Predictive Ability of Serum Amino Acid Levels to Differentiate Fibromyalgia Patients from Healthy Subjects.

BACKGROUND: Fibromyalgia is a complex illness to diagnose and treat. OBJECTIVES: To evaluate a broad range of circulating free amino acid (AA) levels in fibromyalgia patients as well as the ability of the AAs to differentiate fibromyalgia patients from healthy subjects. DESIGN: We carried out a case-control study to evaluate AA levels in 62 patients with fibromyalgia and 78 healthy subjects. This study adheres to the STROBE guidelines. METHODS: AAs content was assayed by HPLC in serum samples. The predictive value of AA levels in fibromyalgia was determined by receiver operating characteristic (ROC) curve and forward binary logistic regression analyses. RESULTS: Fibromyalgia patients showed higher serum levels of aspartic acid, glutamic acid, aminoadipic acid, asparagine, histidine, 3-methyl-histidine, 5-methyl-histidine, glycine, threonine, taurine, tyrosine, valine, methionine, isoleucine, phenylalanine, leucine, ornithine, lysine, branched chain AAs (BCAAs), large neutral AAs, essential AAs (EAAs), non-essential AAs (NEAAs), basic AAs, EAAs/NEAAs ratio, phenylalanine/tyrosine ratio, and global arginine bioavailability ratio than the controls. Serum alanine levels were lower in patients than in controls. According to ROC analysis, most of these AAs may be good markers for differentiating individuals with fibromyalgia from healthy subjects. Results of logistic regression showed that the combination of glutamic acid, histidine, and alanine had the greatest predictive ability to diagnose fibromyalgia. CONCLUSIONS: Our results show an imbalance in serum levels of most AAs in patients with fibromyalgia, which suggest a metabolic disturbance. The determination of serum levels of these AAs may aid in the diagnosis of fibromyalgia, in combination with clinical data of the patient.

Single-Stage Immediate Breast Reconstruction with Acellular Dermal Matrix after Breast Cancer: Comparative Study and Evaluation of Breast Reconstruction Outcomes.

We evaluate postoperative complications, aesthetic results and satisfaction outcomes in patients with breast cancer after intervening with a skin-sparing or nipple-sparing mastectomy with an immediate prosthetic reconstruction with or without a biological mesh. Patients with multifocal breast cancer, ductal carcinoma in situ with an indication for a mastectomy and cT2 tumors with no response to primary systemic treatment were included, whereas patients aged >75 years, with inflammatory carcinoma, and severe circulatory disorders were excluded. Patients in the control group were reconstructed using a prosthesis, whereas the study group included patients reconstructed using a prosthesis and biological acellular porcine dermal mesh (Strattice™). In both groups, the result was assessed using the BREAST-Q instrument. A total of 51 patients (62 intervened breasts) were included in the study group and 38 patients (41 intervened breasts) in the control group. Implant loss and removal occurred in three patients in the study group (5.9%) and nine patients in the control group (24.3%; p = 0.030). Infections appeared in three patients in the study group (4.8%) and three patients in the control group (7.3%; p = 1.00). Skin necrosis appeared in 5 patients in the study group (12.2%) and 11 patients in the control group (21.6%; p = 0.367). Seroma appeared in five patients in the study group (12.2%) and five patients in the control group (8.1%; p = 0.514). The BREAST-Q questionnaire is a comparison between both groups regarding "satisfaction with breasts after surgery" (p = 0.026), "sexual well-being after intervention" (p = 0.010) and "satisfaction with the information received" (p = 0.049). We have noted a statistically significant decrease in implant loss in women receiving an implant with a biological mesh. A higher satisfaction was observed in patients reconstructed using Strattice™, with statistically significant differences in three items.

Glutathione Peroxidase gpx1 to gpx8 Genes Expression in Experimental Brain Tumors Reveals Gender-Dependent Patterns.

