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Fasciíte Necrosante (FN) é uma infecção grave de partes moles caracterizada por necrose rapidamente progressiva, difusa, da fáscia e dos tecidos adjacentes. Em tempos atuais, não existem dados exatos quanto a sua real incidência. Em relação aos casos de FN em mama sem associação com fatores de risco, menos de 20 casos foram descritos na literatura. Relato de Caso: G.C.R.C, sexo feminino, 19 anos, parda, solteira, natural e residente no Estado do Rio de Janeiro. Dá entrada no Pronto Socorro de um hospital público, em Volta Redonda, em fevereiro de 2021, referindo mastalgia e sinais flogísticos em mama direita, sem trauma ou ferida local preexistentes, associados a febre não termometrada há três dias. Notou-se piercing mamilar, implantado há dois anos, sendo retirado durante a abordagem inicial. Após esse procedimento, teve alta para casa e, após 12 horas, retornou ao hospital apresentando, ao exame físico, mama direita hiperemiada na região periareolar e irradiação lateral do processo inflamatório. No dia seguinte à admissão, foi internada no Setor de Ginecologia e Obstetrícia e, em quatro horas, evoluiu com equimose periareolar extensa, avançando com piora dos sinais flogísticos, flictemas de conteúdo serossanguinolento e necrose periareolar. Estipulou-se assim a hipótese diagnóstica de FN. No quarto dia de internação, foi submetida a amplo desbridamento cirúrgico com fasciotomia e retirada de todo tecido necrótico. Permaneceu em antibioticoterapia por 14 dias no Centro de Terapia Intensiva. O quadro ilustrava involução progressiva com redução de secreções seropurulentas e sinais inflamatórios. Após término do esquema antimicrobiano, recebeu alta hospitalar e foi mantida em acompanhamento ambulatorial para manutenção de curativos. No 35° dia após sua alta hospitalar, em abril, a paciente foi submetida a cirurgia plástica reparadora. Realizou-se enxerto de pele com área doadora da região infraumbilical. O procedimento ocorreu sem intercorrências, sendo finalizado com curativo de Brown. Esse é um dos poucos casos registrados de FN em mama, sendo necessários mais estudos quanto à sua patogênese, ao seu diagnóstico e ao seu tratamento para melhor manejo clínico.

The recently emerged SARS-CoV-2 Omicron sublineages, including the BA.2-derived XBB.1.5 (Kraken), XBB.1.16 (Arcturus), and EG.5.1 (Eris), have accumulated several spike mutations that may increase immune escape, affecting vaccine effectiveness. Older adults are an understudied group at significantly increased risk of severe COVID-19. Here we report the neutralizing activities of 177 sera samples from 59 older adults, aged 62-97 years, 1 and 4 months after vaccination with a 4th dose of ChAdOx1-S (Oxford/AstraZeneca) and 3 months after a 5th dose of Comirnaty Bivalent Original/Omicron BA.4/BA.5 vaccine (Pfizer-BioNTech). The ChAdOx1-S vaccination-induced antibodies neutralized efficiently the ancestral D614G and BA.4/5 variants, but to a much lesser extent the XBB.1.5, XBB.1.16, and EG.5.1 variants. The results showed similar neutralization titers between XBB.1.16 and EG.5.1 and were lower compared to XBB.1.5. Sera from the same individuals boosted with the bivalent mRNA vaccine contained higher neutralizing antibody titers, providing a better cross-protection against Omicron XBB.1.5, XBB.1.16 and EG.5.1 variants. Previous history of infection during the epidemiological waves of BA.1/BA.2 and BA.4/BA.5, poorly enhanced neutralization activity of serum samples against XBBs and EG.5.1 variants. Our data highlight the continued immune evasion of recent Omicron subvariants and support the booster administration of BA.4/5 bivalent vaccine, as a continuous strategy of updating future vaccine booster doses to match newly emerged SARS-CoV-2 variants.

In this study we explored the previously established leishmanicidal activity of a complementary set of 24 imidazolium salts (IS), 1-hexadecylimidazole (C 16 Im) and 1-hexadecylpyridinium chloride (C 16 PyrCl) against Leishmania (Leishmania) amazonensis and Leishmania (Leishmania) infantum chagasi . Promastigotes of L. amazonensis and L. infantum chagasi were incubated with 0.1 to 100 μM of the compounds and eight of them demonstrated leishmanicidal activity after 48 h - C 10 MImMeS (IC 50 L. amazonensis = 11.6), C 16 MImPF 6 (IC 50 L. amazonensis = 6.9), C 16 MImBr (IC 50 L. amazonensis = 6), C 16 M 2 ImCl (IC 50 L. amazonensis = 4.1), C 16 M 4 ImCl (IC 50 L. amazonensis = 1.8), (C 10 ) 2 MImCl (IC 50 L. amazonensis = 1.9), C 16 Im (IC 50 L. amazonensis = 14.6), and C 16 PyrCl (IC 50 L. amazonensis = 4).The effect of IS on reactive oxygen species production, mitochondrial membrane potential, membrane integrity and morphological alterations of promastigotes was determined, as well as on L. amazonensis -infected macrophages. Their cytotoxicity against macrophages and human erythrocytes was also evaluated. The IS C 10 MImMeS, C 16 MImPF 6 , C 16 MImBr, C 16 M 2 ImCl, C 16 M 4 ImCl and (C 10 ) 2 MImCl, and the compounds C 16 Im and C 16 PyrCl killed and inhibited the growth of promastigote forms of L. amazonensis and L. infantum chagasi in a concentration-dependent manner, contributing to a better understanding of the structure-activity relationship of IS against Leishmania . These IS induced ROS production, mitochondrial dysfunction, membrane disruption and morphological alterations in infective forms of L. amazonensis and killed intracellular amastigote forms in very low concentrations (IC 50 amastigotes ≤ 0.3), being potential drug candidates against L. amazonensis ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Baldissera, Fazolo, da Silva, de Santana Filho, da Silva, Rivillo Perez, Klitzke, de Oliveira Soares, Rodrigues Júnior, Peres, Dallegrave, Navegantes-Lima, Monteiro, Schrekker and Torres Romão.)

