Since the discovery of ouabain as a cardiotonic steroid hormone present in higher mammals, research about it has progressed rapidly and several of its physiological and pharmacological effects have ...been described. Ouabain can behave as a stress hormone and adrenal cortex is its main source. Direct effects of ouabain are originated due to the binding to its receptor, the Na
/K
-ATPase, on target cells. This interaction can promote Na
transport blockade or even activation of signaling transduction pathways (e.g., EGFR/Src-Ras-ERK pathway activation), independent of ion transport. Besides the well-known effect of ouabain on the cardiovascular system and blood pressure control, compelling evidence indicates that ouabain regulates a number of immune functions. Inflammation is a tightly coordinated immunological function that is also affected by ouabain. Indeed, this hormone can modulate many inflammatory events such as cell migration, vascular permeability, and cytokine production. Moreover, ouabain also interferes on neuroinflammation. However, it is not clear how ouabain controls these events. In this brief review, we summarize the updates of ouabain effect on several aspects of peripheral and central inflammation, bringing new insights into ouabain functions on the immune system.
Anthocyanins are the largest group of water-soluble pigments in the plant kingdom. A number of studies have demonstrated that anthocyanins present antioxidant capacity and show inhibitory effects on ...the growth of some cancer cells. Thus, the goal of this study was to evaluate both the antimutagenicity/antigenotoxicity and mutagenicity/genotoxicity of aqueous extract obtained from the
Solanum melanogena, a possible novel source of anthocyanin, and its main purified anthocyanin extract (delphinidin), using the single cell (comet) assay and micronucleus test. Pretreatment with higher doses of the purified anthocyanin (10 and 20
mg/kg b.w.) led to a statistically significant reduction (
p
<
0.05) in the frequency of micronuclei in polychromatic erythrocytes induced by cyclophosphamide. The pattern of reduction ranged from 48% to 57% independent of concentration. No apparent genotoxicity and mutagenicity was found for either the anthocyanin or delphinidin extracts. Taken together, these results suggest that mice pre-treated with specific compounds present in anthocyanins (delphinidin) displayed a lower incidence of mutations induced by cyclophosphamide. This finding emphasizes the potential of natural colorants to prevent mutations and also the applicability of genotoxic evaluation for improving health. Furthermore, the results presented here could be an additional argument to support the use of anthocyanins in the diet.
High-fat diet (HFD) intake during gestation and lactation has been associated with an increased risk of developing cardiometabolic disorders in adult offspring. We investigated whether metabolic ...alterations resulting from the maternal consumption of HFD are prevented by the addition of omega-3 (ɷ3) in the diet.
Wistar rat dams were fed a control (C: 19% of lipids and ɷ6:ɷ3 = 12), HF (HF: 33% lipids and ɷ6:ɷ3 = 21), or HF enriched with ɷ3 (HFω3: 33% lipids and ɷ6:ɷ3 = 9) diet during gestation and lactation, and their offspring food consumption, murinometric measurements, serum levels of metabolic markers, insulin and pyruvate sensitivity tests were evaluated. The maternal HFD increased body weight at birth, dyslipidemia, and elevated fasting glucose levels in the HF group. The enrichment of ɷ3 in the maternal HFD led to lower birth weight and improved lipid, glycemic, and transaminase biochemical profile of the HFω3 group until the beginning of adulthood. However, at later adulthood of the offspring, there was no improvement in these biochemical parameters.
Our findings show the maternal consumption of high-fat ɷ3-rich diet is able to attenuate or prevent metabolic disruption elicited by HFD in offspring until 90 days old, but not in the long term, as observed at 300 days old of the offspring.
•Maternal HFD increased body weight at birth, promoted dyslipidemia, and elevated fasting glucose levels in the HF group.•Maternal ω3 consumption improved birth weight, lipid, glycemic and transaminase biochemical profile of the young offspring.•However, at later adulthood of the offspring, there was no improvement in the biochemical parameters.
