Extracellular Vesicles miRNA Cargo for Microglia Polarization in Traumatic Brain Injury

Traumatic brain injury (TBI) is one of the major causes of death and disability worldwide, and despite its high dissemination, effective pharmacotherapies are lacking. TBI can be divided into two phases: the instantaneous primary mechanical injury, which occurs at the moment of insult, and the delayed secondary injury, which involves a cascade of biological processes that lead to neuroinflammation. Neuroinflammation is a hallmark of both acute and chronic TBI, and it is considered to be one of the major determinants of the outcome and progression of disease. In TBI one of the emerging mechanisms for cell-cell communication involved in the immune response regulation is represented by Extracellular Vesicles (EVs). These latter are produced by all cell types and are considered a fingerprint of their generating cells. Exosomes are the most studied nanosized vesicles and can carry a variety of molecular constituents of their cell of origin, including microRNAs (miRNAs). Several miRNAs have been shown to target key neuropathophysiological pathways involved in TBI. The focus of this review is to analyze exosomes and their miRNA cargo to modulate TBI neuroinflammation providing new strategies for prevent long-term progression of disease

Functional Role of Non-Muscle Myosin II in Microglia: An Updated Review.

Myosins are a remarkable superfamily of actin-based motor proteins that use the energy derived from ATP hydrolysis to translocate actin filaments and to produce force. Myosins are abundant in different types of tissues and involved in a large variety of cellular functions. Several classes of the myosin superfamily are expressed in the nervous system; among them, non-muscle myosin II (NM II) is expressed in both neurons and non-neuronal brain cells, such as astrocytes, oligodendrocytes, endothelial cells, and microglia. In the nervous system, NM II modulates a variety of functions, such as vesicle transport, phagocytosis, cell migration, cell adhesion and morphology, secretion, transcription, and cytokinesis, as well as playing key roles during brain development, inflammation, repair, and myelination functions. In this review, we will provide a brief overview of recent emerging roles of NM II in resting and activated microglia cells, the principal regulators of immune processes in the central nervous system (CNS) in both physiological and pathological conditions. When stimulated, microglial cells react and produce a number of mediators, such as pro-inflammatory cytokines, free radicals, and nitric oxide, that enhance inflammation and contribute to neurodegenerative diseases. Inhibition of NM II could be a new therapeutic target to treat or to prevent CNS diseases

Beneficial Effects of Spirulina Consumption on Brain Health

Spirulina is a microscopic, filamentous cyanobacterium that grows in alkaline water bodies. It is extensively utilized as a nutraceutical food supplement all over the world due to its high levels of functional compounds, such as phycocyanins, phenols and polysaccharides, with anti-inflammatory, antioxidant, immunomodulating properties both in vivo and in vitro. Several scientific publications have suggested its positive effects in various pathologies such as cardiovascular diseases, hypercholesterolemia, hyperglycemia, obesity, hypertension, tumors and inflammatory diseases. Lately, different studies have demonstrated the neuroprotective role of Spirulina on the development of the neural system, senility and a number of pathological conditions, including neurological and neurodegenerative diseases. This review focuses on the role of Spirulina in the brain, highlighting how it exerts its beneficial anti-inflammatory and antioxidant effects, acting on glial cell activation, and in the prevention and/or progression of neurodegenerative diseases, in particular Parkinson's disease, Alzheimer's disease and Multiple Sclerosis; due to these properties, Spirulina could be considered a potential natural drug

IL-10 plays a pivotal role in anti-inflammatory effects of resveratrol in activated microglia cells

The development of agents that can modulate microglial activation has been suggested as one potential strategy for the treatment or prevention of neurodegenerative diseases. Among these agents, resveratrol, with its anti-inflammatory action, has been described to have neuroprotective effects. In this paper we demonstrate that in LPS-stimulated microglia resveratrol pretreatment reduced, in a dose-dependent manner, pro-inflammatory cytokines IL-1β, TNF-α and IL-6 mRNA expression and increased the release of anti-inflammatory interleukin (IL)-10. Moreover, resveratrol pretreatment up-regulated the phosphorylated forms of JAK1 and STAT3, as well as suppressor of cytokine signaling (SOCS)3 protein expression in LPS activated cells, demonstrating that the JAK-STAT signaling pathway is involved in the anti-inflammatory effect exerted by resveratrol. By supplementing the cultures with an IL-10 neutralizing antibody (IL-10NA) we obtained the opposite effect. Taken together, these data allow us to conclude that the LPS-induced pro-inflammatory response in microglial cells can be markedly reduced by resveratrol, through IL-10 dependent up-regulation of SOCS3, requiring the JAK-STAT signaling pathway

Role of Vitamin E and the Orexin System in Neuroprotection.

Microglia are the first line of defense at the level of the central nervous system (CNS). Phenotypic change in microglia can be regulated by various factors, including the orexin system. Neuroinflammation is an inflammatory process mediated by cytokines, by the lack of interaction of specific receptors such as the OX2-OX2R complex, caused by systemic tissue damage or, more often, associated with direct damage to the CNS. Chronic activation of microglia could lead to long-term neurodegenerative diseases. This review aims to explore how tocopherol (vitamin E) and the orexin system may play a role in the prevention and treatment of microglia inflammation and, consequently, in neurodegenerative diseases thanks to its antioxidant properties. The results of animal and in vitro studies provide evidence to support the use of tocopherol for a reduction in microglia inflammation as well as a greater activation of the orexinergic system. Although there is much in vivo and in vitro evidence of vitamin E antioxidant and protective abilities, there are still conflicting results for its use as a treatment for neurodegenerative diseases that speculate that vitamin E, under certain conditions or genetic predispositions, can be pro-oxidant and harmful

