Temporal analysis of paracetamol-induced hepatotoxicity.

Paracetamol-induced hepatotoxicity (APAP) causes severe damage that may be irreversible. Understanding the evolution of liver injury caused by overdose of the drug is important to assist in the treatment. In the present study, we evaluated the acute intoxication by APAP (500 mg/kg) in periods of 3 and 12 hours in C57BL/6 mice through biochemical, histological, inflammatory parameters, and the redox status. The results showed that in the 3-hour period there was an increase in creatinine dosage and lipid peroxidation (TBARS) compared to the control group. In the period of 12 hours after APAP intoxication all parameters evaluated were altered; there was an increase of ALT, AST, and necrosis, besides the increase of redox status biomarkers as carbonylated protein, TBARS, and MMP-9. We also observed activation of the inflammasome pathway as well as a reduction in the regenerative capacity of hepatocytes with a decrease in binucleated liver cells. In cytochrome gene expression, the mRNA level increased in CYP2E1 isoenzyme and reduced CYP1A2 expression. This study indicated that early treatment is necessary to mitigate APAP-induced acute liver injury, and alternative therapies capable of controlling the progression of intoxication in the liver are needed.

Association among ACE, ESR1 polymorphisms and preeclampsia in Brazilian pregnant women.

BACKGROUND: Genetic, immune and environmental factors are involved in preeclampsia (PE) etiopathogenesis. Considering that hypertension and poor placental perfusion are important features in PE, polymorphisms in the angiotensin-converting enzyme (ACE) and estrogen nuclear receptor 1 (ESR1) genes could be involved in the predisposition and/or development of the disease. The aim of this study was to evaluate if polymorphisms in ACE and ESR1 genes were associated with PE occurrence. MATERIAL AND METHODS: This case-control study included 209 Brazilian pregnant women (107 with severe PE and 102 normotensive controls). The polymorphisms were investigated by polymerase chain reaction (PCR) followed by polyacrylamide gel electrophoresis. RESULTS: No significant difference between PE versus normotensive pregnant women, as well as early versus late PE, was observed when compared the allelic and genotypic frequencies of insertion/deletion polymorphism in intron 16 of the ACE gene and the single nucleotide polymorphisms (SNPs - rs2234693 and rs9340799) of the ESR1 gene. CONCLUSION: This pioneer study involving Brazilian women showed no association among the studied polymorphisms and PE, which suggests that ins/del ACE and SNPs ESR1 do not contribute to this disease occurrence in Brazil.

Annexin A1 Is Involved in the Resolution of Inflammatory Responses during Leishmania braziliensis Infection.

Leishmaniases are diseases caused by several Leishmania species. Leishmania (Viannia) braziliensis can cause localized cutaneous leishmaniasis (LCL), which heals spontaneously, or mucosal leishmaniasis (ML), characterized by chronic and intense inflammation and scanty parasitism. Annexin A1 (AnxA1) is a protein involved in modulation and resolution of inflammation through multiple mechanisms. In the present study, the role of AnxA1 was investigated in L. braziliensis-infected BALB/c mice. AnxA1 levels increased at the peak of tissue lesion and parasitism in infected mice. AnxA1 increased also after L. braziliensis infection of BALB/c (wild-type [WT]) bone marrow derived macrophages. Despite a lower parasite intake, parasite burden in bone marrow-derived macrophages from AnxA1-/- mice was similar to WT and associated with an early increase of TNF-α and, later, of IL-10. AnxA1-/- mice controlled tissue parasitism similarly to WT animals, but they developed significantly larger lesions at later stages of infection, with a more pronounced inflammatory infiltrate and increased specific production of IFN-γ, IL-4, and IL-10. AnxA1-/- mice also presented higher phosphorylation levels of ERK-1/2 and p65/RelA (NF-κB) and inducible NO synthase expression, suggesting that AnxA1 may be involved in modulation of inflammation in this model of experimental leishmaniasis. Finally, assessment of AnxA1 levels in sera from patients with LCL or ML revealed that ML patients had higher levels of serum AnxA1 than did LCL patients or control subjects. Collectively, these data indicate that AnxA1 is actively expressed during L. braziliensis infection. In the absence of AnxA1, mice are fully able to control parasite replication, but they present more intense inflammatory responses and delayed ability to resolve their lesion size.

