Intratumoral Treatment with 5-Androstene-3ß, 17α-Diol Reduces Tumor Size and Lung Metastasis in a Triple-Negative Experimental Model of Breast Cancer.

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.

Potential Novel Risk Factor for Breast Cancer: Toxocara canis Infection Increases Tumor Size Due to Modulation of the Tumor Immune Microenvironment.

Worldwide, breast cancer is the most important type of cancer in women with regard to incidence and prevalence. Several risk factors interact to increase the probability of breast cancer development. Biological environmental contaminants such as infectious agents play a significant role in tumor development, and helminths have been recognized as cancer enhancers or inducers due to their ability to regulate the host immune response. Toxocara canis is a zoonotic and cosmopolite nematode with immuno-regulatory abilities. T. canis infection has been related to T helper type-2 cell (Th2 or type 2) and regulatory responses. Type 2 and regulatory immune responses may favor the development of comorbidities that are usually controlled or eliminated through a type 1 response such as cancer. The aim of this study was to determine whether T. canis infection alters mammary tumor growth through modulation of the immune response. Infected mice developed larger tumors. Tumor immune cell milieu analysis revealed that infection reduced the proportions of CD8+ lymphocytes and increased the proportions of F4/80+ macrophages and CD19+ B cells. These changes were accompanied by a type 2 local response represented by increased amounts of IL-4 and VEGF and a regulatory microenvironment associated with higher IL-10 levels. Thus, this study demonstrates that T. canis infection enhances tumor development and suggests that this is through modulation of the tumor immune microenvironment.

Immune response to chronic Toxocara canis infection in a mice model.

AIMS: The zoonotic nematode Toxocara canis causes larva migrans syndrome that induces an immune response characterized by the production of antibodies and eosinophilia. A Th2 polarization has been associated with the infection, but there are still details of the cellular and humoral immune response that need to be described. Thus, the aim of this study was to describe the systemic host immune response to T canis chronic infection in a mouse model. METHODS AND RESULTS: BALB/c mice were inoculated once with 500 T canis embryonated eggs, per os. After 49 days, the amounts of larval found in brain and muscle tissues were statistically two and four times higher, respectively, than the amounts found in lung, liver, kidney or heart tissues. Splenic proportions of F4/80+ cells, as well as B, cytotoxic T and CD4+ Foxp3+ lymphocytes, were statistically higher (P ≤ .05, P ≤ .01, P ≤ .001 and P ≤ .001, respectively) as compared with control mice. In lymph nodes, some of these proportions changed, with the exception of F4/80+ cells. IgG1 levels in infected mice sera were increased. IL-4, IL-10 and VEGF levels were statistically higher in spleen (P ≤ .05, all) and sera (P ≤ .01, P ≤ .05 and P ≤ .05, respectively) in the infected mice. Also, in infected animals, IL-5 serum levels were increased (P ≤ .01). CONCLUSION: These results suggest that T canis chronic infection in BALB/c mice results in a type 2 response with an incipient regulatory response.

Gestational exposure to the cannabinoid WIN 55,212-2 and its effect on the innate intestinal immune response.

The consequences of marijuana consumption during pregnancy and its effects on the function of the immune system have been little studied. Marijuana is one of the most consumed recreational drugs among pregnant women, and it is known that gestational exposure to marijuana can have serious effects on the offspring after birth. In this study, we challenged the immune system of Wistar rats by infecting them with the parasitic nematode Trichinella spiralis. A treatment group of these animals was prenatally exposed to the cannabinoid WIN 55,212-2; a control group was not exposed. At 5 days of infection, the treated animals were less effective in eliminating intestinal parasites; moreover, this effect was correlated with a deficiency in mucus production, lower recruitment of eosinophils in the duodenum, and a reduced percentage of Tγδ and NK cells. In conclusion, the gestational administration of the synthetic cannabinoid WIN 55,212-2 induces lasting changes to the function of the immune system against infection with T. spiralis in male Wistar rats, making them more susceptible to infection.

Sex-Associated Differential mRNA Expression of Cytokines and Its Regulation by Sex Steroids in Different Brain Regions in a Plasmodium berghei ANKA Model of Cerebral Malaria.

Cerebral malaria (CM) is the major complication associated with death in malaria patients, and its pathogenesis is associated with excessive proinflammatory cytokine production. Notably, the severity and mortality of natural infections with Plasmodium are higher in males than females, suggesting that sexual hormones influence both the pathogenesis of and immune response in CM. However, no studies on inflammation mediators in the brains of both sexes have been reported. In this work, the mRNA expression levels of the proinflammatory cytokines IL-1ß, IFN-γ, TNF-α, and IL-2 were measured in the preoptic area, hypothalamus, hippocampus, olfactory bulb, frontal cortex, and lateral cortex regions of gonadectomized female and male CBA/Ca mice infected with P. berghei ANKA (a recognized experimental CM model). Our findings demonstrate that both infection with P. berghei ANKA and gonadectomy trigger a cerebral sex dimorphic mRNA expression pattern of the cytokines IL-1ß, TNF-α, IFN-γ, and IL-2. This dimorphic cytokine pattern was different in each brain region analysed. In most cases, infected males exhibited higher mRNA expression levels than females, suggesting that sexual hormones differentially regulate the mRNA expression of proinflammatory cytokines in the brain and the potential use of gonadal steroids or their derivates in the immunomodulation of cerebral malaria.

