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.

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.

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.

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.

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 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.

Acute effects of 17 ß-estradiol and genistein on insulin sensitivity and spatial memory in aged ovariectomized female rats.

Aging is characterized by decline in metabolic function and insulin resistance, and both seem to be in the basis of neurodegenerative diseases and cognitive dysfunction. Estrogens prevent age-related changes, and phytoestrogens influence learning and memory. Our hypothesis was that estradiol and genistein, using rapid-action mechanisms, are able to modify insulin sensitivity, process of learning, and spatial memory. Young and aged ovariectomized rats received acute treatment with estradiol or genistein. Aged animals were more insulin-resistant than young. In each age, estradiol and genistein-treated animals were less insulin-resistant than the others, except in the case of young animals treated with high doses of genistein. In aged rats, no differences between groups were found in spatial memory test, showing a poor performance in the water maze task. However, young females treated with estradiol or high doses of genistein performed well in spatial memory task like the control group. Only rats treated with high doses of genistein showed an optimal spatial memory similar to the control group. Conversely, acute treatment with high doses of phytoestrogens improved spatial memory consolidation only in young rats, supporting the critical period hypothesis for the beneficial effects of estrogens on memory. Therefore, genistein treatment seems to be suitable treatment in aged rats in order to prevent insulin resistance but not memory decline associated with aging. Acute genistein treatment is not effective to restore insulin resistance associated to the early loss of ovarian function, although it can be useful to improve memory deficits in this condition.

Selenium and health-related quality of life in menopausal women.

OBJECTIVES: The objective of this study was to evaluate whether there is a relation between serum selenium levels and health-related quality of life (HRQoL) in overweight and obese postmenopausal women. STUDY DESIGN: A cross-sectional study was carried out in 104 overweight and obese postmenopausal women attending a gynaecological clinic for their annual gynaecological examination. MAIN OUTCOME MEASURES: Age, anthropometric parameters, educational level, smoking habits, serum glucose, insulin, lipid profile, C-reactive protein, folic acid, vitamin B12, homocysteine and selenium levels were determined, and the Cervantes Scale was used to evaluate HRQoL. RESULTS: Serum selenium mean value levels were similar in the different groups of HRQoL and there were no differences in the four domains of the Cervantes Scale. When women were classified according to serum selenium tertiles, higher levels of serum cholesterol, low-density lipoprotein cholesterol (LDLc) and triglycerides were found in women in the lowest serum selenium tertile. CONCLUSIONS: In overweight and obese postmenopausal women, serum selenium level is not related to HRQoL but higher levels of cholesterol, LDLc and triglyceride values were detected in women in the lowest serum selenium tertile.

17beta-estradiol treatment is unable to reproduce p85 alpha redistribution associated with gestational insulin resistance in rats.

Maternal metabolic adaptations are essential to ensure proper fetal development. According to changes in insulin sensitivity, pregnancy can be divided into two periods: early pregnancy, characterized by an increase in maternal insulin sensitivity, and late pregnancy, in which there is a significant increase in insulin resistance. The aims of the present work were two-fold: firstly, the molecular mechanisms associated with the development of pregnancy-related insulin resistance in peripheral tissues, mainly retroperitoneal adipose tissue and skeletal muscle, were studied in pregnant rats at 6, 11, and 16 days gestation. Secondly, the role of 17beta-estradiol in this process was elucidated in an animal model consisting of ovariectomized rats treated with 17beta-estradiol to mimic plasma gestational levels. The results support the conclusion that retroperitoneal adipose tissue plays a pivotal role in the decrease in insulin sensitivity during pregnancy, through a mechanism that involves p85 alpha redistribution to the insulin receptor and impairment of Glut4 translocation to the plasma membrane. Treatment with 17beta-estradiol did not reproduce the molecular adaptations that occur during pregnancy, suggesting that other hormonal factors presents in gestation but absent in our experimental model are responsible for p85 alpha redistribution to the insulin receptor.

Relationship between non-genomic actions of estrogens and insulin resistace.