Extensive research efforts in the field of brain tumor studies have led to the reclassification of tumors by the World Health Organization (WHO) and the identification of various molecular subtypes, aimed at enhancing diagnosis and treatment strategies. However, the quest for biomarkers that can provide a deeper understanding of tumor development mechanisms, particularly in the case of gliomas, remains imperative due to their persistently incurable nature. Oxidative stress has been widely recognized as a key mechanism contributing to the formation and progression of malignant tumors, with imbalances in antioxidant defense systems being one of the underlying causes for the excess production of reactive oxygen species (ROS) implicated in tumor initiation. In this study, we investigated the gene expression patterns of the eight known isoforms of glutathione peroxidase (GPx) in brain tissue obtained from male and female control rats, as well as rats with transplacental ethyl nitrosourea (ENU)-induced brain tumors. Employing the delta-delta Ct method for RT-PCR, we observed minimal expression levels of gpx2, gpx5, gpx6, and gpx7 in the brain tissue from the healthy control animals, while gpx3 and gpx8 exhibited moderate expression levels. Notably, gpx1 and gpx4 displayed the highest expression levels. Gender differences were not observed in the expression profiles of these isoforms in the control animals. Conversely, the tumor tissue exhibited elevated relative expression levels in all isoforms, except for gpx4, which remained unchanged, and gpx5, which exhibited alterations solely in female animals. Moreover, except for gpx1, which displayed no gender differences, the relative expression values of gpx2, gpx3, gpx6, gpx7, and gpx8 were significantly higher in the male animals compared to their female counterparts. Hence, the analysis of glutathione peroxidase isoforms may serve as a valuable approach for discerning the behavior of brain tumors in clinical settings.

Physiopathology of Osteoporosis: Nursing Involvement and Management.

Osteoporosis is a major public health problem today. We are facing an aging society where the average life expectancy continues to increase. Osteoporosis affects more than 30% of postmenopausal women due to hormonal changes that occur during this time. Postmenopausal osteoporosis is therefore of particular concern. The aim of this review is to identify the etiology, pathophysiology, diagnosis and treatment of this disease and lay the foundation for the role nurses should play in preventing postmenopausal osteoporosis. Several risk factors are associated with osteoporosis. In addition to age and sex, genetics, ethnicity, diet, or the presence of other disorders determine the development of this disease. The key factors include exercise, a balanced diet, and high levels of vitamin D. This is primarily from a solar source, and infancy is the time when future bone formation is greatest. There are now medications that can complement these preventive measures. The work of nursing staff is not only prevention, but also early detection and early treatment. In addition, imparting information and knowledge about the disease to the population is key to preventing an osteoporosis epidemic. In this study, a detailed description is provided of the biological and physiological disease, the preventive measures currently being researched, the information currently available to the population, and how health professionals address osteoporosis from a preventive perspective.

Suicide, neuroinflammation and other physiological alterations.

Suicide is considered one of the major public health problems worldwide, being the second leading cause of death in the 15-29 age group. It is estimated that every 40s someone in the world commits suicide. The social taboo surrounding this phenomenon as well as the fact that suicide prevention measures currently fail to avoid deaths from this cause, means that more research is needed to understand its mechanisms. The present narrative review on suicide tries to point out several important aspects, such as risk factors or the dynamics of suicide, as well as the current findings in the field of physiology that could offer advances in the understanding of suicide. Subjective measures of risk such as scales and questionnaires are not effective alone, whereas the objective measures can be addressed from physiology. Thus, an increased neuroinflammation in people who take their own lives has been found, with an increase in inflammatory markers such as interleukin-6 and other cytokines in plasma or cerebrospinal fluid. Also, the hyperactivity of the hypothalamic-pituitary-adrenal axis and a decrease in serotonin or in vitamin D levels seems to also be involved. In conclusion, this review could help to understand which factors can trigger an increased risk of dying by suicide, as well as pointing out those alterations that occur in the body when someone attempt to commit suicide or succeeds in taking their own life. There is a need for more multidisciplinary approaches that address suicide to help to raise awareness of the relevance of this problem that causes the death of thousands of people every year.

