Adulto , Anciano , Inhibidores de la Angiogénesis/administración & dosificación , Apoptosis/efectos de los fármacos , Linfocitos B/efectos de los fármacos , Linfocitos B/inmunología , Neoplasias de la Mama/genética , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Proliferación Celular/efectos de los fármacos , Femenino , Humanos , Inmunidad/genética , Yodo/efectos adversos , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , México , Persona de Mediana Edad , RNA-Seq , Células TH1/efectos de los fármacos , Células TH1/inmunología , Células Th17/efectos de los fármacos , Células Th17/inmunología , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunologíaRESUMEN
Neuroblastoma (Nb), the most common extracranial tumor in children, exhibited remarkable phenotypic diversity and heterogeneous clinical behavior. Tumors with MYCN overexpression have a worse prognosis. MYCN promotes tumor progression by inducing cell proliferation, de-differentiation, and dysregulated mitochondrial metabolism. Cyclophosphamide (CFF) at minimum effective oral doses (metronomic therapy) exerts beneficial actions on chemoresistant cancers. Molecular iodine (I2) in coadministration with all-trans retinoic acid synergizes apoptosis and cell differentiation in Nb cells. This work analyzes the impact of I2 and CFF on the viability (culture) and tumor progression (xenografts) of Nb chemoresistant SK-N-BE(2) cells. Results showed that both molecules induce dose-response antiproliferative effects, and I2 increases the sensibility of Nb cells to CFF, triggering PPARγ expression and acting as a mitocan in mitochondrial metabolism. In vivo oral I2/metronomic CFF treatments showed significant inhibition in xenograft growth, decreasing proliferation (Survivin) and activating apoptosis signaling (P53, Bax/Bcl-2). In addition, I2 decreased the expression of master markers of malignancy (MYCN, TrkB), vasculature remodeling, and increased differentiation signaling (PPARγ and TrkA). Furthermore, I2 supplementation prevented loss of body weight and hemorrhagic cystitis secondary to CFF in nude mice. These results allow us to propose the I2 supplement in metronomic CFF treatments to increase the effectiveness of chemotherapy and reduce side effects.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Ciclofosfamida/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Sinergismo Farmacológico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Yodo/farmacología , Neuroblastoma/tratamiento farmacológico , Animales , Antiinfecciosos Locales/farmacología , Antineoplásicos Alquilantes/farmacología , Apoptosis , Biomarcadores de Tumor/genética , Diferenciación Celular , Proliferación Celular , Quimioterapia Combinada , Humanos , Masculino , Ratones , Ratones Desnudos , Neuroblastoma/metabolismo , Neuroblastoma/patología , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Most investigations of iodine metabolism in humans and animals have focused on its role in thyroid function. However, considerable evidence indicates that iodine could also be implicated in the physiopathology of other organs. We review the literature that shows that molecular iodine (I2) exerts multiple and complex actions on the organs that capture it, not including its effects as part of thyroid hormones. This chemical form of iodine is internalized by a facilitated diffusion system that is evolutionary conserved, and its effects appear to be mediated by a variety of mechanisms and pathways. As an oxidized component, it directly neutralizes free radicals, induces the expression of type II antioxidant enzymes, or inactivates proinflammatory pathways. In neoplastic cells, I2 generates iodolipids with nuclear actions that include the activation of apoptotic pathways and the inhibition of markers related to stem cell maintenance, chemoresistance, and survival. Recently, I2 has been postulated as an immune modulator that depending on the cellular context, can function as an inhibitor or activator of immune responses. We propose that the intake of molecular iodine is increased in adults to at least 1 mg/day in specific pathologies to obtain the potential extrathyroid benefits described in this review.
