Kinin B1 receptors mediate depression-like behavior response in stressed mice treated with systemic E. coli lipopolysaccharide

<p>Abstract</p> <p>Background</p> <p>Kinin B₁receptors are inducible molecules up-regulated after inflammatory stimuli. This study evaluated the relevance of kinin B₁receptors in a mouse depression behavior model.</p> <p>Methods</p> <p>Mice were exposed to a 5-min swimming session, and 30 min later they were injected with <it>E. coli </it>lipopolysaccharide (LPS). Depression-like behavior was assessed by determining immobility time in a tail suspension test. Different brain structures were collected for molecular and immunohistochemical studies. Anhedonia was assessed by means of a sucrose intake test.</p> <p>Results</p> <p>Our protocol elicited an increase in depression-like behavior in CF1 mice, as assessed by the tail-suspension test, at 24 h. This behavior was significantly reduced by treatment with the selective B₁receptor antagonists R-715 and SSR240612. Administration of SSR240612 also prevented an increase in number of activated microglial cells in mouse hippocampus, but did not affect a reduction in expression of mRNA for brain-derived neurotrophic factor. The increased immobility time following LPS treatment was preceded by an enhancement of hippocampal and cortical B₁receptor mRNA expression (which were maximal at 1 h), and a marked production of TNFα in serum, brain and cerebrospinal fluid (between 1 and 6 h). The depression-like behavior was virtually abolished in TNF<it>α </it>p55 receptor-knockout mice, and increased B₁receptor mRNA expression was completely absent in this mouse strain. Furthermore, treatment with SSR240612 was also effective in preventing anhedonia in LPS-treated mice, as assessed using a sucrose preference test.</p> <p>Conclusion</p> <p>Our data show, for the first time, involvement of kinin B₁receptors in depressive behavioral responses, in a process likely associated with microglial activation and TNFα production. Thus, selective and orally active B₁receptor antagonists might well represent promising pharmacological tools for depression therapy.</p

Differences in energy utilisation efficiencies of digestible macronutrients in common carp (Cyprinus carpio) and barramundi (Lates calcarifer)

This study aimed to assess macronutrient-specific energy utilisation efficiency (i.e., protein, lipid and carbohydrate) for growth in common carp (an omnivorous species) and barramundi (a carnivorous species) and to assess if species-specific differences exist in energy efficiency of digestible protein (dCP), digestible fat (dFat) and digestible carbohydrates (dCarb). This was achieved by conducting a feeding trial experiment on common carp and by re-analysing data of a recent study on barramundi. A total of four diets were formulated following a 2 × 2 factorial design with 2 dCP-to-dFat ratios and 2 dCP-to-dCarb ratios. For carp, 2 feeding levels were applied such that the overall experimental design was a 2 × 2 × 2 factorial design, however for barramundi, three feeding levels were applied (satiation, 80% initial satiation and 60% initial satiation), resulting in a 2 × 2 × 3 factorial design. For each fish species, multiple regression of retained energy (RE) as a function of dCP, dFat and dCarb (in g.kg-0.8.d−1) was applied to estimate the energy utilisation efficiency of each digestible macronutrient. For carp, dCP, dFat and dCarb show linear relationships to RE, however for barramundi, dCP and dFat were linearly related to RE, but dCarb was curvilinearly related to RE. The estimated energy efficiencies of dCP, dFat and dCarb (respectively, kNE;dCP, kNE;dFat, and kNE;dCarb) for energy retention were 47, 86 and 60%, respectively, showing large degree of similarity with Nile tilapia and pigs. Carp and barramundi had similar kNE;dFat (86 vs. 94%), but different kNE;dCP (47 vs. 64%) and kNE;dCarb (60 vs. 18%). The net energy equations were NE = 11.2 x dCP + 34.1 x dFat +10.4 x dCarb for carp, and NE = 15.9 x dCP + 35.2 x dFat +9.4 x dCarb – 1.9 x (dCarb)2 for barramundi

Lifelong exposure to a low-dose of the glyphosate-based herbicide RoundUp® causes intestinal damage, gut dysbiosis, and behavioral changes in mice

