Macrophage Trafficking as Key Mediator of Adenine-Induced Kidney Injury

Macrophages play a special role in the onset of several diseases, including acute and chronic kidney injuries. in this sense, tubule interstitial nephritis (TIN) represents an underestimated insult, which can be triggered by different stimuli and, in the absence of a proper regulation, can lead to fibrosis deposition. Based on this perception, we evaluated the participation of macrophage recruitment in the development of TIN. Initially, we provided adenine-enriched food to WT and searched for macrophage presence and action in the kidney. Also, a group of animals were depleted of macrophages with the clodronate liposome while receiving adenine-enriched diet. We collected blood and renal tissue from these animals and renal function, inflammation, and fibrosis were evaluated. We observed higher expression of chemokines in the kidneys of adenine-fed mice and a substantial protection when macrophages were depleted. Then, we specifically investigated the role of some key chemokines, CCR5 and CCL3, in this TIN experimental model. Interestingly, CCR5 KO and CCL3 KO animals showed less renal dysfunction and a decreased proinflammatory profile. Furthermore, in those animals, there was less profibrotic signaling. in conclusion, we can suggest that macrophage infiltration is important for the onset of renal injury in the adenine-induced TIN.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Instituto Nacional de Ciencia e Tecnologia de Fluidos Complexos (INCT Complex Fluids)Univ São Paulo, Inst Biomed Sci, Dept Immunol, Lab Transplantat Immunobiol, BR-05508900 São Paulo, BrazilUniversidade Federal de São Paulo, Div Nephrol, Lab Clin & Expt Immunol, BR-04023900 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Biophys, BR-04023062 São Paulo, BrazilUniv São Paulo, Inst Chem, Dept Biochem, BR-05508000 São Paulo, BrazilUniv São Paulo, Sch Med Ribeirao Preto, Dept Biochem & Immunol, BR-14049900 Ribeirao Preto, SP, BrazilUniversidade Federal de São Paulo, Div Nephrol, Lab Clin & Expt Immunol, BR-04023900 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Biophys, BR-04023062 São Paulo, BrazilFAPESP: 2009/54474-8FAPESP: 2012/02270-2FAPESP: 2013/25010-9Web of Scienc

RELAÇÃO ENTRE FONTES DE ADUBAÇÃO NA PRODUÇÃO DE FURANOCUMARINA NO CULTIVO DE CARAPIÁ (Dorstenia brasiliensis)

The use of medicinal plants is widely common, above all, due to traditional knowledge. Among the medicinal species, Dorstenia brasiliensis is important for presenting furanocoumarins, which is a secondary matabolite related to various therapeutic functions. However, there are still no reports on the cultivation or even the relationship of fertilization in the production of this species. The work aimed to evaluate the formation of furanocoumarins and the dry and green weights of rhizomes in the culture of Carapiá (Dorstenia brasiliensis), under edaphoclimatic conditions of Palmeiras de Goiás under the effect of different sources of fertilization. The experiment was carried out in the municipality of Palmeiras de Goiás, at the State University of Goiás - Câmpus Palmeiras de Goiás, from November 2017 to August 2018. A completely randomized design with 3 treatments and 10 repetitions was adopted. The variables tested were the sources of fertilization of bovine, organomineral and mineral manure. When analyzing the relationship of the influence of fertilizer sources to green weight and dry weight, there was no significant difference between treatments, concluding that fertilization did not interfere with these factors. Regarding the interference of fertilization in the levels of psoralen, all treatments obtained statistical difference, and the sources of fertilization used resulted in the lower production of this metabolite. Likewise, the influence of fertilizer sources on the levels of baptapene resulted in a statistical difference between all treatments, so that treatments with fertilizers showed an increase in the production of this compound.O uso de plantas medicinais é amplamente comum, sobretudo, pelo conhecimento tradicional. Dentre as espécies medicinais, a Dorstenia brasiliensis é importante por apresentar furanocumarinas, sendo este um matabólito secundário relacionado a várias funções terapêuticas. Contudo, ainda não existem relatos sobre o cultivo ou mesmo relação da adubação na produção desta espécie. O trabalho teve como objetivo avaliar a formação de furanocumarinas e os pesos, seco e verde, dos rizomas na cultura de Carapiá (Dorstenia brasiliensis), nas condições edafoclimáticas de Palmeiras de Goiás sob o efeito de diferentes fontes de adubação. O experimento foi realizado no município de Palmeiras de Goiás, na Universidade Estadual de Goiás – Câmpus Palmeiras de Goiás, no período de novembro de 2017 a agosto de 2018. Foi adotado o delineamento inteiramente casualizado com 3 tratamentos e 10 repetições. As variáveis testadas foram as fontes de adubação esterco bovino, organomineral e mineral. Quando analisada a relação da influência das fontes de adubação ao peso verde e peso seco não houve diferença significativa entre os tratamentos, concluindo a não interferência da adubação para estes fatores. Com relação a interferência da adubação nos teores de psoraleno, todos os tratamentos obtiveram diferença estatística, sendo que as fontes de adubação utilizadas resultaram na menor produção deste metabólito. Do mesmo modo, a influência das fontes de adubação nos teores de bergapteno resultou em diferença estatística entre todos os tratamentos, de forma que os tratamentos com adubações apresentaram acréscimo na produção deste composto

