Potential of Fiber and Probiotics to Fight Against the Effects of PhIP + DSS-Induced Carcinogenic Process of the Large Intestine.

We determined the in vivo counteracting effect of fiber and probiotic supplementation on colonic mucosal damage and alterations in gut microbiota caused by 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP) and sodium dextran sulfate (DSS). Male Fischer-344 rats were randomly divided into 4 groups: control (standard diet), PhIP + DSS group (standard diet + PhIP + DSS), fiber (fiber diet + PhIP + DSS), and probiotic (probiotic diet + PhIP + DSS). The intake of PhIP + DSS for 3 weeks induced colonic mucosal erosion, crypt loss, and inflammation, and the distal colon was more severely damaged. Fiber alleviated colonic mucosal damage by reducing crypt loss and inflammation, while the probiotic increased colon length. The intake of PhIP + DSS increased the fecal relative abundance of Clostridia UCG014 along the intervention, in contrast to the lower abundances of these taxa found after PhIP + DSS administration in the rats supplemented with probiotics or fiber. Fiber supplementation mitigated the histological damage caused by PhIP + DSS shifting the gut microbiota toward a reduction of pro-inflammatory taxa.

Acute and Preventive Treatment of COVID-19-Related Headache: A Series of 100 Patients.

To describe the need and effectiveness of acute and preventive medications in a series of 100 consecutive patients referred due to COVID-19-related headaches. Patients were aged 48.0 (standard deviation (SD): 12.4), 84% were female, and 56% had a prior history of headache. The most common headache phenotype was holocranial (63%), frontal (48%), pressing (75%), of moderate intensity (7 out of 10), and accompanied by photophobia (58%). Acute medication was required by 93%, with paracetamol (46%) being the most frequently used drug, followed by ibuprofen (44%). The drugs with the highest proportion of a 2 h pain-freedom response were dexketoprofen (58.8%), triptans (57.7%), and ibuprofen (54.3%). Preventive treatment was required by 75% of patients. The most frequently used drugs were amitriptyline (66%), anesthetic blockades (18%), and onabotulinumtoxinA (11%). The drugs with the highest 50% responder rate were amitriptyline (45.5%), mirtazapine (50%), and anesthetic blockades (38.9%). The highest 75% responder rate was experienced following onabotulinumtoxinA (18.2%). In conclusion, most patients required acute medication, with triptans and non-steroidal anti-inflammatory drugs achieving the best responses. Three-quarters of patients required preventive medication. The most frequently used drug was amitriptyline, which obtained the best results. In some treatment-resistant patients, anesthetic blockades and onabotulinumtoxinA were also beneficial.

Immunometabolic Profile Associated with Progressive Damage of the Intestinal Mucosa in Adults Screened for Colorectal Cancer: Association with Diet.

Environmental factors such as diet and lifestyle have been shown to influence the development of some intestinal mucosal lesions that may be precursors of colorectal cancer (CRC). The presence of these alterations seems to be associated with misbalanced immunological parameter levels. However, it is still unclear as to which immunological parameters are altered in each phase of CRC development. In this work, we aimed to study the potential relationships of immunological and metabolic parameters with diet in a CRC-related lesion context. Dietary information was obtained using an annual semi-quantitative food-frequency questionnaire (FFQ) from 93 volunteers classified via colonoscopy examination according to the presence of intestinal polyps or adenocarcinoma. Cytokines, chemokines, and adipokines were determined from serum samples. We observed a reduction in adiponectin according to the damage to the mucosa, accompanied by an increase and decrease in C-X-C motif chemokine ligand 10 (CXCL10) and resistin, respectively, in CRC cases. The presence of aberrant crypt foci (ACF) in the polyp group was associated with higher tumor necrosis factor-alpha (TNF-α) concentrations. Vegetables were directly correlated with adiponectin and resistin levels, while the opposite occurred with red meat. A bioactive compound, soluble pectin, showed a negative association with TNF-α. Future dietary strategies could be developed to modulate specific immunological parameters in the context of CRC.

Differences and similarities between COVID-19 related-headache and COVID-19 vaccine related-headache. A case-control study. / Diferencias y similitudes entre la cefalea relacionada con la COVID-19 y la cefalea relacionada con la vacuna de la COVID-19. Un estudio de casos y controles.