Monocytes play a major role in the initial innate immune response to SARS-CoV-2. Although viral load may correlate with several clinical outcomes in COVID-19, much less is known regarding their impact on innate immune phenotype. We evaluated the monocyte phenotype and mitochondrial function in severe COVID-19 patients (n = 22) with different viral burden (determined by the median of viral load of the patients) at hospital admission. Severe COVID-19 patients presented lower frequency of CD14 + CD16- classical monocytes and CD39 expression on CD14 + monocytes, and higher frequency of CD14 + CD16 + intermediate and CD14-CD16 + nonclassical monocytes as compared to healthy controls independently of viral load. COVID-19 patients with high viral load exhibited increased GM-CSF, PGE-2 and lower IFN-α as compared to severe COVID-19 patients with low viral load (p < 0.05). CD14 + monocytes of COVID-19 patients with high viral load presented higher expression of PD-1 but lower HLA-DR on the cell surface than severe COVID-19 patients with low viral load. All COVID-19 patients presented decreased monocyte mitochondria membrane polarization, but high SARS-CoV-2 viral load was associated with increased mitochondrial reactive oxygen species. In this sense, higher viral load induces mitochondrial reactive oxygen species generation associated with exhaustion profile in CD14 + monocytes of severe COVID-19 patients. Altogether, these data shed light on new pathological mechanisms involving SARS-CoV-2 viral load on monocyte activation and mitochondrial function, which were associated with COVID-19 severity., (Copyright © 2022. Published by Elsevier B.V.)

The C-C chemokine receptor type 5 (CCR5) plays a role in the immunopathogenesis of chronic kidney disease (CKD). Exercise has anti-inflammatory properties that may contribute to the rehabilitation of CKD patients. To date, the impact of the intradialytic exercise on CCR5 expression in monocytes and lymphocytes of CKD patients is unknown. We aimed to evaluate the effects of an acute intradialytic moderate-intensity exercise on CD4+CCR5+ T-cells and CD14+CCR5+ monocytes of elderly individuals with Chronic Kidney Disease (CKD). Eight CKD elderly patients performed a single bout of 20 min intradialytic exercise and a control hemodialysis (HD) session. Blood samples were collected at baseline, during and immediately after the trials. HD therapy increased the peripheral frequency of CD4+CCR5+ T-cells. The systemic CCL5 levels and the peripheral CD14+CCR5+ proportions increased during and after HD therapy. No significant alterations in CD4+CCR5+ and CD14+CCR5+ proportions or CCL5 levels were identified in CKD patients during and after intradialytic exercise. A negative correlation between the peripheral frequency of CD14+CCR5+ and the creatinine levels was identified in the intradialytic exercise session. A single moderate-intensity intradialytic exercise imposes an immunomodulatory impact in CKD elderly patients, preventing an excessive inflammatory response induced by hemodialysis.

Illicit drug use can cause a variety of effects including alterations in the immune system. The aim of this study was to investigate the effects of illicit drugs on circulating lipopolysaccharide (LPS), systemic inflammation and oxidative stress markers in drug users. We evaluated the levels of soluble CD14 (sCD14), LPS, inflammatory (TNF-α and IL-6) and regulatory (IL-10) cytokines, as well as C-reactive protein (CRP), lipid peroxidation (TBARS) and total thiols in the peripheral blood of 81 men included in groups of cannabis (n = 21), cocaine (n = 12), cannabis-plus-cocaine users (n = 27), and non-drug users (n = 21). The use of cannabis plus cocaine leads to higher systemic levels of LPS, CRP, IL-6 and higher IL-6/IL-10 ratio, characterizing a proinflammatory profile. In contrast, a regulatory profile as viewed by lower systemic TNF-α and IL-6 levels and lower TNF-α/IL-10 ratio were observed in cannabis users compared to the control group. Moreover, cocaine users presented a lower content of non-enzymatic antioxidant thiol compared to control group, cannabis group and cannabis plus cocaine group. In conclusion, our results indicate that the use of cannabis contributes to an anti-inflammatory/or regulatory profile while the concomitant cannabis plus cocaine consumption coexists with increased circulating amounts of LPS and proinflammatory status., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: Currently, there is a growing emphasis on the study of intestinal signaling as an influencer in the pathophysiology of neuropsychiatric diseases, and the gut-brain axis is recognized as a communication route through endocrine, immune, and neural pathways (vagus nerve). Studies have shown that diets that modify the microbiota can reduce stress-related behavior and hypothalamic-pituitary-adrenal axis activation. Investigators have used fecal microbiota transplantation (FMT) approaches to demonstrate that stress-related microbiota composition plays a causal role in behavioral changes., Aim: We hypothesized that FMT may present immunomodulatory, biochemical, endocrine, cognitive, and behavioral benefits in stress situations and that these changes can be mediated via the vagus nerve., Methods: Animals were subjected to a chronic mild stress (CMS) protocol. In one experiment, animals were divided into five groups: control, control + FMT, control + FMT + CMS, CMS + saline, and CMS + FMT. The animals received FMT, and behavioral tests were performed; cytokine and carbonyl levels were measured. In a second experiment, animals were submitted to vagotomy and divided into two groups: CMS + FMT and CMS + vagotomy + FMT., Results: Animals submitted to the CMS protocol or that received FMT from stressed animals showed behavioral changes and changes in neuroactive substances (increased IL-6 and TNF-α levels and carbonyl proteins). The FMT of healthy donors improved the analyzed parameters. In addition, vagotomy influenced beneficial FMT results, confirmed by behavioral testing and protein carbonyl in the hippocampus., Conclusion: Manipulation of the microbiota reversed the behavioral and biochemical changes induced by the CMS protocol, and the vagus nerve influenced the gut-brain axis response., (Copyright © 2020. Published by Elsevier B.V.)

Detecting and monitoring cognitive deficits in elderly populations are necessary, as they can impact individuals´ functionality. This integrative review aims to analyze the scientific production on the use of cognitive assessment instruments in Brazilian elderly individuals through articles published in the last five years, indexed in the Web of Science, Pubmed, Scopus and Bireme databases. Inclusion criteria were original articles published in English and Portuguese from 2012 to 2016, the age criterion to define elderly individuals and scores higher than 6 in the adapted CASP. The exclusion criterion was conference abstracts submitted for publication. The final sample consisted of 100 articles. Sixty-one cognitive assessment instruments were used in the studies, especially the Mini-Mental State Examination. This review features the use of cognitive instruments in the Brazilian literature, their different versions and domains evaluated. The literature includes a large number of instruments. The most used tests were the MMSE (version proposed by Brucki et al.), the Verbal Fluency Test ("animal" category) and the Digit Span Memory Test (forward span and backward span). The findings presented in this review are relevant not only for observational and experimental research but also for clinical practice.