The role and effects of glucocorticoid-induced leucine zipper in the context of inflammation resolution.

Glucocorticoid (GC)-induced leucine zipper (GILZ) has been shown to mediate or mimic several actions of GC. This study assessed the role of GILZ in self-resolving and GC-induced resolution of neutrophilic inflammation induced by LPS in mice. GILZ expression was increased during the resolution phase of LPS-induced pleurisy, especially in macrophages with resolving phenotypes. Pretreating LPS-injected mice with trans-activator of transcription peptide (TAT)-GILZ, a cell-permeable GILZ fusion protein, shortened resolution intervals and improved resolution indices. Therapeutic administration of TAT-GILZ induced inflammation resolution, decreased cytokine levels, and promoted caspase-dependent neutrophil apoptosis. TAT-GILZ also modulated the activation of the survival-controlling proteins ERK1/2, NF-κB and Mcl-1. GILZ deficiency was associated with an early increase of annexin A1 (AnxA1) and did not modify the course of neutrophil influx induced by LPS. Dexamethasone treatment resolved inflammation and induced GILZ expression that was dependent on AnxA1. Dexamethasone-induced resolution was not altered in GILZ(-/-) mice due to compensatory expression and action of AnxA1. Our results show that therapeutic administration of GILZ efficiently induces a proapoptotic program that promotes resolution of neutrophilic inflammation induced by LPS. Alternatively, a lack of endogenous GILZ during the resolution of inflammation is compensated by AnxA1 overexpression.

Potential of piperine for neuroprotection in sepsis-associated encephalopathy.

AIMS: Sepsis-associated encephalopathy (SAE) is a common complication that increases mortality and leads to long-term cognitive impairment in sepsis survivors. However, no specific or effective therapy has been identified for this complication. Piperine is an alkaloid known for its anti-inflammatory, antioxidant, and neuroprotective properties, which are important characteristics for treatment of SAE. The objective of this study was to evaluate the neuroprotective effect of piperine on SAE in C57BL/6 mice that underwent cecum ligation and perforation surgery (CLP). MAIN METHODS: C57BL/6 male mice were randomly assigned to groups that underwent SHAM surgery or CLP. Mice in the CLP group were treated with piperine at doses of 20 or 40 mg/kg for short- (5 days) or long-term (10 days) periods after CLP. KEY FINDINGS: Our results revealed that untreated septic animals exhibited increased concentrations of IL-6, TNF, VEGF, MMP-9, TBARS, and NLRP3, and decreased levels of BDNF, sulfhydryl groups, and catalase in the short term. Additionally, the levels of carbonylated proteins and degenerated neuronal cells were increased at both time points. Furthermore, short-term and visuospatial memories were impaired. Piperine treatment reduced MMP-9 activity in the short term and decreased the levels of carbonylated proteins and degenerated neuronal cells in the long term. It also lowered IL-6 and TBARS levels at both time points evaluated. Moreover, piperine increased short-term catalase and long-term BDNF factor levels and improved memory at both time points. SIGNIFICANCE: In conclusion, our data demonstrate that piperine exerts a neuroprotective effect on SAE in animals that have undergone CLP.

Neuroserpin, IL-33 and IL-17A as potential markers of mild symptoms of depressive syndrome in Toxoplasma gondii-infected pregnant women.

Introduction: Depressive syndrome (DS) is a common complication during pregnancy and the postpartum period, and is triggered by multiple organic/genetic and environmental factors. Clinical and biochemical follow-up is essential for the early diagnosis and prognosis of DS. The protozoan Toxoplasma gondii causes infectious damage to the fetus during parasite primary-infection. However, in long-term infections, pregnant women develop immune protection to protect the fetus, although they remain susceptible to pathological or inflammatory effects induced by T. gondii. This study aimed to investigate plasma inflammatory biomarkers in pregnant women seropositive and seronegative for T. gondii, with diagnoses of minor and moderate/severe DS. Methods: Pregnant women (n=45; age=18-39 years) were recruited during prenatal care at health centers in Ouro Preto, Minas Gerais, Brazil. Participants were asked to complete a socio-demographic questionnaire to be submitted to well-standardized DS scale calculators (Beck Depression Inventory Questionnaire, Edinburgh Postnatal Depression Scale, and Major Depressive Episode Module). Additionally, 4 mL of blood was collected for plasma neuroserpin, CCL2, IL-17A, and IL-33 analysis. Results: Pregnant volunteers with chronic T. gondii contact were all IgG+ (44%; n=21) and exhibited increased plasma IL-33, IL-17A, and neuroserpin levels, but not CCL2, compared to uninfected pregnant women. Using Beck's depression inventory, we observed an increase in plasma IL-17A and IL-33 in women with T. gondii infeCction diagnosed with mild DS, whereas neuroserpin was associated with minor and moderate/severe DS. Discussion: Our data suggest a close relationship between DS in pregnant women with chronic T. gondii infection and neurological conditions, which may be partially mediated by plasma neuroserpin, IL-33, and IL-17A levels.