Asunto(s)
Antioxidantes/farmacología , Diferenciación Celular/efectos de los fármacos , Factores Inmunológicos/farmacología , Yodo/metabolismo , Mitocondrias/efectos de los fármacos , Neoplasias/metabolismo , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Yodo/farmacología , Mitocondrias/metabolismo , Neoplasias/inmunología , PPAR gamma/agonistas , PPAR gamma/genética , PPAR gamma/metabolismoRESUMEN
BACKGROUND: Hodgkin lymphoma is a malignant neoplasm of B lymphoid cells whose histologic characteristic is the presence of Reed-Sternberg cells in an inflammatory environment. CASE REPORT: A 37-year-old woman with a history of up to 40°C fever for four months, progressive and bilateral decrease in hearing acuity, weight loss of up to 6 kg, cervical lymphadenopathy, hepatosplenomegaly, and pancytopenia. Auditory sensory neuropathy was confirmed. The patient developed hemophagocytic syndrome, therefore, infectious and autoimmune etiologies were ruled out. The CT scan revealed hepatosplenomegaly with thoracic and abdominal cervical nodes, with loss of fatty hilum. The laboratory tests showed evidence that suggested the reactivation of the Epstein-Barr virus. Through a submandibular node biopsy, the diagnostic conclusion was that lymphocyte-rich classical Hodgkin's lymphoma was present. CONCLUSION: This is the first report in Latin American literature about a patient with hemophagocytic syndrome that is secondary to classic Hodgkin lymphoma and associated with Epstein-Barr infection.
Antecedentes: El linfoma de Hodgkin es una neoplasia maligna de células linfoides tipo B cuya característica histológica es la presencia de células de Reed-Sternberg en un medio inflamatorio. Caso clínico: Mujer de 37 años, con fiebre de hasta 40 °C desde cuatro meses atrás, disminución bilateral y progresiva de la agudeza auditiva, pérdida ponderal de 6 kg, linfadenopatía cervical, hepatoesplenomegalia y pancitopenia. Se corroboró neuropatía sensorial auditiva. La paciente desarrolló síndrome hemofagocítico, por lo que se descartaron procesos infecciosos o autoinmunes. La tomografía reveló hepatoesplenomegalia, ganglios cervicales torácicos y abdominales con pérdida del hilio graso; en los estudios de laboratorio se evidenciaron datos sugerentes de reactivación del virus de Epstein-Barr. Mediante biopsia de ganglio submandibular se concluyó que se trataba de linfoma de Hodgkin tipo clásico rico en linfocitos. Conclusión: La paciente descrita con síndrome hemofagocítico secundario a linfoma de Hodgkin clásico asociado a infección por Epstein-Barr constituye el primero caso reportado en la literatura latinoamericana.
Asunto(s)
Infecciones por Virus de Epstein-Barr/complicaciones , Enfermedad de Hodgkin/complicaciones , Linfohistiocitosis Hemofagocítica/etiología , Adulto , Femenino , HumanosRESUMEN
This study analyzes an oral supplement of molecular iodine (I2), alone and in combination with the neoadjuvant therapy 5-fluorouracil/epirubicin/cyclophosphamide or taxotere/epirubicin (FEC/TE) in women with Early (stage II) and Advanced (stage III) breast cancer. In the Early group, 30 women were treated with I2 (5 mg/day) or placebo (colored water) for 7-35 days before surgery. For the Advanced group, 30 patients received I2 or placebo, along with FEC/TE treatment. After surgery, all patients received FEC/TE + I2 for 170 days. I2 supplementation showed a significant attenuation of the side effects and an absence of tumor chemoresistance. The control, I2, FEC/TE, and FEC/TE + I2 groups exhibited response rates of 0, 33%, 73%, and 100%, respectively, and a pathologic complete response of 18%, and 36% in the last two groups. Five-year disease-free survival rate was significantly higher in patients treated with the I2 supplement before and after surgery compared to those receiving the supplement only after surgery (82% versus 46%). I2-treated tumors exhibit less invasive potential, and significant increases in apoptosis, estrogen receptor expression, and immune cell infiltration. Transcriptomic analysis indicated activation of the antitumoral immune response. The results led us to register a phase III clinical trial to analyze chemotherapy + I2 treatment for advanced breast cancer.
