RESUMO

Introduction: Worldwide, breast cancer is the most important cancer in incidence and prevalence in women. Different risk factors interact to increase the probability of developing it. Biological agents such as helminth parasites, particularly their excretory/secretory antigens, may play a significant role in tumor development. Helminths and their antigens have been recognized as inducers or promoters of cancer due to their ability to regulate the host's immune response. Previously in our laboratory, we demonstrated that chronic infection by Toxocara canis increases the size of mammary tumors, affecting the systemic response to the parasite. However, the parasite does not invade the tumor, and we decided to study if the excretion/secretion of antigens from Toxocara canis (EST) can affect the progression of mammary tumors or the pathophysiology of cancer which is metastasis. Thus, this study aimed to determine whether excretion/secretion T. canis antigens, injected directly into the tumor, affect tumor growth and metastasis. Methods: We evaluated these parameters through the monitoring of the intra-tumoral immune response. Results: Mice injected intratumorally with EST did not show changes in the size and weight of the tumors; although the tumors showed an increased microvasculature, they did develop increased micro and macro-metastasis in the lung. The analysis of the immune tumor microenvironment revealed that EST antigens did not modulate the proportion of immune cells in the tumor, spleen, or peripheral lymph nodes. Macroscopic and microscopic analyses of the lungs showed increased metastasis in the EST-treated animals compared to controls, accompanied by an increase in VEGF systemic levels. Discussion: Thus, these findings showed that intra-tumoral injection of T. canis EST antigens promote lung metastasis through modulation of the tumor immune microenvironment.

Assuntos

RESUMO

BACKGROUND: Toxocara canis (T. canis) is a helminth parasite of zoonotic and veterinary health significance that causes the disease known as Toxocariasis. This disease has been associated with conditions of poverty, especially in tropical climate zones throughout the world. Although it rarely causes important clinical manifestations, T. canis can lead to blindness, meningoencephalitis, or other nervous manifestations in humans. Moreover, some studies show its importance in the development of tumor growth, which have been associated with the parasite's ability to modulate the host's immune response. While different studies have evaluated the immune response during this disease, currently, there are no studies where the infection is analyzed from the perspective of sexual dimorphism. METHODS: To evaluate sex differences in susceptibility, we analyzed lesions and parasite loads in lung and liver at 7 days post-infection. In addition, immune cell subpopulations were analyzed in spleen, mesenteric and peripheral lymph nodes. Finally, the production of cytokines and specific antibodies were determined in the serum. Statical analyses were performed using a Two-way ANOVA and a post-hoc Bonferroni multiple comparison test. RESULTS: Female rats had a higher number of larvae in the liver, while male rats had them in the lungs. The percentages of immune cells were evaluated, and in most cases, no significant differences were observed. Regarding the cytokines production, infection can generate a decrease in Th1 such as IL-1ß in both sexes and IL-6 only in females. In the case of Th2, IL-4 increases only in infected males and IL-5 increases in males while decreasing in females due to the effect of infection. IL-10 also decreases in both sexes as a consequence of the infection, and TGF-ß only in females. Finally, the infection generates the production of antibodies against the parasite, however, their quantity is lower in females. CONCLUSIONS: This study demonstrates that T. canis infection is dimorphic and affects females more than males. This is due to a polarization of the inadequate immune response, which is reflected as a higher parasite load in this sex.

