Prostatic Angiogenic Responses In Late Life: Antiangiogenic Therapy Influences And Relation With The Glandular Microenvironment In The Transgenic Adenocarcinoma Of Mouse Prostate (tramp) Model.

Aging is considered one of the main predisposing factors for the development of prostate malignancies. Angiogenesis is fundamental for tumor growth and its inhibition represents a promising therapeutic approach in cancer treatment. Thus, we sought to determine angiogenic responses and the effects of antiangiogenic therapy in the mouse prostate during late life, comparing these findings with the prostatic microenvironment in the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) model. Male mice (52 week-old FVB) were submitted to treatments with SU5416 (6 mg/kg; i.p.) and/or TNP-470 (15 mg/kg; s.c.). Finasteride was administered (20 mg/kg; s.c.), alone or in association to both inhibitors. The dorsolateral prostate was collected for VEGF, HIF-1α, FGF-2 and endostatin immunohistochemical and Western Blotting analyses and for microvessel density (MVD) count. Senescence led to increased MVD and VEGF, HIF-1α and FGF-2 protein levels in the prostatic microenvironment, similarly to what was observed in TRAMP mice prostate. The angiogenic process was impaired in all the treated groups, demonstrating significantly decreased MVD. Antiangiogenic and/or finasteride treatments resulted in decreased VEGF and HIF-1α levels, especially following TNP-470 administration, either alone or associated to SU5416. The combination of these agents resulted in increased endostatin levels, regardless of the presence of finasteride. Prostatic angiogenesis stimulation during senescence favored the development of neoplastic lesions, considering the pro-angiogenic microenvironment as a common aspect also observed during cancer progression in TRAMP mice. The combined antiangiogenic therapy was more efficient, leading to enhanced imbalance towards angiogenic inhibition in the organ. Finally, finasteride administration might secondarily upregulate the expression of pro-angiogenic factors, pointing to the harmful effects of this therapy. Prostate 75: 484-499, 2015. © 2014 Wiley Periodicals, Inc.

Solid Lipid Nanoparticles As Nucleic Acid Delivery System: Properties And Molecular Mechanisms.

Solid lipid nanoparticles (SLNs) have been proposed in the 1990s as appropriate drug delivery systems, and ever since they have been applied in a wide variety of cosmetic and pharmaceutical applications. In addition, SLNs are considered suitable alternatives as carriers in gene delivery. Although important advances have been made in this particular field, fundamental knowledge of the underlying mechanisms of SLN-mediated gene delivery is conspicuously lacking, an imperative requirement in efforts aimed at further improving their efficiency. Here, we address recent advances in the use of SLNs as platform for delivery of nucleic acids as therapeutic agents. In addition, we will discuss available technology for conveniently producing SLNs. In particular, we will focus on underlying molecular mechanisms by which SLNs and nucleic acids assemble into complexes and how the nucleic acid cargo may be released intracellularly. In discussing underlying mechanisms, we will, when appropriate, refer to analogous studies carried out with systems based on cationic lipids and polymers, that have proven useful in the assessment of structure-function relationships. Finally, we will give suggestions for improving SLN-based gene delivery systems, by pointing to alternative methods for SLNplex assembly, focusing on the realization of a sustained nucleic acid release.

Application Of A Semi-empirical Model For The Evaluation Of Transmission Properties Of Barite Mortar.

The aim of this study was to estimate barite mortar attenuation curves using X-ray spectra weighted by a workload distribution. A semi-empirical model was used for the evaluation of transmission properties of this material. Since ambient dose equivalent, H(⁎)(10), is the radiation quantity adopted by IAEA for dose assessment, the variation of the H(⁎)(10) as a function of barite mortar thickness was calculated using primary experimental spectra. A CdTe detector was used for the measurement of these spectra. The resulting spectra were adopted for estimating the optimized thickness of protective barrier needed for shielding an area in an X-ray imaging facility.

Evaluation Of Characteristic-to-total Spectrum Ratio: Comparison Between Experimental And A Semi-empirical Model.

Primary X-ray spectra were measured in the range of 80-150kV in order to validate a computer program based on a semiempirical model. The ratio between the characteristic and total air Kerma was considered to compare computed results and experimental data. Results show that the experimental spectra have higher first HVL and mean energy than the calculated ones. The ratios between the characteristic and total air Kerma for calculated spectra are in good agreement with experimental results for all filtrations used.

