Dietary (Poly)phenols and the Gut-Brain Axis in Ageing.

As the population ages, the incidence of age-related neurodegenerative diseases is rapidly increasing, and novel approaches to mitigate this soaring prevalence are sorely needed. Recent studies have highlighted the importance of gut microbial homeostasis and its impact on brain functions, commonly referred to as the gut-brain axis, in maintaining overall health and wellbeing. Nonetheless, the mechanisms by which this system acts remains poorly defined. In this review, we will explore how (poly)phenols, a class of natural compounds found in many plant-based foods and beverages, can modulate the gut-brain axis, and thereby promote neural health. While evidence indicates a beneficial role of (poly)phenol consumption as part of a balanced diet, human studies are scarce and mechanistic insight is still lacking. In this regard, we make the case that dietary (poly)phenols should be further explored to establish their therapeutic efficacy on brain health through modulation of the gut-brain axis, with much greater emphasis on carefully designed human interventions.

Immune Escape in Glioblastoma Multiforme and the Adaptation of Immunotherapies for Treatment.

Glioblastoma multiforme (GBM) is the most frequently occurring primary brain tumor and has a very poor prognosis, with only around 5% of patients surviving for a period of 5 years or more after diagnosis. Despite aggressive multimodal therapy, consisting mostly of a combination of surgery, radiotherapy, and temozolomide chemotherapy, tumors nearly always recur close to the site of resection. For the past 15 years, very little progress has been made with regards to improving patient survival. Although immunotherapy represents an attractive therapy modality due to the promising pre-clinical results observed, many of these potential immunotherapeutic approaches fail during clinical trials, and to date no immunotherapeutic treatments for GBM have been approved. As for many other difficult to treat cancers, GBM combines a lack of immunogenicity with few mutations and a highly immunosuppressive tumor microenvironment (TME). Unfortunately, both tumor and immune cells have been shown to contribute towards this immunosuppressive phenotype. In addition, current therapeutics also exacerbate this immunosuppression which might explain the failure of immunotherapy-based clinical trials in the GBM setting. Understanding how these mechanisms interact with one another, as well as how one can increase the anti-tumor immune response by addressing local immunosuppression will lead to better clinical results for immune-based therapeutics. Improving therapeutic delivery across the blood brain barrier also presents a challenge for immunotherapy and future therapies will need to consider this. This review highlights the immunosuppressive mechanisms employed by GBM cancers and examines potential immunotherapeutic treatments that can overcome these significant immunosuppressive hurdles.

Estrogen Promotes Pro-resolving Microglial Behavior and Phagocytic Cell Clearance Through the Actions of Annexin A1.

Local production of estrogen rapidly follows brain tissue injury, but the role this hormone plays in regulating the response to neural damage or in the modulation of mediators regulating inflammation is in many ways unclear. Using the murine BV2 microglia model as well as primary microglia from wild-type and annexin A1 (AnxA1) null mice, we have identified two related mechanisms whereby estradiol can modulate microglial behavior in a receptor specific fashion. Firstly, estradiol, via estrogen receptor ß (ERß), enhanced the phagocytic clearance of apoptotic cells, acting through increased production and release of the protein AnxA1. Secondly, stimulation of either ERß or the G protein coupled estrogen receptor GPER promoted the adoption of an anti-inflammatory/pro-resolving phenotype, an action similarly mediated through AnxA1. Together, these data suggest the hypothesis that locally produced estrogen acts through AnxA1 to exert powerful pro-resolving actions, controlling and limiting brain inflammation and ultimately protecting this highly vulnerable organ. Given the high degree of receptor selectivity in evoking these responses, we suggest that the use of selective estrogen receptor ligands may hold therapeutic promise in the treatment of neuroinflammation, avoiding unwanted generalized effects.

Nonredundant protective properties of FPR2/ALX in polymicrobial murine sepsis.