Correlation between Biomarkers of Pain in Saliva and PAINAD Scale in Elderly People with Cognitive Impairment and Inability to Communicate.

The pain assessment in advanced dementia (PAINAD) appears to be a clinically useful tool. However, the salivary determination of tumor necrosis factor receptor type II (sTNF-RII) and secretory IgA (sIgA) as pain biomarkers is still incipient. The aim was to correlate the PAINAD score with sTNF-RII and sIgA biomarker levels in the saliva of patients with advanced dementia. In this regard, a cross-sectional study was conducted. The sample consisted of 75 elderly patients with a clinical diagnosis of dementia and a global deterioration scale (GDS) score of 5 to 7. The PAINAD scale was determined by a previously trained professional and the collection of salivary samples was performed using the passive secretion method. Human sTNF-RII and sIgA using ELISA kits. The results showed a correlation between the PAINAD scale (numeric, binary, and recoded) and sTNF-RII and sIgA (p < 0.001). No association between the sociodemographic and clinical variables and the PAINAD scale was found (p > 0.05). Between 97.3% and 96.2% of patients with pain on the PAINAD scale also showed pain based on the sTNF-RII levels; in all of them, sIgA levels did not fit the logistic models. Therefore, the correlation highlights the usefulness of this scale and confirms the usefulness of sTNF-RII and sIgA as biomarkers of pain.

Associations Among Nitric Oxide and Enkephalinases With Fibromyalgia Symptoms.

BACKGROUND: Fibromyalgia (FM) is a complex syndrome of uncertain etiology, characterized by the presence of widespread pain. Both nitric oxide and enkephalinases modulate pain perception. OBJECTIVES: The aim of this study was to evaluate the relationships among serum nitric oxide levels, oxytocinase activity, and enkephalin-degrading aminopeptidase (EDA) activity with pain-related clinical manifestations in women with FM. METHODS: We performed an observational case study in a population of 58 women diagnosed with FM. Serum nitric oxide levels were analyzed by an ozone chemiluminescence-based assay. Both serum oxytocinase and EDA activities were fluorometrically determined. Pain threshold and pain magnitude were evaluated using the PainMatcher. The pressure pain thresholds were measured using a digital pressure algometer. We used a visual analog scale, the Central Sensitization Inventory, the Revised Fibromyalgia Impact Questionnaire, and the Beck Anxiety Inventory to assess the global level of pain, the symptoms associated with the central sensitization syndrome, the severity of FM, and the anxiety level, respectively. RESULTS: Multiple linear regression analysis adjusted by age, body mass index, and menopause status revealed significant associations between nitric oxide levels and dominant occiput pressure pain thresholds, nondominant occiput pressure pain thresholds, and FM effects. Significant associations of oxytocinase activity with the visual analog scale and dominant knee pressure pain thresholds were also found. Moreover, results showed a significant association between high EDA activity levels and dominant second-rib pressure pain thresholds. DISCUSSION: Our data have shown significant relationships of serum nitric oxide levels and oxytocinase and EDA activities with some body pressure pain thresholds, the daily activity level, and the global intensity of pain in women with FM. These results suggest that pain, which is the main symptom of this syndrome, may be related to alterations in nitric oxide levels and in oxytocinase and EDA activities in patients with FM.

Circulating levels of ß-endorphin and cortisol in breast cancer.