Numerous experimental and clinical data show that the physiological actions of insulin and sexual steroids interact in target tissues for these hormones. In the other hand, sexual steroids has effects on peripheral tissues, and since the skeletal muscle is the main responsible for peripheral glucose uptake, it would be possible that the sexual steroids induce directly in the muscle a decrease of the sensibility of this tissue to insulin action. Some of the biological actions of the estrogens are too fast like to be compatible with this classical mechanism of action, and this mechanism has been called not classical, non-genomic or rapid actions of the estrogens. Moreover, some experiments have shown that low concentrations of estradiol, induce an increase in the rate of IRS-1 phosphorylation, promotes the association between IRS-1 and the subunit of PI3-k, p85alpha, causes a decrease in the rate of IRS-1 serine phosphorylation and increases the rate of Akt phosphorylation. Therefore, the evidences suggest the existence of a narrow interrelation between the estrogens and insulin sensitivity, but relatively few studies have tried to resolve the molecular base of this relation in insulin-dependent tissues. The resolution of these unknown questions would be able to have a great long-term therapeutic repercussion. In this sense, we should not forget that insulin resistance is the underlying cause of several associated pathologies to the female aging, as Type 2 diabetes, cardio-circulatory pathology or neurodegenerative disease.

Neuroprotective effects of estrogens: cross-talk between estrogen and intracellular insulin signalling.

The incidence of neurodegenerative diseases is higher in postmenopausal women that young women. In this sense, Alzheimer's and Parkinson's diseases, ischemic brain injury and memory or cognitive dysfunction increase dramatically when the ovarian function declines. On the other hand, insulin resistance represents an independent factor in the etiology of age-associated coronary and cerebrovascular disease. Therefore, depression, neurodegenerative diseases such as Alzheimer's and Parkinson's diseases and memory or cognitive dysfunction should be considered, in some cases, a result of metabolic syndrome, and that postmenopausal women are more vulnerable that young women to these diseases Several studies have suggested that the molecular mechanism by which estradiol exerts its neuroprotective effects involves activation of the PI3-k signalling pathway, which is activated by insulin and IGF-1. Therefore, it seems possible that ERalpha can interact with these signalling pathways, mainly with PI3-k and IRS-1, to promote neuroprotective effects in the brain. In particular, IGF-I seems to be particularly important in the process of neuroprotection; it can reverse age-related effects and attenuate the age-related decrease in cerebral glucose utilization. Moreover, gonadal hormones have been found to regulate IGF-I receptor. Therefore, it seems clear that the interaction of both systems plays a role in the prevention of neuronal age-related effects. These findings suggest that by interacting with some components of the IGF-I signalling pathway, ERalpha affects the actions of IGF-I in the brain and suggest future avenues of research. The relationship between insulin resistance states associated with aging in females, and the cross-talk between estradiol and proteins includes in the IRS-1/PI3-k/Akt and IGF-1-IR signalling pathways, will lead to a more complete understanding of the precise mechanism underlying estradiol-mediated neuroprotection. Numerous clinical studies have demonstrated that the incidence of neurodegenerative diseases in higher in postmenopausal women that young women. In this sense, Alzheimer's and Parkinson's disease, ischemic brain injury and memory or cognitive dysfunction increase dramatically when the ovarian function declines. Moreover, estrogen replacement therapy seems to be a good element in order to decrease the risk and/or severity of neurodegenerative conditions, and it would be able to improve some aspects related to memory and learning process.

Chronic estradiol treatment improves brain homeostasis during aging in female rats.

Aging is associated with a reduction in metabolic function, insulin resistance, increased incidence of neurodegenerative diseases, and memory or cognitive dysfunction. In aging females, loss of gonadal function determines the beginning of the period of reduced metabolic function. Estrogens have neuroprotective effects, but the mechanisms by which they exert these effects remain unclear. The effects of estradiol treatment on the activation of the insulin receptor substrate (IRS)-1 signaling pathway, the interactions between estrogen receptor (ER)-alpha and IRS-1 and the p85alpha subunit of phosphatidylinositol-3 kinase, together with the possible effects of estradiol treatment on glucose transporter-3 and -4 levels, were investigated in female rats. The level of expression of each glucose transporter was greater in control and estradiol-treated groups than in the ovariectomized group. Interactions of ERalpha46-IRS-1, ERalpha46-p85alpha, and p85alpha-IRS-1, as well as IRS-1 phosphorylation, appeared to increase with estradiol treatment. The results indicate that estradiol treatment improves some aspects of neuronal homeostasis that are affected by aging; this may indicate that estradiol has neuroprotective effects in female rats. Additional animal studies are required to clarify the neuroprotective role of estradiol in relation to other important molecules involved in the IRS-1-phosphatidylinositol-3 kinase signaling pathway.