Biseugenol Exhibited Anti-Inflammatory and Anti-Asthmatic Effects in an Asthma Mouse Model of Mixed-Granulocytic Asthma

In the present work, the anti-inflammatory and antiasthmatic potential of biseugenol, isolated as the main component from n-hexane extract from leaves of Nectandra leucantha and chemically prepared using oxidative coupling from eugenol, was evaluated in an experimental model of mixed-granulocytic asthma. Initially, in silico studies of biseugenol showed good predictions for drug-likeness, with adherence to Lipinski’s rules of five (RO5), good Absorption, Distribution, Metabolism and Excretion (ADME) properties and no alerts for Pan-Assay Interference Compounds (PAINS), indicating adequate adherence to perform in vivo assays. Biseugenol (20 mg·kg−1) was thus administered intraperitoneally (four days of treatment) and resulted in a significant reduction in both eosinophils and neutrophils of bronchoalveolar lavage fluid in ovalbumin-sensitized mice with no statistical difference from dexamethasone (5 mg·kg−1). As for lung function parameters, biseugenol (20 mg·kg−1) significantly reduced airway and tissue damping in comparison to ovalbumin group, with similar efficacy to positive control dexamethasone. Airway hyperresponsiveness to intravenous methacholine was reduced with biseugenol but was inferior to dexamethasone in higher doses. In conclusion, biseugenol displayed antiasthmatic effects, as observed through the reduction of inflammation and airway hyperresponsiveness, with similar effects to dexamethasone, on mixed-granulocytic ovalbumin-sensitized miceFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)FAPESP: 2018/06088-

Age at symptom onset and death and disease duration in genetic frontotemporal dementia : an international retrospective cohort study