Neurobehavioral stress can promote the growth and progression of different types of cancer because psychological factors can alter immune and endocrine function. ß-endorphin is one of the hormones involved in the bidirectional connection between the immune and neuroendocrine systems that explains the effects of stress on the immune capacity against cancer. Breast cancer (BC) is the most common type of cancer in women and one of the best known to influence the different stressors involved in coping with the disease. Here we evaluated the circulating levels of ß-endorphin and cortisol in premenopausal and postmenopausal women with BC treated or not with neoadjuvant chemotherapy, to understand the neuroendocrine basis that explain the relationship between stress and the development of the disease. In our hands, healthy women show elevated levels of ß-endorphin, levels that are even higher in postmenopausal women. In women with BC, however, significantly lower levels appear, with no differences between premenopausal and postmenopausal women. These data correlate with cortisol levels, which are much higher in women with BC regardless of their hormonal status. Neoadjuvant chemotherapy treatment only improves ß-endorphin levels in postmenopausal women, without recovering the levels of healthy women. In women treated with neoadjuvant chemotherapy, both premenopausal and postmenopausal maintain elevated cortisol levels that are indicative of the stressful situation. Regulation of stress levels by modulation with ß-endorphin could be an alternative pharmacological therapy against tumor growth and development, as well as its ability to promote in patients feelings of well-being that improve the development of their disease.

Putative Involvement of Endocrine Disruptors in the Alzheimer's Disease Via the Insulin-Regulated Aminopeptidase/GLUT4 Pathway.

It has been well established that there is a connection between type II diabetes (DMTII) and Alzheimer's disease (AD). In fact, the increase in AD incidence may be an emerging complication of DMTII. Both pathologies are related to estradiol (E2) exposure; on the one hand, estrogen receptors (ER) are emerging as important modulators of glucose homeostasis through ß-pancreatic cell function; on the other hand, brain bioenergetic and cognitive deficits have been related to the down regulation of brain ERs, contributing to women ageing and AD susceptibility, both related to the reduction in estradiol levels and the deficits in brain metabolism. Here we discuss that environmental contaminants with estrogenic capacity such as bisphenol A (BPA) could develop pharmacological effects similar to those of E2, which could affect ß-pancreatic cell function by increasing the biosynthesis of glucose-induced insulin after extranuclear ER binding. BPA-induced hyperinsulinemia would promote the translocation of glucose transporter 4 (GLUT4), which is located next to insulin-regulated aminopeptidase (IRAP) in intracellular vesicles. In insulin-responsive tissues, IRAP and GLUT 4 are routed together to the cell surface after insulin stimulation. IRAP is also the angiotensin IV (AngIV) receptor, and AngIV associates the brain renin-angiotensin system (bRAS) with AD, since AngIV is related to learning, memory, emotional responses, and processing of sensory information not only through its inhibitory effect on IRAP but also through the stimulation of glucose uptake by increasing the presence of IRAP/GLUT4 at the cell surface. Thus, the IRAP/GLUT4 pathway is an emerging target for pharmacological intervention against AD.

Moderate Beer Consumption Modifies Tumoral Growth Parameters and Pyrrolidone Carboxypeptidase Type-I and Type-II Specific Activities in the Hypothalamus-Pituitary-Mammary Gland Axis in an Animal Model of Breast Cancer.

AIMS: To determine the effect of moderate alcoholic and nonalcoholic beer consumption on tumoral growth parameters, the histopathology, pyrrolidone carboxypeptidase type I (Pcp I), and type II (Pcp II) specific activities in the hypothalamus-pituitary-mammary gland axis, and the circulating levels of estradiol (E2) and progesterone (P4) in rats with N-methyl-N-nitrosourea (NMU) induced mammary tumors. MATERIAL AND METHODS: Food and drink intake, weight gain and tumor growth parameters were collected. The malignant phenotype of the tumor was performed using the Scarff-Bloom-Richardson grading method. Pcp specific activities were fluorometrically analyzed using pyroglutamyl-ß-naphthylamide as substrate. Circulating steroid hormones were determined. RESULTS: Differences were found in tumoral parameters, depending on the drink. Animals that were given alcohol-containing beer (A/C) beer to drink showed the lowest values of hypothalamic Pcp I, in association with the lowest levels of circulating E2. The significant decrease in Pcp I activity in all NMU-treated groups suggest a clear role of the Pcp I in the tumoral process, and A/C beer interferes with it. DISCUSSION: Moderate consumption of alcoholic beer would have beneficial effects against mammary tumors through the modification of the endocrine status mediated by GnRH due to changes on Pcp I and II activities at different levels.

