An accelerated synthesis of dendrimers is presented by combining the thermal azide-alkyne cycloaddition (AAC) and azide substitution reactions. The strategy is among the most user-friendly, flexible, ...modular, and accelerated strategies for the synthesis of dendrimers. Despite AAC being an archetypal click reaction that proceeds with complete atom-economy and is amenable to a high chemical diversity, high temperatures and prolonged reaction times have limited its application in the synthesis of dendrimers. By combining the optimized AAC/azide substitution conditions, simplified workups/purifications, and a strict alignment to green chemistry principles, not only a G5 dendrimer with 96 terminal groups has been synthesized and characterized in less than 12 h, but also the newly formed triazol has been successfully used to promote the easy exploration of the dendritic chemical space, the peripheral decoration of dendrimers, and the straightforward adjustment of dendritic properties.
Optimized reaction conditions and a strict alignment to green chemistry principles allow the accelerated preparation of a G5 dendrimer in less than 12 h by combining the thermal azide-alkyne cycloaddition and azide substitution reactions.
Immune infertility occurs due to the presence of antisperm antibodies (ASA). This type of infertility has a relatively low prevalence (2.6-6.6% in infertile men), and its etiology, risk factors, ...targets, and consequences for male fertility are not completely understood. While it is largely accepted that abnormalities in the blood-testis barrier and/or blood-epididymal barrier are the main factors behind its etiology, and that sperm motility is the most frequently reported altered parameter, few are the well-defined risk factors and ASA targets only now started to be disclosed, with proteins involved in sperm-oocyte interaction rising as the most significant. The development of potential treatments is also limited, being the corticosteroids the more promising. Overall, there are still many knowledge gaps related to immune infertility. With this review, we aimed to gather all the information collected from studies developed in humans in the last decade. Despite the controversial results/inconsistencies, that are not only a result of the complexity of mechanisms/variables involved in ASA infertility but also from the technical approaches to assess ASA and the lack of a consensus regarding the thresholds to be used, this manuscript aims to bring a fresh update on the field. It has become clear that, to obtain more/reliable data, there is a need to assess ASA in all the routine seminal analyses, following WHO recommendations. In this way, it will be possible to obtain consistent and comparable information, that can add to current knowledge. Additionally, multicentric studies with large cohorts are also missing, and future research should take this into consideration.
Post-transplant lymphoproliferative disease (PTLD) is the most common malignancy complicating solid organ transplantation (SOT) in adults and children. PTLD encompasses a spectrum of histopathologic ...features and organ involvement, ranging from benign lymphoproliferation and infectious-mononucleosis like presentation to invasive neoplastic processes such as classical Hodgkin lymphoma. The predominant risk factors for PTLD are Epstein-Barr virus (EBV) serostatus at the time of transplant and the intensity of immunosuppression following transplantation; with EBV-negative recipients of EBV-positive donor organs at the highest risk. In children, PTLD commonly presents in the first two years after transplant, with 80% of cases in the first year, and over 90% of cases associated with EBV-positive B-cell proliferation. Though pediatric kidney transplant recipients are at lower risk (1-3%) for PTLD compared to their other SOT counterparts, there is still a significant risk of morbidity, allograft failure, and an estimated 5-year mortality rate of up to 50%. In spite of this, there is no consensus for monitoring of at-risk patients or optimal management strategies for pediatric patients with PTLD. Here we review pathogenesis and risk factors for the development of PTLD, with current practices for prevention, diagnosis, and management of PTLD in pediatric kidney transplant recipients. We also highlight emerging concepts, current research gaps and potential future developments to improve clinical outcomes and longevity in these patients.
Although the cardioprotective benefits of exercise training are well known, the effects of training on dexamethasone (DEX)-induced arterial stiffness are still unclear. This study was aimed at ...investigating the mechanisms induced by training to prevent DEX-induced arterial stiffness.
Wistar rats were allocated into 4 groups and submitted to combined training (aerobic and resistance exercises, on alternate days, 60% of maximal capacity, for 74 d) or were kept sedentary: sedentary control rats (SC), DEX-treated sedentary rats (DS), combined training control (CT), and DEX-treated trained rats (DT). During the last 14 d, rats were treated with DEX (50 μg/kg per body weight, per day, s.c.) or saline.
