Omentin protects H9c2 cells against docetaxel cardiotoxicity

Background : Association between obesity and cardiovascular diseases is well known, however increased susceptibility of obese patients to develop several cancer types is not so commonly known. Current data suggest that poorer overall survival in cancer patients might be associated to non-cancer-related causes such as higher risk of cardiotoxicity in obese patients treated with chemotherapeutic agents. Omentin, a novel adipokine decreased in obesity, is actually in the spotlight due to its favourable effects on inflammation, glucose homeostasis and cardiovascular diseases. Also, recent data showed that in vitro anthracycline-induced cardiomyocyte apoptosis is counteracted by omentin suggesting its cardioprotective role. Objective: Our aim was to evaluate omentin effects against docetaxel toxicity. Results: Our data indicate that omentin inhibits docetaxel-induced viability loss and that increased viability is associated to decreased caspase-3 expression and cell death. Although omentin reduces NOX4 expression, it failed to reduce docetaxel-induced reactive oxygen species production. Our results indicate that omentin decreases docetaxel-induced endoplasmic reticulum stress, suggesting that cardioprotective role might be associated to ERS inhibition. Conclusion : These data suggest that omentin treatment may contribute to decrease susceptibility to DTX-induced cardiotoxicity.This work was supported by Fundación Mutua Madrileña 2014 (R.L.), Red de Investigación Cardiovascular (RIC) (RD12/0042/0039) an initiative of ISCIII (J.R.G-J), Programa de Consolidación de Unidades de Investigación Competitivas do SUG (GPC 2013-051) of Xunta de Galicia (J.R.G-J) and Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV) (CB16/11/00226) of Instituto de Salud Carlos III (J.R.G-J). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscriptS

Ghrelin effects on neuropeptides in the rat hypothalamus depend on fatty acid metabolism actions on BSX but not on gender

"This is the peer reviewed version of the following article: Lage, R., Vázquez, M.J., Varela, L., Saha, A.K., Vidal-Puig, A., Nogueiras, R., Diéguez, C. and López, M. (2010), Ghrelin effects on neuropeptides in the rat hypothalamus depend on fatty acid metabolism actions on BSX but not on gender. The FASEB Journal, 24: 2670-2679, which has been published in final form at https://doi.org/10.1096/fj.09-150672. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited."The orexigenic effect of ghrelin is mediated by neuropeptide Y (NPY) and agouti-related protein (AgRP) in the hypothalamic arcuate nucleus (ARC). Recent evidence also indicates that ghrelin promotes feeding through a mechanism involving activation of hypothalamic AMP-activated protein kinase (AMPK) and inactivation of acetyl-CoA carboxylase and fatty acid synthase (FAS). This results in decreased hypothalamic levels of malonyl-CoA, increased carnitine palmitoyltransferase 1 (CPT1) activity, and mitochondrial production of reactive oxygen species. We evaluated whether these molecular events are part of a unique signaling cascade or whether they represent alternative pathways mediating the orexigenic effect of ghrelin. Moreover, we examined the gender dependency of these mechanisms, because recent evidence has proposed that ghrelin orexigenic effect is reduced in female rats. We studied in both genders the effect of ghrelin on the expression of AgRP and NPY, as well as their transcription factors: cAMP response-element binding protein (CREB and its phosphorylated form, pCREB), forkhead box O1 (FoxO1 and its phosphorylated form, pFoxO1), and brain-specific homeobox transcription factor (BSX). In addition, to establish a mechanistic link between ghrelin, fatty acid metabolism, and neuropeptides, we evaluated the effect of ghrelin after blockage of hypothalamic fatty acid β oxidation, by using the CPT1 inhibitor etomoxir. Ghrelin-induced changes in the AMPK-CPT1 pathway are associated with increased levels of AgRP and NPY mRNA expression through modulation of BSX, pCREB, and FoxO1, as well as decreased expression of endoplasmic reticulum (ER) stress markers in a gender-independent manner. In addition, blockage of hypothalamic fatty acid β oxidation prevents the ghrelin-promoting action on AgRP and NPY mRNA expression, also in a gender-independent manner. Notably, this effect is associated with decreased BSX expression and reduced food intake. Overall, our data suggest that BSX integrates changes in neuronal metabolic status with ARC-derived neuropeptides in a gender-independent mannerS

Gender differences on healthcare accessibility and outcomes of a electronic inter-clinician consultation program at the cardiology department in a Galician Health Area

