Nutritional strategies cause memory damage and alter biochemical parameters without causing neuroinflammation.

Obesity results from an energy imbalance and has been considered an epidemic due to its increasing rates worldwide. It is classified as a low-grade chronic inflammatory disease and has associated comorbidities. Different nutritional strategies are used for the purpose of weight loss, highlighting low-carbohydrate (LC) diets, ketogenic diets, and intermittent fasting (IF). These strategies can lead to metabolic and behavioral changes as they stimulate different biochemical pathways. Therefore, this study evaluated memory, energy metabolism, neuroinflammation, oxidative stress, and antioxidant defense parameters in mice subjected to an LC diet, ketogenic diet (KD), or IF. Eighty male Swiss mice, 60 days old, were divided into 4 groups: control, LC, KD, or IF. Body weight was measured weekly, and food intake every 48 h. After 15 days of nutritional interventions, the animals were subjected to the behavioral object recognition test and subsequently euthanized. Then, visceral fat was removed and weighed, and the brain was isolated for inflammatory and biochemical analysis. We concluded from this study that the LC and KD strategies could damage memory, IF improves the production of adenosine triphosphate (ATP), and the LC, KD, and IF strategies do not lead to neuroinflammatory damage but present damage at the level of oxidative stress.

Enoxaparin improves COVID-19 by reducing Neutrophils Extracellular Traps (NETs) production.

BACKGROUND: COVID-19 causes consequences such as imbalance of the immune system and thrombotic events. During the infection process, NETs in excess induce a pro-inflammatory response and disseminated intravascular coagulation. We evaluated the role of enoxaparin as a potential inhibitor of NETs. METHODS: K18-hACE2 animals infected with the SARS-CoV-2 virus and a group of 23 individuals admitted to the hospital with COVID-19 treated with enoxaparin or without treatment and controls without the disease were included. RESULTS: Enoxaparin decreased the levels of NETs, reduced the signs of the disease and mitigated lung damage in the animals infected with SARS-CoV-2. These effects were partially associated with prevention of SARS-CoV-2 entry and NETs synthesis. Clinical data revealed that treatment with enoxaparin decreased the levels of inflammatory markers, the levels of NETs in isolated neutrophils and the organ dysfunction. CONCLUSION: This study provides evidence for the beneficial effects of enoxaparin in COVID-19 in addition to its anticoagulant role.

Targeting neutrophils extracellular traps (NETs) reduces multiple organ injury in a COVID-19 mouse model.

BACKGROUND: COVID-19 is characterized by severe acute lung injury, which is associated with neutrophil infiltration and the release of neutrophil extracellular traps (NETs). COVID-19 treatment options are scarce. Previous work has shown an increase in NETs release in the lung and plasma of COVID-19 patients suggesting that drugs that prevent NETs formation or release could be potential therapeutic approaches for COVID-19 treatment. METHODS: Here, we report the efficacy of NET-degrading DNase I treatment in a murine model of COVID-19. SARS-CoV-2-infected K18-hACE2 mice were performed for clinical sickness scores and lung pathology. Moreover, the levels of NETs were assessed and lung injuries were by histopathology and TUNEL assay. Finally, the injury in the heart and kidney was assessed by histopathology and biochemical-specific markers. RESULTS: DNase I decreased detectable levels of NETs, improved clinical disease, and reduced lung, heart, and kidney injuries in SARS-CoV-2-infected K18-hACE2 mice. Furthermore, our findings indicate a potentially deleterious role for NETs lung tissue in vivo and lung epithelial (A549) cells in vitro, which might explain part of the pathophysiology of severe COVID-19. This deleterious effect was diminished by the treatment with DNase I. CONCLUSIONS: Together, our results support the role of NETs in COVID-19 immunopathology and highlight NETs disruption pharmacological approaches as a potential strategy to ameliorate COVID-19 clinical outcomes.