Capsicum baccatum is the most consumed red pepper species in Brazil. Our previous studies demonstrated the anti-inflammatory properties of its crude extract, whose activity is yet to be fully characterized. Herein, we examined the anti-inflammatory in vivo effects of enriched extracts obtained through bioguided fractionation as dichloromethane (DCM), butanol (BUT), and residual aqueous (RAq) extracts and its influence on inflammatory mediators produced by macrophages in vitro. We demonstrated that all C. baccatum extracts presented anti-inflammatory activity in vivo. In addition, we showed that BUT and RAq were more effective in inhibiting the neutrophil migration induced by carrageenan (Cg) to peritoneal cavity and both extracts inhibited paw edema induced by Cg, prostaglandin E2, and histamine in mice. Furthermore, the pretreatment with C. baccatum extracts significantly reduced the levels of myeloperoxidase (MPO) in the paw tissues of mice compared with the carrageenan group. Once again, RAq and BUT caused the greatest reduction in MPO levels. Moreover, it was demonstrated for the first time that C. baccatum inhibited the nitric oxide and tumor necrosis factor-alpha production by lipopolysaccharide/interferon gamma (IFN-γ)-stimulated macrophages. These anti-inflammatory effects seem to be at least, in part, independent of capsaicin. Hence, red pepper has bioactive compounds and might be used to develop food-derived extracts to treat related inflammatory diseases.

The purpose of this study was to compare the peripheral expression of natural killers and CCR5 in a session of low-intensity strength training with vascular occlusion and in high-intensity training. Young males were randomized into session groups of a high-intensity strength training (HI) and a session group of low-intensity strength training with vascular occlusion (LI-BFR). The exercise session consisted in knee extension and bicep curl in 80% 1RM (HI) and 30% 1RM (LI-BFR) with equalized volumes. Blood collection was made before, immediately after and 24 h after each training session. Immunophenotyping was carried out through CD195+ (CCR5) e CD3-CD16+CD56+ (NK) in peripheral blood and analysed by flow cytometry and presented in frequency (%). Peripheral frequency of NK cells showed no significant difference in LI-BFR group in time effect, while a gradual reduction of NK cells was identified in HI group in before-24 h postexercise and after-24 h postexercise comparison. However, significant differences have been found in relative change of NK cells immediately after exercise between sessions. In addition, HI and LI-BFR groups showed a significant reduction in the cells expressed CCR5 during 24 h postsession compared to the postsession, but CCR5 also differed when comparing before-24 h after session in the HI group. No differences were observed amongst the groups. LIO induced CCR5 response similar to the HI session, while the NK cells remained in similar frequency during the studied moments in LI-BFR, but not in HI group, suggesting that local hypoxia created by the blood flow restriction was able to prevent a change in the frequency of peripheral cells and a possible immunosuppression., (© 2015 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd.)

Interleukin (IL)-21 has been intensively studied for use in therapy of autoimmune diseases, cancers, and chronic viruses due to its immunomodulatory properties, especially on CD4(+) and CD8(+) T cells and natural killer (NK) cells. The objective of this study was to produce an optimized form of IL-21 with improved stability. Plasmids encoding the murine IL-21 alone (pIL-21) or IL-21 genetically fused to portions from mouse IgG3 (pIL-21/Ig) were constructed, and the efficiency of expression, protein kinetics, biodisponibility, and function were analyzed. The genetic constructions of pIL-21 and pIL-21/Ig were transfected into HEK 293 cells, and significant levels of functional IL-21 were obtained. The amino acid of murine IL-21 and IgG3 cloned showed 100% identity with correspondent published sequences. At 24 h of incubation, increased levels of IL-21 were detected in the supernatants of pIL-21. At 72 h of culture, the levels of IL-21 in the supernatant of cells transfected with pIL-21/Ig were significantly higher than those secreted by pIL-21-transfected cells. Furthermore, the data showed that our chimeric IL-21/Ig present improved systemic disponibility in BALB/c mice and conserved the intrinsic ability to increase the frequency of CD4(+) T cells, NKT cells, and CD8(+) T cells.

Purpose: To compare the effects of two interval exercises with different intensities on acute inflammatory response in lean and overweight-obese subjects., Methods: Ten lean (BMI<24.9kg/m(2)) and 12 overweight-obese (BMI 25 to <34.9kg/m(2)) males performed two conditions in randomly assigned: (1) high intensity interval exercise (HIIE) 10×60s (85-90%PMax)/75s (50%PMax); (2) moderate intensity interval exercise (MIIE) 10×60s (70-75%PMax)/60s (50%PMax), with blood collections at pre, immediately and 30min post each exercise bouts to evaluate total and differential leukocyte counts, serum creatine kinase (CK), lactate dehydrogenase (LDH) and systemic levels of IL-1ra, IL-6, IL-8, IL-10, IL-17a and CCL2., Results: In lean group, HIIE induced a significant increase in total leukocytes and monocyte, while MIIE session did not change the number of leukocytes. Overweight-obese group presented similar increase in leukocytes, monocytes and lymphocytes in both HIIE and MIIE sessions. At baseline, overweight-obese group showed high levels of CK, IL-8, IL-6 and CCL2 and lower concentrations of IL-10 compared to lean group. The MIIE did not alter the cytokine concentrations in both groups, independently of the time analysis. The HIIE induced significant decrease in IL-8 levels 30min post session in both the groups, and a progressive elevation in IL-10 levels immediately and 30min post in lean and overweight-obese. Regarding IL-6, overweight-obese subjects presented progressive increase either immediately and 30min after HIIE, while lean individuals presented significant increase only 30min after exercise., Conclusions: The acute inflammatory response to interval exercise is intensity-dependent. Although obesity influences the basal concentrations of several cytokines, only HIIE induced important alterations in IL-8 and IL-10 levels, which may have important implications in the control of chronic low-grade inflammation in obesity., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Nociceptin/orphanin FQ is the natural ligand of a Gi-protein coupled receptor named NOP. This peptidergic system is involved in the regulation of mood states and inflammatory responses. The present study aimed to investigate the consequences of blocking NOP signaling in lipopolysaccharide (LPS)-induced sickness and depressive-like behaviors in mice. LPS 0.8mg/kg, ip, significantly induced sickness signs such as weight loss, decrease of water and food intake and depressive-like behavior in the tail suspension test. Nortriptyline (ip, 60min prior the test) reversed the LPS-induced depressive states. The NOP receptor antagonist SB-612111, 30min prior LPS, did not modify LPS-induced sickness signs and depressive-like behavior. However, when injected 24h after LPS, NOP antagonists (UFP-101, icv, and SB-612111, ip) significantly reversed the mood effects of LPS. LPS evoked similar sickness signs and significantly increased tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) plasma levels 6h post-injection in wild-type ((NOP(+/+)) and NOP knockout ((NOP(-/-)) mice. However, LPS treatment elicited depressive-like effects in NOP(+/+) but not in NOP(-/-) mice. In conclusion, the pharmacological and genetic blockade of NOP signaling does not affect LPS evoked sickness signs while reversing depressive-like behavior., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Leishmaniasis is a vectorborne disease caused by Leishmania protozoa, which is a major health problem and a neglected disease common in many regions of the world. Leishmania is an intracellular parasite transmitted by sand flies that causes clinical manifestations ranging from a severe and potentially fatal disease named visceral leishmaniasis to less severe but in many cases disfiguring diseases that mainly affect the skin or mucosal tissues, known as cutaneous leishmaniasis. Despite the detection of Leishmania parasites in the brain and cerebrospinal fluid of human patients and dogs, epidemiological data, as well as information about the mechanisms of central and peripheral nervous system alterations, are poorly described. This review is focused on the current knowledge about the neurological manifestations and immunopathogenic mechanisms in human patients and animals infected with Leishmania., (© 2015 John Wiley & Sons Ltd.)