INTRODUCTION: Headache is a frequent symptom at the acute phase of coronavirus disease 2019 (COVID-19) and also one of the most frequent adverse effects following vaccination. In both cases, headache pathophysiology seems linked to the host immune response and could have similarities. We aimed to compare the clinical phenotype and the frequency and associated onset symptoms in patients with COVID-19 related-headache and COVID-19 vaccine related-headache. SUBJECTS AND METHODS: A case-control study was conducted. Patients with confirmed COVID-19 infection and COVID-19-vaccine recipients who experienced new-onset headache were included. A standardised questionnaire was administered, including demographic variables, prior history of headaches, associated symptoms and headache-related variables. Both groups were matched for age, sex, and prior history of headache. A multivariate regression analysis was performed. RESULTS: A total of 238 patients fulfilled eligibility criteria (143 patients with COVID-19 related-headache and 95 subjects experiencing COVID-19 vaccine related-headache). Patients with COVID-19 related-headache exhibited a higher frequency of arthralgia, diarrhoea, dyspnoea, chest pain, expectoration, anosmia, myalgia, odynophagia, rhinorrhoea, cough, and dysgeusia. Further, patients with COVID-19 related-headache had a more prolonged daily duration of headache and described the headache as the worst headache ever experienced. Patients with COVID-19 vaccine-related headache, experienced more frequently pain in the parietal region, phonophobia, and worsening of the headache by head movements or eye movements. CONCLUSION: Headache caused by SARS-CoV-2 infection and COVID-19 vaccination related-headache have more similarities than differences, supporting a shared pathophysiology, and the activation of the innate immune response. The main differences were related to associated symptoms.

TITLE: Diferencias y similitudes entre la cefalea relacionada con la COVID-19 y la cefalea relacionada con la vacuna de la COVID-19. Un estudio de casos y controles.Introducción. La cefalea es un síntoma frecuente en la fase aguda de la enfermedad por coronavirus 2019 (COVID-19) y también uno de los efectos adversos más comunes tras la vacunación. En ambos casos, la fisiopatología de la cefalea parece estar relacionada con la respuesta inmunitaria del huésped y podría presentar similitudes. Nuestro objetivo fue comparar el fenotipo clínico y la frecuencia de los síntomas asociados y los síntomas de inicio en pacientes con cefalea relacionada con la COVID-19 y cefalea relacionada con la vacuna de la COVID-19. Sujetos y métodos. Se realizó un estudio de casos y controles. Se incluyó a pacientes con infección confirmada por COVID-19 y receptores de la vacuna de la COVID-19 que experimentaron un nuevo inicio de cefalea. Se administró un cuestionario estandarizado que incluyó variables demográficas, antecedentes previos de cefaleas, síntomas asociados y variables relacionadas con la cefalea. Ambos grupos se emparejaron por edad, sexo y antecedentes previos de cefaleas. Se realizó un análisis de regresión multivariante. Resultados. Un total de 238 pacientes cumplieron con los criterios de elegibilidad (143 pacientes con cefalea relacionada con la COVID-19 y 95 sujetos con cefalea relacionada con la vacuna de la COVID-19). Los pacientes con cefalea relacionada con la COVID-19 presentaron una mayor frecuencia de artralgia, diarrea, disnea, dolor torácico, expectoración, anosmia, mialgia, odinofagia, rinorrea, tos y disgeusia. Además, los pacientes con cefalea relacionada con la COVID-19 experimentaron una duración diaria más prolongada de la cefalea y describieron la cefalea como la peor que habían experimentado. Los pacientes con cefalea relacionada con la vacuna de la COVID-19 experimentaron con más frecuencia dolor en la región parietal, fonofobia y empeoramiento de la cefalea por movimientos de la cabeza o de los ojos. Conclusión. La cefalea causada por la infección por el SARS-CoV-2 y la cefalea relacionada con la vacunación de la COVID-19 presentan más similitudes que diferencias, lo que respalda una fisiopatología compartida y la activación de la respuesta inmunitaria innata. Las principales diferencias estuvieron relacionadas con los síntomas asociados.

Long-term outcomes of nummular headache: A series of 168 patients and 1198 patient-years of follow-up.