Paraprobiotics strains accelerate wound repair by stimulating re-epithelialization of NIH-3T3 cells, decreasing inflammatory response and oxidative stress.

The present study aimed to evaluate the potential and specificity of the inflammatory and antioxidant response of Microbe-Associated Molecular Patterns (MAMPs) in NIH-3T3 fibroblast cells, as well as in the healing process of skin wounds. Cells (NIH-3T3) were cultivated in supplemented specific medium. NIH-3T3 cells were treated with MAMPs (Bifidobacterium lactis or Lactobacillus casei or Lactobacillus gasseri or Lactobacillus paracasei or Streptococcus thermophilus), at two concentrations and insulted with LPS or H2O2. Cell viability, myeloperoxidase activity, nitrite/nitrate, oxidative damage and inflammatory parameters were measured. In addition, scratch assay was performed. Significant scratch closure was observed after 24 h and 48 h, and the effect of 0.1 g/mL MAMPs on wound healing was found to be highly statistically significant. In the viability cellular assay, Lactobacillus showed better response in 0.1 g/mL dose, whereas B. lactis and S. thermophilus showed better response in 0.01 g/mL dose. There was reduction in IL-6 and IL-1ß levels in all treatments insulted with LPS. MAMP's showed preventive efficacy in reducing the effects caused by LPS. The MAMP's action in decreasing the production of ROS, inflammatory activity and increasing cell viability, besides significant cell proliferation during wound healing processes suggests remodeling mechanisms and new possibilities for wound healing.

Coagulation biomarkers and coronavirus disease 2019 phenotyping: a prospective cohort study.

BACKGROUND: Because severe acute respiratory syndrome coronarivus 2 (SARS-CoV-2) leads to severe conditions and thrombus formation, evaluation of the coagulation markers is important in determining the prognosis and phenotyping of patients with COVID-19. METHODS: In a prospective study that included 213 COVID-19 patients admitted to the intensive care unit (ICU) the levels of antithrombin, C-reactive protein (CRP); factors XI, XII, XIII; prothrombin and D-dimer were measured. Spearman's correlation coefficient was used to assess the pairwise correlations between the biomarkers. Hierarchical and non-hierarchical cluster analysis was performed using the levels of biomarkers to identify patients´ phenotypes. Multivariate binary regression was used to determine the association of the patient´s outcome with clinical variables and biomarker levels. RESULTS: The levels of factors XI and XIII were significantly higher in patients with less severe COVID-19, while factor XIII and antithrombin levels were significantly associated with mortality. These coagulation biomarkers were associated with the in-hospital survival of COVID-19 patients over and above the core clinical factors on admission. Hierarchical cluster analysis showed a cluster between factor XIII and antithrombin, and this hierarchical cluster was extended to CRP in the next step. Furthermore, a non-hierarchical K-means cluster analysis was performed, and two phenotypes were identified based on the CRP and antithrombin levels independently of clinical variables and were associated with mortality. CONCLUSION: Coagulation biomarkers were associated with in-hospital survival of COVID-19 patients. Lower levels of factors XI, XII and XIII and prothrombin were associated with disease severity, while higher levels of both CRP and antithrombin clustered with worse prognosis. These results suggest the role of coagulation abnormalities in the development of COVID-19 and open the perspective of identifying subgroups of patients who would benefit more from interventions focused on regulating coagulation.

Bacillus strains prevent lipopolysaccharide-induced inflammation in gut and blood of male mice.