Insulin-Regulated Aminopeptidase in Women with Breast Cancer: A Role beyond the Regulation of Oxytocin and Vasopressin.

Insulin-regulated aminopeptidase (IRAP) is the only enzyme known to cleave oxytocin and vasopressin; however, it is also the high-affinity binding site for angiotensin IV (AngIV) receptor type 4 (AT4) ligands and it is related to insulin-dependent glucose transporters through the translocation of the glucose transporter type 4 (GLUT4). Previous studies have demonstrated an association between IRAP activity and the number and size of mammary tumors in an animal model of breast cancer (BC). Also, a highly significant increase in IRAP activity has been found in BC tissue from women patients. Here, we found no changes in circulating IRAP in premenopausal (preMP) women, but it increased significantly in postmenopausal (postMP) women not treated with neoadjuvant chemotherapy (NACH). However, in women treated with NACH, IRAP activity increased in both preMP and postMP women. Two years of follow-up indicated lower levels of IRAP activity in untreated preMP women, but a return to control levels in untreated postMP women, while IRAP activity returned to control levels in women treated with NACH. Circulating oxytocin decreased in both preMP and postMP women during the follow-up period. Differences in Oxytocin appeared between preMP and postMP women treated with NACH, but not in women who were not treated with NACH. On the contrary, circulating vasopressin increased in untreated and treated preMP and postMP women, with most of the differences related to the hormonal status as well as the neoadjuvant treatment during the two year follow-up We propose that IRAP is involved in mechanisms related not only to oxytocin and/or vasopressin regulation, but also to the local mammary RAS through AngIV and its role in glucose transportation through the IRAP/GLUT4 system.

Neoadjuvant chemotherapy modifies serum pyrrolidone carboxypeptidase specific activity in women with breast cancer and influences circulating levels of GnRH and gonadotropins.

PURPOSE: Functional studies have demonstrated that gonadotropin-releasing hormone (GnRH) regulates cell proliferation, apoptosis, and tissue remodeling. GnRH is metabolized by the proteolytic regulatory enzyme pyrrolidone carboxypeptidase (Pcp) (E.C. 3.4.19.3), which is an omega peptidase widely distributed in fluids and tissues. We previously reported a decrease in both rat and human Pcp activity in breast cancer, suggesting that GnRH may be an important local hormonal factor in the pathogenesis of breast cancer. Recently, we have described that postmenopausal women with breast cancer show lower levels of serum Pcp activity than control postmenopausal women. To determine the effect of neoadjuvant chemotherapy (NACT) on serum Pcp specific activity and circulating levels of GnRH, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and steroid hormones 17-ß-estradiol and progesterone in pre- and postmenopausal women diagnosed with infiltrating ductal carcinoma. METHODS: Serum Pcp activity was measured fluorometrically using pyroglutamyl-ß-naphthylamide. Circulating GnRH levels were dosed using a commercial RIA kit. Circulating LH and FSH levels were measured by enzyme immunoassays. Levels of steroid hormones were measured in serum samples by dissociation-enhanced lanthanide fluorescence immunoassay. RESULTS AND CONCLUSION: Our results show the effect of NACT on the hypothalamic-pituitary axis, with the consequent alteration of circulating gonadotropins in premenopausal women with breast cancer. However, the results obtained in postmenopausal women with breast cancer treated with NACT, that is, the significant decrease in the concentration of GnRH and FSH compared to control postmenopausal women, differ from those obtained for premenopausal women. The only difference between pre- and postmenopausal women is their hormonal profile at the beginning of the study, that is, the presence of menopause and the consequent alteration of the hypothalamic-pituitary-gonadal axis.

Altered Serum Oxytocinase and Enkephalin-Degrading Aminopeptidase Activities in Patients With Fibromyalgia.

