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© 2015 El Assar et al. ; Insulin resistance (IR) is frequently associated with endothelial dysfunction and has been proposed to play a major role in cardiovascular disease (CVD). On the other hand, amylin has long been related to IR. However the role of amylin in the vascular dysfunction associated to IR is not well addressed. Therefore, the aim of the study was to assess the effect of acute treatment with amylin on endothelium-dependent vasodilation of isolated mesenteric arteries from control (CR) and insulin resistant (IRR) rats and to evaluate the possible mechanisms involved. Five week-old male Wistar rats received 20% D-fructose dissolved in drinking water for 8 weeks and were compared with age-matched CR. Plasmatic levels of glucose, insulin and amylin were measured. Mesenteric microvessels were dissected and mounted in wire myographs to evaluate endothelium-dependent vasodilation to acetylcholine. IRR displayed a significant increase in plasmatic levels of glucose, insulin and amylin and reduced endothelium-dependent relaxation when compared to CR. Acute treatment of mesenteric arteries with r-amylin (40 pM) deteriorated endothelium-dependent responses in CR. Amylin-induced reduction of endothelial responses was unaffected by the H2O2 scavenger, catalase, but was prevented by the extracellular superoxide scavenger, superoxide dismutase (SOD) or the NADPH oxidase inhibitor (VAS2870). By opposite, amylin failed to further inhibit the impaired relaxation in mesenteric arteries of IRR. SOD, or VAS2870, but not catalase, ameliorated the impairment of endothelium-dependent relaxation in IRR. At concentrations present in insulin resistance conditions, amylin impairs endothelium-dependent vasodilation in mircrovessels from rats with preserved vascular function and low levels of endogenous amylin. In IRR with established endothelial dysfunction and elevated levels of amylin, additional exposure to this peptide has no effect on endothelial vasodilation. Increased superoxide generation through NADPH oxidase activity may be a common link involved in the endothelial dysfunction associated to insulin resistance and to amylin exposure in CR. ; The present work was funded by grants from the Ministerio de Economía y Competitividad and cofunded by Fondos FEDER (Instituto de Salud Carlos III, PI10/02781, PI11/01068, RETICEF RD12/0043), Spanish Government, and by Fundación Mutua Madrileña (AP/103152012).

This Document is Protected by copyright and was first published by Frontiers. All rights reserved. it is reproduced with permission ; Vascular aging is a key process determining health status of aged population. Aging is an independent cardiovascular risk factor associated to an impairment of endothelial function, which is a very early and important event leading to cardiovascular disease. Vascular aging, formerly being considered an immutable and inexorable risk factor, is now viewed as a target process for intervention in order to achieve a healthier old age. A further knowledge of the mechanisms underlying the age-related vascular dysfunction is required to design an adequate therapeutic strategy to prevent or restore this impairment of vascular functionality. Among the proposed mechanisms that contribute to age-dependent endothelial dysfunction, this review is focused on the following aspects occurring into the vascular wall: (1) the reduction of nitric oxide (NO) bioavailability, caused by diminished NO synthesis and/or by augmented NO scavenging due to oxidative stress, leading to peroxynitrite formation (ONOO -); (2) the possible sources involved in the enhancement of oxidative stress; (3) the increased activity of vasoconstrictor factors; and (4) the development of a low-grade pro-inflammatory environment. Synergisms and interactions between all these pathways are also analyzed. Finally, a brief summary of some cellular mechanisms related to endothelial cell senescence (including telomere and telomerase, stress-induced senescence, as well as sirtuins) are implemented, as they are likely involved in the age-dependent endothelial dysfunction, as well as in the lower vascular repairing capacity observed in the elderly. Prevention or reversion of those mechanisms leading to endothelial dysfunction through life style modifications or pharmacological interventions could markedly improve cardiovascular health in older people ; This study is supported by grants from Ministerio de Ciencia e Innovación (Instituto de Salud Carlos III, RETICEF RD06/0013; PI08/1649; SAF2011-28011; SAF2011-24684, Spanish Government, and Sociedad Española de Farmacología/Almirall Prodesfarma

Background: Renal cell carcinoma (RCC) is a heterogeneous and complex disease with only partial response to therapy, high incidence of metastasis and recurrences, and scarce reliable biomarkers indicative of progression and survival. Cancer-associated fibroblasts (CAFs) play an important role supporting and promoting renal cancer progression. Methods: In this study, we analysed fibroblast activation protein-α (FAP) immunohistochemical expression and its soluble isoform (sFAP) in tumour tissues and plasma from 128 patients with renal tumours. Results: FAP is expressed in the cell surface of CAFs of the tumour centre and infiltrating front from clear cell renal cell carcinomas (CCRCC, n = 89), papillary renal cell carcinomas (PRCC, n = 21), and chromophobe renal cell carcinomas (ChRCC, n = 8), but not in the benign tumour renal oncocytoma (RO, n = 10). A high expression of FAP and low levels sFAP are significantly associated with high tumour diameter, high grade, and high pT stage, lymph node invasion, development of early metastases, and worse 5-year cancer specific survival of CCRCC patients. Conclusions: These findings corroborate the potential usefulness of FAP immunohistochemistry and plasma sFAP as a biomarker of CCRCC progression and point to CAF-related proteins as promising immunohistochemical biomarkers for the differential diagnosis of ChRCC and RO. ; Basque Government (ELKARTEK KK2018-00090 and KK-2020/00069). ; 6.639 JCR (2020) Q1, 51/242 Oncology ; 1.818 SJR (2020) Q1, 63/354 Oncology ; No data IDR 2020 ; UEM

