Search

Acute graft-versus-host disease (aGVHD) and cytomegalovirus reactivation are important complications after allogeneic stem cell transplantation (alloHSCT). Here, we evaluated the impact of treatment with alemtuzumab on the occurrence of aGVHD, cytomegalovirus reactivation and survival after alloHSCT. This was a prospective cohort study conducted at the allo-HSCT unit of Hospital das Clínicas, Universidade Federal de Minas Gerais, Brazil, from January 2009 to December 2011. Fifty-seven patients who underwent alloHSCT were included. Forty-five (79%) patients had a malignant disease. Alemtuzumab was administered before the conditioning regimen at a dose of 1 mg/kg in children and 30 mg/day for 2 days in adults or children weighing more than 40 kg (a total dose of 60 mg) with a non-malignant disease or patients with a malignant disease and high-risk for GVHD mortality. Alemtuzumab was used in 23 (40%) patients, of whom 17 received a reduced-intensity conditioning. Eleven patients presented aGVHD (grade 2-4) and only 1 of them received alemtuzumab. Cumulative incidence of aGVHD (grade 2-4) at day 100 after transplantation (D+100) was 4 for patients receiving alemtuzumab and 29% for patients not receiving alemtuzumab. Cumulative incidence of cytomegalovirus reactivation for patients receiving or not alemtuzumab was 62 and 38%, respectively. Sixteen patients died in the first 100 days after alloHSCT, most of them due to bacterial sepsis. Only 2 patients died of aGVHD until D+100. Overall survival was 50% without any impact of alemtuzumab. Alemtuzumab effectively controlled aGVHD but increased the risk of cytomegalovirus reactivation without improving survival.

Graft versus host disease (GVHD) is an immunological disorder triggered by bone marrow transplantation that affects several organs, including the gastrointestinal tract and liver. Fullerenes and their soluble forms, fullerols, are nanocomposites with a closed symmetrical structure with anti-inflammatory and anti-oxidant properties. The present study evaluated the effects of treatment with the fullerol (C60(OH)18-20) in the development and pathogenesis of GVHD in a murine model. Mice with experimental GVHD that were treated with the fullerol showed reduced clinical signs of disease and mortality compared with untreated mice. Treatment with the fullerol decreased the hepatic damage associated with reduced hepatic levels of reactive oxygen species, pro-inflammatory cytokines and chemokines (IFN-γ TNF-α, CCL2, CCL3 and CCL5) and reduced leukocyte accumulation. The amelioration of GVHD after treatment with the fullerol was also associated with reduced intestinal lesions and consequent bacterial translocation to the blood, liver and peritoneal cavity. Moreover, the fullerol treatment alleviated the GVHD while preserving effects of the graft against a leukemia cell line (GFP+P815). In summary, the fullerol was effective in reducing the GVHD inflammatory response in mice and may suggest novel ways to treat this disease.

Intense exercise is a physiological stress capable of inducing the interaction of neutrophils with muscle endothelial cells and their transmigration into tissue. Mechanisms driving this physiological inflammatory response are not known. Here, we investigate whether production of reactive oxygen species is relevant for neutrophil interaction with endothelial cells and recruitment into the quadriceps muscle in mice subjected to the treadmill fatiguing exercise protocol. Mice exercised until fatigue by running for 56.3±6.8 min on an electric treadmill. Skeletal muscle was evaluated by intravital microscopy at different time points after exercise, and then removed to assess local oxidative stress and histopathological analysis. We observed an increase in plasma lactate and creatine kinase (CK) concentrations after exercise. The numbers of monocytes, neutrophils, and lymphocytes in blood increased 12 and 24 hours after the exercise. Numbers of rolling and adherent leukocytes increased 3, 6, 12, and 24 hours post-exercise, as assessed by intravital microscopy. Using LysM-eGFP mice and confocal intravital microscopy technology, we show that the number of transmigrating neutrophils increased 12 hours post-exercise. Mutant gp91phox-/- (non-functional NADPH oxidase) mice and mice treated with apocynin showed diminished neutrophil recruitment. SOD treatment promoted further adhesion and transmigration of leukocytes 12 hours after the exercise. These findings confirm our hypothesis that treadmill exercise increases the recruitment of leukocytes to the postcapillary venules, and NADPH oxidase-induced ROS plays an important role in this process.