Asunto(s)
Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Yodo/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/cirugía , Supervivencia sin Enfermedad , Femenino , Humanos , Persona de Mediana Edad , Terapia Neoadyuvante , Proyectos Piloto , Oligoelementos/administración & dosificaciónRESUMEN
BACKGROUND: The immune system is a crucial component in cancer progression or regression. Molecular iodine (I2) exerts significant antineoplastic effects, acting as a differentiation inductor and immune modulator, but its effects in antitumor immune response are not elucidated. METHODS: The present work analyzed the effect of I2 in human breast cancer cell lines with low (MCF-7) and high (MDA-MB231) metastatic potential under both in vitro (cell proliferation and invasion assay) and in vivo (xenografts of athymic nude mice) conditions. RESULTS: In vitro analysis showed that the 200 µM I2 supplement decreases the proliferation rate in both cell lines and diminishes the epithelial-mesenchymal transition (EMT) profile and the invasive capacity in MDA-MB231. In immunosuppressed mice, the I2 supplement impairs implantation (incidence), tumoral growth, and proliferation of both types of cells. Xenografts of the animals treated with I2 decrease the expression of invasion markers like CD44, vimentin, urokinase plasminogen activator and its receptor, and vascular endothelial growth factor; and increase peroxisome proliferator-activated receptor gamma. Moreover, in mice with xenografts, the I2 supplement increases the circulating level of leukocytes and the number of intratumoral infiltrating lymphocytes, some of them activated as CD8+, suggesting the activation of antitumor immune responses. CONCLUSIONS: I2 decreases the invasive potential of a triple negative basal cancer cell line, and under in vivo conditions the oral supplement of this halogen activates the antitumor immune response, preventing progression of xenografts from laminal and basal mammary cancer cells. These effects allow us to propose iodine supplementation as a possible adjuvant in breast cancer therapy.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Inmunidad Celular/efectos de los fármacos , Yodo/farmacología , Animales , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Movimiento Celular/efectos de los fármacos , Movimiento Celular/inmunología , Proliferación Celular/efectos de los fármacos , Femenino , Factores de Transcripción Forkhead/genética , Humanos , Yodo/uso terapéutico , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Linfocitos Infiltrantes de Tumor/inmunología , Ratones , Ratones Desnudos , Ratones Transgénicos , Invasividad Neoplásica/inmunología , Invasividad Neoplásica/prevención & control , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Mammary cancer has a high incidence in canines and is an excellent model of spontaneous carcinogenesis. Molecular iodine (I2) exerts antineoplastic effects on different cancer cells activating re-differentiation pathways. In co-administration with anthracyclines, I2 impairs chemoresistance installation and prevents the severity of side effects generated by these antineoplastic drugs. This study is a random and double-blind protocol that analyzes the impact of I2 (10 mg/day) in two administration schemes of Doxorubicin (DOX; 30 mg/m2) in 27 canine patients with cancer of the mammary gland. The standard scheme (sDOX) includes four cycles of DOX administered intravenously for 20 min every 21 days, while the modified scheme (mDOX) consists of more frequent chemotherapy (four cycles every 15 days) with slow infusion (60 min). In both schemes, I2 or placebo (colored water) was supplemented daily throughout the treatment. RESULTS: mDOX attenuated the severity of adverse events (VCOG-CTCAE) in comparison with the sDOX group. The overall tumor response rate (RECIST criteria) for all dogs was 18% (interval of reduction 48-125%), and no significant difference was found between groups. I2 supplementation enhances the antineoplastic effect in mDOX, exhibiting a significant decrease in the tumor epithelial fraction, diminished expression of chemoresistance (MDR1 and Survivin) and invasion (uPA) markers and enhanced expression of the differentiation factor known as peroxisome proliferator-activated receptors type gamma (PPARγ). Significant tumor lymphocytic infiltration was also observed in both I2-supplemented groups. The ten-month survival analysis showed that the entire I2 supplementation (before and after surgery) induced 67-73% of disease-free survival, whereas supplementation in the last period (only after surgery) produced 50% in both schemes. CONCLUSIONS: The mDOX+I2 scheme improves the therapeutic outcome, diminishes the invasive capacity, attenuates the adverse events and increases disease-free survival. These data led us to propose mDOX+I2 as an effective treatment for canine mammary cancer.