The EV antibody database: An interactive database of curated antibodies for extracellular vesicle and nanoparticle research.

Antibodies are critical tools for research into extracellular vesicles (EVs) and other extracellular nanoparticles (ENPs), where they can be used for their identification, characterization, and isolation. However, the lack of a centralized antibody platform where researchers can share validation results thus minimizing wasted personnel time and reagents, has been a significant obstacle. Moreover, because the performance of antibodies varies among assay types and conditions, detailed information on assay variables and protocols is also of value. To facilitate sharing of results on antibodies that are relevant to EV/ENP research, the EV Antibody Database has been developed by the investigators of the Extracellular RNA Communication Consortium (ERCC). Hosted by the ExRNA Portal (https://exrna.org/resources/evabdb/), this interactive database aggregates and shares results from antibodies that have been tested by research groups in the EV/ENP field. Currently, the EV Antibody Database includes modules for antibodies tested for western Blot, EV Flow Cytometry, and EV Sandwich Assays, and holds 110 records contributed by 6 laboratories from the ERCC. Detailed information on antibody sources, assay conditions, and results is provided, including negative results. We encourage ongoing expert input and community feedback to enhance the database's utility, making it a valuable resource for comprehensive validation data on antibodies and protocols in EV biology.

Crosstalk between the plasminogen/plasmin system and inflammation resolution.

The plasminogen/plasmin (Plg/Pla) system, best known for its classical role in thrombolysis, has been recently highlighted as a regulator of other biological processes in mammals, including key steps involved in the resolution of inflammation. Inflammation resolution is a complex process coordinated by different cellular effectors, notably leukocytes, and active mediators, and is initiated shortly after the inflammatory response begins. Once the inflammatory insult is eliminated, an effective and timely engagement of proresolution programs prevents persistent inflammation, thereby avoiding excessive tissue damage, fibrosis, and the development of autoimmunity. Interestingly, recent studies demonstrate that Plg/Pla and their receptor, plasminogen receptor KT (Plg-RKT), regulate key steps in inflammation resolution. The number of studies investigating the involvement of the Plg/Pla system in these and other aspects of inflammation, including degradation of extracellular matrices, immune cell migration, wound healing, and skeletal growth and maintenance, highlights key roles of the Plg/Pla system during physiological and pathologic conditions. Here, we discuss robust evidence in the literature for the emerging roles of the Plg/Pla system in key steps of inflammation resolution. These findings suggest that dysregulation in Plg production and its activation plays a role in the pathogenesis of inflammatory diseases. Elucidating central mechanisms underlying the role of Plg/Pla in key steps of inflammation resolution either in preclinical models of inflammation or in human inflammatory conditions, can provide a rationale for the development of new pharmacologic interventions to promote resolution of inflammation, and open new pathways for the treatment of thromboinflammatory conditions.

Upregulation of IL-33, CCL2, and CXCL16 levels in Brazilian pregnant women infected by Toxoplasma gondii.