AIMS: The protective effects of Bacillus amyloliquefaciens(CCT7935), Bacillus subtilis(CCT7935), Bacillus licheniformis (CCT 7836), and Bacillus coagulans (CCT 0199) against lipopolysaccharide (LPS)-induced intestinal inflammation were investigated. METHODS AND RESULTS: Male Swiss mice were assigned into six groups: control group, LPS group, LPS + B. subtilis (CCT7935) group, LPS +   B. licheniformis (CCT 7836) group, LPS +   B. amyloliquefaciens (CCT7935) group, and LPS   + B. coagulans (CCT 0199) group. Each mouse of the groups Bacillus received 1 × 109 colony-forming units of Bacillus once daily by oral gavage during 30 days. Twenty-four hours after the last dose of Bacillus, all groups, except the control group, were intraperitoneally injected with LPS in the single dose of 15 mg kg-1. The mice were euthanized 24 h after the LPS administration. Histological alterations, myeloperoxidase activity, and nitrite levels were analyzed in the gut of mice and the inflammatory cytokines were analyzed in the gut and in the blood. The results demonstrate that the mice challenged with LPS presented the villi shortened and damaged, which were significantly protected by B. coagulans and B. amyloliquefaciens. Furthermore, all Bacillus tested were effective in preventing against the increase of myeloperoxidase activity, while B. amyloliquefaciens and B. subtilis prevented the increase of nitrite and IL-1ß levels in the gut of mice induced with LPS was decreased only B. subtilis. LPS also elevated the IL-1 ß, IL-6, and IL-10 levels in the blood, and these alterations were significantly suppressed by Bacillus, especially by B. subtilis. CONCLUSIONS: The study suggests that the Bacillus investigated in this study might be effective therapeutic agents for preventing intestinal inflammation, because they decrease the inflammatory process an protect against tissue damage.

Mesoporous silica nanoparticles adsorb aflatoxin B1 and reduce mycotoxin-induced cell damage.

The present study examined the effects of mesoporous silica nanoparticles (MSNs) on its adsorption capacity of aflatoxin B1 (AFB1). Moreover, the study evaluated the toxicity of MSNs with AFB1 using NIH3T3 cells and hemolysis test. The obtained MSNs were spherical, irregular-like in shape, having a mean size of 39.97 ± 7.85 nm and a BET surface area of 1195 m2/g. At 0.1 mg mL-1 concentration of MSN, the AFB1 adsorption capacity was 30%, which reached 70% when the MSN concentration increased to 2.0 mg mL-1. Our findings showed that AFB1 was adsorbed (∼67%) in the first few minutes on being in contact with MSNs, reaching an adsorption capacity of ∼70% after 15 min. Thereafter, the adsorption capacity remained constant in solution, demonstrating that the MSNs adsorbed toxins even beyond overnight. MSN treatment (0.5-2.0 mg mL-1) using NIH3T3 cells did not result in any reduction in cell viability. In addition, MSN treatment completely reversed the cytotoxic effect of AFB1 at all concentrations. Hemolysis test also revealed no hemolysis in MSNs evaluated alone and in those combined with AFB1. To the best of our knowledge, this study is the first to demonstrate that MSN can reduce cell toxicity produced by AFB1 due to its potential to adsorb mycotoxins.

Postmortem Evidence of Brain Inflammatory Markers and Injury in Septic Patients: A Systematic Review.

OBJECTIVES: Sepsis is a life-threatening organ dysfunction caused by a host's unregulated immune response to eliminate the infection. After hospitalization, sepsis survivors often suffer from long-term impairments in memory, attention, verbal fluency, and executive functioning. To understand the effects of sepsis and the exacerbated peripheral inflammatory response in the brain, we asked the question: What are the findings and inflammatory markers in the brains of deceased sepsis patients? To answer this question, we conducted this systematic review by the recommendations of Preferred Reporting Items for Systematic Reviews and Meta-Analyses. DATA SOURCES: Relevant studies were identified by searching the PubMed/National Library of Medicine, PsycINFO, EMBASE, Bibliographical Index in Spanish in Health Sciences, Latin American and Caribbean Health Sciences Literature, and Web of Science databases for peer-reviewed journal articles published on April 05, 2021. STUDY SELECTION: A total of 3,745 articles were included in the primary screening; after omitting duplicate articles, animal models, and reviews, 2,896 articles were selected for the study. These studies were selected based on the title and abstract, and 2,772 articles were still omitted based on the exclusion criteria. DATA EXTRACTION: The complete texts of the remaining 124 articles were obtained and thoroughly evaluated for the final screening, and 104 articles were included. DATA SYNTHESIS: The postmortem brain had edema, abscess, hemorrhagic and ischemic injuries, infarction, hypoxia, atrophy, hypoplasia, neuronal loss, axonal injuries, demyelination, and necrosis. CONCLUSIONS: The mechanisms by which sepsis induces brain dysfunction are likely to include vascular and neuronal lesions, followed by the activation of glial cells and the presence of peripheral immune cells in the brain.