Asunto(s)
Antineoplásicos/uso terapéutico , Enfermedades de los Perros/tratamiento farmacológico , Doxorrubicina/uso terapéutico , Yodo/uso terapéutico , Neoplasias Mamarias Animales/tratamiento farmacológico , Terapia Neoadyuvante/veterinaria , Animales , Antineoplásicos/administración & dosificación , Perros , Doxorrubicina/administración & dosificación , Femenino , Yodo/administración & dosificación , Terapia Neoadyuvante/métodosRESUMEN
Oxidative stress and inflammation are involved in the development and/or progression of benign prostatic hyperplasia (BPH). Molecular iodine (I2) induces antiproliferative and apoptotic effects in prostate cancer cells, but it is unknown if I2 regulates oxidative stress in the normal and/or tumoral prostate. The purpose of this study was to analyze the effects of I2 and celecoxib (Cxb) on oxidative stress and inflammation in a model of prostatic hyperplasia. Cxb was used as positive control of cyclooxygenase-2 (COX-2) inhibition. Prostatic hyperplasia was induced in male Wistar rats (170g) with testosterone (5mg/kg/week, for three weeks). One week before hyperplasia induction, I2 (25mg/day/rat) or Cxb (1.25mg/day/rat) was supplied for four weeks in the drinking water. Prostatic hyperplasia was evaluated by histological analysis, DNA content, and/or proliferating cell nuclear antigen (PCNA) expression. Lipoperoxidation (malondialdehyde) and nitrite (NO2-) levels were analyzed by colorimetric methods, while nitric oxide synthase (NOS), COX, and myeloperoxidase (MPO) enzymes were analyzed using RT-PCR, immunoblotting, and/or enzymatic assays. Levels of 15-F2t-isoprostanes, prostaglandins (PGE2), leukotrienes (LTB4), and tumor necrosis factor alpha (TNFα) were measured by ELISA. Control testosterone-treated animals exhibited hyperplasia in the dorsolateral prostate, as well as increments in almost all oxidative parameters except for COX-1, TNFα, or MPO. I2 and Cxb prevented epithelial hyperplasia (DNA content) and oxidative stress induction generated by testosterone in almost the same intensity, and the minimum I2 dose required was 2.5mg/rat. The antioxidant capacity of I2 was also analyzed in a cell-free system, showing that this element inhibited the conversion of nitrate (NO3-) to NO2-. I2 did not modify the prostatic oxidative state in testosterone untreated rats. In summary, our data showed that antiproliferative and antioxidant effects of I2 involve the inhibition of NOS and the COX-2 pathway. Further studies are necessary to analyze the therapeutic and/or adjuvant effects of I2 with first-line medications used to treat BPH.
Asunto(s)
Antineoplásicos/uso terapéutico , Yodo/uso terapéutico , Estrés Oxidativo/efectos de los fármacos , Próstata/efectos de los fármacos , Hiperplasia Prostática/tratamiento farmacológico , Animales , Celecoxib/uso terapéutico , Ciclooxigenasa 2/metabolismo , Modelos Animales de Enfermedad , Humanos , Peroxidación de Lípido/efectos de los fármacos , Masculino , Próstata/fisiología , Hiperplasia Prostática/inducido químicamente , Ratas , Ratas Wistar , Testosterona/administración & dosificaciónRESUMEN
Increasing evidence suggests that alterations in early nutrition programme physiological changes in adulthood. In the present study, we determined the effects of undernutrition during gestation and lactation on the programming of thyroid function in adult rat offspring. Perinatal undernutrition was achieved by a 40% food restriction in female Wistar rats from the mating day to weaning. On postpartum day 21, the offspring of the control and food-restricted dams were weaned and given free access to a commercial diet until adulthood. The results showed that undernourished rats exhibited decreased 3,5,3'-triiodothyronine (T3) levels but had normal thyroxine (T4) and thyrotropin (TSH) levels at weaning; on day 90, these rats displayed a significant flip, exhibiting normalised T3 (total and free) and total T4 levels, but low free T4 and persistently higher TSH levels, which were maintained even on postnatal day 140. This profile was accompanied by a scarce fat depot, a lower RMR and an exacerbated sympathetic brown adipose tissue (BAT) tone (deiodinase type 2 expression) in basal conditions. Moreover, when a functional challenge (cold exposure) was applied, the restricted group exhibited partial changes in TSH (29 v. 100%) and T4 (non-response v. 17%) levels, a significant decrease in leptin levels (75 v. 32%) and the maintenance of a sympathetic BAT over-response (higher noradrenaline levels) in comparison with the control group. The findings of the present study suggest that undernutrition during the perinatal period produces permanent changes in the hypothalamus-pituitary-thyroid axis with consequent low body weight and decreased RMR and facultative thermogenesis. We hypothesise that these changes predispose individuals to exhibiting adult subclinical hypothyroidism.