BACKGROUND: Since the first description of nummular headache (NH), more than 500 cases have been described, delineating its clinical phenotype and response to treatment. However, data on the natural history of NH and outcomes during long-term follow-up are not currently available. The present study aimed to describe the long-term outcomes and follow-up of a large series of patients with NH. METHODS: A descriptive observational ambisective study with a series of cases was conducted. The study population included adult patients with primary NH and a minimum of 12 months of follow-up. Demographic variables, previous medical history, clinical phenotype, diagnosis and treatment of NH, temporal pattern, and long-term evolution were analysed. RESULTS: In total, 168 patients were enrolled and followed for a median [interquartile range (IQR)] of 80.5 (55-118.5) months. The temporal pattern after NH onset was chronic in 67.9% and, at diagnosis, the median (IQR) number of pain days per month was 20 [10-30] days with 138 (82.1%) patients with ≥8 days of pain per month. Preventive treatment was needed by 112 (66.7%) patients. The most frequently used drugs were gabapentin (69/112; 61.6%), onabotulinumtoxinA (38/112; 33.9%), amitriptyline (31/112; 27.7%) and lamotrigine (21/112; 18.7%). Response to preventive treatment was at least partial in 91/112 (81.3%) patients. At the end of follow-up, 81 (48.2%) patients had inactive NH. Of patients with active NH, the median (IQR) number of headache days per month was 3 (1-12) days and patients had ≥8 days of pain in 35 (20.8%) cases. CONCLUSIONS: Long-term outcomes of NH were positive in most patients. After a median of 6.7 years of follow-up, 48% of cases were inactive. Two-thirds of patients required preventive treatment, and 80% of them were treatment-responsive. In NH cases that remained symptomatic, the headache frequency was lower, and the proportion of patients with chronic NH decreased from 68% to 11%.

Dietary Xenobiotics Derived from Food Processing: Association with Fecal Mutagenicity and Gut Mucosal Damage.

Whereas the mechanisms underlying the association of toxic dietary xenobiotics and cancer risk are not well established, it is plausible that dietary pattern may affect the colon environment by enhancing or reducing exposure to mutagens. This work aimed to investigate the association between xenobiotics intake and different stages of intestinal mucosal damage and colorectal cancer (CRC) screening and examine whether these associations may be mediated by altered intestinal mutagenicity. This was a case control study with 37 control subjects, 49 patients diagnosed with intestinal polyps, and 7 diagnosed with CRC. Lifestyle, dietary, and clinical information was registered after colonoscopy. For xenobiotics intake estimation the European Prospective Investigation into Cancer (EPIC) and the Computerized Heterocyclic Amines Resource for Research in Epidemiology of Disease (CHARRED) databases were used. The mutagenicity of fecal supernatants was assayed by the Ames test and light microscopy was used for the presence of aberrant crypt formation. Among all the potential carcinogens studied, the polyp group showed higher intakes of ethanol and dibenzo (a) anthracene (DiB(a)A). Besides, intakes between 0.75 and 1.29 µg/d of total polycyclic aromatic hydrocarbons (PAHs) were related with a higher risk of belonging to the polyp group. On the contrary, an intake of wholegrain cereals greater than 50 g/d was associated with a reduction in the relative risk of belonging to the polyp group. Heterocyclic amines (HAs) such as 2-amino-1-methyl-6-phenylimidazo (4,5,b) pyridine (PhIP) were associated with an increased level of mutagenicity in polyps. This study is of great interest for the identification of possible therapeutic targets for the early prevention of colon cancer through diet.

Treatment of Primary Nummular Headache: A Series of 183 Patients from the NUMITOR Study.

Nummular headache (NH) is a primary headache characterized by superficial coin-shaped pain. NUMITOR (NCT05475769) is an observational study evaluating the responder rate of preventive drugs in NH patients. The treatment response was assessed between weeks 8 and 12 compared with the baseline. Patients were included between February 2002 and October 2022. Demographic and clinical variables were assessed; treatment response was estimated by 50%, 30%, and 75% responder rates and treatment discontinuation due to inadequate tolerability. A total of 183 out of 282 patients fulfilled eligibility criteria and completed the study. Patients were aged 49.5 (standard deviation (SD): 16.8) years, and 60.7% were female. NH phenotype was a parietal circular pain of four centimeters' diameter, moderate intensity, and oppressive quality. At baseline, patients had 25 (interquartile range) pain days per month. Preventive treatment was used by 114 (62.3%) patients. The highest 50% and 75% responder rates corresponded to onabotulinumtoxinA (62.5%, 47.5%), followed by gabapentin (43.7%, 35.2%). Oral preventive drugs were not tolerated by 12.9-25%. The present study provides class IV evidence of the effectiveness of oral preventive drugs and onabotulinumtoxinA in the treatment of primary NH. OnabotulinumtoxinA was the most effective and best-tolerated drug, positioning it as first-line treatment of NH.