Sepsis is characterized by overlapping phases of excessive inflammation temporally aligned with an immunosuppressed state, defining a complex clinical scenario that explains the lack of successful therapeutic options. Here we tested whether the formyl-peptide receptor 2/3 (Fpr2/3)--ortholog to human FPR2/ALX (receptor for lipoxin A4)--exerted regulatory and organ-protective functions in experimental sepsis. Coecal ligature and puncture was performed to obtain nonlethal polymicrobial sepsis, with animals receiving antibiotics and analgesics. Clinical symptoms, temperature, and heart function were monitored up to 24 h. Peritoneal lavage and plasma samples were analyzed for proinflammatory and proresolving markers of inflammation and organ dysfunction. Compared with wild-type mice, Fpr2/3(-/-) animals exhibited exacerbation of disease severity, including hypothermia and cardiac dysfunction. This scenario was paralleled by higher levels of cytokines [CXCL1 (CXC receptor ligand 1), CCL2 (CC receptor ligand 2), and TNFα] as quantified in cell-free biological fluids. Reduced monocyte recruitment in peritoneal lavages of Fpr2/3(-/-) animals was reflected by a higher granulocyte/monocyte ratio. Monitoring Fpr2/3(-/-) gene promoter activity with a GFP proxy marker revealed an over threefold increase in granulocyte and monocyte signals at 24 h post-coecal ligature and puncture, a response mediated by TNFα. Treatment with a receptor peptido-agonist conferred protection against myocardial dysfunction in wild-type, but not Fpr2/3(-/-), animals. Therefore, coordinated physio-pharmacological analyses indicate nonredundant modulatory functions for Fpr2/3 in experimental sepsis, opening new opportunities to manipulate the host response for therapeutic development.

Endogenous annexin A1 is a novel protective determinant in nonalcoholic steatohepatitis in mice.

UNLABELLED: Annexin A1 (AnxA1) is an effector of the resolution of inflammation and is highly effective in terminating acute inflammatory responses. However, its role in chronic settings is less investigated. Because changes in AnxA1 expression within adipose tissue characterize obesity in mice and humans, we queried a possible role for AnxA1 in the pathogenesis of nonalcoholic steatohepatitis (NASH), a disease commonly associated with obesity. NASH was induced in wild-type (WT) and AnxA1 knockout (AnxA1 KO) C57BL/6 mice by feeding a methionine-choline deficient (MCD) diet up to 8 weeks. In MCD-fed WT mice, hepatic AnxA1 increased in parallel with progression of liver injury. This mediator was also detected in liver biopsies from patients with NASH and its degree of expression inversely correlated with the extent of fibrosis. In both humans and rodents, AnxA1 production was selectively localized in liver macrophages. NASH in AnxA1 KO mice was characterized by enhanced lobular inflammation resulting from increased macrophage recruitment and exacerbation of the M1 phenotype. Consistently, in vitro addition of recombinant AnxA1 to macrophages isolated from NASH livers down-modulated M1 polarization through stimulation of interleukin-10 production. Furthermore, the degree of hepatic fibrosis was enhanced in MCD-fed AnxA1 KO mice, an effect associated with augmented liver production of the profibrotic lectin, galectin-3. Accordingly, AnxA1 addition to isolated hepatic macrophages reduced galectin-3 expression. CONCLUSIONS: Macrophage-derived AnxA1 plays a functional role in modulating hepatic inflammation and fibrogenesis during NASH progression, suggesting the possible use of AnxA1 analogs for therapeutic control of this disease.

Chemerin15 inhibits neutrophil-mediated vascular inflammation and myocardial ischemia-reperfusion injury through ChemR23.

Neutrophil activation and adhesion must be tightly controlled to prevent complications associated with excessive inflammatory responses. The role of the anti-inflammatory peptide chemerin15 (C15) and the receptor ChemR23 in neutrophil physiology is unknown. Here, we report that ChemR23 is expressed in neutrophil granules and rapidly upregulated upon neutrophil activation. C15 inhibits integrin activation and clustering, reducing neutrophil adhesion and chemotaxis in vitro. In the inflamed microvasculature, C15 rapidly modulates neutrophil physiology inducing adherent cell detachment from the inflamed endothelium, while reducing neutrophil recruitment and heart damage in a murine myocardial infarction model. These effects are mediated through ChemR23. We identify the C15/ChemR23 pathway as a new regulator and thus therapeutic target in neutrophil-driven pathologies.