Mechanisms Of Insulin Resistance In The Amygdala: Influences On Food Intake.

Obesity is increasing worldwide and is triggered, at least in part, by enhanced caloric intake. Food intake is regulated by a complex mechanism involving the hypothalamus and hindbrain circuitries. However, evidences have showing that reward systems are also important in regulating feeding behavior. In this context, amygdala is considered a key extra-hypothalamic area regulating feeding behavior in human beings and rodents. This review focuses on the regulation of food intake by amygdala and the mechanisms of insulin resistance in this brain area. Similar to the hypothalamus the anorexigenic effect of insulin is mediated via PI3K (phosphoinositide 3-kinase)/Akt (protein kinase B) pathway in the amygdala. Insulin decreases NPY (neuropeptide Y) and increases oxytocin mRNA levels in the amygdala. High fat diet and saturated fatty acids induce inflammation, ER (endoplasmic reticulum) stress and the activation of serine kinases such as PKCθ (protein kinase C theta), JNK (c-Jun N-terminal kinase) and IKKβ (inhibitor of nuclear factor kappa-B kinase beta) in the amygdala, which have an important role in insulin resistance in this brain region. Overexpressed PKCθ in the CeA (central nucleus of amygdala) of rats increases weight gain, food intake, insulin resistance and hepatic triglycerides content. The inhibition of ER stress ameliorates insulin action/signaling, increases oxytocin and decreases NPY gene expression in the amygdala of high fat feeding rodents. Those data suggest that PKCθ and ER stress are main mechanisms of insulin resistance in the amygdala of obese rats and play an important role regulating feeding behavior.

Exercise Increases Pancreatic β-cell Viability In A Model Of Type 1 Diabetes Through Il-6 Signaling.

Type 1 diabetes (T1D) is provoked by an autoimmune assault against pancreatic β cells. Exercise training enhances β-cell mass in T1D. Here, we investigated how exercise signals β cells in T1D condition. For this, we used several approaches. Wild-type and IL-6 knockout (KO) C57BL/6 mice were exercised. Afterward, islets from control and trained mice were exposed to inflammatory cytokines (IL-1β plus IFN-γ). Islets from control mice and β-cell lines (INS-1E and MIN6) were incubated with serum from control or trained mice or medium obtained from 5-aminoimidazole-4 carboxamide1-β-d-ribofuranoside (AICAR)-treated C2C12 skeletal muscle cells. Subsequently, islets and β cells were exposed to IL-1β plus IFN-γ. Proteins were assessed by immunoblotting, apoptosis was determined by DNA-binding dye propidium iodide fluorescence, and NO(•) was estimated by nitrite. Exercise reduced 25, 75, and 50% of the IL-1β plus IFN-γ-induced iNOS, nitrite, and cleaved caspase-3 content, respectively, in pancreatic islets. Serum from trained mice and medium from AICAR-treated C2C12 cells reduced β-cell death, induced by IL-1β plus IFN-γ treatment, in 15 and 38%, respectively. This effect was lost in samples treated with IL-6 inhibitor or with serum from exercised IL-6 KO mice. In conclusion, muscle contraction signals β-cell survival in T1D through IL-6.-Paula, F. M. M., Leite, N. C., Vanzela, E. C., Kurauti, M. A., Freitas-Dias, R., Carneiro, E. M., Boschero, A. C., and Zoppi, C. C. Exercise increases pancreatic β-cell viability in a model of type 1 diabetes through IL-6 signaling.

Enhanced Glucose-induced Intracellular Signaling Promotes Insulin Hypersecretion: Pancreatic Beta-cell Functional Adaptations In A Model Of Genetic Obesity And Prediabetes.