Unlabelled: Leishmaniasis has emerged as the third most prevalent parasite-borne disease worldwide after malaria and filariasis, with about 350 million people at risk of infection. Antileishmanial drugs currently available have various limitations, mainly because of the parasite resistance and side effects. The search of new antileishmanial drugs is ventured throughout the world., Purpose: The purpose of this study was to assess the leishmanicidal activity of lipophilic extracts of eight Hypericum species against promastigote forms of Leishmania (Leishmania) amazonensis., Material and Methods: The dried and powered materials of aerial parts of H. andinum Gleason, H. brevistylum Choisy, H. caprifoliatum Cham. & Schltdl., H. carinatum Griseb., H. linoides A. St.-Hil., H. myrianthum Cham. & Schltdl., H. polyanthemum Klotzsch ex Reichardt and H. silenoides Juss. were extracted by static maceration with n-hexane. Extracts were evaporated to dryness under reduced pressure and stored at -20°C until biological evaluation and HPLC analysis. The metabolites investigated were dimeric phloroglucinol derivatives, benzophenones and benzopyrans. The yields were expressed as mean of three injections in mg of compound per g of extract (mg/g extract). The effect of Hypericum species on the viability of infective forms of L. (L.) amazonensis was determined using a hemocytometer. Amphotericin B was used as a standard drug. The 50% inhibitory concentration (IC50) values for each extract were determined by linear regression analysis. The cytotoxic effects of extracts were assessed on peritoneal macrophages of BALB/c mice by MTT assay. The concentration that causes 50% of macrophage cytotoxicity (CC50) was determined by linear regression analysis. The selectivity index (SI) of the extracts was determined considering the following equation: CC50 against mammalian cells/IC50 against L. amazonensis., Results: We demonstrated that H. carinatum, H. linoides and H. polyanthemum were able to kill the parasites in a dose dependent manner. These extracts presented low cytotoxicity against murine macrophages. At 48h of incubation H. polyanthemum presented significant leishmanicidal activity with a 50% inhibitory concentration (IC50) of 36.1µg/ml. The leishmanicidal activity of H. myrianthum was significantly lower than that presented by H. polyanthemum, H. carinatum and H. linoides extracts. H. brevistylum and H. caprifoliatum showed significant leishmanicidal activity only at high concentrations (500 and 1000µg/ml), while H. andinum and H. silenoides were ineffective., Conclusion: The promising results demonstrate the importance of the species of the genus Hypericum as source of compounds potentially useful for the treatment of leishmaniasis., (Copyright © 2014 Elsevier GmbH. All rights reserved.)

The neuropeptide nociceptin/orphanin FQ (N/OFQ) is the endogenous ligand of the G-protein-coupled receptor NOP. Cells from the immune system express the precursor preproN/OFQ and the NOP receptor, as well as secrete N/OFQ. The activation of the N/OFQ-NOP pathway can regulate inflammatory and immune responses. Several immune activities, including leukocyte migration, cytokine and chemokine production, and lymphocytes proliferation are influenced by NOP activation. It was demonstrated that cytokines and other stimuli such as Toll-like receptor agonist (e.g., lipopolysaccharide) induce N/OFQ production by cells from innate and adaptive immune response. In this context, N/OFQ could modulate the outcome of inflammatory diseases, such as sepsis and immune-mediated pathologies by mechanisms not clearly elucidated. In fact, clinical studies revealed increased levels of N/OFQ under sepsis, arthritis, and Parkinson's disease. Preclinical and clinical studies pointed to the blockade of NOP receptor signaling as successful strategy for the treatment of inflammatory diseases. This review is focused on experimental and clinical data that suggest the participation of N/OFQ-NOP receptor activation in the modulation of the immune response, highlighting the immunomodulatory potential of NOP antagonists in the inflammatory and immunological disturbances., (© 2015 Elsevier Inc. All rights reserved.)