Oestrogen and immunomodulation: new mechanisms that impact on peripheral and central immunity.

The regulation of the immune response to infection or tissue damage is a complex interplay of multiple factors, but it has long been recognised that steroid hormones can exert powerful modulatory effects at all levels of the innate and adaptive immune systems. Although most attention has been paid to glucocorticoids given their widespread clinical use, it is becoming increasingly clear that sex steroid hormones, and in particular the principle female sex steroid oestrogen, exerts potent effects upon the immune response. In this review, we will discuss the latest findings on the impact of oestrogen upon various cellular components of the immune system, and how this hormone can offer new opportunities to pharmacologically harness the immune response.

Estrogen actions in the brain and the basis for differential action in men and women: a case for sex-specific medicines.

The classic view of estrogen actions in the brain was confined to regulation of ovulation and reproductive behavior in the female of all mammalian species studied, including humans. Burgeoning evidence now documents profound effects of estrogens on learning, memory, and mood as well as neurodevelopmental and neurodegenerative processes. Most data derive from studies in females, but there is mounting recognition that estrogens play important roles in the male brain, where they can be generated from circulating testosterone by local aromatase enzymes or synthesized de novo by neurons and glia. Estrogen-based therapy therefore holds considerable promise for brain disorders that affect both men and women. However, as investigations are beginning to consider the role of estrogens in the male brain more carefully, it emerges that they have different, even opposite, effects as well as similar effects in male and female brains. This review focuses on these differences, including sex dimorphisms in the ability of estradiol to influence synaptic plasticity, neurotransmission, neurodegeneration, and cognition, which, we argue, are due in a large part to sex differences in the organization of the underlying circuitry. There are notable sex differences in the incidence and manifestations of virtually all central nervous system disorders, including neurodegenerative disease (Parkinson's and Alzheimer's), drug abuse, anxiety, and depression. Understanding the cellular and molecular basis of sex differences in brain physiology and responses to estrogen and estrogen mimics is, therefore, vitally important for understanding the nature and origins of sex-specific pathological conditions and for designing novel hormone-based therapeutic agents that will have optimal effectiveness in men or women.

Independent influences of sex steroids of systemic and central origin in a rat model of Parkinson's disease: A contribution to sex-specific neuroprotection by estrogens.

This review considers evidence which reveals considerable complexity and sex differences in the response of the nigrostriatal dopaminergic (NSDA) system to hormonal influences. This pathway degenerates in Parkinson's disease (PD) and sex hormones contribute to sex differences in PD, where men fare worse than women. Here we discuss evidence from animal studies which allows us to hypothesize that, contrary to expectations, the acclaimed neuroprotective property of physiological concentrations of estradiol arises not by promoting NSDA neuron survival, but by targeting powerful adaptive responses in the surviving neurons, which restore striatal DA functionality until over 60% of neurons are lost. Estrogen generated locally in the NSDA region appears to promote these adaptive mechanisms in females and males to preserve striatal DA levels in the partially injured NSDA pathway. However, responses to systemic steroids differ between the sexes. In females there is general agreement that gonadal steroids and exogenous estradiol promote striatal adaptation in the partially injured NSDA pathway to protect against striatal DA loss. In contrast, the balance of evidence suggests that in males gonadal factors and exogenous estradiol have negligible or even harmful effects. Sex differences in the organization of NSDA-related circuitry may well account for these differences. Compensatory mechanisms and sexually dimorphic hard-wiring are therefore likely to represent important biological substrates for sex dimorphisms. As these processes may be targeted differentially by systemic steroids in males and females, further understanding of the underlying processes would provide valuable insights into the potential for hormone-based therapies in PD, which would need to be sex-specific. Alternatively, evidence that estrogen generated locally is protective in the injured male NSDA pathway indicates the great therapeutic potential of harnessing central steroid synthesis to ameliorate neurodegenerative disorders. A clearer understanding of the relative contributions and inter-relationships of central and systemic steroids within the NSDA system is an important goal for future studies.

Annexin A1 regulates hormone exocytosis through a mechanism involving actin reorganization.