RoundUp® (RUp) is a comercial formulation containing glyphosate (N-(phosphono-methyl) glycine), and is the world’s leading wide-spectrum herbicide used in agriculture. Supporters of the broad use of glyphosate-based herbicides (GBH) claim they are innocuous to humans, since the active compound acts on the inhibition of enzymes which are absent in human cells. However, the neurotoxic effects of GBH have already been shown in many animal models. Further, these formulations were shown to disrupt the microbiome of different species. Here, we investigated the effects of a lifelong exposure to low doses of the GBH-RUp on the gut environment, including morphological and microbiome changes. We also aimed to determine whether exposure to GBH-RUp could harm the developing brain and lead to behavioral changes in adult mice. To this end, animals were exposed to GBH-RUp in drinking water from pregnancy to adulthood. GBH-RUp-exposed mice had no changes in cognitive function, but developed impaired social behavior and increased repetitive behavior. GBH-Rup-exposed mice also showed an activation of phagocytic cells (Iba-1–positive) in the cortical brain tissue. GBH-RUp exposure caused increased mucus production and the infiltration of plama cells (CD138-positive), with a reduction in phagocytic cells. Long-term exposure to GBH-RUp also induced changes in intestinal integrity, as demonstrated by the altered expression of tight junction effector proteins (ZO-1 and ZO-2) and a change in the distribution of syndecan-1 proteoglycan. The herbicide also led to changes in the gut microbiome composition, which is also crucial for the establishment of the intestinal barrier. Altogether, our findings suggest that long-term GBH-RUp exposure leads to morphological and functional changes in the gut, which correlate with behavioral changes that are similar to those observed in patients with neurodevelopmental disorders

Pitavastatin Reduces Inflammation in Atherosclerotic Plaques in Apolipoprotein E-Deficient Mice with Late Stage Renal Disease

Objectives: Chronic renal disease (CRD) accelerates atherosclerosis and cardiovascular calcification. Statins reduce low-density lipoprotein-cholesterol levels in patients with CRD, however, the benefits of statins on cardiovascular disease in CRD remain unclear. This study has determined the effects of pitavastatin, the newest statin, on arterial inflammation and calcification in atherogenic mice with CRD. Methods and Results: CRD was induced by 5/6 nephrectomy in cholesterol-fed apolipoprotein E-deficient mice. Mice were randomized into three groups: control mice, CRD mice, and CRD mice treated with pitavastatin. Ultrasonography showed that pitavastatin treatment significantly attenuated luminal stenosis in brachiocephalic arteries of CRD mice. Near-infrared molecular imaging and correlative Mac3 immunostaining demonstrated a significant reduction in macrophage accumulation in pitavastatin-treated CRD mice. Pitavastatin treatment reduced levels of osteopontin in plasma and atherosclerotic lesions in CRD mice, but did not produce a significant reduction in calcification in atherosclerotic plaques as assesses by histology. CRD mice had significantly higher levels of phosphate in plasma than did control mice, which did not change by pitavastatin. In vitro, pitavastatin suppressed the expression of osteopontin in peritoneal macrophages stimulated with phosphate or calcium/phosphate in concentrations similar to those found in human patients with CRD. Conclusion: Our study provides in vivo evidence that pitavastatin reduces inflammation within atherosclerotic lesions in CRD mice

Racionalidade terapêutica: elementos médico-sanitários nas demandas judiciais de medicamentos