Lithothamnion muelleri (Hapalidiaceae) is a marine red alga, which is a member of a group of algae with anti-inflammatory, antitumor, and immunomodulatory properties. The present study evaluated the effects of treatment with Lithothamnion muelleri extract (LM) in a model of acute graft-versus-host disease (GVHD), using a model of adoptive splenocyte transfer from C57BL/6 donors into B6D2F1 recipient mice. Mice treated with LM showed reduced clinical signs of disease and mortality when compared with untreated mice. LM-treated mice had reduced tissue injury, less bacterial translocation, and decreased levels of proinflammatory cytokines and chemokines (interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), chemokine (C-C motif) ligand 2 (CCL2), chemokine (C-C motif) ligand 3 (CCL3) and chemokine (C-C motif) ligand 5 (CCL5)). The polysaccharide-rich fraction derived from LM could inhibit leukocyte rolling and adhesion in intestinal venules, as assessed by intravital microscopy. LM treatment did not impair the beneficial effects of graft-versus-leukaemia (GVL). Altogether, our studies suggest that treatment with Lithothamnion muelleri has a potential therapeutic application in GVHD treatment.

PAF is a potent lipid mediator involved in several manifestations of acute inflammation, including leukocyte influx, leukocyte interaction with endothelium, and production of inflammatory cytokines. The present study evaluated the relevance of PAFR for the pathogenesis of acute GVHD using a model of adoptive transfer of splenocytes from WT or PAFR(-/-) C57BL/6J to B6D2F1 mice. Mice, which received PAFR(-/-) splenocytes or treatment with the PAFR antagonist, showed reduced clinical signs of disease and no mortality. In GVHD mice receiving PAFR(-/-) splenocytes, there was deceased bacterial translocation and tissue injury. Furthermore, production of proinflammatory cytokines and chemokines (TNF-α, IFN-γ, CCL2, CCL3, and CCL5) and accumulation of CD8(+) cells in intestine and liver were reduced in mice transplanted with the PAFR(-/-) splenocyte. Mechanistically, an absence or pharmacological blockade of PAFR was associated with decreased rolling and adhesion of leukocytes to the mesenteric microcirculation, as assessed by intravital microscopy. Despite decreased GVHD, there was maintained GVL activity when PAFR(-/-) leukocytes were transferred into WT mice. In conclusion, PAFR on donor leukocytes plays a critical role in GVHD by mediating leukocyte influx and cytokine production in target tissues. PAFR antagonist may potentially be useful in the treatment of GVHD in bone marrow-transplanted patients.

PI(3)Kγ is thought to mediate leukocyte migration to injured tissues and may be important in the pathogenesis of various T-lymphocyte-dependent pathologies, including autoimmune and inflammatory diseases. The present study evaluated the relevance of PI(3)Kγ in donor cells for the pathogenesis of acute GVHD using a model of adoptive transfer of splenocytes from WT or PI(3)Kγ(-/-) C57BL/6J mice to B6D2F1 mice, and mice that received PI(3)Kγ(-/-) cells showed reduced clinical signs of disease, bacterial translocation, tissue injury, and lethality rates. This was associated with reduced production of proinflammatory cytokines and chemokines (TNF-α, IFN-γ, CCL2, CCL3, and CCL5) and reduced infiltration of CD8(+), CD4(+), and CD11c(+) cells in the small intestine. Mechanistically, in addition to decreasing production of proinflammatory mediators, absence or pharmacological blockade of PI(3)Kγ was associated with decreased rolling and adhesion of leukocytes to the mesenteric microcirculation, as assessed by intravital microscopy. Despite decreased GVHD, there was maintained GVL activity when PI(3)Kγ(-/-) leukocytes were transferred into WT mice. In conclusion, PI(3)Kγ plays a critical role in GVHD by mediating leukocyte influx and activation in tissues. PI(3)Kγ inhibitors may be useful in the treatment of GVHD in patients undergoing BMT.