Immunomodulatory Effect of Bifidobacterium, Lactobacillus, and Streptococcus Strains of Paraprobiotics in Lipopolysaccharide-Stimulated Inflammatory Responses in RAW-264.7 Macrophages.

The discovery of the potential of paraprobiotics to exert different immunological benefits suggests that further studies should be carried out to determine their potential and mechanisms of action in modulating the immune system. The objective of this study was to investigate the immune response of several microbial-associated molecular patterns (MAMPS) used at different doses in macrophage cell lines RAW-264.7 stimulated with lipopolysaccharide (LPS). Two experiments were conducted. The first was performed to determine a dose response curve for each paraprobiotic (Bifidobacterium lactis, Lactobacillus casei, Lactobacillus gasseri, Lactobacillus paracasei, and Streptococcus thermophilus). Further experiments were carried using only two doses (0.01 g/ml and 0.1 g/ml). RAW-264.7 cells were cultivated in Dubelcco's Modified Eagle's medium supplemented with fetal bovine serum and penicillin/streptomycin. Cells were incubated with LPS (1 µg/ml) and six concentrations of MAMPs were added. RAW-264.7 viability, myeloperoxidase activity, nitrite/nitrate concentration, reactive oxygen species production, oxidative damage, and inflammatory parameters were measured. In the LPS group, there was a significant reduction in cell viability. Myeloperoxidase and nitrite/nitrate concentrations demonstrated a better effect at 0.01 and 0.1 g/ml doses. There was a significant reduction in interleukin-6 (IL-6) levels at 0.1 g/ml dose in all paraprobiotics. IL-10 levels decreased in the LPS group and increased at 0.1 g/ml dose in all paraprobiotics. The dichlorofluorescin diacetate results were reinforced by the observed in oxidative damage. Paraprobiotics are likely to contribute to the improvement of intestinal homeostasis, immunomodulation, and host metabolism.

Modulation of microglial phenotypes improves sepsis-induced hippocampus-dependent cognitive impairments and decreases brain inflammation in an animal model of sepsis.

BACKGROUND: In order to modulate microglial phenotypes in vivo, M1 microglia were depleted by administration of gadolinium chloride and the expression of M2 microglia was induced by IL-4 administration in an animal model of sepsis to better characterize the role of microglial phenotypes in sepsis-induced brain dysfunction. METHODS: Wistar rats were submitted to sham or cecal ligation and perforation (CLP) and treated with IL-4 or GdCl3. Animals were submitted to behavioral tests 10 days after surgery. In a separated cohort of animals at 24 h, 3 and 10 days after surgery, hippocampus was removed and cytokine levels, M1/M2 markers and CKIP-1 levels were determined. RESULTS: Modulation of microglia by IL-4 and GdCl3 was associated with an improvement in long-term cognitive impairment. When treated with IL-4 and GdCl3, the reduction of pro-inflammatory cytokines was apparent in almost all analyzed time points. Additionally, CD11b and iNOS were increased after CLP at all time points, and both IL-4 and GdCl3 treatments were able to reverse this. There was a significant decrease in CD11b gene expression in the CLP+GdCl3 group. IL-4 treatment was able to decrease iNOS expression after sepsis. Furthermore, there was an increase of CKIP-1 in the hippocampus of GdCl3 and IL-4 treated animals 10 days after CLP induction. CONCLUSIONS: GdCl3 and IL-4 are able to manipulate microglial phenotype in an animal models of sepsis, by increasing the polarization toward an M2 phenotype IL-4 and GdCl3 treatment was associated with decreased brain inflammation and functional recovery.