This study aims to assess the oxidative stress in leprosy patients under multidrug therapy (MDT; dapsone, clofazimine and rifampicin), evaluating the nitric oxide (NO) concentration, catalase (CAT) and superoxide dismutase (SOD) activities, glutathione (GSH) levels, total antioxidant capacity, lipid peroxidation, and methemoglobin formation. For this, we analyzed 23 leprosy patients and 20 healthy individuals from the Amazon region, Brazil, aged between 20 and 45 years. Blood sampling enabled the evaluation of leprosy patients prior to starting multidrug therapy (called MDT 0) and until the third month of multidrug therapy (MDT 3). With regard to dapsone (DDS) plasma levels, we showed that there was no statistical difference in drug plasma levels between multibacillary (0.518±0.029 µg/mL) and paucibacillary (0.662±0.123 µg/mL) patients. The methemoglobin levels and numbers of Heinz bodies were significantly enhanced after the third MDT-supervised dose, but this treatment did not significantly change the lipid peroxidation and NO levels in these leprosy patients. In addition, CAT activity was significantly reduced in MDT-treated leprosy patients, while GSH content was increased in these patients. However, SOD and Trolox equivalent antioxidant capacity levels were similar in patients with and without treatment. These data suggest that MDT can reduce the activity of some antioxidant enzyme and influence ROS accumulation, which may induce hematological changes, such as methemoglobinemia in patients with leprosy. We also explored some redox mechanisms associated with DDS and its main oxidative metabolite DDS-NHOH and we explored the possible binding of DDS to the active site of CYP2C19 with the aid of molecular modeling software.

In order to investigate the effects of two non-nucleoside reverse transcriptase inhibitors (NNRTIs) on the DNA damage in vivo, nevirapine (NVP; 3.3 mg/kg), efavirenz (EFV; 10 mg/kg) or saline were administered orally. Acute effects were analyzed 24 h after the administration of a single NNRTI dose, and subchronic effects 24 h after the last dose. Peripheral blood, brain, heart and liver samples were subjected to genotoxicity analyses and polychromatic erythrocytes from the bone marrow to micronucleus test. The micronucleus test did not reveal any significant differences between animals from the acute or subchronic groups. Comet assay showed that acute and subchronic NNRTI treatment did not cause any significant DNA damage in heart, liver or peripheral blood cells. However, increased damage indexes and frequencies were observed in the brain of mice, subchronically treated with EFV. This result suggests for the first time that this drug might induce genotoxicity in the brain., (Copyright © 2014 Elsevier B.V. All rights reserved.)

In order to improve the understanding of the toxicity of pentavalent antimony (Sb(V)), we investigated the acute effects of meglumine antimoniate (MA) on the oxidative stress in heart, liver, kidney, spleen and brain tissue of mice. Levels of lipoperoxidation and protein carbonylation were measured to evaluate the oxidative status, whereas superoxide dismutase/catalase activity and glutathione levels were recorded to examine the antioxidative status. We observed that MA caused significant protein carbonylation in the heart, spleen and brain tissue. Increased lipoperoxidation was found in the liver and brain tissue. An imbalance between superoxide dismutase and catalase activities could be observed in heart, liver, spleen and brain tissue. Our results suggest that MA causes oxidative stress in several vital organs of mice. This indicates that the production of highly reactive oxygen and nitrogen species induced by MA might be involved in some of its toxic adverse effects., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Unlabelled: Southern Brazil has the highest prevalence rate of AIDS in the country and is the only region in the Americas where HIV-1 subtype C prevails., Objective: We evaluated the epidemiologic and clinical characteristics of pregnant women living with HIV/AIDS in the South region of Santa Catarina, Brazil., Methods: All pregnant women with HIV infection attending the obstetric outpatient clinic of Criciúma, State of Santa Catarina, in 2007 (n = 46) were invited to participate. Data of 36 eligible participants were obtained through a standardized questionnaire., Results: The great majority were young, with a steady partner, low family income, low education level and referring early first sexual intercourse. Many reported use of illicit non-injecting drugs (55.5%) and unprotected sex with partners that were HIV-positive (57.7%), injecting drug user (22.2%), male inmate (19.4%), truck driver (13.8%), with history of sexually transmitted disease (11.1%) or men who have sex with men (MSM) (2.8%). Most (66.7%) of the participants had their HIV diagnosis done during the pregnancy, 7 (19.4%) had a previous history of HIV mother-to-child transmission. Therapy based on highly active antiretroviral therapy (94%) was initiated at 19.3 weeks on average and 33% showed irregular antiretroviral adherence., Conclusion: These results confirm previous data on HIV epidemiology in Brazil and suggest that the women partners' sexual behavior and unprotected sexual intercourse are important aspects of HIV epidemic. Additional efforts in education, prophylaxis and medication adherence are needed.

The highly active antiretroviral therapy completely changed the clinical evolution of HIV infection, reducing the morbidity and mortality among human immunodeficiency virus (HIV)-1 infected patients. Therefore, in the present study we evaluated the effect of chronic efavirenz (EFV) and nevirapine (NVP) administration on mitochondrial respiratory chain complexes activities (I, II, II-III, IV) in different brain regions of mice. Mice were orally administered via gavage with EFV 10 mg/kg, NVP 3.3 mg/kg or vehicle (controls) once a day for 36 days. We observed that the complex IV activity was inhibited by both EFV and NVP in cerebral cortex, striatum and hippocampus of mice, but not in cerebellum, as compared to control group. In contrast, chronic EFV and NVP administration did not alter complexes I, II and II-III. We speculated that brain energy metabolism dysfunction could be involved in the CNS-related adverse effects.

Nevirapine (NVP) and efavirenz (EFV) belong to the class of anti-HIV drugs called non-nucleoside reverse transcriptase inhibitors (NNRTIs), commonly used as part of highly active antiretroviral therapy (HAART). Although the HAART is able to bring down viral load to undetectable levels and restore immune function, their prolonged use causes several adverse effects. It has been demonstrated that both NVP and EFV are able to cross the blood-brain barrier, causing important central nervous system-related side effects. Thus, this study investigated the effects of chronic administration of EFV (10 mg/kg) and NVP (3.3 mg/kg) in mice submitted to two distinct series of experiments, which aimed to evaluate: (1) the emotional behavior (elevated plus-maze, forced swimming, and open-field test) and (2) the cognitive performance (object recognition and inhibitory avoidance test) of mice. Our results demonstrated that EFV, but not NVP, reduced the exploration to open arms in the elevated plus-maze test. Neither NVP nor EFV altered mouse behavior in the forced swimming and open-field tests. Both drugs reduced the recognition index in the object recognition test, but only EFV significantly impaired the aversive memory assessed in the inhibitory avoidance test 24 h after training. In conclusion, our findings point to a genuine anxiogenic-like effect to EFV, since it reduced exploration to open arms of elevated plus-maze test without affecting spontaneous locomotion. Additionally, both drugs impaired recognition memory, while only the treatment with EFV impaired significantly aversive memory.