Background: Renal cancer is one of the most frequent malignancies in Western countries, with an unpredictable clinical outcome, partly due to its high heterogeneity and the scarcity of reliable biomarkers of tumour progression. (Pro)renin receptor (PRR) is a novel receptor of the renin-angiotensin system (RAS) that has been associated with the development and progression of some solid tumours by RAS-dependent and -independent mechanisms. (2) Methods: In this study, we analysed the immunohistochemical expression of PRR at the centre and border in a series of 83 clear-cell renal cell (CCRCCs), 19 papillary (PRCC) and 7 chromophobe (ChRCC) renal cell carcinomas, and the benign tumour renal oncocytoma (RO, n = 11). (3) Results: PRR is expressed in all the tumour subtypes, with higher mean staining intensity in ChRCCs and ROs. A high expression of PRR at the tumour centre and at the infiltrative front of CCRCC tissues is significantly associated with high grade, tumour diameter, local invasion and stage, and with high mortality risk by UCLA integrated staging system (UISS) scale. (4) Conclusions: These findings indicate that PRR is associated with the development and progression of renal tumours. Its potential as a novel biomarker for RCC diagnosis/prognosis and as a promising therapeutic target should be taken into account in the future. ; Basque Government (ELKARTEK KK2018-00090 and KK-2020/00069) ; 3.992 JCR (2021) Q2, 60/172 Medicine, General & Internal ; 0.658 SJR (2021) Q2, 56/119 Clinical Biochemistry ; No data IDR 2021 ; UEM

53 p.-7 fig. ; BACKGROUND AND PURPOSE FM19G11 up-regulates mammalian target of rapamycin (mTOR)/hypoxia inducible factor-1α (HIF-1α) and PI3K/Akt pathways, which are involved in endothelial function. We evaluated the effects of FM19G11 on defective endothelial vasodilatation in arteries from rats and humans and investigated the mechanisms involved. ; EXPERIMENTAL APPROACH Effects of chronic in vivo administration of FM19G11 on aortic endothelial vasodilatation were evaluated together with ex vivo treatment in aortic and mesenteric arteries from control and insulin-resistant rats (IRR). Its effects on vasodilator responses of penile arteries (HPRAs) and corpus cavernosum (HCC) from men with vasculogenic erectile dysfunction (ED) (model of human endothelial dysfunction) were also evaluated. Vascular expression of phosphorylated-endothelial NOS (p-eNOS), phosphorylated-Akt (p-Akt) and HIF-1α was determined by immunodetection and cGMP by ELISA. ; KEY RESULTS Chronic administration of FM19G11 reversed the impaired endothelial vasodilatation in IRR. Ex vivo treatment with FM19G11 also significantly improved endothelium-dependent vasodilatation in aorta and mesenteric arteries from IRR. These effects were accompanied by the restoration of p-eNOS and cGMP levels in IRR aorta and were prevented by either NOS or PI3K inhibition. p-Akt and p-eNOS contents were increased by FM19G11 in aortic endothelium of IRR. FM19G11-induced restoration of endothelial vasodilatation was unaffected by mTOR/HIF-1α inhibitors. FM19G11 also restored endothelial vasodilatation in HPRA and HCC from ED patients. ; CONCLUSIONS AND IMPLICATIONS Stimulation of the PI3K/Akt/eNOS pathway by FM19G11 alleviates impaired NO-mediated endothelial vasodilatation in rat and human arteries independently of mTOR/HIF-1α activation. This pharmacological strategy could be beneficial for managing pathological conditions associated with endothelial dysfunction, such as ED. ; This research work was supported by grants from the Ministerio de Economía y Competitividad (Instituto de Salud Carlos III, PI10/02781, PI11/01068, PI12/01628, S2010/BMD-2353, RETICEF RD12/0043), Spanish Government, and the Fundación Mutua Madrileña (AP103152012). ; Peer reviewed

27 p.-4 tab. ; Background The expression of certain genes involved in response to oxidative stress is likely related to aging-related outcomes, such as frailty in old age. Given nutrition's substantial impact in aging and age-related diseases, one of its mechanisms might be through influencing gene expression. ; Objective This study aimed to investigate the association between nutrition and the expression of 15 genes related to cellular response to stress in older community-dwelling individuals. ; Methods A nested case-control study of 350 participants (mean ± SEM age: 76.5 ± 6.9 y, 42.9% men, 22% frail according to Fried's criteria) was selected from the Toledo Study for Healthy Aging. Blood-derived RNA was retro-transcribed into complementary DNA. TaqMan Arrays were used for determining gene expression. The Mini Nutritional Assessment (MNA) and the PREDIMED (PREvención con DIeta MEDiterranea) questionnaire measured nutritional status and adherence to the Mediterranean diet (MD), respectively. Data were reweighed so that inference from linear and logistic regression models applied to the original sampling population. ; Results Higher MNA scores were associated with higher expressions of the gene coding for sirtuin-1 (SIRT1), regardless of age, sex, and Charlson comorbidity score (P = 0.04) and even after adjusting for frailty status (P = 0.016) and level of adherence to the MD (P = 0.04). Malnutrition risk and SIRT1 gene expression were inversely associated (P = 0.0045) independently of frailty status (P = 0.0045) and level of adherence to the MD (P = 0.0075). ; Conclusions In older individuals, improvement in nutritional status is positively associated with SIRT1 gene expression independently of frailty status or adherence to the MD. These findings may provide potential biomarkers and targets for health interventions among the elderly. ; The research leading to these results has received funding from the European Union's Seventh Framework Programme (FP7/2007–2013) under grant agreement number 305483 (to LR-M)—FRAILOMIC Project, and from the Ministry of Economy and Competitiveness, cofinanced by FEDER funds (Instituto de Salud Carlos III), Spanish Government, grants PI15/01160 (to JA), PI15/00674 (to LR-M), and CIBERFES CB16/10/00464 (to LR-M). ; Peer reviewed