Effects of Estrogen and Phytoestrogen Treatment on an In Vitro Model of Recurrent Stroke on HT22 Neuronal Cell Line.

An increase of stroke incidence occurs in women with the decline of estrogen levels following menopause. This ischemic damage may recur, especially soon after the first insult has occurred. We evaluated the effects of estrogen and phytoestrogen treatment on an in vitro recurrent stroke model using the HT22 neuronal cell line. HT22 cells were treated with 17ß-estradiol or genistein 1 h after the beginning of the first of two oxygen and glucose deprivation/reoxygenation (OGD/R) cycles. During the second OGD, there was a deterioration of some components of the electron transport chain, such as cytochrome c oxidase subunit 1 with a subsequent increase of reactive oxygen species (ROS) production. Accordingly, there was also an increase of apoptotic phenomena demonstrated by poly(ADP-ribose) polymerase 1 cleavage, Caspase-3 activity, and Annexin V levels. The recurrent ischemic injury also raised the hypoxia-inducible factor 1α and glucose transporter 1 levels, as well as the ratio between the lipidated and cytosolic forms of microtubule-associated protein 1A/1B-light chain 3 (LC3-II/LC3-I). We found a positive effect of estradiol and genistein treatment by partially preserving the impaired cell viability after the recurrent ischemic injury; however, this positive effect does not seem to be mediated neither by blocking apoptosis processes nor by decreasing ROS production. This work contribute to the better understanding of the molecular mechanisms triggered by recurrent ischemic damage in neuronal cells and, therefore, could help with the development of an effective treatment to minimize the consequences of this pathology.

Evidence for clock genes circadian rhythms in human full-term placenta.

Biological rhythms are driven by endogenous biological clocks; in mammals, the master clock is located in the suprachiasmatic nucleus (SCN) of the hypothalamus. This master pacemaker can synchronize other peripheral oscillators in several tissues such as some involved in endocrine or reproductive functions. The presence of an endogenous placental clock has received little attention. In fact, there are no studies in human full-term placentas. To test the existence of an endogenous pacemaker in this tissue we have studied the expression of circadian locomoter output cycles kaput (Clock), brain and muscle arnt-like (Bmal)1, period (Per)2, and cryptochrome (Cry)1 mRNAs at 00, 04, 08, 12, 16, and 20 hours by qPCR. The four clock genes studied are expressed in full-term human placenta. The results obtained allow us to suggest that a peripheral oscillator exists in human placenta. Data were analyzed using Fourier series where only the Clock and Bmal1 expression shows a circadian rhythm.

Loss of GLUT4 induces metabolic reprogramming and impairs viability of breast cancer cells.

Metabolic reprogramming strategies focus on the normalization of metabolism of cancer cells and constitute promising targets for cancer treatment. Here, we demonstrate that the glucose transporter 4 (GLUT4) has a prominent role in basal glucose uptake in MCF7 and MDA-MB-231 breast cancer cells. We show that shRNA-mediated down-regulation of GLUT4 diminishes glucose uptake and induces metabolic reprogramming by reallocating metabolic flux to oxidative phosphorylation. This reallocation is reflected on an increased activity of the mitochondrial oxidation of pyruvate and lower lactate release. Altogether, GLUT4 inhibition compromises cell proliferation and critically affects cell viability under hypoxic conditions, providing proof-of-principle for the feasibility of using pharmacological approaches to inhibit GLUT4 in order to induce metabolic reprogramming in vivo in breast cancer models.

Effects of resveratrol on ovarian response to controlled ovarian hyperstimulation in ob/ob mice.