Congenital toxoplasmosis can cause neurological and eye damage, behavioral alterations, or death in fetuses or babies born to Toxoplasma gondii-infected women. Several pieces of evidence suggest that socioeconomic, environmental, and inflammatory patterns linked to the maternal immune response partly drive the pathogenesis of this disease. However, immunoregulation induced by T. gondii infection during gestation is not completely understood. The aim of this study was to assess the association between T. gondii seropositivity and concentrations of plasma markers (CCL2, CXCL16, IL-17, and IL-33) in Brazilian pregnant women. Inflammatory markers were measured by immunoassays in the plasma of 131 pregnant women (13 to 46 years old). The prevalence of T. gondii infections was 45.8% (n = 60) in this population. The concentrations of CCL2, CXCL16, and IL-33 were higher in T. gondii-seropositive than in seronegative pregnant women, while the opposite was observed for IL-17 levels. In IgG+ women, a strong correlation between IL-17 and IL-33 (r = 0.7508, p = 0.0001) and a moderate correlation between CXCL16/IL-17 (r = 0.7319, p = 0.0001) and CXCL16/CCL2 (r = 0.3519, p = 0.0098) was observed. In uninfected women, a strong correlation was found between IL-17 and CXCL16 (r = 0.6779, p = 0.0001) but moderate between IL-17 and IL-33 (r = 0.4820, p = 0.0001). In summary, our data suggest that plasma upregulation of CCL2, CXCL16, and IL-33 might exert a potential protective role in the mother/fetus/parasite axis and, in addition, multiparous women are more likely to be infected with T. gondii than primiparous women.

The imbalance in the relationship between inflammatory and regulatory cytokines during gestational toxoplasmosis can be harmful to fetuses: A systematic review.

Objective: To evaluate the available information on inflammatory and regulatory plasma mediators in pregnant women (PW) diagnosed with toxoplasmosis. Source: The PubMed, Embase, Scopus, and Lilacs databases were evaluated until October 2022. Study eligibility criteria: This review was carried out following the PRISMA and registered on the PROSPERO platform (CRD42020203951). Studies that reported inflammatory mediators in PW with toxoplasmosis were considered. Evaluation methods: After excluding duplicate articles, two authors independently carried out the process of title and abstract exclusion, and a third resolved disagreements when necessary. The full text was evaluated to detect related articles. The extraction table was built from the following data: Author, year of publication, journal name and impact factors, country, study design, number of gestations and maternal age (years), gestational period, diagnosis of toxoplasmosis, levels of inflammatory markers, laboratory tests, and clinical significance. Methodological quality was assessed using Joanna Briggs Institute tools. Results: Of the 1,024 studies reported, only eight were included. Of the 868 PW included in this review, 20.2% were IgM+/IgG- and 50.8% were IgM-/IgG+ to T. gondii, and 29.0% uninfected. Infected PW presented higher plasma levels ofIL-5, IL-6, IL-8, IL-17, CCL5, and IL-10. Regarding the methodological quality, four studies obtained high quality. Data from this review pointed out the maintenance of the inflammatory pattern during pregnancy with a closely related to the parasite. Conclusion: Immune status in PW defined the course of the T. gondii infection, where the equilibrium between inflammatory and regulatory cytokines mitigated the harmful placenta and fetus effects. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD420203951.

Neuroserpin: A potential biomarker for early-onset severe preeclampsia.

Preeclampsia is a hypertensive disease of pregnancy associated with intense inflammatory and pro-coagulant responses. Neuroserpin is a serine protease inhibitor that has been involved in neurological and immune processes and has not yet been investigated in preeclampsia. Herein, we evaluated neuroserpin levels in association with other inflammatory mediators (IL-17A, IL-33, and CXCL-16) during severe preeclampsia. The mediators' plasma levels were measured by immunoassays in 24 pregnant women with severe preeclampsia (early preeclampsia: N = 17, late preeclampsia: N = 7), 34 normotensive pregnant women, and 32 non-pregnant women. In general, pregnancy was associated with higher levels of neuroserpin, IL-17A, IL-33, and CXCL-16 than the non-pregnant state. However, this increase was attenuated in pregnancies complicated by severe preeclampsia. Although neuroserpin levels did not differ between normotensive pregnant women and pregnant women with severe preeclampsia, neuroserpin levels tended to be lower in early-onset than in late-onset severe preeclampsia. There were positive correlations between neuroserpin and IL-17A, neuroserpin and CXCL-16, and IL-17A and CXCL-16 levels in women with severe preeclampsia. In addition, although the risk for developing severe preeclampsia was higher in older women in this study, maternal age did not significantly influence the mediators' levels, nor their correlations in the preeclampsia group. In summary, our data suggest that neuroserpin might be a potential biomarker for early-onset severe preeclampsia and, that the imbalance among neuroserpin, IL-17A, IL-33, and CXCL-16 levels may be associated with the pathogenesis of preeclampsia, regardless of the maternal age.