Apolipoprotein E (APOE=gene, apoE=protein) is a known factor regulating the inflammatory response that may have regenerative effects during tissue recovery from injury. We investigated whether apoE ...deficiency reduces the healing effect of alanyl-glutamine (Ala-Gln) treatment, a recognized gut-trophic nutrient, during tissue recovery after 5-FU-induced intestinal mucositis. APOE-knockout (APOE-/-) and wild-type (APOE+/+) C57BL6J male and female mice (N=86) were given either Ala-Gln (100 mM) or phosphate buffered saline (PBS) by gavage 3 days before and 5 days after a 5-fluorouracil (5-FU) challenge (450 mg/kg, via intraperitoneal injection). Mouse body weight was monitored daily. The 5-FU cytotoxic effect was evaluated by leukometry. Intestinal villus height, villus/crypt ratio, and villin expression were monitored to assess recovery of the intestinal absorptive surface area. Crypt length, mitotic, apoptotic, and necrotic crypt indexes, and quantitative real-time PCR for insulin-like growth factor-1 (IGF-1) and B-cell lymphoma 2 (Bcl-2) intestinal mRNA transcripts were used to evaluate intestinal epithelial cell turnover. 5-FU challenge caused significant weight loss and leukopenia (P<0.001) in both mouse strains, which was not improved by Ala-Gln. Villus blunting, crypt hyperplasia, and reduced villus/crypt ratio (P<0.05) were found in all 5-FU-challenged mice but not in PBS controls. Ala-Gln improved villus/crypt ratio, crypt length and mitotic index in all challenged mice, compared with PBS controls. Ala-Gln improved villus height only in APOE-/- mice. Crypt cell apoptosis and necrotic scores were increased in all mice challenged by 5-FU, compared with untreated controls. Those scores were significantly lower in Ala-Gln-treated APOE+/+ mice than in controls. Bcl-2 and IGF-1 mRNA transcripts were reduced only in the APOE-/- -challenged mice. Altogether our findings suggest APOE-independent Ala-Gln regenerative effects after 5-FU challenge.
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by joint destruction and severe morbidity. Cigarette smoking (CS) can exacerbate the incidence and severity of RA. Although ...Th17 cells and the Aryl hydrocarbon receptor (AhR) have been implicated, the mechanism by which CS induces RA development remains unclear. Here, using transcriptomic analysis, we show that
is specifically induced in Th17 cells in the presence of either AhR agonist or CS-enriched medium.
thus induced is packaged into extracellular vesicles produced by Th17 and acts as a proinflammatory mediator increasing osteoclastogenesis through the down-regulation of COX2. In vivo, articular knockdown of
in murine arthritis models reduces the number of osteoclasts in the joints. Clinically, RA patients express higher levels of
than do healthy individuals. This increase is further elevated by cigarette smoking. Together, these results reveal a hitherto unrecognized mechanism by which CS could exacerbate RA and further advance understanding of the impact of environmental factors on the pathogenesis of chronic inflammatory diseases.
Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease of the CNS that causes disability in young adults as a result of the irreversible accumulation of neurological deficits. ...Although there are potent disease-modifying agents for its initial relapsing-remitting phase, these therapies show limited efficacy in secondary progressive MS (SPMS). Thus, there is an unmet clinical need for the identification of disease mechanisms and potential therapeutic approaches for SPMS. Here, we show that the sphingosine 1-phosphate receptor (S1PR) modulator fingolimod (FTY720) ameliorated chronic progressive experimental autoimmune encephalomyelitis in nonobese diabetic mice, an experimental model that resembles several aspects of SPMS, including neurodegeneration and disease progression driven by the innate immune response in the CNS. Indeed, S1PR modulation by FTY720 in murine and human astrocytes suppressed neurodegeneration-promoting mechanisms mediated by astrocytes, microglia, and CNS-infiltrating proinflammatory monocytes. Genome-wide studies showed that FTY720 suppresses transcriptional programs associated with the promotion of disease progression by astrocytes. The study of the molecular mechanisms controlling these transcriptional modules may open new avenues for the development of therapeutic strategies for progressive MS.
Metabolism has been shown to control peripheral immunity, but little is known about its role in central nervous system (CNS) inflammation. Through a combination of proteomic, metabolomic, ...transcriptomic, and perturbation studies, we found that sphingolipid metabolism in astrocytes triggers the interaction of the C2 domain in cytosolic phospholipase A2 (cPLA2) with the CARD domain in mitochondrial antiviral signaling protein (MAVS), boosting NF-κB-driven transcriptional programs that promote CNS inflammation in experimental autoimmune encephalomyelitis (EAE) and, potentially, multiple sclerosis. cPLA2 recruitment to MAVS also disrupts MAVS-hexokinase 2 (HK2) interactions, decreasing HK enzymatic activity and the production of lactate involved in the metabolic support of neurons. Miglustat, a drug used to treat Gaucher and Niemann-Pick disease, suppresses astrocyte pathogenic activities and ameliorates EAE. Collectively, these findings define a novel immunometabolic mechanism that drives pro-inflammatory astrocyte activities, outlines a new role for MAVS in CNS inflammation, and identifies candidate targets for therapeutic intervention.