DEX increased PWV (+44% vs +5% m/s, for DS vs SC, p<0.001) and increased aortic COL 3 protein level (+75%) in DS. In addition, PWV was correlated with COL3 levels (r=0.682, p<0.0001). Aortic elastin and COL1 protein levels remained unchanged. On the other hand, the trained and treated groups showed lower PWV values (-27% m/s, p<0.001) vs DS and lower values of aortic and femoral COL3 compared with DS.
As DEX is widely used in several situations, the clinical relevance of this study is that the maintenance of good physical capacity throughout life can be crucial to alleviate some of its side effects, such as arterial stiffness.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Dexamethasone (DEX)-induced arterial stiffness is an important side-effect, associated with hypertension and future cardiovascular events, which can be counteracted by exercise training. The aim of ...this study was to evaluate the mechanisms induced by combined training to attenuate arterial stiffness and hypertension in spontaneously hypertensive rats treated or not with dexamethasone. Spontaneously hypertensive rats (SHR) underwent combined training for 74 days and were treated with dexamethasone (50 µg/kg
s. c
.) or saline solution during the last 14 days. Wistar rats were used as controls. Echocardiographic parameters, blood pressure (BP) and pulse wave velocity (PWV), as well as histological analyses of the heart and aorta, carotid and femoral arteries were performed. At the beginning, SHR had higher BP and PWV compared with Wistar rats. After 60 days, while BP increased in sedentary SHR, combined exercise training decreased BP and PWV. After 74d, the higher BP and PWV of sedentary SHR was accompanied by autonomic imbalance to the heart, cardiac remodeling, and higher arterial collagen deposition. DEX treatment did not change these parameters. On the other hand, trained SHR had reduced BP and PWV, which was associated with better autonomic balance to the heart, reduced myocardial collagen deposition, as well as lower arterial collagen deposition. The results of this study suggest that combined training, through the reduction of aortic collagen deposition, is an important strategy to reduce arterial stiffness in spontaneously hypertensive rats, and these lower responses were maintained regardless of dexamethasone treatment.
Raman Microspectroscopy represents an innovative tool for the assessment of sperm biochemical features otherwise undetectable by routine semen analysis. Previously, it was shown that induced DNA ...damage can be detected in smeared sperm by this technique. This novel readout may be of value for clinical settings especially if it can be transferred to living cells. Yet, starting with living sperms this study was carried-out using a variety of conditions to disclose the Raman features of sperm nuclei under different hydration conditions and UV exposure. Human sperm were immobilized and Raman spectra were obtained from individual sperm as repeated measurements. To create conditions with controlled DNA damage, sperm samples were exposed to ultraviolet light. Several media were used to evaluate their effect on Raman spectra in aqueous conditions. To substantiate differences between the experimental conditions, the spectra were analyzed by Principal Component Analysis. We observed that spectra of sperm nuclei obtained in different solutions showed a qualitatively unchanged spectral pattern showing the principal signals related to DNA. Evaluating the effect of ultraviolet light generated the finding that spectra representing DNA damage were only observed in dry conditions but not in aqueous medium. Thus, Raman microspectroscopy was successfully applied for sperm analysis in different conditions, among them in live spermatozoa in aqueous solution during the initial measurement, revealing the principle use of this technique. However, implementation of Raman spectroscopy as a technique for clinical sperm analysis and selection may be especially relevant when DNA evaluation can be established using live sperm.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Glucocorticoids have important anti-inflammatory and immunomodulatory activities. Dexamethasone (Dex), a synthetic glucocorticoid, induces insulin resistance, hyperglycemia, and hypertension. The ...hypertensive mechanisms of Dex are not well understood. Previously, we showed that exercise training prior to Dex treatment significantly decreases blood vessel loss and hypertension in rats. In this study, we examined whether the salutary effects of exercise are associated with an enhanced metabolic profile. Analysis of the NAD and ATP content in the tibialis anterior muscle of trained and non-trained animals indicated that exercise increases both NAD and ATP; however, Dex treatment had no effect on any of the experimental groups. Likewise, Dex did not change NAD and ATP in cultured endothelial cells following 24 h and 48 h of incubation with high concentrations. Reduced VEGF-stimulated NO production, however, was verified in endothelial cultured cells. Reduced NO was not associated with changes in survival or the BH4 to BH2 ratio. Moreover, Dex had no effect on bradykinin- or shear-stress-stimulated NO production, indicating that VEGF-stimulated eNOS phosphorylation is a target of Dex's effects. The PTP1B inhibitor increased NO in Dex-treated cells in a dose-dependent fashion, an effect that was replicated by the glucocorticoid receptor inhibitor, RU486. In combination, these results indicate that Dex-induced endothelial dysfunction is mediated by glucocorticoid receptor and PTP1B activation. Moreover, since exercise reduces the expression of PTP1B and normalized insulin resistance in aging rats, our findings indicate that exercise training by reducing PTP1B activity counteracts Dex-induced hypertension in vivo.