Asunto(s)
Hipotiroidismo/etiología , Fenómenos Fisiológicos Nutricionales del Lactante , Desnutrición/complicaciones , Fenómenos Fisiologicos de la Nutrición Prenatal , Glándula Tiroides/fisiopatología , Hormonas Tiroideas/sangre , Tejido Adiposo Pardo/metabolismo , Animales , Metabolismo Basal , Peso Corporal , Frío , Femenino , Humanos , Hipotiroidismo/sangre , Hipotiroidismo/metabolismo , Hipotiroidismo/fisiopatología , Recién Nacido , Lactancia , Leptina/sangre , Desnutrición/sangre , Desnutrición/fisiopatología , Norepinefrina/sangre , Embarazo , Efectos Tardíos de la Exposición Prenatal , Ratas , Ratas Wistar , TermogénesisRESUMEN
BACKGROUND: Seaweed is an important dietary component and a rich source of iodine in several chemical forms in Asian communities. Their high consumption of this element (25 times higher than in Western countries) has been associated with the low incidence of benign and cancerous breast and prostate disease in Japanese people. SUMMARY: We review evidence showing that, in addition to being a component of the thyroid hormone, iodine can be an antioxidant as well as an antiproliferative and differentiation agent that helps to maintain the integrity of several organs with the ability to take up iodine. In animal and human studies, molecular iodine (I2) supplementation exerts a suppressive effect on the development and size of both benign and cancerous neoplasias. Investigations by several groups have demonstrated that these effects can be mediated by a variety of mechanisms and pathways, including direct actions, in which the oxidized iodine dissipates the mitochondrial membrane potential, thereby triggering mitochondrion-mediated apoptosis, and indirect effects through iodolipid formation and the activation of peroxisome proliferator-activated receptors type gamma, which, in turn, trigger apoptotic or differentiation pathways. CONCLUSIONS: We propose that the International Council for the Control of Iodine Deficient Disorders recommend that iodine intake be increased to at least 3 mg/day of I2 in specific pathologies to obtain the potential extrathyroidal benefits described in the present review.
Asunto(s)
Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Yodo/farmacología , Animales , Mama/metabolismo , Proliferación Celular/efectos de los fármacos , Femenino , Humanos , Yodo/efectos adversos , Yodo/deficiencia , Yodo/metabolismo , Masculino , PPAR gamma , Próstata/metabolismoRESUMEN
BACKGROUND: Evidence indicates that iodine per se could be implicated in the physiology of several organs that can internalize it. In thyroid and breast cancer, iodine treatments inhibit cell proliferation and induce apoptosis through a direct (mitochondria) and/or indirect effect (iodolipid generation). Here, we determined the uptake of iodide (I(-) ) and iodine (I(2) ), as well as the antiproliferative and apoptotic effects of 6-iodolactone (6-IL) and both forms of iodine in human prostate cells lines. METHODS: Non-cancerous (RWPE-1) and cancerous (LNCaP, DU-145) cells, as well as nude mice xenotransplanted with DU-145 cells were used as cancer models. Iodine uptake was analyzed with radioactive tracers, transporter expression by qRT-PCR, cell proliferation by blue trypan, apoptosis by enzyme immunoassay or fluorescence, BAX and BCL-2 by western-blot, and caspsase 3 by enzymatic assay. RESULTS: All three cell lines take up both forms of iodine. In RWPE-1 cells, I(-) uptake depends on the Na(+) /I(-) symporter (NIS), whereas it was independent of NIS in LNCaP and DU-145 cells. Antiproliferative effects of iodine and 6-IL were dose and time dependent; RWPE-1 was most sensitive to I(-) and 6-IL, whereas LNCaP was more sensitive to I(2) . In the three cell lines both forms of iodine activated the intrinsic apoptotic pathway (increasing the BAX/BCL-2 index and caspases). Iodine supplementation impaired growth of the DU-145 tumor in nude mice. CONCLUSION: Normal and cancerous prostate cells can take up iodine, and depending on the chemical form, it exerts antiproliferative and apoptotic effects both in vitro and in vivo.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Antineoplásicos/farmacología , Ácidos Araquidónicos/farmacología , Yodo/farmacología , Próstata/efectos de los fármacos , Neoplasias de la Próstata/tratamiento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/secundario , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Expresión Génica , Humanos , Yodo/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Próstata/metabolismo , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patologíaRESUMEN