Targeting epimastigotes of Trypanosoma cruzi with a peptide isolated from a phage display random library.

Chagas disease, also known as American trypanosomiasis, is a potentially life-threatening illness caused by the protozoan parasite Trypanosoma cruzi, which is transmitted by insects of the family Reduviidae. Since conventional treatments with nitroheterocyclic drugs show serious adverse reactions and have questionable efficiency, different research groups have investigated polypeptide-based approaches to interfere with the parasite cell cycle in other Trypanosomatids. These strategies are supported by the fact that surface players are candidates to develop surface ligands that impair function since they may act as virulence factors. In this study, we used a phage display approach to identify peptides from one library-LX8CX8 (17 aa) (where X corresponds to any amino acid). After testing different biopanning conditions using live or fixed epimastigotes, 10 clones were sequenced that encoded the same peptide, named here as EPI18. The bacteriophage expressing EPI18 binds to epimastigotes from distinct strains of T. cruzi. To confirm these results, this peptide was synthetized, biotinylated, and assayed using flow cytometry and confocal microscopy analyses. These assays confirmed the specificity of the binding capacity of EPI18 toward epimastigote surfaces. Our findings suggest that EPI18 may have potential biotechnological applications that include peptide-based strategies to control parasite transmission.

Nuxcell Neo® improves vaccine efficacy in antibody response.

Current vaccination protocols raise concerns about the efficacy of immunization. There is evidence that changes in the gut microbiota can impact immune response. The formation of the gut microbiota in newborns plays a crucial role in immunity. Probiotic bacteria and prebiotics present important health-promoting and immunomodulatory properties. Thus, we hypothesize that pro and prebiotic supplementation can improve the efficacy of vaccination in newborns. In this protocol, newborn mice were used and treated with a single-dose rabies vaccine combined with Nuxcell Neo® (2 g/animal/week) for 3 weeks. Samples were collected on days 7, 14, and 21 after vaccination for analysis of cytokines and concentration of circulating antibodies. Our results show an increased concentration of antibodies in animals vaccinated against rabies and simultaneously treated with Nuxcell Neo® on days 14 and 21 when compared to the group receiving only the vaccine. In the cytokine levels analysis, it was possible to observe that there weren't relevant and significant changes between the groups, which demonstrates that the health of the animal remains stable. The results of our study confirm the promising impact of the use of Nuxcell Neo® on the immune response after vaccination.

Prophylactic Minocycline for Delirium in Critically Ill Patients: A Randomized Controlled Trial.