Obesity is associated with insulin resistance and is known to be a risk factor for type-2 diabetes. In obese individuals, pancreatic beta-cells try to compensate for the increased insulin demand in order to maintain euglycemia. Most studies have reported that this adaptation is due to morphological changes. However, the involvement of beta-cell functional adaptations in this process needs to be clarified. For this purpose, we evaluated different key steps in the glucose-stimulated insulin secretion (GSIS) in intact islets from female ob/ob obese mice and lean controls. Obese mice showed increased body weight, insulin resistance, hyperinsulinemia, glucose intolerance and fed hyperglycemia. Islets from ob/ob mice exhibited increased glucose-induced mitochondrial activity, reflected by enhanced NAD(P)H production and mitochondrial membrane potential hyperpolarization. Perforated patch-clamp examination of beta-cells within intact islets revealed several alterations in the electrical activity such as increased firing frequency and higher sensitivity to low glucose concentrations. A higher intracellular Ca(2+) mobilization in response to glucose was also found in ob/ob islets. Additionally, they displayed a change in the oscillatory pattern and Ca(2+) signals at low glucose levels. Capacitance experiments in intact islets revealed increased exocytosis in individual ob/ob beta-cells. All these up-regulated processes led to increased GSIS. In contrast, we found a lack of beta-cell Ca(2+) signal coupling, which could be a manifestation of early defects that lead to beta-cell malfunction in the progression to diabetes. These findings indicate that beta-cell functional adaptations are an important process in the compensatory response to obesity.

Surgical Treatment Of Type 2 Diabetes In Subjects With Mild Obesity: Mechanisms Underlying Metabolic Improvements.

This study aims to assess the clinical and physiological effects of Roux-en-Y gastric bypass (RYGBP) on type 2 diabetes associated with mild obesity (body mass index [BMI] 30-34.9 kg/m(2)) over 24 months postsurgery. In this prospective trial, 36 mildly obese subjects (19 males) with type 2 diabetes using oral antidiabetic drugs with (n = 24) or without insulin (n = 12) underwent RYGBP. Follow-up was conducted at baseline and 3, 6, 12, and 24 months postsurgery. The following endpoints were considered: changes in HbA1c, fasting glucose and insulin, antidiabetic therapy, BMI, oral glucose insulin sensitivity [OGIS, from meal tolerance test (MTT)], beta-cell secretory function [ΔCP(0-30)/ΔGlu(0-30) (ΔC-peptide/Δglucose ratio, MTT 0-30 min), disposition index (DI = OGIS [Symbol: see text] ΔCP(0-30)/ΔGlu(0-30)], glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) [incremental area under the curve (AUCi)], adiponectin, C-reactive protein, and lipids. All subjects achieved normal-to-overweight BMI after 3 months. Over 24 months, 31/36 (86 %) subjects presented HbA1c <7 % [complete and partial remission of diabetes in 9/36 (22 %) and 1/36 (3 %), respectively]. Since 3 months postsurgery, improvements were observed in OGIS [290 (174) to 373 (77) ml/min/m(2), P = 0.009], ΔCP(0-30)/ΔGlu(0-30) [0.24 (0.19) to 0.52 (0.34) ng/mg, P = 0.001], DI [7.16 (8.53) to 19.8 (15.4) (ng/mg) (ml/min/m(2)), P = 0.001], GLP-1 AUCi [0.56 (0.64) to 3.97 (3.86) ng/dl [Symbol: see text] 10 min [Symbol: see text] 103, P = 0.000], and GIP AUCi [30.2 (12.6) to 27.0 (20.2) ng/dl [Symbol: see text] 10 min [Symbol: see text] 103, P = 0.004]. At baseline and after 12 months, subjects with diabetes nonremission had longer diabetes duration, higher HbA1c, lower beta-cell secretory function, and higher first 30-min GIP AUCi, compared with those with remission. RYGBP improves the glucose metabolism in subjects with type 2 diabetes and mild obesity. This effect is associated with improvement of insulin sensitivity, beta-cell secretory function, and incretin secretion.

Pollination Ecology Of Two Species Of Elleanthus (orchidaceae): Novel Mechanisms And Underlying Adaptations To Hummingbird Pollination.