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•Sphingolipid drives astrocyte pathogenic activities via cPLA2-MAVS-NF-κB•cPLA2 displaces HK2 from MAVS, limiting the metabolic support of neurons by astrocytes•Miglustat suppresses astrocyte cPLA2-MAVS-NF-κB pro-inflammatory signaling•Miglustat is a candidate drug for repurposing to treat secondary progressive MS
By exploring the immunometabolic pathways that drive pro-inflammatory astrocyte activities, sphingolipid metabolism is identified as a promising therapeutic target in CNS inflammation.
Epidemiological studies have provided evidence that high consumption of tomatoes effectively reduces the risk of reactive oxygen species (ROS)-mediated diseases such as cancer. Tomatoes are rich ...sources of lycopene, a potent singlet oxygen-quenching carotenoid. In addition to its antioxidant properties, lycopene shows an array of biological effects including antimutagenic and anticarcinogenic activities. In the present study, the chemopreventive action of lycopene was examined on DNA damage and clastogenic or aneugenic effects of H
2O
2 and
n-nitrosodiethylamine (DEN) in the metabolically competent human hepatoma cell line (HepG2 cells). Lycopene at concentrations of 10, 25, and 50
μM, was tested under three protocols: before, simultaneously, and after treatment with the mutagen, using the comet and micronucleus assays. Lycopene significantly reduced the genotoxicity and mutagenicity of H
2O
2 in all of the conditions tested. For DEN, significant reductions of primary DNA damage (comet assay) were detected when the carotenoid (all of the doses) was added in the cell culture medium before or simultaneously with the mutagen. In the micronucleus test, the protective effect of lycopene was observed only when added prior to DEN treatment. In conclusion, our results suggest that lycopene is a suitable agent for preventing chemically-induced DNA and chromosome damage.
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•NTZ interferes in intracranial T. crassiceps cysticerci metabolism.•NTZ induces gluconeogenesis in intracranial T. crassiceps cysticerci.•NTZ enhances the fatty acids oxidation in ...intracranial T. crassiceps cysticerci.
Neurocysticercosis is the most frequent helminthiasis of the central nervous system and is caused by the presence of Taenia solium cysticerci. Nitazoxanide (NTZ) is an antifolate containing the pyrrolopyrimidine-based nucleus that exerts its antiprotozoal activity due to interference with the pyruvate:ferredoxin oxidoreductase (PFOR) enzyme which is essential to anaerobic energy metabolism. The aim of this work was to determine the effect of NTZ on the energetic metabolism of Taenia crassiceps cysticerci intracranially inoculated BALB /c mice. The infected animals were treated with a single oral dose of NTZ 30 days after the inoculation. Analysis of the organic acids was performed through high performance liquid chromatography. Glucose was detected only in the treated groups, alongside with a significant decrease in lactate, pyruvate and oxaloacetate concentrations which indicate an increase in gluconeogenesis. The non-detection of alpha-ketoglutarate indicated the use of the fumarate reductase pathway in all groups. It was possible to confirm the drugs mode of action due to the non-detection of acetate in the treated groups. There was an increase in the fatty acids oxidation. Therefore it was possible to observe that NTZ induces gluconeogenesis as well as the increase of alternative energetic pathways such as fatty acids oxidation in T. crassiceps cysticerci.
The groundwork for malaria elimination does not currently consider the potential of Plasmodium zoonotic cycles that involve non-human primates (NHPs) in sylvatic environments. Since vivax malaria is ...less responsive to control measures, finding Plasmodium vivax infected NHPs adds even more concern.
Both Free-living monkeys in forest fragments inside the urban area and captive monkeys from a local zoo had blood samples tested for Plasmodium species.
In this study, among the Neotropical monkeys tested, three (4.4%), one captive and two free-living, were found to be naturally infected by P. vivax.
This important finding indicates that it is necessary to estimate the extent to which P. vivax NHP infection contributes to the maintenance of malaria transmission to humans. Therefore, the discussion on wildlife conservation and management must be incorporated into the malaria elimination agenda.
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