BACKGROUND: Delirium is a potentially severe form of acute encephalopathy. Minocycline has neuroprotective effects in animal models of neurologic diseases; however, data from human studies remain scarce. RESEARCH QUESTION: Does the neuroprotective effect of minocycline prevent delirium occurrence in critical ill patients? STUDY DESIGN AND METHODS: This study was a randomized, placebo-controlled, double-blind trial conducted in four ICUs. Patients aged 18 years or older were eligible and randomized to receive minocycline (100 mg, twice daily) or placebo. The primary outcome was delirium incidence within 28 days or before ICU discharge. Secondary outcomes included days in delirium during ICU stay, delirium/coma-free days, length of mechanical ventilation, ICU length of stay, ICU mortality, and hospital mortality. The kinetics of various inflammatory (IL-1ß, IL-6, IL-10, and C-reactive protein) and brain-related biomarkers (brain-derived neurotrophic factor and S100B) were used as exploratory outcomes. RESULTS: A total of 160 patients were randomized, but one patient in the placebo group died before treatment; thus the data from 159 patients were analyzed (minocycline, n = 84; placebo, n = 75). After the COVID-19 pandemic it was decided to stop patient inclusion early. There was a small but significant decrease in delirium incidence: 17 patients (20%) in the minocycline arm compared with 26 patients (35%) in the placebo arm (P = .043). No other delirium-related outcomes were modified by minocycline treatment. Unexpectedly, there was a significant decrease in hospital mortality (39% vs. 23%; P = .029). Among all analyzed biomarkers, only plasma levels of C-reactive protein decreased significantly after minocycline treatment (F = 0.75, P = .78, within time; F = 4.09, P = .045, group × time). INTERPRETATION: Our findings in this rather small study signal a possible positive effect of minocycline on delirium incidence. Further studies are needed to confirm the benefits of this drug as a preventive measure in critically ill patients. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT04219735; URL: www. CLINICALTRIALS: gov.

Bifidobacterium lactis CCT 7858 Improves Gastrointestinal Symptoms by Antibiotics Treatment: a Double-Blind, Randomized, Placebo-Controlled Trial.

Diarrhea is one of the most frequent side effects of antibiotic treatment and occurs in 25 to 40% of patients in use. One potential strategy to prevent this side effect is the concurrent use of probiotics. This study evaluated the efficacy of the strain Bifidobacterium lactis CCT 7858 in the prevention of diarrhea and improvement of gastrointestinal symptoms in hospitalized patients using antibiotics. This was a randomized, blinded, placebo-controlled clinical trial. This study included 104 patients in antibiotic treatment. Patients were randomized into two groups: placebo (maltodextrin) and intervention (strain Bifidobacterium lactis CCT 7858 at 9 × 1010 CFU concentration; GABBIA® Biotecnology, Santa Catarina, Brazil). Patients were supplemented depending on the duration of antibiotic therapy, and both were evaluated with scales in two moments: before and after treatment. We included 104 hospitalized patients. In follow-up, 38 (74.5%) of the B. lactis group have no reported diarrhea. In secondary outcomes, in five day strong abdominal distension was reported in 4 (7,3) placebo group and not reported in B. lactis. Abdominal noises, nausea, and vomiting were not registered in any group. B. lactis strain has been considered safe and with several benefits, including reduction of soft stools and gastrointestinal symptoms how abdominal noise, pain and distension, as well reduction of diarrhea.

Zebrafish as a potential model for stroke: A comparative study with standardized models.

Animal models of cerebral ischemia have improved our understanding of the pathophysiology and mechanisms involved in stroke, as well as the investigation of potential therapies. The potential of zebrafish to model human diseases has become increasingly evident. The availability of these models allows for an increased understanding of the role of chemical exposure in human conditions and provides essential tools for mechanistic studies of disease. To evaluate the potential neuroprotective properties of minocycline against ischemia and reperfusion injury in zebrafish and compare them with other standardized models. In vitro studies with BV-2 cells were performed, and mammalian transient middle cerebral artery occlusion (tMCAO) was used as a comparative standard with the zebrafish stroke model. Animals were subjected to ischemia and reperfusion injury protocols and treated with minocycline. Infarction size, cytokine levels, oxidative stress, glutamate toxicity, and immunofluorescence for microglial activation, and behavioral test results were determined and compared. Administration of minocycline provided significant protection in the three stroke models in different parameters analyzed. Both experimental models complement each other in their particularities. The proposal also strengthens the findings in the literature in rodent models and allows the validation of alternative models so that they can be used in further research involving diseases with ischemia and reperfusion injury.

Comparative effects of fresh and sterile fecal microbiota transplantation in an experimental animal model of necrotizing enterocolitis.