Nociceptin/orphanin FQ (N/OFQ) is a seventeen-amino acid peptide that is the endogenous ligand of a G-protein-coupled receptor (NOP). Various immune cells express the precursor protein and secrete N/OFQ as well as display binding sites for this peptide. The functional capacity of NOP receptor was demonstrated in vitro and in vivo studies by the ability of N/OFQ to induce chemotaxis of immune cells, to regulate the expression of cytokines and other inflammatory mediators, and to control cellular and humoral immunity. In this context, N/OFQ could modulate the outcome of some inflammatory diseases, such as sepsis and autoimmune pathologies by mechanisms not clearly elucidated yet. In fact, human body fluid revealed increased levels of N/OFQ under sepsis, arthritis, and Parkinson's diagnose. Preclinical studies pointed to the blockade of NOP receptor signaling as successful in treating these experimental conditions. Further preclinical and clinical studies are required to investigate the potential of NOP ligands in treating inflammatory diseases.

Previous studies have shown that venoms of social wasps and bees exhibit strong anticoagulant activity. The present study describes the anticoagulant and fibrinogen-degrading pharmacological properties of the venom of Polybia occidentalis social wasp. The results demonstrated that this venom presented anticoagulant effect, inhibiting the coagulation at different steps of the clotting pathway (intrinsic, extrinsic and common pathway). The venom inhibited platelet aggregation and degraded plasma fibrinogen, possibly containing metal-dependent metalloproteases that specifically cleave the Bβ-chain of fibrinogen. In conclusion, fibrinogenolytic and anticoagulant properties of this wasp venom find a potential application in drug development for the treatment of thrombotic disorders. For that, further studies should be carried out in order to identify and isolate the active compounds responsible for these effects.

Background: The aim of this study was to examine the effects of the N-methyl-D-aspartate receptor (NMDAR) channel blocker dizocilpine (MK-801) on lung injury in rats submitted to experimental sepsis induced by cecal ligation and perforation (CLP)., Methods: Adult male Wistar rats submitted to CLP were given a single systemic injection of MK-801 (subcutaneously at 0.3 mg/kg) administered 4 or 7 h after CLP induction. Twelve hours after CLP BAL was performed to determine total cell count, protein content, and inflammatory parameters. In addition, lung was excised for histopathologic analyses and determination of NMDAR subunits content. In a separate cohort of animals mortality was recorded for 5 days., Results: Animals submitted to sepsis induced by CLP showed an increase in the content of NMDAR subunits NR1 and NR2A in the lung. Administration of MK-801 4 h after CLP induction resulted in a decrease in BAL fluid cellular content and decreased levels of proinflammatory cytokines. In addition, MK-801 decreased lung oxidative stress markers and histopathologic alterations and improved survival., Conclusions: These findings indicate that NMDAR blockade might represent a promising novel therapeutic strategy for the treatment of sepsis and inflammatory disorders.

In the present article, we report data on the possible antigenotoxic activity of Mikania laevigata extract (MLE) after acute intratracheal instillation of coal dust using the comet assay in peripheral blood, bone marrow, and liver cells and the micronucleus test in peripheral blood of Wistar rats. The animals were pretreated for 2 weeks with saline solution (groups 1 and 2) or MLE (100 mg/kg) (groups 3 and 4). On day 15, the animals were anesthetized with ketamine (80 mg/kg) and xylazine (20 mg/kg), and gross mineral coal dust (3 mg/0.3 mL saline) (groups 2 and 4) or saline solution (0.3 mL) (groups 1 and 3) was administered directly in the lung by intratracheal administration. Fifteen days after coal dust or saline instillation, the animals were sacrificed, and the femur, liver, and peripheral blood were removed. The results showed a general increase in the DNA damage values at 8 hours for all treatment groups, probably related to surgical procedures that had stressed the animals. Also, liver cells from rats treated with coal dust, pretreated or not with MLE, showed statistically higher comet assay values compared to the control group at 14 days after exposure. These results could be expected because the liver metabolizes a variety of organic compounds to more polar by-products. On the other hand, the micronucleus assay results did not show significant differences among groups. Therefore, our data do not support the antimutagenic activity of M. laevigata as a modulator of DNA damage after acute coal dust instillation.

Leishmaniasis causes high morbidity and mortality in tropical and subtropical areas. Mast cells can be activated by Leishmania or Leishmania products in vitro and in vivo. Several innate immunity mediators, including some released by mast cells, play roles in the outcome of the disease. In this study, we examined whether pharmacological inactivation of mast cells before infection with L. major interferes with the progressive disease in BALB/c mice. The results show that, when mast cells are degranulated before challenge with L. major, susceptible mice become more resistant to infection, as measured by decrease of lesion size and lower parasite loads. Mast cell degranulation reduced IL-4 production. Moreover, mast cells degranulation enhanced mRNA expression for IFN-gamma, inducible nitric oxide, CCL2 and CCL5 in response to infection. Mast cell degranulation also decreased parasite loads in IL-4 KO animals, indicating that mediators other than IL-4 are involved in susceptibility in vivo. Taken together, our results disclose a role for mast cells in the induction of susceptibility to infection. This work contributes to a better understanding of the role of mast cells in Leishmania infection, and suggests a new field of study for strategies to contain the parasite, restricting its dissemination.

Venoms of several animals have been used to study various physiopathologic processes, and also to offer opportunity to design and develop new therapeutic drugs. We briefly review certain wasp venom components and their biological effects, which may be potential sources of novel pharmacologically active compounds.

Nevirapine (NVP) and efavirenz (EFV) are antiretroviral drugs belonging to potent class of non-nucleoside reverse transcriptase inhibitors (NNRTIs) widely used for the treatment human immunodeficiency virus (HIV) infection. It has been demonstrated that NVP and EFV are able to cross the blood-brain barrier and arrive at the central nervous system (CNS), causing important adverse effects related to their presence within this tissue. Considering that the exact mechanisms responsible for CNS toxicity associated with NVP and EFV remain unknown and that creatine kinase (CK) plays an important role in cell energy homeostasis, in the present work we evaluated CK activity in brain of mice after chronic administration of these drugs. Our results demonstrated that NVP and EFV significantly inhibited CK activity in cerebellum, hippocampus, striatum and cortex of mice. Although it is difficult to extrapolate our findings to the human condition, the inhibition of brain CK activity by NVP and EFV may be associated with neurological adverse symptoms of these drugs.