Aims To assess the longer-term results (hospital admissions and mortality) in women versus men referred to a cardiology department from primary care using an e-consultation in our outpatient care programme. Methods We selected 61,306 patients (30,312 women and 30,994 men) who visited the cardiology service at least once between 2010 and 2021: 69.1% (19,997 women and 20,462 men) were attended in e-consultation (from 2013 to 2021) and 30.9% (8920 women and 9136 men) in in-person consultations (from 2010 to 2012) without gender differences in the proportion of patients attended in each period. Using an interrupted time series regression model, we analysed the impact of incorporating e-consultation into the healthcare model and evaluated the elapsed time to cardiology care, heart failure (HF), cardiovascular (CV), and all-cause hospital admissions and mortality during the one-year after cardiology consultation. Results The introduction of e-consultation substantially decreased waiting times to cardiology care; during the in-person consultation period, the mean delay for cardiology care was 57.9 (24.8) days in men and 55.8 (22.8) days in women. During the e-consultation period, the waiting time to cardiology care was markedly reduced to 9.41 (4.02) days in men and 9.46 (4.18) in women. After e-consultation implantation, there was a significant reduction in the 1-year rate of hospital admissions and mortality, both in women and men iRR [IC 95%]: 0.95 [0.93–0.96] for HF, 0.90 [0.89–0.91] for CV and 0.70 [0.69–0.71] for all-cause hospitalization; and 0.93 [0.92–0.95] for HF, 0.86 [0.86–0.87] for CV and 0.88 [0.87–0.89] for all-cause mortality in women; and 0.91 [0.89–0.92] for HF, 0.90 [0.89–0.91] for CV and 0.72 [0.71–0.73] for all-cause hospitalization; and 0.96 [0.93–0.97] for HF, 0.87 [95% CI: 0.86–0.87] for CV and 0.87 [0.86–0.87] for all-cause mortality, in men. Conclusion Compared with the in-person consultation period, an outpatient care programme that includes an e-consultation significantly reduced waiting time to cardiology care and was safe, with a lower rate of hospital admissions and mortality in the first year, without significative gender differencesS

The impact of inter-clinician electronic consultation in patients diagnosed with atrial fibrillation in primary care

Background An early diagnosis and early initiation of oral anticoagulants (OAC) are main determinants for outcomes in patients with atrial fibrillation (AF). Inter-clinician electronic consultations (e-consultations) program for the general practitioner referrals to cardiologist may improve health care access by reducing the elapsed time for cardiology care. Objective To evaluate the effect of a reduced elapsed time to care after a inter-clinician e-consultations program implementation (2013–2019) in comparison with previous in-person consultation (2010–2012) in the outpatient health care management in a Cardiology Department. Methodology We included 10,488 patients with AF from 1 January 2010, to 31 December 2019. Until 2012, all patients attended an in-person consultation (2010–2012). In 2013, we instituted an e-consult program (2013–2019) for all primary care referrals to cardiologists that preceded patient's in-person consultation when considered. The shared electronic patient dossier (EPD) was available between GP and cardiologist, and any change in therapy advice from cardiologist was directly implemented in this EPD. Results During the e-consultation period (2013–2019) were referred 6627 patients by GPs to cardiology versus 3861 during the in-person consultation (2010–2012). The e-consultation implementation was associated with a reduction in the elapsed time to anticoagulation prescription (177.6 ± 8.9 vs. 22.5 ± 8.1 days, p < .001), and an increase of OAC use (61% [95% IC: 19.6%–102.4%], p < .001). The e-consult program implementation was associated with a reduction in the 1-year CV mortality (.48 [95% CI: .30–.75]) and all-cause mortality (.42 [95% CI: .29–.62]). The OAC reduces the stroke mortality (.15 [95% CI: .06–.39]) and CV mortality (.43 [95% CI: .29–.62]) and all-cause mortality (.23 [95% CI: .17–.31]). Conclusion A shared EPD-based inter-clinician e-consultation program significantly reduced the elapsed time for cardiology consultation and initiation of OAC. The implementation of this program was associated with a lower risk of stroke and cardiovascular/all-cause mortalityS

Bioelectronics-on-a-chip for cardio myoblast proliferation enhancement using electric field stimulation

Background: Cardio myoblast generation from conventional approaches is laborious and time-consuming. We present a bioelectronics on-a-chip for stimulating cells cardio myoblast proliferation during culture. Method: The bioelectronics chip fabrication methodology involves two different process. In the first step, an aluminum layer of 200 nm is deposited over a soda-lime glass substrate using physical vapor deposition and selectively removed using a Q-switched Nd:YVO4 laser to create the electric tracks. To perform the experiments, we developed a biochip composed of a cell culture chamber fabricated with polydimethylsiloxane (PDMS) with a glass coverslip or a cell culture dish placed over the electric circuit tracks. By using such a glass cover slip or cell culture dish we avoid any toxic reactions caused by electrodes in the culture or may be degraded by electrochemical reactions with the cell medium, which is crucial to determine the effective cell-device coupling. Results: The chip was used to study the effect of electric field stimulation of Rat ventricular cardiomyoblasts cells (H9c2). Results shows a remarkable increase in the number of H9c2 cells for the stimulated samples, where after 72 h the cell density double the cell density of control samples. Conclusions: Cell proliferation of Rat ventricular cardiomyoblasts cells (H9c2) using the bioelectronics-on-a-chip was enhanced upon the electrical stimulation. The dependence on the geometrical characteristics of the electric circuit on the peak value and homogeneity of the electric field generated are analyzed and proper parameters to ensure a homogeneous electric field at the cell culture chamber are obtained. It can also be observed a high dependence of the electric field on the geometry of the electrostimulator circuit tracks and envisage the potential applications on electrophysiology studies, monitoring and modulate cellular behavior through the application of electric fieldsThis work was partially supported by Mineco through the projects FIS 2015–71933-REDT and RTI 2018–097063-B-I00, Consellería de Educación Program for Development of a Strategic Grouping in Materials – AeMAT Grant No. ED431E2018/08, Xunta de Galicia ref. ED431B2017/64. Xunta de Galicia, Spain, under Galician Programme for Research Innovation and Growth 2011–2015 (I2C Plan)S