INTRODUCTION: Necrotizing Enterocolitis (NEC) is a serious intestinal disease that affects premature neonates, causing high mortality, despite the technological development in neonatal intensive care, with antibiotics, parenteral nutrition, surgery, and advanced life support. The correction of dysbiosis with fecal microbiome transplantation (FMT) has shown beneficial effects in experimental models of the disease. The different forms of administration and conservation of FMT and mixed results depending on several factors lead to questions about the mechanism of action of FMT. This study aimed to compare the effectiveness of fresh, sterile FMT and probiotic treatment under parameters of inflammation, oxidative stress, and tissue damage in a neonatal model of NEC. METHODS: One-day-old Wistar rats were used to induce NEC model. Animals were divided in five groups: Control + saline; NEC + saline; NEC + fresh FMT; NEC + sterile FMT and NEC+ probiotics. Parameters of inflammatory response and oxidative damage were measured in the gut, brain, and serum. It was also determined gut histopathological alterations. RESULTS: Proinflammatory cytokines were increased in the NEC group, and IL-10 levels decreased in the gut, brain, and serum. Fresh and sterile FMT decreased inflammation when compared to the use of probiotics. Oxidative and histological damage to the intestine was apparent in the NEC group, and both FMT treatments had a protective effect. CONCLUSION: Fresh and sterile FMT effectively reduced the inflammatory response, oxidative damage, and histological alterations in the gut and brain compared to an experimental NEC model.

Enriched environment causes epigenetic changes in hippocampus and improves long-term cognitive function in sepsis.

Sepsis is defined as a life-threatening organ dysfunction caused by an inappropriate host response to infection. The presence of oxidative stress and inflammatory mediators in sepsis leads to dysregulated gene expression, leading to a hyperinflammatory response. Environmental conditions play an important role in various pathologies depending on the stimulus it presents. A standard environment condition (SE) may offer reduced sensory and cognitive stimulation, but an enriched environment improves spatial learning, prevents cognitive deficits induced by disease stress, and is an important modulator of epigenetic enzymes. The study evaluated the epigenetic alterations and the effects of the environmental enrichment (EE) protocol in the brain of animals submitted to sepsis by cecal ligation and perforation (CLP). Male Wistar rats were divided into sham and CLP at 24 h, 72 h, 10 days and 30 days after sepsis. Other male Wistar rats were distributed in a SE or in EE for forty-five days. Behavioral tests, analysis of epigenetic enzymes:histone acetylase (HAT), histone deacetylase (HDAC) and DNA methyltransferase (DNMT), biochemical and synaptic plasticity analyzes were performed. An increase in HDAC and DNMT activities was observed at 72 h, 10 days and 30 days. There was a positive correlation between epigenetic enzymes DNMT and HDAC 24 h, 10 days and 30 days. After EE, HDAC and DNMT enzyme activity decreased, cognitive impairment was reversed, IL1-ß levels decreased and there was an increase in PSD-95 levels in the hippocampus. Interventions in environmental conditions can modulate the outcomes of long-term cognitive consequences associated with sepsis, supporting the idea of the potential benefits of EE.

Effects of different probiotic strains B. lactis, L. rhamnosus and L. reuteri on brain-intestinal axis immunomodulation in an endotoxin-induced inflammation.