The glucocorticoid-regulated protein annexin A1 is a potent inhibitor of hormone exocytosis in the neuroendocrine system, acting in a paracrine/juxtacrine manner. The signaling mechanism employed by annexin A1 in this process is uncertain, although we have recently presented evidence for a role of the formyl peptide receptor in vivo. We sought to characterize the mechanism of action of annexin A1 on exocytosis using the release of adrenocorticotrophin from the corticotroph-like cell line AtT20 as an in vitro model system. Through the comparison of adrenocorticotrophin release from cells expressing either wild-type annexin A1 or mutant forms, we show a critical involvement of phosphorylation on serine 27 and 45 in the translocation of the protein to the membrane and its inhibitory action on exocytosis. Moreover, we show, for the first time, that annexin A1-dependent inhibition of adrenocorticotrophin release involves the enhancement of actin polymerization to prevent exocytosis via formyl peptide receptor and Rho kinase signaling pathways. This finding has significant implications for the inhibitory actions of annexin A1 on exocytosis in other endocrine and immune contexts.

Striatal susceptibility to a dopaminergic neurotoxin is independent of sex hormone effects on cell survival and DAT expression but is exacerbated by central aromatase inhibition.

The aim of this study was to investigate further the hormone-dependent processes underlying sex differences in neurotoxic responses within the rat nigrostriatal dopaminergic (NSDA) pathway after partial lesioning with 6-OHDA, a state thought to mimic the early stages of Parkinson's disease where, in humans and animal models alike, males appear to be more susceptible. Contrary to our hypotheses, hormone manipulations (gonadectomy +/- oestrogen or androgen treatment) failed to alter survival of tyrosine hydroxylase immunoreactive cells in the substantia nigra pars compacta (SNc) after lesioning; this indicates that, unlike inherent sex differences in toxin-induced striatal dopamine depletion, sex differences in cell loss were not hormonally generated, and that hormone-dependent changes in dopamine depletion can occur independently of cell survival. In addition, hormonally induced changes in striatal expression of the dopamine transporter (DAT), an important factor for 6-OHDA toxicity, did not correlate with hormonal influences on striatal dopamine loss and, in males, central inhibition of aromatase prior to 6-OHDA infusion exacerbated striatal dopamine loss with no effect on SNc tyrosine hydroxylase-immunoreactive survival, suggesting locally generated oestrogen is neuroprotective. These results support the novel view that sex steroid hormones produced peripherally and centrally play a significant, sex-specific role within the sexually dimorphic NSDA pathway to modulate plastic, compensatory responses aimed at restoring striatal dopamine functionality, without affecting cell loss.

Sex dimorphisms in the neuroprotective effects of estrogen in an animal model of Parkinson's disease.

The incidence of certain neurological disorders, including Parkinson's disease, appears to be more prevalent in men. Studies involving estrogen treatment of ovariectomised rodents attribute this largely to the neuroprotective effects of estrogen. However, a neuroprotective role for physiological levels of circulating hormones in males and females is less clear. Using the 6-hydroxydopamine (6-OHDA) model of Parkinson's disease to lesion the nigrostriatal dopaminergic (NSDA) pathway, we have shown that in females, endogenously produced estrogen is neuroprotective, whereas in males, gonadal factors increase striatal 6-OHDA toxicity. Intriguingly, estrogen, but not dihydrotestosterone, a nonaromatizable androgen, reversed the effects of orchidectomy on lesion size, raising the novel the hypothesis that enhanced male susceptibility may be attributable to the effects of endogenous testosterone only after its aromatization to estrogen. Thus, estrogen appears to exert opposite effects in the NSDA in males and females, being neuroprotective in females, but not in males, where it may even exacerbate neurodegenerative responses, with important implications for the clinical potential of estrogen-related compounds as neuroprotective agents. Preliminary experiments support the hypothesis that sex differences in the adult NSDA may result from the organisational actions of gonadal steroids during the critical neonatal period for the masculinization of the brain. Further studies are needed to determine whether this early organisation of a sexually differentiated neural circuitry may contribute to the emergence of neurodegenerative conditions such as Parkinson's disease.