OBJETIVO: Caracterizar os principais elementos processuais, médico-científicos e sanitários que respaldam as decisões das demandas judiciais individuais por medicamentos consideradas essenciais. MÉTODOS: Estudo descritivo retrospectivo com base em 27 ações julgadas em 2ª instância no Estado do Rio de Janeiro em 2006. Os processos originais foram solicitados ao Arquivo Central do Tribunal de Justiça do Estado do Rio de Janeiro, fotografados e analisados na íntegra. RESULTADOS: Todas as ações incluíram prescrição e atestado médicos. As prescrições estavam em desacordo com a legislação. Não houve perícia médica em nenhuma das ações e em 7,4% constavam exames complementares. Apesar da escassa informação médica contida nos autos, todos os pedidos foram deferidos. CONCLUSÕES: O acolhimento de demandas judiciais carentes de subsídios clínicos e diagnósticos traz embaraços de ordem gerencial e sanitária ao sistema de saúde, pois comprometem a assistência farmacêutica regular e fomentam o uso irracional de medicamentos.OBJETIVO: Caracterizar los principales elementos procesales, medico-científicos y sanitarios que respaldan las decisiones de las demandas judiciales individuales por medicamentos consideradas esenciales. MÉTODOS: Estudio descriptivo retrospectivo con base en 27 acciones juzgadas en 2ª instancia en el estado de Rio de Janeiro, Sureste de Brasil, en 2006. Los procesos originales fueron solicitados al Archivo Central del Tribunal de Justicia del Estado de Rio de Janeiro, fotografiados y analizados de forma íntegra. RESULTADOS: Todas las acciones incluyeron prescripción y atestados médicos. Las prescripciones estaban en desacuerdo con la legislación. No hubo pericia médica en ninguna de las acciones y en 7,4% constaban exámenes complementarios. A pesar de la escasa información médica contenida en los autos, todos los pedidos fueron deferidos. CONCLUSIONES: El acogimiento de demandas judiciales carentes de subsidios clínicos y diagnósticos trae complicaciones de tipo gerencial y sanitaria al sistema de salud, ya que comprometen la asistencia farmacéutica regular y fomentan el uso irracional de medicamentos.OBJECTIVE: To characterize the main medical, scientific and health-related procedural elements upon which decisions are made in individual lawsuits demanding medicines that are considered essential to the Court of Justice. METHODS: Retrospective descriptive study based on 27 cases ruled on by the Court of Appeals in Rio de Janeiro, Southeastern Brazil, in 2006. The original proceedings were solicited from the Central Archive of the Court of Justice of the State of Rio de Janeiro and were photographed and analyzed in full. RESULTS: Prescriptions and medical certificates were present in 100% of the lawsuits. All prescriptions lacked conformity to legislation. No expert medical reports were added, and only 7.4% of the lawsuits presented complementary examinations. In spite of the scarcity of medical information present in the records, all of the demands were granted. CONCLUSIONS: The admission of judicial demands devoid of clinical and diagnostic substantiation results in managerial and health-related constraints on the health system. Besides creating havoc in standard pharmaceutical services, badly justified medicine demands may compromise rational drug use

MDL28170, a Calpain Inhibitor, Affects Trypanosoma cruzi Metacyclogenesis, Ultrastructure and Attachment to Rhodnius prolixus Midgut

BACKGROUND: Trypanosoma cruzi is the etiological agent of Chagas' disease. During the parasite life cycle, many molecules are involved in the differentiation process and infectivity. Peptidases are relevant for crucial steps of T. cruzi life cycle; as such, it is conceivable that they may participate in the metacyclogenesis and interaction with the invertebrate host. METHODOLOGY/PRINCIPAL FINDINGS: In this paper, we have investigated the effect of the calpain inhibitor MDL28170 on the attachment of T. cruzi epimastigotes to the luminal midgut surface of Rhodnius prolixus, as well as on the metacyclogenesis process and ultrastructure. MDL28170 treatment was capable of significantly reducing the number of bound epimastigotes to the luminal surface midgut of the insect. Once the cross-reactivity of the anti-Dm-calpain was assessed, it was possible to block calpain molecules by the antibody, leading to a significant reduction in the capacity of adhesion to the insect guts by T. cruzi. However, the antibodies were unable to interfere in metacyclogenesis, which was impaired by the calpain inhibitor presenting a significant reduction in the number of metacyclic trypomastigotes. The calpain inhibitor also promoted a direct effect against bloodstream trypomastigotes. Ultrastructural analysis of epimastigotes treated with the calpain inhibitor revealed disorganization in the reservosomes, Golgi and plasma membrane disruption. CONCLUSIONS/SIGNIFICANCE: The presence of calpain and calpain-like molecules in a wide range of organisms suggests that these proteins could be necessary for basic cellular functions. Herein, we demonstrated the effects of MDL28170 in crucial steps of the T. cruzi life cycle, such as attachment to the insect midgut and metacyclogenesis, as well as in parasite viability and morphology. Together with our previous findings, these results help to shed some light on the functions of T. cruzi calpains. Considering the potential roles of these molecules on the interaction with both invertebrate and vertebrate hosts, it is interesting to improve knowledge on these molecules in T. cruzi

description of the methodological approach

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Constraints on Energy Intake in Fish: The Link between Diet Composition, Energy Metabolism, and Energy Intake in Rainbow Trout