Assuntos

RESUMO

Metastasis remains the leading cause of mortality in prostate cancer patients. The presence of tumor cells in lymph nodes is an established prognostic indicator for several cancer types, such as melanoma, breast, oral, pancreatic, and cervical cancers. Emerging evidence highlights the role of microRNAs enclosed within extracellular vesicles as facilitators of molecular communication between tumors and metastatic sites in the lymph nodes. This study aims to investigate the potential diagnostic utility of EV-derived microRNAs in liquid biopsies for prostate cancer. By employing microarrays on paraffin-embedded samples, we characterized the microRNA expression profiles in metastatic lymph nodes, non-metastatic lymph nodes, and primary tumor tissues of prostate cancer. Differential expression of microRNAs was observed in metastatic lymph nodes compared to prostate tumors and non-metastatic lymph node tissues. Three microRNAs (miR-140-3p, miR-150-5p, and miR-23b-3p) were identified as differentially expressed between tissue and plasma samples. Furthermore, we evaluated the expression of these microRNAs in exosomes derived from prostate cancer cells and plasma samples. Intriguingly, high Gleason score samples exhibited the lowest expression of miR-150-5p compared to control samples. Pathway analysis suggested a potential regulatory role for miR-150-5p in the Wnt pathway and bone metastasis. Our findings suggest EV-derived miR-150-5p as a promising diagnostic marker for identifying patients with high-grade Gleason scores and detecting metastasis at an early stage.

RESUMO

Parkinson's disease is a neurodegenerative disorder characterized by oxidative stress and immune activation in the nigro-striatal pathway. Simvastatin regulates cholesterol metabolism and protects from atherosclerosis disease. Simvastatin-tween 80 was administered 7 days before sterotaxic intrastriatal administration of MPP+ (1-methyl-4-phenylpyridine) in rats. Fluorescent lipidic product formation, dopamine levels, and circling behavior were considered damage markers. Twenty-four hours and six days after, the animal group lesioned with MPP+ showed significant damage in relation to the control group. Animals pretreated with simvastatin significantly reduced the MPP+-induced damage compared to the MPP+ treated group. As apoptosis promotes neuroinflammation and neuronal degeneration in Parkinson's disease, and since there is not currently a proteomic map of the nigro-striatum of rats and assuming a high homology among the identified proteins in other rat tissues, we based the search for rat protein homologs related to the establishment of inflammation response. We demonstrate that most proteins related to inflammation decreased in the simvastatin-treated rats. Furthermore, differential expression of antioxidant enzymes in striated tissue of rat brains was found in response to simvastatin. These results suggest that simvastatin could prevent striatal MPP+-induced damage and, for the first time, suggest that the molecular mechanisms involved in this have a protective effect.

Assuntos

RESUMO

Breast cancer treatment failure is related to low response rates, high costs, and long-term toxicities. Thus, it is necessary to find less toxic, cheaper, and more effective treatments. In situ administration ensures drug delivery to tumor cells and decreases systemic toxic effects. The androstene-3ß, 17α-diol (α-AED) reduces breast tumor cell proliferation and is an ideal candidate to treat mammary tumors. This study aims to identify the in vitro and in vivo effects of α-AED on a triple-negative mammary tumor model. An in vitro biphasic steroid effect was observed in mouse and human mammary tumor cells treated with α-AED. In this sense, cells treated with higher doses (100 and 200 µM) showed an antiproliferative effect. The α-AED administrated intratumorally reduced average tumor weight and increased the percentage of natural killer cells (NK), plasmatic, and plasmablast cells in mice tumors. Of note, VEGF levels in all α-AED-treated tumors was lower than in the control and vehicle groups. The tumor in situ increased response was reflected systemically by higher anti-4T1 IgG concentration in serum from α-AED-treated mice, but no other associated systemic changes were detected. The reduction in tumor size for the local injection of α-AED is associated with the anti-proliferative effect of this steroid, and the lower local levels of VEGF may be related to the imperceptible macroscopic metastasis in α-AED-treated mice. The above suggests that α-AED may be used in clinical studies to prove its efficacy as an alternative breast tumor treatment or in conjunction with already established therapies.