Relationships among floral biology, floral micromorphology and pollinator behaviour in bird-pollinated orchids are important issues to understand the evolution of the huge flower diversity within Orchidaceae. We aimed to investigate floral mechanisms underlying the interaction with pollinators in two hummingbird-pollinated orchids occurring in the Atlantic forest. We assessed floral biology, nectar traits, nectary and column micromorphologies, breeding systems and pollinators. In both species, nectar is secreted by lip calli through spaces between the medial lamellar surfaces of epidermal cells. Such form of floral nectar secretion has not been previously described. Both species present functional protandry and are self-compatible yet pollinator-dependent. Fruit sets in hand-pollination experiments were more than twice those under natural conditions, evidencing pollen limitation. The absence of fruit set in interspecific crosses suggests the existence of post-pollination barriers between these synchronopatric species. In Elleanthus brasiliensis, fruits resulting from cross-pollination and natural conditions were heavier than those resulting from self-pollination, suggesting advantages to cross-pollination. Hummingbirds pollinated both species, which share at least one pollinator species. Species differences in floral morphologies led to distinct pollination mechanisms. In E. brasiliensis, attachment of pollinaria to the hummingbird bill occurs through a lever apparatus formed by an appendage in the column, another novelty to the knowledge of orchids. In E. crinipes, pollinaria attachment occurs by simple contact with the bill during insertion into the flower tube, which fits tightly around the bill. The novelties described here illustrate the overlooked richness in ecology and morphophysiology in Orchidaceae. This article is protected by copyright. All rights reserved.

The Biopsychosocial Spiritual Model Applied To The Treatment Of women With Breast Cancer, Through Rime Intervention (relaxation, mental Images, Spirituality).

This postdoctoral study on the application of the RIME intervention in women that had undergone mastectomy and were in treatment, aimed to promote psychospiritual and social transformations to improve the quality of life, self-esteem and hope. A total of 28 women participated and were randomized into two groups. Brief Psychotherapy (PB) (average of six sessions) was administered in the Control Group, and RIME (three sessions) and BP (average of five sessions) were applied in the RIME Group. The quantitative results indicated a significant improvement (38.3%) in the Perception of Quality of Life after RIME according to the WHOQOL, compared both to the BP of the Control Group (12.5%), and the BP of the RIME Group (16.2%). There was a significant improvement in Self-esteem (Rosenberg) after RIME (14.6%) compared to the BP of the Control Group (worsened 35.9%), and the BP of the RIME Group (8.3%). The improvement in well-being, considering the focus worked on (Visual Analog Scale), was significant in the RIME Group (bad to good), as well as in the Control Group (unpleasant to good). The qualitative results indicated that RIME promotes creative transformations in the intrapsychic and interpersonal dimensions, so that new meanings and/or new attitudes emerge into the consciousness. It was observed that RIME has more strength of psychic structure, ego strengthening and provides a faster transformation that BP, therefore it can be indicated for crisis treatment in the hospital environment.

Reduction Of Oxidative Damage And Inflammatory Response In The Diaphragm Muscle Of Mdx Mice Using Iron Chelator Deferoxamine.

Oxidative stress and inflammatory processes strongly contribute to pathogenesis in Duchenne muscular dystrophy (DMD). Based on evidence that excess iron may increase oxidative stress and contribute to the inflammatory response, we investigated whether deferoxamine (DFX), a potent iron chelating agent, reduces oxidative stress and inflammation in the diaphragm (DIA) muscle of mdx mice (an experimental model of DMD). Fourteen-day-old mdx mice received daily intraperitoneal injections of DFX at a dose of 150 mg/kg body weight, diluted in saline, for 14 days. C57BL/10 and control mdx mice received daily intraperitoneal injections of saline only, for 14 days. Grip strength was evaluated as a functional measure, and blood samples were collected for biochemical assessment of muscle fiber degeneration. In addition, the DIA muscle was removed and processed for histopathology and Western blotting analysis. In mdx mice, DFX reduced muscle damage and loss of muscle strength. DFX treatment also resulted in a significant reduction of dystrophic inflammatory processes, as indicated by decreases in the inflammatory area and in NF-κB levels. DFX significantly decreased oxidative damage, as shown by lower levels of 4-hydroxynonenal and a reduction in dihydroethidium staining in the DIA muscle of mdx mice. The results of the present study suggest that DFX may be useful in therapeutic strategies to ameliorate dystrophic muscle pathology, possibly via mechanisms involving oxidative and inflammatory pathways.

Partial-hepatectomized (70%) Model Shows A Correlation Between Hepatocyte Growth Factor Levels And Beta-cell Mass.

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Key Endothelial Cell Angiogenic Mechanisms Are Stimulated By The Circulating Milieu In Sickle Cell Disease And Attenuated By Hydroxyurea.