Objective and Design: The aim of this study was to investigate the effects of ethanol exposure on epigenetic markers in bone marrow (BM) and their impact on inflammatory response during Aspergillus fumigatus infection., Results: Chronic ethanol exposure decreased H3K27me3 enrichment in the Il6 promoter region while increased H3K4me3 enrichment in Tnf. Chimeric mice were generated by transplanting BM from mice exposed to ethanol or water. Infection of ethanol-chimeric mice culminated in higher clinical scores, although there was no effect on mortality. However, previous chronic exposure to ethanol affects persistently the inflammatory response in lung tissue, demonstrated by increased lung damage, neutrophil accumulation and IL-6, TNF and CXCL2 production in ethanol-chimeric mice, resulting in a decreased neutrophil infiltration into the alveolar space. Neutrophil killing and phagocytosis were also significantly lower. Moreover, BM derived macrophages (BMDM) from ethanol-chimeric mice stimulated with A. fumigatus conidia exhibited higher levels of TNF, CXCL2 and IL-6 release and a higher killing activity. The Il6 promoter of BMDM from ethanol-chimeric mice exhibited a reduction in H3K27me3 enrichment, a finding also observed in BM donors exposed to ethanol., Conclusions: These evidences demonstrate that prior chronic alcohol exposure of bone-marrow modify immune effector cells functions impairing the inflammatory response during A. fumigatus infection. These findings highlight the persistent impact of chronic ethanol exposure on infectious disease outcomes., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Spinal cord injury (SCI) is often accompanied by gastrointestinal dysfunction due to the disconnection of the spinal autonomic nervous system. Gastrointestinal dysfunction reportedly upregulates intestinal permeability, leading to bacterial translocation of the gut microbiome to the systemic circulation, which further activates systemic inflammation, exacerbating neuronal damage. Mesenchymal stem cells (MSC) reportedly ameliorate SCI. Here, we aimed to investigate their effect on the associated gastrointestinal dysfunction. Human amnion-derived MSC (AMSCs) were intravenously transplanted one day after a rat model of midthoracic SCI. Biodistribution of transplanted cells, behavioral assessment, and histological evaluations of the spinal cord and intestine were conducted to elucidate the therapeutic effect of AMSCs. Bacterial translocation of the gut microbiome was examined by in situ hybridization and bacterial culture of the liver. Systemic inflammations were examined by blood cytokines, infiltrating immune cells in the spinal cord, and the size of the peripheral immune tissue. AMSCs released various neurotrophic factors and were mainly distributed in the liver and lung after transplantation. AMSC-transplanted animals showed smaller spinal damage and better neurological recovery with preserved neuronal tract. AMSCs transplantation ameliorated intestinal dysfunction both morphologically and functionally, which prevented translocation of the gut microbiome to the systemic circulation. Systemic inflammations were decreased in animals receiving AMSCs in the chronic phase. Intravenous AMSC administration during the acute phase of SCI rescues both spinal damage and intestinal dysfunction. Reducing bacterial translocation may contribute to decreasing systemic inflammation. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a potentially curative therapy for patients suffering from hematological malignancies via the donor immune system driven graft- versus -leukemia effect. However, the therapy is mainly limited by severe acute and chronic graft- versus -host disease (GvHD), both being life-threatening complications after allo-HCT. GvHD develops when donor T cells do not only recognize remaining tumor cells as foreign, but also the recipient's tissue, leading to a severe inflammatory disease. Typical GvHD target organs include the skin, liver and intestinal tract. Currently all approved strategies for GvHD treatment are immunosuppressive therapies, with the first-line therapy being glucocorticoids. However, therapeutic options for glucocorticoid-refractory patients are still limited. Novel therapeutic approaches, which reduce GvHD severity while preserving GvL activity, are urgently needed. Targeting kinase activity with small molecule inhibitors has shown promising results in preclinical animal models and clinical trials. Well-studied kinase targets in GvHD include Rho-associated coiled-coil-containing kinase 2 (ROCK2), spleen tyrosine kinase (SYK), Bruton's tyrosine kinase (BTK) and interleukin-2-inducible T-cell kinase (ITK) to control B- and T-cell activation in acute and chronic GvHD. Janus Kinase 1 (JAK1) and 2 (JAK2) are among the most intensively studied kinases in GvHD due to their importance in cytokine production and inflammatory cell activation and migration. Here, we discuss the role of kinase inhibition as novel treatment strategies for acute and chronic GvHD after allo-HCT. [ABSTRACT FROM AUTHOR]