The hypothesis was tested that fish fed to satiation with iso-energetic diets differing in macronutrient composition will have different digestible energy intakes (DEI) but similar total heat production. Four iso-energetic diets (2×2 factorial design) were formulated having a contrast in i) the ratio of protein to energy (P/E): high (HP/E) vs. low (LP/E) and ii) the type of non-protein energy (NPE) source: fat vs. carbohydrate which were iso-energetically exchanged. Triplicate groups (35 fish/tank) of rainbow trout were hand-fed each diet twice daily to satiation for 6 weeks under non-limiting water oxygen conditions. Feed intake (FI), DEI (kJ kg−0.8 d−1) and growth (g kg−0.8 d−1) of trout were affected by the interaction between P/E ratio and NPE source of the diet (P<0.05). Regardless of dietary P/E ratio, the inclusion of carbohydrate compared to fat as main NPE source reduced DEI and growth of trout by ∼20%. The diet-induced differences in FI and DEI show that trout did not compensate for the dietary differences in digestible energy or digestible protein contents. Further, changes in body fat store and plasma glucose did not seem to exert a homeostatic feedback control on DEI. Independent of the diet composition, heat production of trout did not differ (P>0.05). Our data suggest that the control of DEI in trout might be a function of heat production, which in turn might reflect a physiological limit related with oxidative metabolism

Direct evidence for phosphorus limitation on Amazon forest productivity

The productivity of rainforests growing on highly weathered tropical soils is expected to be limited by phosphorus availability1. Yet, controlled fertilization experiments have been unable to demonstrate a dominant role for phosphorus in controlling tropical forest net primary productivity. Recent syntheses have demonstrated that responses to nitrogen addition are as large as to phosphorus2, and adaptations to low phosphorus availability appear to enable net primary productivity to be maintained across major soil phosphorus gradients3. Thus, the extent to which phosphorus availability limits tropical forest productivity is highly uncertain. The majority of the Amazonia, however, is characterized by soils that are more depleted in phosphorus than those in which most tropical fertilization experiments have taken place2. Thus, we established a phosphorus, nitrogen and base cation addition experiment in an old growth Amazon rainforest, with a low soil phosphorus content that is representative of approximately 60% of the Amazon basin. Here we show that net primary productivity increased exclusively with phosphorus addition. After 2 years, strong responses were observed in fine root (+29%) and canopy productivity (+19%), but not stem growth. The direct evidence of phosphorus limitation of net primary productivity suggests that phosphorus availability may restrict Amazon forest responses to CO2 fertilization4, with major implications for future carbon sequestration and forest resilience to climate change.The authors acknowledge funding from the UK Natural Environment Research Council (NERC), grant number NE/L007223/1. This is publication 850 in the technical series of the BDFFP. C.A.Q. acknowledges the grants from Brazilian National Council for Scientific and Technological Development (CNPq) CNPq/LBA 68/2013, CNPq/MCTI/FNDCT no. 18/2021 and his productivity grant. C.A.Q., H.F.V.C., F.D.S., I.A., L.F.L., E.O.M. and S.G. acknowledge the AmazonFACE programme for financial support in cooperation with Coordination for the Improvement of Higher Education Personnel (CAPES) and the National Institute of Amazonian Research as part of the grants CAPES-INPA/88887.154643/2017-00 and 88881.154644/2017-01. T.F.D. acknowledges funds from FundacAo de Amparo a Pesquisa do Estado de SAo Paulo (FAPESP), grant 2015/50488-5, and the Partnership for Enhanced Engagement in Research (PEER) programme grant AID-OAA-A-11-00012. L.E.O.C.A. thanks CNPq (314416/2020-0)