OBJECTIVE: To evaluate antidiabetic and anti-inflammatory effects of resveratrol on the ovarian response to controlled ovarian hyperstimulation (COH) in obesity-related infertility. DESIGN: Experimental. SETTING: University laboratory. ANIMAL(S): Sixteen female ob/ob mice and 16 female C57BL/6J mice undergoing COH. INTERVENTION(S): Wild-type placebo group; wild-type resveratrol group; ob/ob mice placebo group; ob/ob mice resveratrol group. Resveratrol 3.75 mg/kg daily for 20 days and undergoing COH protocol. MAIN OUTCOME MEASURE(S): Body and reproductive system weight, food intake, fasting blood glucose, plasma insulin and T levels, and Homeostatic Index of Insulin Resistance; interleukin-6 and tumor necrosis factor-α levels in adipose tissue by Western blot; assessment of quality and quantity of oocytes retrieved; and quantitative analysis of ovarian follicles. RESULT(S): Plasma insulin and T levels decreased and Homeostatic Index of Insulin Resistance improved in ob/ob mice treated with resveratrol. Interleukin-6 and tumor necrosis factor-α levels were significantly reverted back to near normalcy after resveratrol treatment in obese mice. Administration of resveratrol resulted in a significantly higher number of oocytes collected in wild-type mice. The number of primary, growing, preovulatory, and atretic follicles was found to be decreased in the group of obese mice treated with resveratrol when compared with the obese control group. CONCLUSION(S): Resveratrol administration could exert benefits against loss of ovarian follicles, and these actions may be mediated, at least in part, via anti-inflammatory, insulin-sensitizing, and antihyperandrogenism effects. These observations further validate the therapeutic potential of resveratrol to preserve ovarian reserve in conditions associated with obesity. Our results suggest the possible clinical use of resveratrol to enhance the ovarian response to COH in normal-weight females.

Assessment of follicular fluid leptin levels and insulin resistance as outcome predictors in women undergoing in vitro fertilization-intracytoplasmic sperm injection.

OBJECTIVE: To analyze follicular fluid leptin (FFL) levels, abdominal obesity, and insulin resistance as predictors of in vitro fertilization (IVF)-intracytoplasmic sperm injection (ICSI) outcome. DESIGN: Observational study. SETTING: Academic medical center. PATIENT(S): A sample of 130 infertile women aged 26-40 years without polycystic ovary syndrome. INTERVENTION(S): Measurement of FFL levels in controlled ovarian hyperstimulation cycles with an antagonist and agonist protocol for IVF-ICSI. MAIN OUTCOME MEASURE(S): Live birth rate. RESULT(S): Mean FFL values were significantly higher in pregnancies not ending in a live birth, even after adjustment for waist circumference and insulin resistance. A multivariable model obtained with the use of logistic binary regression analysis showed that waist circumference and insulin resistance had no influence over IVF-ICSI outcomes, but a higher number of follicles, lower serum progesterone levels on the day before α-hCG administration, and lower FFL concentrations were significantly associated with a higher probability of having a live birth. The multivariate model reached a sensitivity of 87% and a specificity of 71% for predicting the possibility of pregnancy ending in a live birth. CONCLUSION(S): High FFL levels were associated with abdominal obesity, insulin resistance, and a lower live birth rate after IVF-ICSI. Further investigations are warranted to define the precise roles of leptin, obesity, and insulin resistance on IVF-ICSI outcomes.

Effects of estradiol and genistein on the insulin signaling pathway in the cerebral cortex of aged female rats.

Menopause leads to a decrease in estrogen production that increases central insulin resistance, contributing to the development of neurodegenerative diseases. We have evaluated the influence of aging and estradiol or genistein treatments on some key stages of the insulin signaling pathway in the cerebral cortex. Young and aged female Wistar rats were ovariectomized and treated acutely with 17ß-estradiol (1.4µg/kg body weight), two doses of genistein (10 or 40mg/kg body weight), or vehicle. The cortical expression of several key insulin signaling pathway components was analyzed by western blotting. Our results showed an age-related deterioration in the interactions between the regulatory subunit of phosphatidylinositol 3-kinase (p85α) and the activated form of insulin receptor substrate 1 (p-IRS1tyr612), as well as between p85α and the 46kDa isoform of the estrogen receptor α (ERα46). Moreover, aging also decreased the translocation of glucose transporter-4 (GLUT4) to the plasma membrane. 17ß-Estradiol but not genistein reduced the negative impact of aging on central insulin sensitivity by favoring this GLUT4 translocation, and therefore could be neuroprotective against the associated neurodegenerative diseases. However, protein kinase B (Akt) activation by genistein suggests that other possible mechanisms are involved in the neuroprotective effects of this phytoestrogen during the aging process.

Immune modulating capability of two exopolysaccharide-producing Bifidobacterium strains in a Wistar rat model.