Key points: Fractalkine receptor antagonist inhibited neutrophil recruitment to masseter muscles and exacerbated fatigability during masticatory activity.Fractalkine‐mediated neutrophil recruitment is required for both upregulation of myokines (CXCL1, interleukin‐6) and enhanced GLUT4 translocation in response to masticatory activity.Fractalkine and intercellular adhesion molecule‐1 expression in endothelial cells increased in response to masticatory activity.In vitro experiments demonstrated that contracting myotubes lack the ability to upregulate fractalkine but revealed that endothelial fractalkine upregulation is induced using a conditioned medium of contracting myotubes. Physical exercise stimulates neutrophil recruitment within working skeletal muscle, although its underlying mechanisms remain ill‐defined. By employing a masticatory behaviour (gnawing) model, we demonstrate the importance of intramuscular paracrine and autocrine systems that are triggered by muscle contractile activity and reliant upon fractalkine/CX3CL1‐mediated signals. These signals were revealed to be required for achieving proper GLUT4 translocation and glucose uptake to meet the glucose demands for fatigue alleviation. Specifically, fractalkine expression and neutrophil recruitment both increased in the masseter muscle tissues upon masticatory activity. Importantly, a fractalkine antagonist inhibited neutrophil accumulation and exacerbated fatigability during masticatory activity. We found that fractalkine‐dependent neutrophil recruitment is required for both upregulation of myokines (i.e. CXCL1 and interleukin‐6) and enhanced GLUT4 translocation in response to gnawing activity. Immunofluorescence analysis of masseter muscles demonstrated that fractalkine and intercellular adhesion molecule‐1 expression are both upregulated in endothelial cells but not in myofibres. The in vitro exercise model further revealed that contractile activity failed to stimulate fractalkine upregulation in myotubes, implying that fractalkine is not a myokine (myofibre‐derived factor). Nevertheless, endothelial fractalkine expression was markedly stimulated by a conditioned medium from the contracting myotubes. Moreover, intercellular adhesion molecule‐1, a key adhesion molecule for neutrophils, was upregulated in endothelial cells by fractalkine. Taken together, our findings strongly suggest that endothelial fractalkine serves as a key factor for organizing a physiologically beneficial intramuscular microenvironment by recruiting neutrophils in response to relatively mild exercise (i.e. masticatory muscle activity). Key points: Fractalkine receptor antagonist inhibited neutrophil recruitment to masseter muscles and exacerbated fatigability during masticatory activity.Fractalkine‐mediated neutrophil recruitment is required for both upregulation of myokines (CXCL1, interleukin‐6) and enhanced GLUT4 translocation in response to masticatory activity.Fractalkine and intercellular adhesion molecule‐1 expression in endothelial cells increased in response to masticatory activity.In vitro experiments demonstrated that contracting myotubes lack the ability to upregulate fractalkine but revealed that endothelial fractalkine upregulation is induced using a conditioned medium of contracting myotubes. [ABSTRACT FROM AUTHOR]

In this article, we aim to reflect on the emergence and manipulation of social feelings in the context of intense transformations, called cold periods in history by Durkheim. The event known in the mainstream media as the 'gay kit', and political and religious articulations surrounding its suppression in 2011, is the empirical basis for our analysis. As a counterpoint, we will identify narratives and conservative activism organized around Bill No. 6583/2013, also known as the Family Statute, which has been the subject of numerous public debates, especially in 2015. In both cases, we reflect on social fears, morally based panic and on the situated activation of the rhetoric of loss by politicians with religious conservative liberal profiles. [ABSTRACT FROM AUTHOR]