OBJECTIVES: Fibromyalgia (FM) is a chronic pain condition of unclear etiology. We have analyzed, for the first time, the activity of a broad spectrum of aminopeptidases (APs) in patients with FM and controls to investigate whether they are involved in the pathophysiology of this syndrome. METHOD: In this case-control study, we fluorometrically measured specific AP activities in serum samples of 75 patients with FM and 29 healthy controls. The predictive value of AP activities in FM was determined by receiver operating characteristic (ROC) analysis. RESULTS: Oxytocinase activity was higher in patients with FM than in controls (p < .001). A subgroup of patients with FM (n = 18; 24%) showed low levels of enkephalin-degrading aminopeptidase (EDA) activity when compared with the healthy controls (p < .001) and with the rest of FM patients (p < .001). There were no significant differences in the activity levels of aminopeptidase A, aminopeptidase B, aspartyl aminopeptidase, insulin-regulated aminopeptidase, pyroglutamyl aminopeptidase, or aminopeptidase N between FM patients and controls. According to ROC analysis, oxytocinase activity may be a good marker for differentiating individuals with FM from healthy subjects. CONCLUSIONS: Our findings show that serum oxytocinase activity is increased in patients with FM, which could alter the metabolism of peptides with analgesic effects such as oxytocin and enkephalins. The determination of serum oxytocinase activity may aid in FM diagnosis. Additionally, we have identified a subpopulation of FM patients with abnormally low serum EDA activity.

The Delicate Equilibrium between Oxidants and Antioxidants in Brain Glioma.

Gliomas are the most frequent brain tumors in the adult population and unfortunately the adjuvant therapies are not effective. Brain tumorigenesis has been related both to the increased levels of free radicals as inductors of severe damages in healthy cells, but also with the reduced response of endogenous enzyme and non-enzymatic antioxidant defenses. In turn, both processes induce the change to malignant cells. In this review, we analyzed the role of the imbalance between free radicals production and antioxidant mechanism in the development and progression of gliomas but also the influence of redox status on the two major distinctive forms of programmed cell death related to cancer: apoptosis and autophagy. These data may be the reference to the development of new pharmacological options based on redox microenvironment for glioma treatment.

Differential Effects of Doxazosin on Renin-Angiotensin-System- Regulating Aminopeptidase Activities in Neuroblastoma and Glioma Tumoral Cells.

BACKGROUND: It has been described that doxazosin, an antihypertensive drug, also promotes glioblastoma cells death by inhibiting cell proliferation, arresting cell cycle and inducing apoptosis. Doxazosin has also demonstrated several modulator effects on renin-angiotensin system (RAS)- regulating aminopeptidase activities, which are highly involved in tumor growth in experimental glioma. Therefore, it remains to elucidate if the anti-tumoral effects of doxazosin could also be mediated by the proteolytic regulatory components of the RAS. OBJECTIVE: To analyze the effects of doxazosin on cell growth and on RAS-regulating proteolytic regulatory aspartyl aminopeptidase (ASAP), aminopeptidase A (APA), aminopeptidase N (APN), aminopeptidase B (APB) and insulin-regulated aminopeptidase (IRAP) specific activities in the human neuroblastoma NB69 and astroglioma U373-MG tumoral cell lines. METHODS: Human neuroblastoma NB69 and astroglioma U373-MG cell lines were treated with doxazosin 50-500 µM for 24h or 48h. The effects on cell growth and on RAS-regulating aminopeptidase specific activities were analyzed. RESULTS: Doxazosin treatments promote a concentration-dependent inhibition on cell growth in both NB69 and U373-MG cells, being NB69 cells more sensitive to the drug than U373-MG cells. However, its effects on RAS-regulating aminopeptidase specific activities depend on the concentration used, the duration of the treatment and the cell type. These data confirm the existence of a different dynamic progression of RAS cascade in each tumoral cell line as a consequence of the treatment with doxazosin and time of action, which also implies a very dynamic metabolism of the peptides which participate in each step of RAS cascade. CONCLUSION: Our results indicate that doxazosin modifies the proteolytic regulatory enzymes of RAS cascade, modulating the bioactive efficacy of the different angiotensin peptides, and therefore, of their functional roles as initiators/promoters of cell proliferation as autocrine/paracrine mediators.