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•Dexamethasone (Dex) induces hypertension that is ameliorated by exercise training.•Dex causes skeletal muscle (tibialis anterior) microvascular rarefaction.•Dex does not modify NAD or ATP levels in vivo or in cultured endothelial cells.•Dex alters VEGF but not bradykinin or shear stress-mediated NO activation.•Glucocorticoid receptor or PTPB1 inhibition improves NO signaling in Dex-treatments.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Adherence to healthy behaviors reduces risks of cardiovascular disease and death in the general population. However, among people with kidney disease, a group at higher risk for cardiovascular ...disease, such benefits have not been established.
We pooled data from three cohort studies with a total of 27,271 participants. Kidney function was categorized on the basis of eGFR (≥60, 45 to <60, and <45 ml/min per 1.73 m
). We used proportional hazard frailty models to estimate associations between healthy behaviors (not smoking, at recommended body mass index BMI, physical activity, healthy diet, and moderate to no alcohol intake) and outcomes (all-cause death, major coronary events, ischemic stroke, and heart failure events).
All recommended lifestyle behaviors were significantly associated with lower risks of death, regardless of eGFR. Not smoking (versus current) and any moderate to vigorous physical activity (versus none) was significantly associated with reduced risks of major coronary and heart failure events, regardless of eGFR. Any (versus no) moderate or vigorous physical activity significantly associated with decreased risk of ischemic stroke events only among those with eGFR ≥60. Moderate to no daily alcohol intake (versus excessive) was significantly associated with an increased risk of major coronary events, regardless of eGFR. For heart failure events, a BMI of 18.5 to 30 associated with decreased risk, regardless of eGFR. Across all eGFR categories, the magnitude of risk reduction for death and all cardiovascular outcomes increased with greater numbers of recommended lifestyle behaviors.
Recommended lifestyle behaviors are associated with lower risk of death and cardiovascular disease events among individuals with or without reduced kidney function, supporting lifestyle behaviors as potentially modifiable risk factors for people with kidney disease.
We compared the parameters related to glucose homeostasis, and liver and muscle proteomes in fluorosis-susceptible (A/J; S) and fluorosis-resistant (129P3/J; R) mice in response to fluoride (F) ...exposure and exercise. Ninety male mice (45 R-mice and 45 S-mice) were randomized into three groups: (SI; RI) No-F, No-Exercise, (SII; RII) 50 ppm F, No-Exercise, (SIII; RIII) 50 ppm F, Exercise. Overall, mean F concentrations in the plasma and femur were significantly higher in R-mice compared with S-mice. In R-mice, exercise resulted in an increase in F accumulation in the femur. In S-mice, the mean plasma glucose level was significantly higher in Group II compared with Groups I and III. There was an increase in liver proteins involved in energy flux and antioxidant enzymes in non-exercise groups (I, II) of S-mice in comparison with the corresponding groups of R-mice. The results also showed a decrease in muscle protein expression in Group I S-mice compared with their R-mice counterparts. In conclusion, the findings suggest an increased state of oxidative stress in fluorosis-susceptible mice that might be exacerbated by the treatment with F. In addition, fluorosis-susceptible mice have plasma glucose levels higher than fluorosis-resistant mice on exposure to F, and this is not affected by exercise.
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