Assuntos

RESUMO

Phthalates and bisphenols are ubiquitous environmental pollutants with the ability to perturb different systems. Specifically, they can alter the endocrine system, and this is why they are also known as endocrine-disrupting compounds (EDCs). Interestingly, they are related to the development and progression of breast cancer (BC), but the threshold concentrations at which they trigger that are not well established. OBJECTIVES: The aim of this study was to compare the concentration measures of parent EDCs in three groups of women (without BC, with BC, and BC survivors) from two urban populations in Mexico, to establish a possible association between EDCs and this disease. We consider the measure of the parent compounds would reflect the individual's exposure. METHODS: The levels of di-ethyl-hexyl-phthalate (DEHP), butyl-benzyl-phthalate (BBP), di-n-butyl phthalate (DBP) and di-ethyl-phthalate (DEP), bisphenol A (BPA) and bisphenol S (BPS) were determined by gas chromatograph-mass spectrometry in 102 subjects, including 37 women without any pathological disease, 46 patients with BC and 19 women survivals of BC of Mexico and Toluca City. RESULTS: All phthalates were detected in 100% of women, two of them were significantly higher in patients with different BC subtypes in Mexico City. Differential increases were observed mainly in the serum concentration of phthalates in women with BC compared to women without disease between Mexico and Toluca City. In addition, when performing an analysis of the concentrations of phthalates by molecular type of BC, DEP and BBP were found mainly in aggressive and poorly differentiated types of BC. It should be noted that female BC survivors treated with anti-hormonal therapy showed lower levels of BBP than patients with BC. BPA and BPS were found in most samples from Mexico City. However, BPS was undetectable in women from Toluca City. DISCUSSION: The results of our study support the hypothesis of a positive association between exposure to phthalates and BC incidence.

Assuntos

RESUMO

Notwithstanding that most biomedical research today focuses on the pandemic caused by the SARs-CoV-2 virus, there are many unresolved diseases that are almost forgotten worldwide [...].

RESUMO

Mast cells (MCs) play a crucial role during Leishmania infections, which is transmitted through the bite of an infected sand fly that injects saliva together with the parasite. Sand fly saliva is a complex fluid that modulates the host immune response. In addition, hormonal factors modulate the host immune response and alter susceptibility to infections. Thus, to assess the impact of male sex hormones on the mast-cell (MC) response to Leishmania infections, we orchiectomized male mice, infected them with the parasite in the presence of sand fly salivary proteins, and analyzed the inflammatory response of MCs. Our results showed that the MC response to the parasite and vector salivary proteins differed between orchiectomized and sham-operated mice. In orchiectomized mice, MC showed a retarded activation pattern, associated with slower degranulation and weaker TNF-α, histamine, and tryptase staining in response to the infection with Leishmania mexicana combined with vector-salivary proteins, as compared to sham mice. Furthermore, neutrophil infiltration was slower in orchiectomized mice, and numbers of infected macrophages and lesion sizes were smaller. Our results show that, during Leishmania infection, male sex hormones modulate the mast-cell response against the parasite and salivary proteins of the sand fly vector, inducing an intense inflammatory response. Their absence in orchiectomized mice retards the inflammatory response, enabling better control of the infection and slower disease progression.

RESUMO

Breast cancer (BC) metastasis represents the main physiopathology leading to poor prognosis and death. Bisphenol A (BPA) is a pollutant, classified as an endocrine-disrupting chemical compound with estrogenic properties, their exposure in the early stages of neonatal life leads to an increase in the size and weight of breast tumors and induces cellular changes in the tumoral immune microenvironment where cytokines play a key role. Thus, we used female BALB/c mice exposed neonatally to a single dose of BPA. Once mice reached sexual maturity, a mammary tumor was induced, injecting 4T1 cells in situ. After 25 days of injection, we evaluated endocrine alterations, cytokine expression, tissue alterations denoted by macro or micro-metastasis in the lung, and cell infiltration induced by metastasis. We found that BPA neonatal treatment did not show significant endocrine alterations. Noteworthy, BPA led to an augmented rate of metastasis to the lung associated with higher intratumoral expression of IL-1ß, IL-6, IFN-γ, TNF-α, and VEGF. Our data suggest that cytokines are key players in the induction of BC metastasis and that BPA (an environmental pollutant) should be considered as a risk factor in the clinical history of patients as a possible inductor of BC metastasis.