Plasmin and plasminogen prevent sepsis severity by reducing neutrophil extracellular traps and systemic inflammation.

Sepsis is a lethal syndrome characterized by systemic inflammation and abnormal coagulation. Despite therapeutic advances, sepsis mortality remains substantially high. Herein, we investigated the role of the plasminogen/plasmin (Plg/Pla) system during sepsis. Plasma levels of Plg were significantly lower in mice subjected to severe compared with nonsevere sepsis, whereas systemic levels of IL-6, a marker of sepsis severity, were higher in severe sepsis. Plg levels correlated negatively with IL-6 in both septic mice and patients, whereas plasminogen activator inhibitor-1 levels correlated positively with IL-6. Plg deficiency render mice susceptible to nonsevere sepsis induced by cecal ligation and puncture (CLP), resulting in greater numbers of neutrophils and M1 macrophages, liver fibrin(ogen) deposition, lower efferocytosis, and increased IL-6 and neutrophil extracellular trap (NET) release associated with organ damage. Conversely, inflammatory features, fibrin(ogen), and organ damage were substantially reduced, and efferocytosis was increased by exogenous Pla given during CLP- and LPS-induced endotoxemia. Plg or Pla protected mice from sepsis-induced lethality and enhanced the protective effect of antibiotics. Mechanistically, Plg/Pla-afforded protection was associated with regulation of NET release, requiring Pla-protease activity and lysine binding sites. Plg/Pla are important host-protective players during sepsis, controlling local and systemic inflammation and collateral organ damage.

Fibrinolysis in COVID-19: Impact on Clot Lysis and Modulation of Inflammation.

COVID-19 is a multisystem disease caused by SARS-CoV-2 and is associated with an imbalance between the coagulation and fibrinolytic systems. Overall, hypercoagulation, hypofibrinolysis and fibrin-clot resistance to fibrinolysis predispose patients to thrombotic and thromboembolic events. In the lungs, the virus triggers alveolar and interstitial fibrin deposition, endothelial dysfunction, and pulmonary intravascular coagulation, all events intrinsically associated with the activation of inflammation and organ injury. Adding to the pathogenesis of COVID-19, there is a positive feedback loop by which local fibrin deposition in the lungs can fuel inflammation and consequently dysregulates coagulation, a process known as immunothrombosis. Therefore, fibrinolysis plays a central role in maintaining hemostasis and tissue homeostasis during COVID-19 by cleaning fibrin clots and controlling feed-forward products of coagulation. In addition, components of the fibrinolytic system have important immunomodulatory roles, as evidenced by studies showing the contribution of Plasminogen/Plasmin (Plg/Pla) to the resolution of inflammation. Herein, we review clinical evidence for the dysregulation of the fibrinolytic system and discuss its contribution to thrombosis risk and exacerbated inflammation in severe COVID-19. We also discuss the current concept of an interplay between fibrinolysis and inflammation resolution, mirroring the well-known crosstalk between inflammation and coagulation. Finally, we consider the central role of the Plg/Pla system in resolving thromboinflammation, drawing attention to the overlooked consequences of COVID-19-associated fibrinolytic abnormalities to local and systemic inflammation.

Piperine as Therapeutic Agent in Paracetamol-Induced Hepatotoxicity in Mice.

High doses of paracetamol (APAP) can cause irreversible liver damage. Piperine (P) inhibits cytochrome P450, which is involved in the metabolism of various xenobiotics, including paracetamol. We evaluated the hepatoprotective effects of piperine with or without N-acetylcysteine (NAC) in APAP-induced hepatotoxicity. The mice were treated with two doses of piperine (P20 or P40) and/or NAC at 2 h after administration of APAP. The NAC+P20 and NAC+P40 groups showed a reduced area of necrosis, MMP-9 activity, and Casp-1 expression. Furthermore, the NAC+P20 group was the only treatment that reduced alanine aminotransferase (ALT) and increased the levels of sulfhydryl groups (-SH). In the NAC+P40 group, NLRP-3 expression was reduced. Aspartate aminotransferase (AST), thiobarbituric acid-reactive substances (TBARS), and IL-1ß expression decreased in the NAC, NAC+P20, and NAC+P40 groups compared to the APAP group. The liver necrosis area, TNF levels, carbonylated protein, and IL-18 expression decreased in the P40, NAC, NAC+P20, and NAC+P40 groups compared to the APAP group. The cytokine IL-6 was reduced in all treatments. Piperine can be used in combination with NAC to treat APAP-induced hepatotoxicity.