As hypoxia-induced inflammatory angiogenesis may contribute to sickle cell disease manifestations, we compared the angiogenic molecular profiles of plasma from sickle cell disease individuals and correlated these with in vitro endothelial cell-mediated angiogenesis-stimulating activity and in vivo neovascularization. Bioplex demonstrated that plasma from steady-state sickle cell anemia patients presented elevated concentrations of pro-angiogenic factors (Angiopoietin-1, basic fibroblast growth factor, vascular endothelial growth factor, vascular endothelial growth factor-D and placental growth factor) and displayed potent pro-angiogenic activity, significantly augmenting endothelial cell proliferation, migration and capillary-like structure formation. In vivo neovascularization of Matrigel plugs was significantly greater in sickle cell disease mice, compared with non-sickle cell disease mice, consistent with an upregulation of angiogenesis in the disease. In plasma from patients with hemoglobin SC disease without proliferative retinopathy, anti-angiogenic endostatin and thrombospondin-2 were significantly elevated. In contrast, plasma from hemoglobin SC individuals with proliferative retinopathy displayed a pro-angiogenic profile and had more significant effects on endothelial cell proliferation and capillary formation than plasma of patients without retinopathy. Hydroxyurea therapy was associated with significant reductions in plasma angiogenic factor profile, in association with an inhibition of endothelial cell-mediated angiogenic mechanisms and neovascularization. Thus, sickle cell anemia and retinopathic hemoglobin SC individuals present a highly angiogenic circulating milieu, capable of stimulating key endothelial cell-mediated angiogenic mechanisms. Combination anti-angiogenic therapy for preventing progression of unregulated neovascularization and associated manifestations in sickle cell disease, such as pulmonary hypertension, may be indicated; furthermore, the benefits and drawbacks of the potent anti-angiogenic effects of hydroxyurea should be clarified.

Interaction Between Fiscal And Monetary Policy In A Dynamic Nonlinear Model.

The objective of this study is to verify the dynamics between fiscal policy, measured by public debt, and monetary policy, measured by a reaction function of a central bank. Changes in monetary policies due to deviations from their targets always generate fiscal impacts. We examine two policy reaction functions: the first related to inflation targets and the second related to economic growth targets. We find that the condition for stable equilibrium is more restrictive in the first case than in the second. We then apply our simulation model to Brazil and United Kingdom and find that the equilibrium is unstable in the Brazilian case but stable in the UK case.

Enhanced D1 And D2 Inhibitions Induced By Low-frequency Trains Of Conditioning Stimuli: Differential Effects On H- And T-reflexes And Possible Mechanisms.

Mechanically evoked reflexes have been postulated to be less sensitive to presynaptic inhibition (PSI) than the H-reflex. This has implications on investigations of spinal cord neurophysiology that are based on the T-reflex. Preceding studies have shown an enhanced effect of PSI on the H-reflex when a train of ~10 conditioning stimuli at 1 Hz was applied to the nerve of the antagonist muscle. The main questions to be addressed in the present study are if indeed T-reflexes are less sensitive to PSI and whether (and to what extent and by what possible mechanisms) the effect of low frequency conditioning, found previously for the H-reflex, can be reproduced on T-reflexes from the soleus muscle. We explored two different conditioning-to-test (C-T) intervals: 15 and 100 ms (corresponding to D1 and D2 inhibitions, respectively). Test stimuli consisted of either electrical pulses applied to the posterior tibial nerve to elicit H-reflexes or mechanical percussion to the Achilles tendon to elicit T-reflexes. The 1 Hz train of conditioning electrical stimuli delivered to the common peroneal nerve induced a stronger effect of PSI as compared to a single conditioning pulse, for both reflexes (T and H), regardless of C-T-intervals. Moreover, the conditioning train of pulses (with respect to a single conditioning pulse) was proportionally more effective for T-reflexes as compared to H-reflexes (irrespective of the C-T interval), which might be associated with the differential contingent of Ia afferents activated by mechanical and electrical test stimuli. A conceivable explanation for the enhanced PSI effect in response to a train of stimuli is the occurrence of homosynaptic depression at synapses on inhibitory interneurons interposed within the PSI pathway. The present results add to the discussion of the sensitivity of the stretch reflex pathway to PSI and its functional role.