Formyl Peptide Receptor (FPR)1 Modulation by Resveratrol in an LPS-Induced Neuroinflammatory Animal Model

Among therapeutic approaches that have been investigated, targeting of receptors implicated in managing neuroinflammation has been described. One such family of receptors comprises the formyl peptide receptors (FPRs) whose ligands could play a role in host defense. The murine FPR gene family includes at least six members while in humans there are only three. The two most important members are the Fpr1 and Fpr2. Fpr1encodes murine FPR1, which is considered the murine orthologue of human FPR. Resveratrol, a non-flavonoid polyphenol rich in red wine and grapes, apart from its beneficial health effects and anti-inflammatory properties, has been reported to reduce neuroinflammation in different neurodegenerative disease models. Resveratrol anti-inflammatory responses involve the activation of the protein deacetylase sirtuin 1 (SIRT1) gene. In this work we have investigated in an LPS-based murine model of neuroinflammation the role of FPR1, examining not only if this receptor undergoes a reduction of its expression during neuroinflammation, but also whether treatment with resveratrol was able to modulate its expression leading to an amelioration of neuroinflammatory picture in a murine model of neuroinflammation. Results of this work showed that FPR1 together with SIRT1 resulted upregulated by resveratrol treatment and that this increase is associated with an amelioration of the neuroinflammatory picture, as demonstrated by the induction of IL-10 and IL1-RA expression and the downregulation of proinflammatory mediators, such as TNF-α and IL-1β. The expression and the modulation of FPR1 by resveratrol may be evaluated in order to propose a novel anti-inflammatory and pro-resolving therapeutic approach for the reduction of the detrimental effects associated with neuro-inflammation based neurodegenerative diseases and also as a promising strategy to promote human health by a diet rich in antioxidative bioactive compounds

New Promising Therapeutic Avenues of Curcumin in Brain Diseases

Curcumin, the dietary polyphenol isolated from Curcuma longa (turmeric), is commonly used as an herb and spice worldwide. Because of its bio-pharmacological effects curcumin is also called "spice of life", in fact it is recognized that curcumin possesses important proprieties such as anti-oxidant, anti-inflammatory, anti-microbial, antiproliferative, anti-tumoral, and anti-aging. Neurodegenerative diseases such as Alzheimer's Diseases, Parkinson's Diseases, and Multiple Sclerosis are a group of diseases characterized by a progressive loss of brain structure and function due to neuronal death; at present there is no effective treatment to cure these diseases. The protective effect of curcumin against some neurodegenerative diseases has been proven by in vivo and in vitro studies. The current review highlights the latest findings on the neuroprotective effects of curcumin, its bioavailability, its mechanism of action and its possible application for the prevention or treatment of neurodegenerative disorders

Inflammatory Response Modulation by Vitamin C in an MPTP Mouse Model of Parkinson's Disease

Vitamin C (Vit C) is anutrient present in many foods, particularly citrus fruits, green vegetables, tomatoes, and potatoes. Vit C is studied for its applications in the prevention and management of different pathologies, including neurodegenerative diseases. Neuroinflammation is a defense mechanism activated by a stimulus or an insult that is aimed at the preservation of the brain by promoting tissue repair and removing cellular debris; however, persistent inflammatory responses are detrimental and may lead to the pathogenesis and progression of neurodegenerative diseases like Parkinson's disease (PD) and Alzheimer's disease. PD is one of the most common chronic progressive neurodegenerative disorders, and oxidative stress is one of the most important factors involved in its pathogenesis and progression.Due to this, research on antioxidant and anti-inflammatory compounds is an important target for counteracting neurodegenerative diseases, including PD. In the central nervous system, the presence of Vit C in the brain is higher than in other body districts, but why and how this occurs is still unknown. In this research, Vit C, with its anti-inflammatory and anti-oxidative properties, is studied to better understand its contribution to brain protection; in particular, we have investigated the neuroprotective effects of Vit C in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced animal model of PD and its role in the modulation of neuroinflammation. First, we observed that Vit C significantly decreased the MPTP-induced loss of tyrosine hydroxylase (TH)-positive dopaminergic neuronal cells in the substantia nigra, as well as microglial cell activation and astrogliosis. Furthermore, gait and spontaneous locomotor activity, evaluated by an automated treadmill and the Open Field test, respectively, were partially ameliorated by Vit C treatment in MPTP-intoxicated animals. In relation to neuroinflammation, results show that Vit C reduced the protein and mRNA expression of inflammatory cytokines such as IL-6, TLR4, TNF-α, iNOS, and CD40, while anti-inflammatory proteins such as IL-10, CD163, TGF-β, and IL-4 increased. Interestingly, we show for the first time that Vit C reduces neuroinflammation by modulating microglial polarization and astrocyte activation. Moreover, Vit C was able to reduce NLRP3 activation, which is linked to the pathogenesis of many inflammatory diseases, including neuroinflammatory disorders. In conclusion, our study provides evidence that Vit C may represent a new promising dietary supplement for the prevention and alleviation of the inflammatory cascade of PD, thus contributing to neuroprotection

Deferral of assessment of pulmonary embolism

We evaluated a simplified algorithm for safely postponing diagnostic imaging for pulmonary embolism (PE). At the index visit, patients were identified as being at high or low risk of PE; the former received full dosage low molecular weight heparin while the latter were left untreated until performance of diagnostic imaging (max 72 hours). During this period, no thromboembolic events occurred in low-risk patients (0/211, 0.% [upper 95% CI 0.9%]); only one event occurred in those at high-risk (1/125, 0.8% [upper 95% CI, 1.2]). Our study demonstrates that diagnostic imaging for PE can be safely deferred for up to 3 days