Protein restriction during pregnancy affects lung development and promotes oxidative stress and inflammation in C57 BL/6 mice offspring.

OBJECTIVES: The present study aimed to evaluate the effects of maternal protein restriction during pregnancy on the lungs of 1-d and 31-d old offspring of C57BL/6 mice. METHODS: The C57BL/6 mice (8-10 wk) were used for breeding. After pregnancy confirmation, female mice were randomly divided into a control group (CG) receiving a standard diet (22% protein) and a protein-restriction group (PRG) receiving a low-protein diet (6% protein). In the low-protein diet, protein was replaced by carbohydrate. After parturition, female mice that received the low-protein diet were fed the standard diet. Male offspring were euthanized 1 d and 31 d after birth for subsequent analysis. We evaluated the effects of a protein-restricted diet during gestation in pulmonary organogenesis, lung oxidative stress, and pulmonary inflammatory response of the offspring. RESULTS: PRG mice 1 d after birth showed lower body and lung mass, length, relative mass, lung density, and erythrocyte count compared with CG mice. There was an increase in alveolar airspace density and a higher mean linear intercept (Lm), greater oxidative damage, and inflammation in PRG mice compared with CG mice. At 31 d after birth, PRG mice had lower body mass, length, and lung mass values compared with CG mice. PRG mice showed greater recruitment of inflammatory cells to the airways. In addition, there was increased collagen deposition in the lungs, altered inflammatory mediators, and greater oxidative damage compared with CG mice. CONCLUSIONS: Protein restriction during pregnancy reduces the body weight of offspring and promotes inflammation and oxidative stress, resulting in a simplification of the lung structure.

Insights into IL-33 on inflammatory response during in vitro infection by Trypanosoma cruzi.

Inflammatory and regulatory cytokines play an important role in the immunopathogenesis of Trypanosoma cruzi infection. Interleukin (IL)-33 is a member of the IL-1 superfamily of cytokines whose expression/production is upregulated following pro-inflammatory stimulation to alert the immune system in response to tissue stress or damage. The aim of this study was to evaluate the inflammatory profile induced in cultured J774 cells stimulated or not with IL-33 (10 ng/mL), with live parasites (1 × 106 metacyclic trypomastigote forms) and/or total antigen, TcAg (100 µg/mL) and with both, IL-33 and TcAg/T. cruzi. The cultures were evaluated at 24 h and 48 h after addition of the stimuli. For this, the supernatants were collected for the measurement of TNF, IL-17, CCL2, and IL-10 by ELISA and of nitrite by the Griess method. TNF, IL-17, and CCL2 concentrations were elevated in the presence of TcAg or live T. cruzi parasites at 24 h, and the addition of IL-33 potentiated these effects at 48 h. In addition, the T. cruzi-amastigote forms reduced in those infected J774 cells stimulated with IL-33 at 48 h. In conclusion, the IL-33 elevated the production of the TNF, IL-17, and CCL2 in cultured J774 cells stimulated with T. cruzi and/or its antigen and reduced the intracellular parasites, providing impetus to new investigations on its potential actions on the parasite-induced inflammation.

The deleterious impact of exposure to different inhaled anesthetics is time dependent.