Glutathione (GSH) has an important dual role in parasite-host relationship in Leishmania major infection. Our previous studies showed that both antioxidant systems, glutathione and trypanothione/trypanothione reductase, participate in the protection of Leishmania against the toxic effect of nitrogen-derived reactive species. On the other hand, GSH also is very important to the modulation of the effective immune response, inducting NO production and leishmanicidal activity of macrophages. In the present study, we investigated the role of host GSH during the course of L. major infection, analysing the size of footpad lesions and parasite load from mice treated with two GSH modulators, N-acethyl-l-cysteine (NAC) and buthionine sulphoximine (BSO). Resistant mice treated with BSO, which depletes GSH develop exacerbated lesions, but only harbour higher parasite load in their lesions 2 weeks post-infection. Although the NAC treatment does not affect the footpad lesions development in susceptible BALB/c mice, it significantly reduced the tissue parasitism in the lesions throughout the course of infection. Interestingly, the treatment with BSO did not change the course of L. major infection on susceptible mice when compared with nontreated mice. These results suggest that GSH is an important antioxidant modulator during anti-Leishmania immune response in vivo.

Leishmania amazonensis infection leads to progressive diseases in a majority of inbred strains of mice. Glutathione (GSH) participates in a large number of cellular phenomena and seems to be essential for several immune functions, including host defense during leishmaniasis. In this study, we evaluated the effects of N-acetyl-L: -cysteine (NAC), as GSH supplement, on the course of L. amazonensis infection in susceptible BALB/c mice. The treatment with NAC (200 mg/kg daily) was effective in raising GSH levels in both lymph node and spleen cells. Although this treatment did not change the footpad swelling development in L. amazonensis-infected mice, it caused a significant decrease in the number of parasites recovered from the footpad lesion and draining popliteal lymph node. Our data suggest that intracellular Leishmania killing in vivo was improved by the augment of GSH levels through NAC administration.

The mechanism by which the salivary gland lysate (SGL) of Lutzomyia longipalpis enables Leishmania infection remains under investigation. One possibility is that saliva promotes cellular recruitment leading to development of skin lesions. In this study, we investigated leukocyte recruitment induced by L. major, L. major + SGL, or SGL alone into the peritoneal cavity of BALB/c mice. The administration of L. major with or without SGL induced neutrophil migration six hours after infection. Interestingly, after seven days, the BALB/c mice still had eosinophils and mononuclear cells in their peritoneal cavities. Flow cytometric analysis showed an increase in the CD4(+) CD45RB(low) T cell subset (effector or memory cells) compared with the CD4(+) CD45RB(high) subset (naive cells). Moreover, the co-injection of L. major with SGL enhanced production of interleukin-10. These results suggest that SGL can facilitate Leishmania infection by modulating leukocyte recruitment and Th2 cytokine production at the inflammatory focus.

The aim of this work was to evaluate the larvicidal effect of andiroba oil, Carapa guyanensis, against 2 strains of Aedes aegypti. After 8 h after exposure to oil, the lethal concentration (LC)90 and LC95 values for the GCZ (temephos-resistant) strain larvae were 80 and 86 ppm (1st instars), 98 and 106 (2nd instars), 166 and 182 (3rd instars), and 192 and 202 ppm (4th instars), respectively. TheLC90 and LC95 values for the Rockefeller strain larvae were 164 and 182 ppm (1st instars), 212 and 224 (2nd instars), 210 and 226 (3rd instars), and 450 and 490 ppm (4th instars), respectively. Comparison of the 2 laboratory strains of Ae. aegypti in the present study demonstrated significant variation in the susceptibility of larvae to andiroba oil. Whether a higher susceptibility of field populations of Ae. aegypti to andiroba oil occurs remains to be investigated.

Glutathione is the major intracellular antioxidant thiol protecting mammalian cells against oxidative stress induced by oxygen- and nitrogen-derived reactive species. In trypanosomes and leishmanias, trypanothione plays a central role in parasite protection against mammalian host defence systems by recycling trypanothione disulphide by the enzyme trypanothione reductase. Although Kinetoplastida parasites lack glutathione reductase, they maintain significant levels of glutathione. The aim of this study was to use Leishmania donovani trypanothione reductase gene mutant clones and different Leishmania species to examine the role of these two individual thiol systems in the protection mechanism against S-nitroso-N-acetyl-D,L-penicillamine (SNAP), a nitrogen-derived reactive species donor. We found that the resistance to SNAP of different species of Leishmania was inversely correlated with their glutathione concentration but not with their total low-molecular weight thiol content (about 0.18 nmol/10(7) parasites, regardless Leishmania species). The glutathione concentration in L. amazonensis, L. donovani, L. major, and L. braziliensis were 0.12, 0.10, 0.08, and 0.04 nmol/10(7) parasites, respectively. L. amazonensis, that have a higher level of glutathione, were less susceptible to SNAP (30 and 100 microM). The IC50 values of SNAP determined to L. amazonensis, L. donovani, L. major, and L. braziliensis were 207.8, 188.5, 160.9, and 83 microM, respectively. We also observed that L. donovani mutants carrying only one trypanothione reductase allele had a decreased capacity to survive (approximately 40%) in the presence of SNAP (30-150 microM). In conclusion, the present data suggest that both antioxidant systems, glutathione and trypanothione/trypanothione reductase, participate in protection of Leishmania against the toxic effect of nitrogen-derived reactive species.

This study aimed to verify Leptospira spp. serovar infections in stray dogs in Itapema, Santa Catarina, Brazil. Serum samples were collected from 590 stray dogs and tested against 25 Leptospira spp. serovars using the microscopic agglutination test. Prevalence of anti-leptospiral antibodies against one or more serovars was 10.5%. The most frequent serovar was pyrogenes, positive in 26 (18.0%) samples, followed by canicola with 20 (13.8%) and icterohaemorragiae and copenhageni with 18 (12.5%, with antibody titers from 1:100 to 1:3,200). Significant prevalence (10.4 to 11.1%) was also detected against serovars castellonis, butembo, and grippothyphosa.