This study evaluated the effect of an acute high-intensity interval exercise (HIIE) session on the function of human neutrophils. Twelve sedentary men performed a HIIE session (8 bouts of 60 s at 90% of peak power, intercalated with 75 s of active recovery at 30 W). Neutrophils were collected before, 30 min and 24 h after the exercise session for the evaluation of phagocytic capacity, expression of phagocytic receptors, reactive oxygen species generation, and redox status. 24 h after the HIIE session, an increase was observed in both neutrophil phagocytic capacity and yeast-induced generation of reactive oxygen species, which indicates neutrophil priming in response to an acute HIIE session. Neutrophils also presented an increase in superoxide dismutase activity 24 h after the exercise. Improvement in neutrophil function was accompanied by increased serum levels of IL-8 and increased concentration of plasma lactate dehydrogenase. Our findings show a late activating effect of one HIIE session on neutrophils. We propose that priming of neutrophils by HIIE may play a role in skeletal muscle inflammation after exercise. [ABSTRACT FROM AUTHOR]

In this article, we aim to reflect on the emergence and manipulation of social feelings in the context of intense transformations, called cold periods in history by Durkheim. The event known in the mainstream media as the ‘gay kit’, and political and religious articulations surrounding its suppression in 2011, is the empirical basis for our analysis. As a counterpoint, we will identify narratives and conservative activism organized around Bill No. 6583/2013, also known as the Family Statute, which has been the subject of numerous public debates, especially in 2015. In both cases, we reflect on social fears, morally based panic and on the situated activation of the rhetoric of loss by politicians with religious conservative liberal profiles. [ABSTRACT FROM AUTHOR]

A large number of researches have led to a substantial growth of knowledge about exercise and oxidative stress. Initial investigations reported that physical exercise generates free radical-mediated damages to cells; however, in recent years, studies have shown that regular exercise can upregulate endogenous antioxidants and reduce oxidative damage. Yet, strenuous exercise perturbs the antioxidant system by increasing the reactive oxygen species (ROS) content. These alterations in the cellular environment seem to occur in an exercise type-dependent manner. The source of ROS generation during exercise is debatable, but now it is well established that both contracting and relaxing skeletal muscles generate reactive oxygen species and reactive nitrogen species. In particular, exercises of higher intensity and longer duration can cause oxidative damage to lipids, proteins, and nucleotides in myocytes. In this review, we summarize the ROS effects and interplay of antioxidants in skeletal muscle during physical exercise. Additionally, we discuss how ROS-mediated signaling influences physical exercise in antioxidant system. [ABSTRACT FROM AUTHOR]

Platelet-activating factor (PAF) is a bioactive lipid mediator which serves as a reciprocal messenger between the immune and nervous systems. PAF, a pluripotent inflammatory mediator, is extensively expressed in many cells and tissues and has either beneficial or detrimental effects on the progress of inflammation-related neuropathology. Its wide distribution and various biological functions initiate a cascade of physiological or pathophysiological responses during development or diseases. Current evidence indicates that excess PAF accumulation in CNS diseases exacerbates the inflammatory response and pathological consequences, while application of PAF inhibitors or PAFR antagonists by blocking this signaling pathway significantly reduces inflammation, protects cells, and improves the recovery of neural functions. In this review, we integrate the current findings of PAF signaling in CNS diseases and elucidate topics less appreciated but important on the role of PAF signaling in neurological diseases. We propose that the precise use of PAF inhibitors or PAFR antagonists that target the specific neural cells during the appropriate temporal window may constitute a potential therapy for CNS diseases. [ABSTRACT FROM AUTHOR]