Several groups, including ours, have reported that iodine exhibited antiproliferative and apoptotic effects in various cancer cells only if this element is supplemented as molecular iodine, or as iodide, to cells that are able to oxidize it with the enzyme thyroperoxidase. In this study, we analyzed the effect of various concentrations of iodine and/or iodide in the dimethylbenz[a]anthracene (DMBA) mammary cancer model in rats. The results show that 0.1% iodine or iodide increases the expression of peroxisome proliferator-activated receptor type γ (PPARγ), triggering caspase-mediated apoptosis pathways in damaged mammary tissue (DMBA-treated mammary gland) as well as in frank mammary tumors, but not in normal mammary gland. DMBA treatment induces the expression of lactoperoxidase, which participates in the antineoplastic effect of iodide and could be involved in the pro-neoplastic effect of estrogens, increasing the formation of DNA adducts. In conclusion, our results show that a supplement of 0.1% molecular iodine/potassium iodide (0.05/0.05%) exert antineoplastic effects, preventing estrogen-induced DNA adducts and inducing apoptosis through PPARγ/caspases in pre-cancer and cancerous cells. Since this iodine concentration does not modify the cytology (histology, apoptosis rate) or physiology (triiodothyronine and thyrotropin) of the thyroid gland, we propose that it be considered as an adjuvant treatment for premenopausal mammary cancer.
Asunto(s)
Antineoplásicos/uso terapéutico , Aductos de ADN/efectos de los fármacos , Estrógenos/farmacología , Yodo/uso terapéutico , Lactoperoxidasa/metabolismo , Neoplasias Mamarias Experimentales/prevención & control , Yoduro de Potasio/uso terapéutico , 9,10-Dimetil-1,2-benzantraceno/toxicidad , Animales , Apoptosis/efectos de los fármacos , Western Blotting , Carcinógenos/toxicidad , Caspasa 3/metabolismo , Daño del ADN/efectos de los fármacos , Femenino , Neoplasias Mamarias Experimentales/inducido químicamente , Neoplasias Mamarias Experimentales/metabolismo , PPAR gamma/genética , PPAR gamma/metabolismo , ARN Mensajero/genética , Ratas , Ratas Sprague-Dawley , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Glándula Tiroides/efectos de los fármacosRESUMEN
Thyronines are essential for the development of the male reproductive system, including the prostate gland. Metabolically active 3,5,3' triiodothyronine (T(3)) is generated mainly by the extrathyroidal, enzymatic 5'deiodination of the prohormone thyroxine (T(4)), which is catalyzed by deiodinases type 1 (D1) and type 2 (D2). Prostate D1 activity is highly expressed during puberty and declines with age, but continuous, long-term sexual activity prevents this reduction. The aims of this study were to characterize the changes in prostatic D1 activity in response to consecutive ejaculations and to determine whether sympathetic input participates in the local T(3) generation (D1 activity). D1 activity was analyzed in prostates of sexually experienced, 4-mo-old male rats after one to five ejaculations. D1 activity, T(3) concentrations, and the T(3)-dependent gene ornithine decarboxylase (Odc) were measured after the fourth ejaculation in prostates of intact, sham, and sympathectomized (Smpx, hypogastric nerve) rats. D1 activity was evaluated by the radio-iodine-release method; T(3) was measured by radioimmunoassay and Odc expression by real-time PCR. Data showed a gradual increase of prostate D1 activity in response to consecutive ejaculations. The highest activity was found after the fourth ejaculation, and it decreased after the fifth. The increase of prostate D1 activity after ejaculation was blocked in Smpx males as compared to intact or sham animals. The changes in D1 activity correlate with prostatic T(3) concentrations and Odc expression. Circulating levels of T(3) were not affected by consecutive ejaculations or by Smpx. These findings indicate that the postejaculatory increase in prostatic generation of T(3) depends on sympathetic input.