Samples of feces from dogs seized by the health surveillance program of Itapema city, SC, were studied. From 158 samples examined 121 (76.6%) were positive, with a prevalence of Ancylostoma spp (70.9%), followed by Toxocara canis (14.5%), Trichuris vulpis (13.9%), Isospora spp (6.3%) and Dipylidium caninum (1.9%).

Andiroba Carapa guianensis Aubl. Meliacea is known to possess repellent activity against many mosquito species. We evaluated the larvicidal effect of dry-scratched seed kernels of andiroba against a sylvatic F1 progeny and a laboratory-colonized population of Aedes albopictus (Skuse). The 3rd instar of F1 treated with 0.5 to 2% of C. guianensis for 24 and 48 hours, had mortality with LC50 of 0.74 (0.56-0.90%) and 0.68 (0.53-0.84%), respectively, and the 4th instar 0.66 (0.52-0.80%) and 0.55 (0.20-0.91%), respectively. For the 3rd instars of laboratory-colonized larvae, the treatment with 0.5 to 4% of C. guianensis induced mortality after 24 hours with LC50 of 1.81 (1.39-2.22%), and an LC50 of 1.82 (1.57-2.07%) to the 4th instar. This is the 1st report of the larvicidal effect of C. guianensis on mosquitoes.

Leishmania major infection in C57BL/6 mice is controlled by the activation of a Th1 response and nitric oxide (NO) production by macrophages. TNF-alpha is considered one of the most important cytokines involved in this response. In the present study, we investigated the expression of nitric oxide synthase (iNOS) in the inflammatory cells present in the lesion and draining lymph nodes, and the cytokine production by lymph node cells in animals treated with anti-TNF-alpha. Our results demonstrated that mice treated with anti-TNF-alpha presented an increase in the number of parasites and the size of lesion, but they were able to control the infection. The increase in the lesion size correlated to the reduction of iNOS activity in the draining lymph nodes. Furthermore, the anti-TNF-alpha treatment also reduced the expression of iNOS in the macrophages, but did not affect the iNOS expression in the neutrophils. The anti-TNF-alpha mAb did not reduce the iNOS expression in IFN-gamma-stimulated L. major infected neutrophils in vitro. Anti-TNF-alpha mAb treatment caused an increase in the production of IFN-gamma and IL-10 by the lymph node cells from infected mice. Consequently, these results suggest that neutrophils do not respond to anti-TNF-alpha treatment and might be a source of NO to control L. major infection under these experimental conditions.

The aim of this investigation was to examine whether macrophage and Leishmania major glutathione were involved in either host or parasite protection against NO cytotoxicity. Buthionine sulfoximine (BSO), an inhibitor of gamma-glutamylcysteine synthase, caused a complete and irreversible depletion of macrophage glutathione, but only a 20% and reversible decrease in L. major glutathione. Glutathione-depleted macrophages, when activated with IFN-gamma/LPS, released less than 60% of the NO produced by untreated macrophages, resulting in a corresponding decrease in their leishmanicidal activity. BSO-treated macrophages were more susceptible to the cytotoxic effects of the NO donor SNAP. Treatment of macrophages with 1,3-bis(chloroethyl)-1-nitrosourea (BCNU), an inhibitor of glutathione reductase and trypanothione reductase or with Br-Octane, a glutathione-S-transferase substrate, resulted in a transient decrease in glutathione levels and did not increase the susceptibility of the macrophages to SNAP. Treatment of the promastigote forms of L. major with BCNU resulted in an 80% decrease in total glutathione concentration with no concomitant change in viability. However, this treatment rendered the parasites more susceptible to SNAP. Finally, macrophage glutathione protected the internalized L. major from SNAP. Overall, these results demonstrate that glutathione is an essential protective component against NO cytotoxicity on both macrophages and parasites.

In order to investigate the ability of rat peritoneal eosinophils to produce nitric oxide (NO) induced by cytokines in vitro, these cells were activated with several cytokines (IL-5, IL-8, Rantes, TNF-alpha, IFN-gamma) in association or not with LPS. Under these conditions, we were able to detect nitrite in the incubation medium when the eosinophils were stimulated with IFN-gamma or IL-8 in the presence of LPS. LPS alone also induced nitrite production. Significant levels of nitrite in the medium were already present after 12 h of stimulation and increased steadily within the next 48 h. Regarding NO synthase, its highest activity was achieved at 12 h after IFN-gamma/LPS stimulation. After this peak, the enzymatic activity reduced gradually to control levels 48 h after the stimulation. The simultaneous addition of the NO synthase inhibitor L-NIO (100 microM) to the eosinophil suspension blocked nitrite production and NO synthase activity. On the other hand, neither IL-5, Rantes nor TNF-alpha were able to induce the release of nitrite in the presence or absence of LPS. To evaluate the microbicidal effect of these cells against the Leishmania parasite, eosinophils were infected with Leishmania major. It was observed that these cells were able to produce nitrite and to kill the parasite after activation with LPS/IFN-gamma. Moreover, L-NIO blocked this leishmanicidal activity and the nitrite production. Our results suggest that activated eosinophils release NO which is involved in their microbicidal activity against Leishmania major.

There are several experimental evidences that nitric oxide (NO) is involved in the microbicidal activity of macrophages against a number of intracellular pathogens including Leishmania major, Trypanozoma cruzi, Toxoplasma gondii. It is also well known that eosinophils (EO) have microbicidal activity against many parasites such as Schistosoma mansoni, Trichinella spiralis, T. cruzi and L. amazonensis. The purpose of this study was to investigate if NO is involved in the microbicidal activity of EO against L. major. Eosinophils harvested from peritoneal cavity of rats released spontaneously after 24 and 48 hr a small amount of nitrite. This release was enhanced by the treatment of cells with IFN-gamma (200 IU/ml). This release was blocked by addition of the NO synthase inhibitor, L-NIO (100 microM) into the culture. To determinate the leishmanicidal activity of eosinophils the parasites were incubated with activated eosinophils with IFN-gamma and the ability of surviving parasites to incorporate [(3)H] thymidine was evaluated. IFN-gamma-activated eosinophils were able to kill L. major and to release high levels of nitrite. The ability to destroy L. major and the release of NO were completely blocked by L-NIO. These results indicate that activated eosinophils release NO which is involved in the microbicidal activity of these cells against L. major.