Assuntos

RESUMO

The interaction of the nervous, immune, and endocrine systems is crucial in maintaining homeostasis in vertebrates, and vital in mammals. The spleen is a key organ that regulates the neuroimmunoendocrine system. The Taenia crassiceps mouse system is an excellent experimental model to study the complex host-parasite relationship, particularly sex-associated susceptibility to infection. The present study aimed to determine the changes in neurotransmitters, cytokines, sex steroids, and sex-steroid receptors in the spleen of cysticercus-infected male and female mice and whole parasite counts. We found that parasite load was higher in females in comparison to male mice. The levels of the neurotransmitter epinephrine were significantly decreased in infected male animals. The expression of IL-2 and IL-4 in the spleen was markedly increased in infected mice; however, the expression of Interleukin (IL)-10 and interferon (IFN)-γ decreased. We also observed sex-associated differences between non-infected and infected mice. Interestingly, the data show that estradiol levels increased in infected males but decreased in females. Our studies provide evidence that infection leads to changes in neuroimmunoendocrine molecules in the spleen, and these changes are dimorphic and impact the establishment, growth, and reproduction of T. crassiceps. Our findings support the critical role of the neuroimmunoendocrine network in determining sex-associated susceptibility to the helminth parasite.

RESUMO

Public concern has emerged about the effects of endocrine-disrupting compounds (EDCs) on neuropsychiatric disorders. Preclinical evidence suggests that exposure to EDCs is associated with the development of major depressive disorder (MDD) and could result in neural degeneration. The interaction of EDCs with hormonal receptors is the best-described mechanism of their biological activity. However, the dysregulation of the hypothalamic-pituitary-gonadal adrenal axis has been reported and linked to neurological disorders. At a worldwide level and in Mexico, the incidence of MDD has recently been increasing. Of note, in Mexico, there are no clinical associations on blood levels of EDCs and the incidence of the MDD. Methodology: Thus, we quantified for the first time the serum levels of parent compounds of two bisphenols and four phthalates in patients with MDD. The levels of di-ethyl-hexyl-phthalate (DEHP), butyl-benzyl-phthalate (BBP), di-n-butyl phthalate (DBP), and di-ethyl-phthalate (DEP), bisphenol A (BPA), and bisphenol S (BPS) in men and women with or without MDD were determined with a gas chromatograph-mass spectrometer. Results/conclusion: We found significant differences between concentrations of BBP between controls and patients with MDD. Interestingly, the serum levels of this compound have a dysmorphic behavior, being much higher in women (~500 ng/mL) than in men (≤10 ng/mL). We did not observe significant changes in the serum concentrations of the other phthalates or bisphenols tested, neither when comparing healthy and sick subjects nor when they were compared by gender. The results point out that BBP has a critical impact on the etiology of MDD disorder in Mexican patients, specifically in women.

Assuntos

RESUMO

Primary neuroendocrine differentiation in prostate cancer occurs infrequently and represents a therapeutic challenge at present due to the poor prognosis involved. We present the case of a patient with de novo neuroendocrine prostate cancer who later developed metastases to adrenals bilaterally which were initially managed surgically.

RESUMO

Malaria is the most lethal parasitic disease in the world. Mortality and severity in symptoms are higher in men than women, suggesting that oestrogens, which are in higher concentration in females than in males, may regulate the immune response against malaria. Tamoxifen, a selective oestrogen receptor modulator used in breast cancer treatment due to its antagonistic effect on oestrogen receptors α and ß, is also studied because of its potential therapeutic use for several parasitic diseases. However, most studies, including one in malaria, have not addressed the immunomodulatory role of tamoxifen. In this work, we evaluated the effect of tamoxifen on the immune response of CBA/Ca mice against Plasmodium berghei ANKA. This study showed for the first time that tamoxifen increased parasite load, aggravated symptoms by decreasing body temperature and body weight, and worsened anaemia. Additionally, tamoxifen significantly increased the splenic index and the percentages of CD4+ and NK+ cells on day eight post-infection. By contrast, tamoxifen decreased both CD8+ and B220+ populations in the spleen and decreased the serum levels of IL-2, IL-6, and IL-17. Our findings support the notion that tamoxifen is a potent immunomodulator in malaria-infected mice and suggest caution when administering it to malaria-infected women with breast cancer.