Circulating renin-angiotensin system-regulating specific aminopeptidase activities in pre- and post- menopausal women with breast cancer treated or not with neoadyuvant chemotherapy. A two years follow up study.

We have previously described changes in several circulating renin-angiotensin system (RAS)-regulating aminopeptidase activities in pre- and postmenopausal women with breast cancer treated or not with neoadjuvant chemotherapy. Women with breast cancer presented a reduced catabolism of angiotensin II (AngII) when compared to healthy individuals, although specific enzyme activities were different between pre- and post- menopausal women. In addition, neoadjuvant chemotherapy in breast cancer patients caused changes in aminopeptidase activities leading to increased AngII catabolism independently of hormonal status. Here we extend the aminopeptidase analysis to three time points of the patient follow-up (6, 12, and 24 months). No changes occur in enzyme activities during this time period and the effects of therapy remain unaltered overtime both in pre- and in postmenopausal women.

Gender Differences in the Antioxidant Response to Oxidative Stress in Experimental Brain Tumors.

BACKGROUND: Brain tumorigenesis is related to oxidative stress and a decreased response of antioxidant defense systems. As it is well known that gender differences exist in the incidence and survival rates of brain tumors, it is important to recognize and understand the ways in which their biology can differ. OBJECTIVE: To analyze gender differences in redox status in animals with chemically-induced brain tumors. METHODS: Oxidative stress parameters, non-enzyme and enzyme antioxidant defense systems are assayed in animals with brain tumors induced by transplacental N-ethyl-N-nitrosourea (ENU) administration. Both tissue and plasma were analyzed to know if key changes in redox imbalance involved in brain tumor development were reflected systemically and could be used as biomarkers of the disease. RESULTS: Several oxidative stress parameters were modified in tumor tissue of male and female animals, changes that were not reflected at plasma level. Regarding antioxidant defense system, only glutathione (GSH) levels were decreased in both brain tumor tissue and plasma. Superoxide dismutase (SOD) and catalase (CAT) activities were decreased in brain tumor tissue of male and female animals, but plasma levels were only altered in male animals. However, different protein and mRNA expression patterns were found for both enzymes. On the contrary, glutathione peroxidase (GPx) activity showed increased levels in brain tumor tissue without gender differences, being protein and gene expression also increased in both males and female animals. However, these changes in GPx were not reflected at plasma level. CONCLUSION: We conclude that brain tumorigenesis was related to oxidative stress and changes in brain enzyme and non-enzyme antioxidant defense systems with gender differences, whereas plasma did not reflect the main redox changes that occur at the brain level.

Catecholamine and Indolamine Pathway: A Case-Control Study in Fibromyalgia.

OBJECTIVES: Fibromyalgia (FM) is a complex syndrome characterized by widespread pain. Its etiology is unclear, and diagnosis is difficult. The aim of this study was to assess plasma levels of monoamine neurotransmitters (catecholamines, indolamines, and intermediate metabolites) in patients with FM and healthy controls to investigate possible alterations in the metabolism of these molecules in FM. We also examined potential relationships between monoamine neurotransmitters and clinical features of FM. The predictive value of these molecules in FM was determined by receiver operating characteristic analysis. METHOD: We measured plasma catecholamines (epinephrine, norepinephrine, and dopamine), as well as indolamines and intermediary metabolites (serotonin or 5-hydroxytryptamine [5-HT], 5-hydroxyindolacetic acid [5-HIAA], 5-hydroxytryptophan [5-HTP], and N-acetyl-5-hydroxytryptamine [Nac-5-HT]) in 35 women with FM and 12 age-matched healthy women. RESULTS: Higher levels of norepinephrine and lower levels of dopamine, 5-HT, 5-HIAA, and 5-HTP were found in women with FM in comparison with controls. Epinephrine and Nac-5-HT levels did not differ significantly between groups. Higher norepinephrine levels were associated with worse physical health status in FM patients. Also, plasma norepinephrine levels > 694.69 pg/ml might be an accurate predictor of FM. CONCLUSIONS: These findings show evidence of the dysregulation of the catecholamine and indolamine pathway in patients with FM, which may contribute to the physiopathology of this syndrome. In addition, the determination of plasma norepinephrine levels could help in the FM diagnosis.