Immunoregulatory Role of Cannabinoids during Infectious Disease.

Although the endocannabinoid system (ECS) is involved in the regulation of several physiological processes, including sleep and the immune response, its role during infections has not been fully studied. It is well known that the use of this drug increases susceptibility to infections because of the impact on the modulation of the immune system. Concerning the medicinal or recreational use of marijuana, its influence on the course of an infection, whether this has been caused by bacteria, viruses, parasites, and to a lesser degree, fungi, has been reported. Furthermore, there is evidence suggesting the involvement of the ECS in the control and elimination of infectious agents such as bacteria, viruses, and some protozoa; in the case of fungi, few studies are available so far. The purpose of this review is to present the existing studies related to infections and the ECS, the microbicidal effects of compounds isolated from Cannabis sativa, and the association between marijuana use and the development of rare pathologies in specific diseases.

The endocrine-immune network during taeniosis by Taenia solium: The role of the pituitary gland.

It is well known that sex hormones play an important role during Taenia solium infection; however, to our knowledge no studies exist concerning the immune response following complete or lobe-specific removal of the pituitary gland during T. solium infection. Thus, the aim of this work was to analyze in hamsters, the effects of lack of pituitary hormones on the duodenal immune response, and their impact on T. solium establishment and development. Thus, in order to achieve this goal, we perform anterior pituitary lobectomy (AL, n = 9), neurointermediate pituitary lobectomy (NIL, n = 9) and total hypophysectomy (HYPOX, n = 8), and related to the gut establishment and growth of T. solium, hematoxylin-eosin staining of duodenal tissue and immunofluorescence of duodenal cytokine expression and compared these results to the control intact (n = 8) and control infected group (n = 8). Our results indicate that 15 days post-infection, HYPOX reduces the number and size of intestinally recovered T. solium adults. Using semiquantitative immunofluorescent laser confocal microscopy, we observed that the mean intensity of duodenal IFN-γ and IL-12 Th1 cytokines was mildly expressed in the infected controls, in contrast with the high level of expression of these cytokines in the NIL infected hamsters. Likewise, the duodenum of HYPOX animals showed an increase in the expression of Th2 cytokines IL-5 and IL-6, when compared to control hamsters. Histological analysis of duodenal mucosa from HYPOX hamsters revealed an exacerbated inflammatory infiltrate located along the lamina propria and related to the presence of the parasite. We conclude that lobe-specific pituitary hormones affect differentially the T. solium development and the gut immune response.

Gender-associated differential expression of cytokines in specific areas of the brain during helminth infection.

Intraperitoneal infection with Taenia crassiceps cysticerci in mice alters several behaviors, including sexual, aggressive, and cognitive function. Cytokines and their receptors are produced in the central nervous system (CNS) by specific neural cell lineages under physiological and pathological conditions, regulating such processes as neurotransmission. This study is aimed to determine the expression patterns of cytokines in various areas of the brain in normal and T. crassiceps-infected mice in both genders and correlate them with the pathology of the CNS and parasite counts. IL-4, IFN-γ, and TNF-α levels in the hippocampus and olfactory bulb increased significantly in infected male mice, but IL-6 was downregulated in these regions in female mice. IL-1ß expression in the hippocampus was unaffected by infection in either gender. Our novel findings demonstrate a clear gender-associated pattern of cytokine expression in specific areas of the brain in mammals that parasitic infection can alter. Thus, we hypothesize that intraperitoneal infection is sensed by the CNS of the host, wherein cytokines are important messengers in the host-parasite neuroimmunoendocrine network.

Regulation of intestinal immune response by selective removal of the anterior, posterior, or entire pituitary gland in Trichinella spiralis infected golden hamsters.

The influence of anterior pituitary hormones on the gastrointestinal tract of humans and animals has been previously reported. Hypophysectomy (HYPOX) in the rat causes atrophy of the intestinal mucosa, and reduction of gastric secretion and intestinal absorption, as well as increased susceptibility to bacterial and viral infections. However, to our knowledge, no findings have been published concerning the immune response following HYPOX during worm infection, particularly that which is caused by the nematode Trichinella spiralis. The aim of this work was to analyze the effects of total or partial HYPOX on colonization of T. spiralis in the intestinal lumen, together with duodenal and splenic cytokine expression. Our results indicate that 5 days post infection, only neurointermediate pituitary lobectomy (NIL) reduces the number of intestinally recovered T. spiralis larvae. Using semiquantitative inmunofluorescent laser confocal microscopy, we observed that the mean intensity of all tested Th1 cytokines was markedly diminished, even in the duodenum of infected controls. In contrast, a high level of expression of these cytokines was noted in the NIL infected hamsters. Likewise, a significant decrease in the fluorescence intensity of Th2 cytokines (with the exception of IL-4) was apparent in the duodenum of control and sham infected hamsters, compared to animals with NIL surgeries, which showed an increase in the expression of IL-5 and IL-13. Histology of duodenal mucosa from NIL hamsters showed an exacerbated inflammatory infiltrate located along the lamina propria, which was related to the presence of the parasite. We conclude that hormones from each pituitary lobe affect the gastrointestinal immune responses to T. spiralis through various mechanisms.