The study evaluated the effects of supplementation with three different probiotic strains Bifidobacterium lactis (LACT GB™), Lactobacillus rhamnosus (RHAM GB™) and Lactobacillus reuteri (REUT GB™) on brain-intestinal immunomodulation in an animal model of LPS-induced inflammation. Fifty mice Balb/C were distributed into five groups: control; lipopolysaccharide (LPS); LPS + B. lactis (LACT GB™); LPS + L. rhamnosus (RHAM GB™); and LPS + L. reuteri (REUT GB™). The animals were supplemented with their respective probiotic microorganisms daily, for 30 days, at a concentration of 1 × 109 CFU/animal/day. After 30 days of supplementation, animals received the inflammatory insult by LPS (15 mg/kg). Behavioral tests, oxidative stress and inflammation were performed, as well as gut and brain histology. In the behavioral test, LPS + B. lactis group was less anxious than the other groups. Serum interleukin IL-1ß and IL-6 levels increased in all groups that received the LPS insult, and there was a reduction in inflammation in the supplemented groups when compared to the LPS group in brain and gut. There is a reduction in myeloperoxidase activity and oxidative stress in groups supplemented with probiotics. In intestine histological analysis occurs damage to the tissue integrity in the LPS group, in the other hand, occurs preservation of integrity in the probiotic supplemented animals. In the brain, infiltrates of perivascular inflammatory cells can be seen in the LPS group. The three probiotic studies showed efficient immunomodulating activity and ensured integrity of the intestinal barrier function, even after the severe insult by LPS. These results show the important role of probiotics in the gut-brain axis. Graphical abstract illustratively represents the gut-brain axis and how different probiotic strains influence the immunomodulatory response releasing different pro- and anti-inflammatory cytokines, and their role in the balance of dysbiosis.

Sepsis, immunosuppression and the role of epigenetic mechanisms.

Introduction: Sepsis has pro- and anti-inflammatory processes caused by infectious agents. Sepsis survivors have impaired immune response due to immunosuppression. Gene expression during the inflammatory process is guided by transcriptional access to chromatin, with post-translational changes made in histones that determine whether the loci of the inflammatory gene are active, balanced, or suppressed. For this, a review literature was performed in PubMed included 'sepsis' and 'epigenetic' and 'immunosuppression' terms until May 2020.Areas covered: This review article explores the relationship between epigenetic mechanisms and the pathophysiology of sepsis. Epigenetic changes, vulnerable gene expression, and immunosuppression are related to inflammatory insults that can modify the dynamics of the central nervous system. Therefore, it is important to investigate the timing of these changes and their dynamics during the disease progression.Expert opinion: Epigenetic changes are associated with the main stages of sepsis, from the pathogen-host interaction to inflammation and immunosuppression. These changes are key regulators of gene expression during physiological and pathological conditions. Thus, epigenetic markers have significant prognostic and diagnostic potential in sepsis, and epigenetic changes can be explored in combination with therapeutic strategies in experimental models of the disease.

Kava decreases the stereotyped behavior induced by amphetamine in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Kava extract (Piper methysticum) is a phytotherapic mainly used for the treatment of anxiety. Although the reported effects of Kava drinking improving psychotic symptoms of patients when it was introduced to relieve anxiety in aboriginal communities, its effects on models of psychosis-like symptoms are not investigated. AIM OF THE STUDY: To investigate the effects of Kava extract on behavioral changes induced by amphetamine (AMPH) and its possible relation with alterations in monoamine oxidase (MAO) activity. MATERIALS AND METHODS: Mice received vehicle or Kava extract by gavage and, 2 h after vehicle or AMPH intraperitoneally. Twenty-five minutes after AMPH administration, behavioral (elevated plus maze, open field, stereotyped behavior, social interaction and Y maze) and biochemical tests (MAO-A and MAO-B activity in cortex, hippocampus and striatum) were sequentially evaluated. RESULTS: Kava extract exhibited anxiolytic effects in plus maze test, increased the locomotor activity of mice in open field test and decreased MAO-A (in cortex) and MAO-B (in hippocampus) activity of mice. Kava extract prevented the effects of AMPH on stereotyped behavior and, the association between Kava/AMPH increased the number of entries into arms in Y maze test as well as MAO-B activity in striatum. However, Kava extract did not prevent hyperlocomotion induced by AMPH in open field test. The social interaction was not modified by Kava extract and/or AMPH. CONCLUSION: The results showed that Kava extract decreased the stereotyped behavior induced by AMPH at the same dose that promotes anxiolytic effects, which could be useful to minimize the psychotic symptoms in patients.