Immunology developed under the notion of the immune system exists to fight pathogens. Recently, the discovery of interactions with commensal microbiota that are essential to human health initiated a change in this old paradigm. Here, we argue that the immune system has major physiological roles extending far beyond defending the host. Immune and inflammatory responses share the core property of sensing, defining the immune system also as a sensory system. The inference with the immune system collects, interprets, and stores information, while creating an identity of self, places it in close relationship to the nervous system, which suggests that these systems may have a profound evolutionary connection. [ABSTRACT FROM AUTHOR]

Background Corneal suturing is a surgical procedure used in patients with corneal trauma or transplants. It was reported that endogenous neutrophils are brightly labelled in gene-targeted mice expressing enhanced green fluorescent protein (eGFP) under the control of the endogenous lysozyme M promoter (LysM-eGFP mice). Methods We applied intravital imaging methods to analyse in vivo the dynamics of LysM-positive granulocytes (neutrophils) in LysM-eGFP mice with corneal sutures and examined their role in the elicitation of neutrophil infiltration. Results We found that in the presuturing state, neutrophils strongly positive for LysM were located in the periphery of the corneal stromal layer; none were present in the centre of the cornea. After introducing a corneal suture, neutrophils accumulated in limbal vessels and then migrated to the corneal side and the conjunctival side, suggesting that they derived from limbal vessels. Thereafter they accumulated towards the central corneal area, arriving at the suture about 7 h after its placement. Although corneal sutures may elicit the continuous infiltration of neutrophils, their number was markedly decreased by day 1 after suture removal and continued to decrease thereafter. Conclusions Our results showed that corneal sutures may elicit the continuous infiltration of neutrophils. [ABSTRACT FROM AUTHOR]

Increase in the practice of sport by more and more numerous people in the Western countries is associated with an increase in muscle injuries, and in demand for improving muscle function and acceleration of muscle recovery after damage. Most of the treatments used target inflammation. Indeed, several lines of experimental evidence in animal models that are supported by human studies identify inflammatory cells, and particularly macrophages, as essential players in skeletal muscle regeneration. Macrophages act not only through their immune functions, but also control myogenesis and extracellular matrix remodeling by directly acting on myogenic precursors and fibro‐adipogenic precursors. In light of these recent biological advances, the question of early treatment aiming at blunting inflammation after exercise‐induced muscle injury is discussed. The February 2016 issue contains a Special Feature on the Effects of exercise on the immune system and metabolism coming into the Olympic year. The role of the immune system in exercise is complex and challenging. Too little exercise can depress the immune system. In contrast, too much exercise can also lead to a compromised immune system. This is a challenge that athletes face as they prepare for competition. Immunology & Cell Biology thanks the coordinators of this Special Feature ‐ Mark Febbraio and Graeme Lancaster ‐ for their planning and input. [ABSTRACT FROM AUTHOR]

The aim of the present study was the assessment of the antioxidant effects of polyphenolic extracts derived from the stems of three Greek grape varieties (Moshomayro, Mavrotragano and Mandilaria) in endothelial (EA.hy926) and muscle (C2C12) cells. We also investigated the effects of the polyphenolic composition on the antioxidant effects of the grape stem extracts. For this purpose, the endothelial and muscle cells were treated with low non-cytotoxic concentrations of the extracts for 24 h in order to assess the effects of the extracts on cellular redox status using oxidative stress biomarkers. The oxidative stress markers were thiobarbituric acid reactive substances (TBARS), protein carbonyl (CARB) levels, reactive oxygen species (ROS) levels and glutathione (GSH) levels. The results revealed that treatment of the EA.hy926 cells with Mandilaria extract significantly decreased the TBARS levels by 14.8% and the CARB levels by 25.9%, while it increased the GSH levels by 15.8% compared to the controls. Moreover, treatment of the EA.hy926 cells with Mavrotragano extract significantly increased the GSH levels by 20.2%, while it significantly decreased the TBARS and CARB levels by 12.5% and 16.6%, respectively. Treatment of the C2C12 cells with Mandilaria extract significantly decreased the TBARS levels by 47.3%, the CARB levels by 39.0% and the ROS levels by 21.8%, while it increased the GSH levels by 22.6% compared to the controls. Moreover, treatment of the C2C12 cells with Mavrotragano significantly decreased the TBARS, CARB and ROS levels by 36.2%, 35.9% and 16.5%, respectively. In conclusion, to the best of our knowledgel, our results demonstrate for the first time that treatment with grape stem extracts at low concentrations improves the redox status of endothelial and muscle cells. Thus, grape stem extracts may be used for developing antioxidant food supplements or biofunctional foods. However, it was also found that the polyphenolic composition of grape stem extracts affects their antioxidant capacity. For example, the results suggested that trans-resveratrol, gallic acid, (+)-catechin, ferulic acid, caffeic acid, quercetin, coumaric acid and kaempferol may be essential for the antioxidant activity of grape stem extracts. [ABSTRACT FROM AUTHOR]