RESUMO

Toxoplasmosis is a zoonotic disease caused by the apicomplexa protozoan parasite Toxoplasma gondii. This disease is a health burden, mainly in pregnant women and immunocompromised individuals. Dehydroepiandrosterone (DHEA) has proved to be an important molecule that could drive resistance against a variety of infections, including intracellular parasites such as Plasmodium falciparum and Trypanozoma cruzi, among others. However, to date, the role of DHEA on T. gondii has not been explored. Here, we demonstrated for the first time the toxoplasmicidal effect of DHEA on extracellular tachyzoites. Ultrastructural analysis of treated parasites showed that DHEA alters the cytoskeleton structures, leading to the loss of the organelle structure and organization as well as the loss of the cellular shape. In vitro treatment with DHEA reduces the viability of extracellular tachyzoites and the passive invasion process. Two-dimensional (2D) SDS-PAGE analysis revealed that in the presence of the hormone, a progesterone receptor membrane component (PGRMC) with a cytochrome b5 family heme/steroid binding domain-containing protein was expressed, while the expression of proteins that are essential for motility and virulence was highly reduced. Finally, in vivo DHEA treatment induced a reduction of parasitic load in male, but not in female mice.

RESUMO

Bisphenol A (BPA) is an endocrine-disruptor compound that exhibits estrogenic activity. BPA is used in the production of materials such as polycarbonate plastics, epoxy resins and dental sealants. Whereas, the endocrine modulating activity of BPA and its effects on reproductive health have been widely studied, its effects on the function of the immune system are poorly characterized. This might be attributable to the different BPA doses used in a diversity of animal models. Moreover, most studies of the effect of BPA on the immune response are limited to in vitro and in vivo studies that have focused primarily on the impact of BPA on the number and proportion of immune cell populations, without evaluating its effects on immune function in response to an antigenic challenge or infectious pathogens. In this review, we discuss the current literature on the effects of BPA on the function of immune system that potentially increases the susceptibility to infections by the virtue of acting as a pro-inflammatory molecule. Thus, it appears that BPA, while by such an impact might be useful in the control of certain disease states that are helped by an inflmmatory response, it can worsen the prognosis of diseases that are adversely affected by inflammation.

Assuntos

RESUMO

Phthalates are endocrine disrupting compounds (EDCs) used as plasticizers in a wide array of daily-use products, from flooring and automotive parts to medical devices and are even present in the children�s toys. Since these compounds are not covalently bound other molecules, they leach from these synthetic products, causing a high level of human exposure to them. EDCs exert several endocrine effects, most typically, reduced biosynthesis of the male hormone, testosterone and disturbances in estrogen, androgen, PPAR-gamma and AhR that control complex immunoendocrine regulatory networks. Besides impacting the developmental processes and long-term adverse effects, since cells of the immune system express endocrine receptors, and synthetize and respond to several hormones and other endocrine ligands, phthalates also cause dysregulation of immune system.

Assuntos

RESUMO

The communication between neuroendocrine and immune system maintains a bidirectional complex network. Both systems jointly act during a parasite infection to maintain homeostasis and to eliminate such pathogens. Parasites interfere with the synthesis, secretion, metabolism, action, and elimination of endogenous hormones, as well as with the immune system in the host. Here, we aim to address as how parasite colonization disrupts the normal homeostasis of endocrine organs of the host, likely due to the exacerbated immune response, or by the impact of the parasite directly affecting endocrine tissues.