Fermented dairy products are the usual carriers for the delivery of probiotics to humans, Bifidobacterium and Lactobacillus being the most frequently used bacteria. In this work, the strains Bifidobacterium animalis subsp. lactis IPLA R1 and Bifidobacterium longum IPLA E44 were tested for their capability to modulate immune response and the insulin-dependent glucose homeostasis using male Wistar rats fed with a standard diet. Three intervention groups were fed daily for 24 days with 10% skimmed milk, or with 10(9) cfu of the corresponding strain suspended in the same vehicle. A significant increase of the suppressor-regulatory TGF- ß cytokine occurred with both strains in comparison with a control (no intervention) group of rats; the highest levels were reached in rats fed IPLA R1. This strain presented an immune protective profile, as it was able to reduce the production of the proinflammatory IL-6. Moreover, phosphorylated Akt kinase decreased in gastroctemius muscle of rats fed the strain IPLA R1, without affecting the glucose, insulin, and HOMA index in blood, or levels of Glut-4 located in the membrane of muscle and adipose tissue cells. Therefore, the strain B. animalis subsp. lactis IPLA R1 is a probiotic candidate to be tested in mild grade inflammation animal models.

17ß-estradiol activates glucose uptake via GLUT4 translocation and PI3K/Akt signaling pathway in MCF-7 cells.

The relationship between estrogen and some types of breast cancer has been clearly established. However, although several studies have demonstrated the relationship between estrogen and glucose uptake via phosphatidylinositol 3-kinase (PI3K)/Akt in other tissues, not too much is known about the possible cross talk between them for development and maintenance of breast cancer. This study was designed to test the rapid effects of 17ß-estradiol (E2) or its membrane-impermeable form conjugated with BSA (E2BSA) on glucose uptake in a positive estrogen receptor (ER) breast cancer cell line, through the possible relationship between key components of the PI3K/Akt signaling pathway and acute steroid treatment. MCF-7 human breast cancer cells were cultured in standard conditions. Then 10 nM E2 or E2BSA conjugated were administered before obtaining the cell lysates. To study the glucose uptake, the glucose fluorescent analog 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-d-glucose was used. We report an ER-dependent activation of some of the key steps of the PI3K/Akt signaling pathway cascade that leads cells to improve some mechanisms that finally increase glucose uptake capacity. Our data suggest that both E2 and E2BSA enhance the entrance of the fluorescent glucose analog 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-d-glucose, and also activates PI3K/Akt signaling pathway, leading to translocation of glucose transporter 4 to the plasma membrane in an ERα-dependent manner. E2 enhances ER-dependent rapid signaling triggered, partially in the plasma membrane, allowing ERα-positive MCF-7 breast cancer cells to increase glucose uptake, which could be essential to meet the energy demands of the high rate of proliferation.

17ß-Estradiol and genistein acute treatments improve some cerebral cortex homeostasis aspects deteriorated by aging in female rats.

Aging is associated with decreased insulin sensitivity and impaired cerebral glucose homeostasis. These changes increase neural sensitivity to metabolic damage contributing to cognitive decline, being the decrease in plasma estrogen following menopause one of the main factors involved in aged females. Phytoestrogens as genistein are structurally similar to 17ß-estradiol, bind to estrogen receptors, and can evoke both estrogenic and anti-estrogenic effects. Estrogens and phytoestrogens have neuroprotective potential, but the physiological mechanisms are not fully understood. Young and aged female Wistar rats were ovariectomized and treated acutely with 17ß-estradiol (1.4µg/kg body weight), genistein (10 or 40 mg/kg body weight), or vehicle. Cortical expression of glucose transporter-3 (GLUT-3) and -4 (GLUT-4), cytochrome c oxidase (CO), estrogen receptor-α (ERα) and -ß (ERß) was measured by Western blotting. There was an age-related decline in GLUT-4, CO and ERß levels. Both drugs, estradiol and genistein, were able to reverse GLUT-3 downregulation in the cortex following late ovariectomy. However, genistein was the only treatment able to restore completely GLUT-4 levels in aged rats. In contrast, estradiol was more potent than genistein at increasing CO, a marker of cerebral oxidative metabolism. As regards ER levels, estradiol increased the ERα67 quantity diminished by late ovariectomy, while genistein did the same with the other ERα isoform, ERα46, highlighting drug-specific differences in expression changes for both isoforms. On the other hand, no treatment-related differences were found regarding ERß levels. Therefore, genistein like estradiol could be suitable treatments against cortical metabolic dysfunction caused by aging. These treatments may hold promise as neuroprotective strategies against diabetes and age-related neurodegenerative diseases.