Asunto(s)
Fibras Adrenérgicas/fisiología , Eyaculación/fisiología , Próstata/inervación , Próstata/metabolismo , Triyodotironina/metabolismo , Animales , Copulación/fisiología , Masculino , Ratas , Ratas WistarRESUMEN
We analyzed the participation of N-methyl-d-aspartate (NMDA) receptors in the neuronal damage caused by adult-onset hypothyroidism. Wistar rats were randomly assigned into four groups. The euthyroid group received tap water. The hypothyroid group received methimazole (60 mg/kg) in their drinking water to induce hypothyroidism. Two more groups of rats received the antithyroid treatment and were injected daily with the NMDA antagonist ketamine (15 mg/kg, sc) or MK-801 (0.5mg/kg, ip). Treatments were administered during 4 weeks. At the end of the respective treatments rats were deeply anaesthetized and perfused intracardially with 0.9% NaCl followed by 4% paraformaldehyde. The brains were removed from the skull, and coronal brain sections (7microm thick) were obtained. Neurons were counted in the CA1, CA2, CA3, and CA4 hippocampal regions differentiating between normal and atrophic cells by an experimenter blind to the treatment. The percentage of neuronal damage found in the MMI group was significantly greater in the hippocampal regions compared to the euthyroid group. In contrast, both NMDA antagonists were able to prevent the neuronal damage secondary to hypothyroidism in all hippocampal regions. Our results suggest that the neuronal damage caused in the hippocampus of adult-onset hypothyroid rats requires activation of NMDA channels.
Asunto(s)
Hipocampo/patología , Hipotiroidismo/patología , Neuronas/patología , Receptores de N-Metil-D-Aspartato/fisiología , Animales , Antitiroideos , Recuento de Células , Maleato de Dizocilpina/farmacología , Hipotiroidismo/inducido químicamente , Hipotiroidismo/metabolismo , Ketamina/farmacología , Masculino , Metimazol , Distribución Aleatoria , Ratas , Ratas Wistar , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidoresRESUMEN
The onset of adult hypothyroidism causes neuronal damage in the CA3 hippocampal region, which is attenuated by T(4) administration. We analyzed the expression of molecular proliferation markers (Cyclin D1 and PCNA), cellular damage-arrest (p53 and p21), and apoptosis (Bax/Bcl-2 index) in the hippocampus of hypothyroid (methimazole; 60 mg/kg) or thyroid replaced (T(4), 20 microg/kg; MMI+T(4) or T(3), 20 microg/kg; MMI+T(3)) adult male rats. Histological analysis showed that hypothyroid animals exhibit significant neuronal damage in all regions of the hippocampus accompanied by the triggering of the apoptotic pathway (increases in p53, p21 and the Bax/Bcl-2 index) and no changes in proliferation (Cyclin D1 and PCNA). MMI+T(4) replaced animals were completely protected with no changes in molecular markers. In contrast, MMI+T(3) replaced animals showed partial protection in which, although pro-apoptotic effects remained (increase in the Bax/Bcl-2), proliferative mechanisms were triggered (increase in p53, Cyclin D1 and PCNA expression). Our results indicate that thyroid hormones participate in the maintenance of the hippocampal neuronal population even in adulthood, suggesting that THs have different physiological roles as neuronal survival factors: T(4) prevents the activation of apoptotic pathways, whereas T(3) activates cell differentiation and proliferation mechanisms.