Assuntos

RESUMO

Breast cancer is one of the most common malignancies and the second leading cause of death in women. Despite efforts for its early detection, its worldwide incidence continues to increase. Thus, identification of risk factors for its development and new targets for its therapy are of vital importance. Environmental pollutants derived from human activity have been associated with predisposition to the development of cancer. Bisphenol A (BPA) is an endocrine disruptor compound (EDC) widely used in the manufacture of polycarbonates, and it has affinity for the estrogen receptor (ER). Scientific evidence has proposed an association between increased incidence of breast cancer and BPA exposure at lower doses. Among worldwide concerns with BPA exposure, different industries proceeded to replace BPA with analogs such as bisphenol S (BPS), which is now employed in products labelled as BPA-free. Nevertheless, recent studies exhibit that its exposure results in altered mammary gland development and morphogenesis; and promotes breast cancer cell proliferation. Of note, most of the effects of both BPA and BPS have been performed in estrogen-dependent breast cancer models. However, gaps in knowledge still exist on the roles and mechanisms that both compounds, specifically BPS, may play in cancer initiation and development in hormone-dependent and other types of breast cancer. Thus, the aim of the present study was to deepen the understanding of biological targets modulated by these ubiquitous pollutants in different breast cancer cell lines, representing two scenarios of this pathology: hormone-dependent and hormone-independent breast cancer. Results point out that both compounds induced proliferation in ER positive cells, not showing this effect in the ER-negative breast cancer cells. Different targets modified at the proteomic level in both breast cancer scenarios were also identified. Stem cell markers (eg. CD44) and invasion proteins (eg. MMP-14) were importantly increased by BPA and BPS in ER-positive breast cancer cells. In contrast, growth factors and associated receptors such as EGFR and TGF-ß were induced by BPS in the ER-negative breast cancer cells; both pollutants induced an increase of vascular endothelial growth factor (VEGF) protein secretion. This finding suggests that the use of BPS must be considered with more caution than BPA, since it can act independently of the presence of the hormonal receptor. These findings show new evidence that BPA and BPS exposure can contribute to breast cancer development and progression. Our results suggest that both BPA and BPS must be considered equally as outstanding risk factors for this pathology.

Assuntos

RESUMO

Previously, we have demonstrated that ß-estradiol-3-benzoate (EB) has a protective effect on the neurodegenerative experimental model of Parkinson's disease. The protective effect is through the induction of the expression of paraoxonase-2 (PON2) in the striatum. PON2 has proven to have antioxidant and anti-inflammatory activity, this protein has a beneficial effect in MPP+ model in rats decreasing the lipid peroxidation and the oxidative stress. Furthermore, the molecular effect and the pathway by which EB induces protection were not further pursued. This study shows the regulation by EB of the anti-inflammatory effect through the modulation of cytokines, antioxidant enzymes and PON2 in the rat striatum. Rats were gonadectomized and 30 days after were randomly assigned into four experimental groups; only vehicles (Control group); EB treatment (EB group); MPP+ injury (M group); EB plus MPP+ injured (EB/M group). EB treatment consisted of 100 µg of the drug administered every 48 h for 11 days. Results showed that EB (group EB/M) treatment decrease significantly (40%) the number of ipsilateral turns respect to the M group and prevents significantly the dopamine (DA) decreased induced by MPP+ (~75%). This results are correlate with a significant decrease in the level of lipid peroxidation (60%) of the EB/M group respect to the M group. The EB treatment showed protection against neurotoxicity induced with MPP+, this could be due to EB capacity to prevent the increase in the expression level of proinflammatory cytokines TNF-α, IL-1 and IL-6 induced by MPP+. While, TGF-ß1 and TGF-ß3 expression was reduced in the rats treated only with MPP+, in the rats of EB/M group the expression of both cytokines was increased. EB protective effect against MPP+ neurotoxicity is related to antioxidant effect of PON2, pro-inflammatory cytokines and GSHR but not to SOD2, catalase, GPX1 or GPX4.

Assuntos