In this study, the effects of exposure to isoflurane, sevoflurane and desflurane on the oxidative response and inflammation at different times was analyzed in the lungs of adult C57BL/6 mice. 120 animals were divided into 3 groups (n = 40): Isoflurane (ISO), Sevoflurane (SEV) and Desflurane (DES) and exposed to these anesthetics for 1 h (n = 10), 2 h (n = 10) and 3 h (n = 10), at a minimum alveolar concentration (MAC) equal to 1. The control group (CG) (n = 10) was exposed to ambient air. 24 h after the experimental protocol, the animals were euthanized and the bronchoalveolar lavage fluid (BALF), blood and lung tissue samples were collected. In the BALF, animals exposed to isoflurane for 2 h and 3 h showed a greater influx of leukocytes, especially macrophages compared to the CG. The ISO3h had lower leukocyte counts in the peripheral blood compared to CG, ISO1h and ISO2h. There was an increase in CCL-2 levels in the ISO3h compared to the CG. Superoxide dismutase activity was higher in ISO1h compared to CG. The activity of catalase was higher in the ISO1h and ISO2h compared to the CG. The lipid peroxidation, as well as carbonylated protein were higher in the ISO3h compared to the CG (p < 0.05). Similar results were observed in the exposure of SEV and DES compared to inflammation and redox imbalance in different periods. This study demonstrated that time is a determinant to promote a local and systemic inflammatory response to different inhalational anesthetics in a healthy murine model.

Longitudinal assessment of leukotriene B4, lipoxin A4, and resolvin D1 plasma levels in pregnant women with risk factors for preeclampsia.

OBJECTIVES: We carried out a longitudinal study to compare leukotriene B4 (LTB4), lipoxin A4 (LXA4), and resolvin D1 (RvD1) levels in pregnant women with risk factors for PE - who did (N = 11) or did not develop (N = 17) this clinical condition. DESIGN & METHODS: For both groups, plasma levels of the lipid mediators were measured using immunoassays at 12-19, 20-29, and 30-34 weeks of gestation. RESULTS: LTB4 tended to be upregulated throughout gestation in women who developed PE. Moreover, this increase was significant at 30-34 weeks. Although LXA4 levels also tended to be higher in the PE group, this difference was not significant for the evaluated gestational periods. Pregnant women with PE had lower RvD1 levels and a low RvD1/LTB4 ratio at 30-34 weeks, compared to those in the normotensive pregnant women. Contrarily, RvD1 levels increased at weeks 12-19 in pregnant women who developed PE. Particularly, LXA4 and RvD1 levels were higher at 30-34 weeks than those at 20-29 weeks considering both groups of women. We observed an interaction between the gestational outcome and the gestational period in case of RvD1. CONCLUSIONS: The imbalance among LTB4, LXA4, and RvD1 levels in these preeclamptic women is consistent with the excessive inflammation that underlies the pathogenesis of PE. Although our data highlight the potential for the use of these lipid mediators as clinical markers for PE development, future longitudinal studies must be carried out to confirm these findings.

Hepatoprotective, antioxidant, anti-inflammatory, and antiviral activities of silymarin against mayaro virus infection.

Infection caused by Mayaro virus (MAYV) is responsible for causing acute nonspecific fever, in which the majority of patients develop incapacitating and persistent arthritis/arthralgia. Mayaro fever is a neglected and underreported disease without treatment or vaccine, which has gained attention in recent years after the competence of Aedes aegypti to transmit MAYV was observed in the laboratory, coupled with the fact that cases are being increasingly reported outside of endemic forest areas, calling attention to the potential of an urban cycle arising in the near future. Thus, to mitigate the lack of information about the pathological aspects of MAYV, we previously described the involvement of oxidative stress in MAYV infection in cultured cells and in a non-lethal mouse model. Additionally, we showed that silymarin, a natural compound, attenuated MAYV-induced oxidative stress and inhibited MAYV replication in cells. The antioxidant and anti-MAYV effects prompted us to determine whether silymarin could also reduce oxidative stress and MAYV replication after infection in an immunocompetent animal model. We show that infected mice exhibited reduced weight gain, hepatomegaly, splenomegaly, anaemia, thrombocytopenia, leukopenia, increased liver transaminases, increased pro-inflammatory cytokines and liver inflammation, increased oxidative damage biomarkers, and reduced antioxidant enzyme activity. However, in animals infected and treated with silymarin, all these parameters were reversed or significantly improved, and the detection of viral load in the liver, spleen, brain, thigh muscle, and footpad was significantly reduced. This work reinforces the potent hepatoprotective, antioxidant, anti-inflammatory, and antiviral effects of silymarin against MAYV infection, demonstrating its potential against Mayaro fever disease.