Aging and substitutive hormonal therapy influence in regional and subcellular distribution of ERα in female rat brain.

Estrogens are not only critical for sexual differentiation it is well-known for the role of 17ß-estradiol (E2) in the adult brain modulating memory, learning, mood and acts as a neuroprotector. E2 exerts its actions through two classical receptors: estrogen receptor alpha (ERα) and estrogen receptor beta (ERß). The distribution of both receptors changes from one brain area to another, E2 being able to modulate their expression. Among the classical features of aging in humans, we find cognitive impairment, dementia, memory loss, etc. As estrogen levels change with age, especially in females, it is important to know the effects of low E2 levels on ERα distribution; results from previous studies are controversial regarding this issue. In the present work, we have studied the effects of long-term E2 depletion as well as the ones of E2 treatment on ERα brain distribution of ovariectomized rats along aging in the diencephalon and in the telencephalon. We have found that ovariectomy causes downregulation and affects subcellular localization of ERα expression during aging, meanwhile prolonged estrogen treatment produces upregulation and overexpression of the receptor levels. Our results support the idea of the region-specific neuroprotection mechanisms mediated by estradiol.

Neuroprotective role of estrogens: relationship with insulin/IGF-1 signaling.

Postmenopausal women have an elevated risk of developing a neurodegenerative disease. These clinical observation supported by basic research, suggest that estrogens are neuroprotective. Insulin resistance represents an independent factor in the etiology of age-associated disease and metabolic syndrome should be considered as a contributing factor to the higher post-menopausal vulnerability to neurological disorders. Elucidating the relationship between insulin resistance associated with aging in females, and the cross-talk between estradiol, insulin, and insulin-like growth factor (IGF-1) signaling pathways, will lead to a more complete understanding of the mechanism underlying estradiol-mediated neuroprotection. In past decades, estrogen replacement therapy (ERT) was commonly used as a palliative therapy during menopause, but the mid-term and long-term effects of estrogen as possible promoters of breast cancer and the increased risk of coronary illness or stroke, has limited current usage. A deeper understanding of the molecular mechanisms common to all forms of neurodegenerative diseases may hasten the development of protective strategies against chronic age-related deterioration and acute illness, ultimately providing a better quality of life for the elderly.

Soy isoflavones, diet and physical exercise modify serum cytokines in healthy obese postmenopausal women.

OBJECTIVES: Evaluate the effect of diet, physical exercise, and a daily oral intake of a soy isoflavones extract (Fisiogen(®)) contained 200 mg of Glycine max, which corresponded to 80 mg of isoflavone (60.8 mg of genistein, 16 mg of daidzein and 3.2 mg of glicitein) on leptin and other adipokines plasma levels in healthy obese postmenopausal women. METHODS: A multicentric randomized longitudinal prospective cohort study was conducted in a sample of 87 healthy obese postmenopausal women. Patients were randomly assigned to a 1200 kcal diet and exercise group (control group) or a group of 1200 kcal diet, exercise, and daily oral intake of daily oral intake of a soy isoflavones extract (Fisiogen(®)) contained 200 mg of Glycine max, which corresponded to 80 mg of isoflavone (60.8 mg of genistein, 16 mg of daidzein and 3.2 mg of glicitein) (soy isoflavones group) along 6 months. Main outcome measures were: anthropometric measures, body composition, leptin, adiponectin, TNF-alpha, homocysteine, C-reactive protein, glucose, insulin, lipid profile and oestradiol serum levels, Kupperman index and Cervantes Scale. RESULTS: Mean serum leptin and TNF-alpha levels declined after 6 months in both groups of the study, but only women in the soy isoflavones group showed a significant increase of mean serum levels of adiponectin. CONCLUSIONS: Diet, physical exercise and daily oral intake of a soy isoflavones extract (Fisiogen(®)) contained 200 mg of Glycine max, which corresponded to 80 mg of isoflavone (60.8 mg of genistein, 16 mg of daidzein and 3.2 mg of glicitein) have a beneficial effect on serum leptin, adiponectin and TNF-α in healthy obese postmenopausal women after 6 months of treatment.