Anti-Inflammatory and Antitumor Effects of Hydroxytyrosol but Not Oleuropein on Experimental Glioma In Vivo. A Putative Role for the Renin-Angiotensin System.

Functional roles of the angiotensin peptides of the renin-angiotensin system (RAS) cascade can be analyzed through their corresponding proteolytic regulatory enzymes aspartyl aminopeptidase (ASAP), aminopeptidase A (APA), aminopeptidase B (APB), aminopeptidase N (APN) and insulin-regulated aminopeptidase (IRAP). These enzyme activities generate active or inactive angiotensin peptides that alter the ratios between their bioactive forms, regulating several important processes such as the regulation of cardiovascular functions, body water regulation, normal memory consolidation and retrieval, but also cell growth, differentiation and apoptosis or the inflammatory response. We have previously described that the treatment with hydroxytyrosol but not with oleuropein or with the mixture of both compounds led to the significant inhibition of tumor growth in an in vivo glioma model by mechanisms not only related to redox balance. Using this glioma model, here we analyze the effects of the phenolic compounds oleuropein and hydroxytyrosol in circulating RAS-regulating ASAP, APA, APN, APB and IRAP specific activities and the pro-inflammatory cytokines IL-6 and TNFα to understand the relationship between the antitumor and anti-inflammatory effects of hydroxytyrosol, but not oleuropein, and the components of the RAS. We found that oleuropein increased all the activities analyzed and promoted a pro-inflammatory status, whereas hydroxytyrosol only modified ASAP and IRAP activities and promotes an anti-inflammatory status. When administrated together, oleuropein overrode the effects of hydroxytyrosol. Our results suggest a role for angiotensin III and angiotensin 1-7 in both tumor growth inhibition and anti-inflammatory response promoted by hydroxytyrosol.

Redox status in the sentinel lymph node of women with breast cancer.

BACKGROUND: Lymphatic metastasis is regulated in multiple steps including the transit of tumor cells via the lymphatic vessels and the successful seeding in draining lymph nodes. Thus, several molecular signals and cellular changes must be involved in this complex process to facilitate tumor cell entry, colonization, and survival in the lymph node. To our knowledge, the present work explores, for the first time in the literature, the redox status (oxidative stress parameters and enzymatic and non-enzymatic antioxidant defense systems) in the sentinel lymph node (SLN) of women with breast cancer. PATIENTS AND METHODS: SLNs from 75 women with breast cancer were identified using the one-step nucleic acid amplification (OSNA) method as negative (n = 43), with micrometastases (n = 13), or with macrometastases (n = 19). It will allow us to gain knowledge about the pro-oxidant/antioxidant mechanisms involved in the processes of distant metastases in breast cancer and also to assess whether these parameters may be alternative techniques for staging. RESULTS: We found different levels of lipid peroxidation in SLNs with micrometastases (increased) and macrometastases (decreased), a decrease in carbonyl group content in SLNs with macrometastases only, and an increase in total antioxidant capacity (TAC) in SNLs with micrometastases and macrometastases. A decrease in the levels of reduced glutathione (GSH) also appears in the SLNs with macrometastases only. Finally, we show increased levels of superoxide dismutase (SOD) and catalase (CAT) activity in SLNs with micrometastases and macrometastases, and decreased levels of glutathione peroxidase (GPx) activity in SNLs with macrometastases but not with micrometastases. CONCLUSIONS: Redox status of lymph node microenvironment participates in the progression of metastatic breast cancer.