1-Methylnicotinamide (MNA), which was initially considered to be a biologically inactive endogenous metabolite of nicotinamide, has emerged as an anti-thrombotic and anti-inflammatory agent with the capacity to release prostacyclin (PGI2). In the present study, we characterized the effects of MNA on exercise capacity and the endothelial response to exercise in diabetic mice. Eight-week-old db/db mice were untreated or treated with MNA for 4 weeks (100 mg·kg-1), and their exercise capacity as well as NO- and PGI2-dependent response to endurance running were subsequently assessed. MNA treatment of db/db mice resulted in four-fold and three-fold elevation of urine concentrations of MNA and its metabolites (Met-2PY + Met-4PY), respectively (P<0.01), but did not affect HbA1c concentration, fasting glucose concentration or lipid profile. However, insulin sensitivity was improved (P<0.01). In MNA-treated db/db mice, the time to fatigue for endurance exercise was significantly prolonged (P<0.05). Post-exercise Δ6-keto-PGF1α (difference between mean concentration in the sedentary and exercised groups) tended to increase, and post-exercise leukocytosis was substantially reduced in MNA-treated animals. In turn, the post-exercise fall in plasma concentration of nitrate was not affected by MNA. In conclusion, we demonstrated for the first time that MNA improves endurance exercise capacity in mice with diabetes, and may also decrease the cardiovascular risk of exercise. [ABSTRACT FROM AUTHOR]

Intense exercise evokes a rapid and transient increase in circulating cell-free DNA (cf-DNA), a phenomenon that is commonly observed in a variety of acute and chronic inflammatory conditions. While the potential value of cf-DNA for the prediction of disease outcome and therapeutic response is well documented, the release mechanisms and biological relevance of cf-DNA have long remained enigmatic. The discovery of neutrophil extracellular traps (NETs) provided a novel mechanistic explanation for increased cf-DNA levels. Now there is increasing evidence that NETs may contribute to cf-DNA in diverse infectious, non-infectious and autoinflammatory conditions, as well as in response to acute exercise. NETs have now been firmly established as a fundamental immune mechanism used by neutrophils to respond to infection and tissue injury. On the other side, aberrant formation of NETs appears to be a driving force in the pathogenesis of autoimmunity and cardiovascular disease. Thus, the emergence of NETs in the 'exercising vasculature' raises important questions considering beneficial effects, as well as occasional adverse effects, of exercise on immune homeostasis. This review gives an overview of the current state of research into the mechanisms of how NETs are released, contribute to host defence and participate in inflammatory disorders. We discuss the impact of exercise-induced NETs, considering a potentially beneficial role in the prevention of lifestyle-related diseases, as well as putative detrimental effects that may arise in elite sports. Finally, we propose that exercise-induced cf-DNA responses could be exploited for diagnostic/prognostic purposes to identify individuals who are at increased risk of cardiovascular events or autoimmunity. [ABSTRACT FROM AUTHOR]