Background: Frontotemporal dementia is a heterogenous neurodegenerative disorder, with about a third of cases being genetic. Most of this genetic component is accounted for by mutations in GRN, MAPT, and C9orf72. In this study, we aimed to complement previous phenotypic studies by doing an international study of age at symptom onset, age at death, and disease duration in individuals with mutations in GRN, MAPT, and C9orf72. Methods: In this international, retrospective cohort study, we collected data on age at symptom onset, age at death, and disease duration for patients with pathogenic mutations in the GRN and MAPT genes and pathological expansions in the C9orf72 gene through the Frontotemporal Dementia Prevention Initiative and from published papers. We used mixed effects models to explore differences in age at onset, age at death, and disease duration between genetic groups and individual mutations. We also assessed correlations between the age at onset and at death of each individual and the age at onset and at death of their parents and the mean age at onset and at death of their family members. Lastly, we used mixed effects models to investigate the extent to which variability in age at onset and at death could be accounted for by family membership and the specific mutation carried. Findings: Data were available from 3403 individuals from 1492 families: 1433 with C9orf72 expansions (755 families), 1179 with GRN mutations (483 families, 130 different mutations), and 791 with MAPT mutations (254 families, 67 different mutations). Mean age at symptom onset and at death was 49\ub75 years (SD 10\ub70; onset) and 58\ub75 years (11\ub73; death) in the MAPT group, 58\ub72 years (9\ub78; onset) and 65\ub73 years (10\ub79; death) in the C9orf72 group, and 61\ub73 years (8\ub78; onset) and 68\ub78 years (9\ub77; death) in the GRN group. Mean disease duration was 6\ub74 years (SD 4\ub79) in the C9orf72 group, 7\ub71 years (3\ub79) in the GRN group, and 9\ub73 years (6\ub74) in the MAPT group. Individual age at onset and at death was significantly correlated with both parental age at onset and at death and with mean family age at onset and at death in all three groups, with a stronger correlation observed in the MAPT group (r=0\ub745 between individual and parental age at onset, r=0\ub763 between individual and mean family age at onset, r=0\ub758 between individual and parental age at death, and r=0\ub769 between individual and mean family age at death) than in either the C9orf72 group (r=0\ub732 individual and parental age at onset, r=0\ub736 individual and mean family age at onset, r=0\ub738 individual and parental age at death, and r=0\ub740 individual and mean family age at death) or the GRN group (r=0\ub722 individual and parental age at onset, r=0\ub718 individual and mean family age at onset, r=0\ub722 individual and parental age at death, and r=0\ub732 individual and mean family age at death). Modelling showed that the variability in age at onset and at death in the MAPT group was explained partly by the specific mutation (48%, 95% CI 35\u201362, for age at onset; 61%, 47\u201373, for age at death), and even more by family membership (66%, 56\u201375, for age at onset; 74%, 65\u201382, for age at death). In the GRN group, only 2% (0\u201310) of the variability of age at onset and 9% (3\u201321) of that of age of death was explained by the specific mutation, whereas 14% (9\u201322) of the variability of age at onset and 20% (12\u201330) of that of age at death was explained by family membership. In the C9orf72 group, family membership explained 17% (11\u201326) of the variability of age at onset and 19% (12\u201329) of that of age at death. Interpretation: Our study showed that age at symptom onset and at death of people with genetic frontotemporal dementia is influenced by genetic group and, particularly for MAPT mutations, by the specific mutation carried and by family membership. Although estimation of age at onset will be an important factor in future pre-symptomatic therapeutic trials for all three genetic groups, our study suggests that data from other members of the family will be particularly helpful only for individuals with MAPT mutations. Further work in identifying both genetic and environmental factors that modify phenotype in all groups will be important to improve such estimates. Funding: UK Medical Research Council, National Institute for Health Research, and Alzheimer's Society

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

Cellular and Molecular Tissue Response to Triple Antibiotic Intracanal Dressing

Introduction: The aim of this study was to characterize the response of mouse subcutaneous tissue to triple antibiotic paste (TAP) using conventional light microscopy and real-time PCR (qRT-PCR). Methods: Polyethylene tubes containing TAP or calcium hydroxide (CH) (ie, the control group) were implanted in mouse subcutaneous tissue. Animals that received empty tubes or no tubes were used as additional controls. After periods of 7, 21, and 63 days postimplantation, the specimens were removed and subjected to histologic processing. The number of inflammatory cells and vessels, vessel areas, vascular density, and relative percentage of collagen were evaluated. Gene expression of proinflammatory (interleukin-1 beta, tumor necrosis factor alpha, and interleukin 17) and anti-inflammatory (transforming growth factor beta) cytokines and angiogenic factors (vascular endothelial growth factor and hypoxia-inducible factor-1 alpha) was quantified by 7 and 21 days postimplantation. Results were analyzed using the Student t test, analysis of variance, and the Tukey test (alpha = 0.05). Results: TAP induced an exuberant inflammatory and angiogenic response, with higher numbers of inflammatory cells, higher vascular area and density, and lower relative percentage of collagen compared with CH. In general, the expression of genes involved in inflammation and angiogenesis was higher in the TAP group compared with animals that received CH or empty tubes. Conclusions: The response of mouse subcutaneous tissue to TAP was characterized by exuberant and persistent inflammatory and angiogenic responses with no repair and high gene expression of biomarkers associated with inflammation and angiogenesis.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP