The pro-resolving lipid mediator Maresin 1 ameliorates pain responses and neuroinflammation in the spared nerve injury-induced neuropathic pain: A study in male and female mice

Specialized pro-resolving mediators (SPMs) have recently emerged as promising therapeutic approaches for neuropathic pain (NP). We evaluated the effects of oral treatment with the SPM Maresin 1 (MaR1) on behavioral pain responses and spinal neuroinflammation in male and female C57BL/6J mice with spared nerve injury (SNI)-induced NP. MaR1, or vehicle, was administered once daily, on post-surgical days 3 to 5, by voluntary oral intake. Sensory-discriminative and affective-motivational components of pain were evaluated with von Frey and place escape/avoidance paradigm (PEAP) tests, respectively. Spinal microglial and astrocytic activation were assessed by immunofluorescence, and the spinal concentration of cytokines IL-1 & beta;, IL-6, IL-10, and macrophage colony-stimulating factor (M-CSF) were evaluated by multiplex immunoassay. MaR1 treatment reduced SNI-induced mechanical hypersensitivity on days 7 and 11 in both male and female mice, and appeared to ameliorate the affective component of pain in males on day 11. No definitive conclusions could be drawn about the impact of MaR1 on the affective-motivational aspects of pain in female mice, since repeated suprathreshold mechanical stimulation of the affected paw in the dark compartment did not increase the preference of vehicle-treated SNI females for the light side, during the PEAP test session (a fundamental assumption for PAEP's validity). MaR1 treatment also reduced ipsilateral spinal microglial and astrocytic activation in both sexes and marginally increased M-CSF in males, while not affecting cytokines IL-1 & beta;, IL-6 and IL-10 in either sex. In summary, our study has shown that oral treatment with MaR1 (i) produces antinociception even in an already installed peripheral NP mouse model, and (ii) this antinociception may extend for several days beyond the treatment time-frame. These therapeutic effects are associated with attenuated microglial and astrocytic activation in both sexes, and possibly involve modulation of M-CSF action in males.& nbsp;This work was supported by University of Porto/Faculty of Medicine (https://sigarra.up.pt/fmup) and ESF - European Social Fund (https://ec. europa.eu/esf/home.jsp), through NORTE2020 - North Portugal Regional Operational Programme [NORTE-08-5369-FSE-000011-Doctoral Programmes - LTS' PhD fellowship], and by Fundacao Grunenthal Portugal (https://www. fundacaogrunenthal.pt), Bolsa Jovens Investigadores em Dor 2018 - LTS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Impact of biological agents and tissue engineering approaches on the treatment of rheumatic diseases

The treatment of rheumatic diseases has been the focus of many clinical studies aiming to achieve the best combination of drugs for symptom reduction. Although improved understanding of the pathophysiology of rheumatic diseases has led to the identification of effective therapeutic strategies, its cure remains unknown. Biological agents are a breakthrough in the treatment of these diseases. They proved to be more effective than the other conventional therapies in refractory inflammatory rheumatic diseases. Among them, tumor necrosis factor inhibitors are widely used, namely Etanercept, Infliximab, or Adalimumab, alone or in combination with disease-modifying antirheumatic drugs. Nevertheless, severe adverse effects have been detected in patients with history of recurrent infections, including cardiac failure or malignancy. Currently, most of the available therapies for rheumatic diseases do not have sufficient tissue specificity. Consequently, high drug doses must be administrated systemically, leading to adverse side effects associated with its possible toxicity. Drug delivery systems, by its targeted nature, are excellent solutions to overcome this problem. In this review, we will describe the state-of-the-art in clinical studies on the treatment of rheumatic diseases, emphasizing the use of biological agents and target drug delivery systems. Some alternative novel strategies of regenerative medicine and its implications for rheumatic diseases will also be discussed.The authors state that there is no conflict of interests, including financial, relationships, or affiliations relevant for the subject. M. Alves da Silva and A. Martins acknowledge the Portuguese Foundation for Science and Technology for their Ph.D. grants and European NoE EXPERTISSUES (NMP3-CT-2004-500283)

Longer duration of obesity is associated with a reduction in urinary angiotensinogen in prepubertal children

Background: We aimed to study the impact of obesity on urinary excretion of angiotensinogen (U-AGT) in prepubertal children, focusing on the duration of obesity and gender. Also, we aimed to evaluate whether plasma angiotensinogen (P-AGT) and hydrogen peroxide (H2O2) play a role in the putative association. Methods: Cross-sectional evaluation of 305 children aged 8–9 years (160 normal weight, 86 overweight, and 59 obese). Anthropometric measurements and 24-h ambulatory blood pressure monitoring were performed. Angiotensinogen (AGT) was determined by a commercial enzyme-linked immunosorbent assay (ELISA) kit and H2O2 by a microplate fluorometric assay. Results: U-AGT and P-AGT levels were similar across body mass index (BMI) groups and between sexes. However, boys who were overweight/obese since the age of 4 years presented lower levels of U-AGT compared with those of normal weight at the same age. In children who were overweight/obese since the age of 4, urinary H2O2 decreased with P-AGT. Conclusions: A higher duration of obesity was associated with decreased U-AGT in boys, thus reflecting decreased intrarenal activity of the renin–angiotensin system. Also, children with a longer duration of obesity showed an inverse association between urinary H2O2 and P-AGT. Future studies should address whether these results reflect an early compensatory mechanism to limit obesity-triggered renal dysfunction.This project was supported by funds from Fundo Europeu de Desenvolvimento Regional (FEDER) from Programa Operacional Factores de Competitividade – COMPETE (FCOMP-01-0124-FEDER-028751), by national funds from the Portuguese Foundation for Science and Technology (FCT) (PTDC/DTP-PIC/0239/2012) and by Calouste Gulbenkian Foundation, that granted the study design and data collection and analysis. Liane Correia-Costa was supported by FCT (grant SFRH/SINTD/95898/2013), Teresa Sousa was supported by FCT and POPH/FSE (EC) (Ciência 2008 and SFRH/BPD/112005) and Franz Schaefer was supported by the ERA-EDTA Research Programme and the KfH Foundation for Preventive Medicine. The Epidemiology Research Unit (EPIUnit) is funded by FCT (UID/DTP/04750/2013)

Impact of physical activity on redox status and nitric oxide bioavailability in nonoverweight and overweight/obese prepubertal children

Nutritional status might contribute to variations induced by physical activity (PA) in redox status biomarkers. We investigated the influence of PA on redox status and nitric oxide (NO) production/metabolism biomarkers in nonoverweight and overweight/obese prepubertal children. We performed a cross-sectional evaluation of 313 children aged 8-9 years (163 nonoverweight, 150 overweight/obese) followed since birth in a cohort study (Generation XXI, Porto, Portugal). Plasma total antioxidant status (P-TAS), plasma and urinary isoprostanes (P-Isop, U-Isop), urinary hydrogen peroxide (U-H2O2), myeloperoxidase (MPO) and plasma and urinary nitrates and nitrites (P-NOx, U-NOx) were assessed, as well as their association with variables of reported PA quantification (categories of PA frequency (>1x/week and ≤1x/week)and continuous PA index (obtained by the sum of points)) in a questionnaire with increasing ranks from sedentary to vigorous activity levels. U-NOx was significantly higher in children who presented higher PA index scores and higher PA frequency. Separately by BMI classes, U-NOx was significantly higher only in nonoverweight children who practiced PA more frequently (p = 0.037). In overweight/obese children, but not in nonoverweight, P-TAS was higher among children with higher PA frequency (p = 0.007). Homeostasis model assessment index (HOMA-IR) was significantly lower in more active overweight/obese children, but no differences were observed in nonoverweight children. In the fully adjusted multivariate linear regression models for P-TAS, in the overweight/obese group, children with higher PA frequency presented higher P-TAS. In the U-NOx models, U-NOx significantly increased with PA index, only in nonoverweight children. Our results provide additional evidence in support of a protective effect of physical activity, in nonoverweight by increasing NO bioavailability and in overweight/obese children by enhancing systemic antioxidant capacity and insulin sensitivity. These results highlight the importance of engaging in regular physical exercise, particularly among overweight/obese children, in which a positive association between oxidant status and cardiometabolic risk markers has been described.This project was supported by FEDER funds from Programa Operacional Factores de Competitividade – COMPETE [FCOMP-01-0124-FEDER-028751], by national funds from the Portuguese Foundation for Science and Technology (FCT), Lisbon, Portugal [PTDC/DTP-PIC/0239/2012] and by Calouste Gulbenkian Foundation. Liane Correia-Costa was supported by FCT [SFRH/SINTD/95898/2013] and Teresa Sousa was supported by FCT and POPH/FSE (EC) [Ciência 2008 and SFRH/BPD/112005]

Evaluation of urinary cysteinyl leukotrienes as biomarkers of severity and putative therapeutic targets in COVID-19 patients

Background Cysteinyl leukotrienes (CysLT) are potent inflammation-promoting mediators, but remain scarcely explored in COVID-19. We evaluated urinary CysLT (U-CysLT) relationship with disease severity and their usefulness for prognostication in hospitalized COVID-19 patients. The impact on U-CysLT of veno-venous extracorporeal membrane oxygenation (VV-ECMO) and of comorbidities such as hypertension and obesity was also assessed. Methods Blood and spot urine were collected in severe (n = 26), critically ill (n = 17) and critically ill on VV-ECMO (n = 17) patients with COVID-19 at days 1-2 (admission), 3-4, 5-8 and weekly thereafter, and in controls (n = 23) at a single time point. U-CysLT were measured by ELISA. Routine markers, prognostic scores and outcomes were also evaluated. Results U-CysLT did not differ between groups at admission, but significantly increased along hospitalization only in critical groups, being markedly higher in VV-ECMO patients, especially in hypertensives. U-CysLT values during the first week were positively associated with ICU and total hospital length of stay in critical groups and showed acceptable area under curve (AUC) for prediction of 30-day mortality (AUC: 0.734, p = 0.001) among all patients. Conclusions U-CysLT increase during hospitalization in critical COVID-19 patients, especially in hypertensives on VV-ECMO. U-CysLT association with severe outcomes suggests their usefulness for prognostication and as therapeutic targets.This work was supported by a RESEARCH 4 COVID-19 grant (project 519, reference number: 613690173) from FCT-Fundacao para a Ciencia e a Tecnologia (special support for rapid implementation projects for innovative response solutions to COVID-9 pandemic). CS-P is a recipient of a Ph.D. fellowship from FCT and MedInUP (UI/BD/150816/2020). P-PT was supported by a research contract within the scope of the RIFF-HEART project funded by FEDER via COMPETE, Portugal 2020-Operational Programme for Competitiveness and Internationalization (POCI) (POCI-01-0145-FEDER-032188) and by FCT (PTDC/MEC-CAR/32188/2017). Open access funding provided by FCT|FCCN (b-on)

Proinflammatory and endothelial activation profiles in hospitalized COVID-19 patients: impact of arterial hypertension and previous treatment with renin-angiotensin-aldosterone inhibitors

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Age and calcium sources in laying hen feed affect calcium digestibility.

Abstract: The apparent calcium (Ca) digestibility coefficient (ADC) and true digestibility coefficient (TDC) of different inorganic calcium sources were determined in laying hens of different ages. Three Ca digestibility tests were carried out, each assessing 240 Lohmann Brown lineage laying hens distributed in a completely randomized design. Nine dietary treatments were arranged in a 3 × 3 factorial design consisting of three ages (40, 50 and 70 weeks) × three Ca (dicalcium phosphate (DCP) sources, fine (FL) and coarse (CL)) limestone, comprising eight replicates per treatment of six birds per experimental unit. Regarding the DCP, the ADC was higher (P 0.05) of age on the ADC was noted for either FL or CL. Comparing Ca sources, DCP exhibited a higher (P 0.05). Endogenous loss values of 790, 860 and 930 mg·kg&#8722;1 of consumed dry matter were observed at 40, 50 and 70 weeks, respectively. For the TDC, no interaction (P > 0.05) was observed between Ca sources and bird age. The highest TDC value (P > 0.05) was found in birds fed DCP (0.786) followed by FL (0.637) and CL (0.534). In addition, birds at 40 weeks of age (0.714) exhibited higher TDC values (P < 0.05) compared to animals at 50 weeks of age (0.608). The findings reported herein demonstrate that the true digestibility is greater in the youngest birds and that consumed the DCP and the FL in relation to the birds that consumed the CL

Urinary fibrogenic cytokines ET-1 and TGF-beta 1 are associated with urinary angiotensinogen levels in obese children

BACKGROUND:Fibrogenic cytokines are recognized as putative drivers of disease activity and histopathological deterioration in various kidney diseases. We compared urinary transforming growth factor β1 (U-TGF-β1) and endothelin 1 (U-ET-1) levels across body mass index classes and assessed their association with the level of urinary angiotensinogen (U-AGT), a biomarker of intrarenal renin-angiotensin-aldosterone system (RAAS). METHODS:The was a cross-sectional evaluation of 302 children aged 8-9 years. Ambulatory blood pressure (BP), insulin resistance (HOMA-IR), aldosterone level and renal function were evaluated. U-ET-1, U-TGF-β1 and U-AGT levels were determined by immunoenzymatic methods. RESULTS:Obese children presented with the lowest levels of U-ET-1 and U-TGF-β1, but the difference was only significant for U-ET-1. In obese children, the median levels of both U-ET-1 and U-TGF-β1 tended to increase across tertiles (T1-T3) of U-AGT (U-ET-1: T1, 19.9 (14.2-26.3); T2, 32.5 (23.3-141.6); T3, 24.8 (18.7-51.5) ng/g creatinine, p = 0.007; U-TGF-β1: T1, 2.2 (1.8-4.0); T2, 4.3 (2.7-11.7); T3, 4.9 (3.8-10.1) ng/g creatinine, p = 0.004]. In multivariate models, in the obese group, U-ET-1 was associated with HOMA-IR and aldosterone and U-AGT levels, and U-TGF-β1 was associated with U-AGT levels and 24 h-systolic BP. CONCLUSIONS:Whereas the initial hypothesis of higher levels of urinary fibrogenic cytokines in obese children was not confirmed in our study, both TGF-β1 and U-ET-1 levels were associated with U-AGT level, which likely reflects an early interplay between tissue remodeling and RAAS in obesity-related kidney injury

Oxidative stress and nitric oxide are increased in obese children and correlate with cardiometabolic risk and renal function

Oxidative stress and nitric oxide (NO) appear to represent important links between obesity and cardiovascular, metabolic and/or renal disease. We investigated whether oxidative stress and NO production/metabolism are increased in overweight and obese prepubertal children and correlate with cardiometabolic risk and renal function. We performed a cross-sectional evaluation of 313 children aged 8-9 years. Anthropometrics, 24-h ambulatory blood pressure, pulse wave velocity (PWV), insulin resistance (homoeostasis model assessment index (HOMA-IR)), inflammatory/metabolic biomarkers, estimated glomerular filtration rate (eGFR), plasma total antioxidant status (TAS), plasma and urinary isoprostanes (P-Isop, U-Isop), urinary hydrogen peroxide (U-H2O2), and plasma and urinary nitrates and nitrites (P-NOx, U-NOx) were compared among normal weight, overweight and obese groups, according to WHO BMI z-score reference. U-Isop were increased in the obese group, whereas U-NOx were increased in both overweight and obese children. U-Isop were positively correlated with U-H2O2, myeloperoxidase (MPO), high-sensitivity C-reactive protein, HOMA-IR and TAG. TAS correlated negatively with U-Isop and MPO and positively with PWV. HOMA-IR and U-H2O2 were associated with higher U-Isop, independently of BMI and eGFR, and total cholesterol and U-H2O2 were associated with U-NOx, independently of BMI, eGFR values and P-NOx concentration. In overweight and obese children, eGFR decreased across P-NOx tertiles (median: 139·3 (25th, 75th percentile 128·0, 146·5), 128·0 (25th, 75th percentile 121·5, 140·4), 129·5 (25th, 75th percentile 119·4, 138·3), P for linear trend=0·003). We conclude that oxidant status and NO are increased in relation to fat accumulation and, even in young children, they translate into higher values of cardiometabolic risk markers and affect renal function