Experimental cerebral malaria (ECM) is characterized by a strong immune response, with leukocyte recruitment, blood-brain barrier breakdown and hemorrhage in the central nervous system. Phosphatidylinositol 3-kinase γ (PI3Kγ) is central in signaling diverse cellular functions. Using PI3Kγ-deficient mice (PI3Kγ-/-) and a specific PI3Kγ inhibitor, we investigated the relevance of PI3Kγ for the outcome and the neuroinflammatory process triggered by Plasmodium berghei ANKA (PbA) infection. Infected PI3Kγ-/- mice had greater survival despite similar parasitemia levels in comparison with infected wild type mice. Histopathological analysis demonstrated reduced hemorrhage, leukocyte accumulation and vascular obstruction in the brain of infected PI3Kγ-/- mice. PI3Kγ deficiency also presented lower microglial activation (Iba-1+ reactive microglia) and T cell cytotoxicity (Granzyme B expression) in the brain. Additionally, on day 6 post-infection, CD3+CD8+ T cells were significantly reduced in the brain of infected PI3Kγ-/- mice when compared to infected wild type mice. Furthermore, expression of CD44 in CD8+ T cell population in the brain tissue and levels of phospho-IkB-α in the whole brain were also markedly lower in infected PI3Kγ-/- mice when compared with infected wild type mice. Finally, AS605240, a specific PI3Kγ inhibitor, significantly delayed lethality in infected wild type mice. In brief, our results indicate a pivotal role for PI3Kγ in the pathogenesis of ECM. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effect of Lithothamnium sp (LTT) supplement, a calcium-rich alga widely used for mineral reposition, on strain-induced (orthodontic tooth movement [OTM]) and infection-induced bone resorption (periodontal disease [PD]) in mice. Materials and Methods: Mice were divided into two bone resorption models: one with an orthodontic appliance and the other with PD induced by the oral inoculation of Aggregatibacter actinomycetencomitans (Aa). Both groups were fed a regular diet (vehicle), LTT-rich diet (LTT), or calcium-rich diet (CaC03). Alveolar bone resorption (ABR), the number of osteoclasts, and the levels of tumor necrosis factor α (TNF-α), calcium, and vitamin D3 were evaluated. Results: The number of osteoclasts was reduced in LTT and CaC03 mice, which led to diminished OTM and infection-induced alveolar bone loss. In addition, LTT- and calcium-treated groups also presented decreased levels of TNF-α in periodontal tissues and increased levels of calcium in serum. Conclusions: These results indicate that the LTT supplement Influences ABR, probably due to its calcium content, by affecting osteoclast function and local inflammatory response, thus modulating OTM and PD. [ABSTRACT FROM AUTHOR]

Metastatic malignant melanoma is a frequently fatal cancer. In recent years substantial therapeutic progress has occurred with the development of targeted kinase inhibitors and immunotherapeutics. Targeted therapies often result in rapid clinical benefit however responses are seldom durable. Immune therapies can result in durable disease control but responses may not be immediate. Optimal cancer therapy requires both rapid and durable cancer control and this can likely best be achieved by combining targeted therapies with immunotherapeutics. To achieve this, a detailed understanding of the immune consequences of the various kinase inhibitors, in development, clinical trial and currently used to treat melanoma is required. [ABSTRACT FROM AUTHOR]

The aim of the present study was to evaluate the potential of calcium supplementation from Lithothamnium muelleri algae on metabolic and inflammatory parameters in mice with increased adiposity. Male mice were fed and divided during 8 weeks in: control (C), a high refined carbohydrate-containing diet (HC), HC diet supplemented with 1% of Lithothamnion muelleri algae (HC + A) and HC diet supplemented with 0.9% calcium carbonate (HC + C). Animals fed HC diet had increased body weight gain and adiposity, serum glucose and cholesterol, glucose intolerance and decreased insulin sensitivity, compared to control diet. However, the HC + A and HC + C groups did not prevent these aspects and were not able to change the CD14 + cells population in adipose tissue of animals fed HC diet. Calcium supplementation with Lithothamnium muelleri algae and calcium carbonate had no protective effect against the development of adiposity, metabolic and inflammatory alterations induced by HC diet. [ABSTRACT FROM AUTHOR]