The Treatment With the SGLT2 Inhibitor Empagliflozin Modifies the Hepatic Metabolome of Male Zucker Diabetic Fatty Rats Towards a Protective Profile

[Abstract] The EMPA-REG OUTCOME (Empagliflozin, Cardiovascular Outcome Event Trial in patients with Type 2 Diabetes Mellitus (T2DM)) trial evidenced the potential of sodium-glucose cotransporter 2 (SGLT2) inhibitors for the treatment of patients with diabetes and cardiovascular disease. Recent evidences have shown the benefits of the SGLT2 inhibitor empagliflozin on improving liver steatosis and fibrosis in patients with T2DM. Metabolomic studies have been shown to be very useful to improve the understanding of liver pathophysiology during the development and progression of metabolic hepatic diseases, and because the effects of empagliflozin and of other SGLT2 inhibitors on the complete metabolic profile of the liver has never been analysed before, we decided to study the impact on the liver of male Zucker diabetic fatty (ZDF) rats of a treatment for 6 weeks with empagliflozin using an untargeted metabolomics approach, with the purpose to help to clarify the benefits of the use of empagliflozin at hepatic level. We found that empagliflozin is able to change the hepatic lipidome towards a protective profile, through an increase of monounsaturated and polyunsaturated glycerides, phosphatidylcholines, phosphatidylethanolamines, lysophosphatidylinositols and lysophosphatidylcholines. Empagliflozin also induces a decrease in the levels of the markers of inflammation IL-6, chemerin and chemerin receptor in the liver. Our results provide new evidences regarding the molecular pathways through which empagliflozin could exert hepatoprotector beneficial effects in T2DM.This work was supported by Boehringer Ingelheim Pharma GmbH and Co., by the National Institute of Health “Fondo de Investigaciones Sanitarias del Instituto de Salud Carlos III” Madrid, Spain (PI15/00681, PI17/00409, PI18/00821, PI20/00902, RETICS Programme RD16/0012/0014 and CIBER de Enfermedades Cardiovasculares (CIBERCV)); European Regional Development Fund (FEDER) and European Union framework MSCA-RISE-H2020 Programme (Project number 734899). AH-A was funded by predoctoral research grants from Xunta de Galicia and FPU Program of the Spanish Ministry of Science, Innovation and Universities (Spain); MF-S was funded by the predoctoral research grants “Programa Científico do Centro de Investigación en Medicina Molecular e Enfermidades Crónicas (CiMUS) (Spain) and Xunta de Galicia; and AV-L was funded by the predoctoral research grant from the PFIS Program of the Spanish Ministry of Science and Instituto de Salud Carlos III (Spain

Plasma miR-486-5p Expression Is Upregulated in Atrial Fibrillation Patients with Broader Low-Voltage Areas

Atrial fibrillation (AF) is the most common arrhythmia worldwide, affecting 1% of the population over 60 years old. The incidence and prevalence of AF are increasing globally, representing a relevant health problem, suggesting that more advanced strategies for predicting risk stage are highly needed. miRNAs mediate several processes involved in AF. Our aim was to identify miRNAs with a prognostic value as biomarkers in patients referred for AF ablation and its association with LVA extent, based on low-voltage area (LVA) maps. In this study, we recruited 44 AF patients referred for catheter ablation. We measured the expression of 84 miRNAs in plasma from peripheral blood in 3 different groups based on LVA extent. Expression analysis showed that miR-486-5p was significantly increased in patients with broader LVA (4-fold, p = 0.0002; 5-fold, p = 0.0001). Receiver operating characteristic curve analysis showed that miR-486-5p expression could predict atrium LVA (AUC, 0.8958; p = 0.0015). Also, miR-486-5p plasma levels were associated with AF-type (AUC, 0.7137; p = 0.0453). In addition, miR-486-5p expression was positively correlated with LVA percentage, left atrial (LA) area, and LA volume (r = 0.322, p = 0.037; r = 0.372, p = 0.015; r = 0.319, p = 0.045, respectively). These findings suggest that miR-486-5p expression might have prognostic significance in LVA extent in patients with AFThis research was funded by Xunta de Galicia: Programa de Consolidación de Unidades de Investigación Competitivas do SUG (GRC 2019/02), the Centro Singular de Investigación de Galicia acreditación 2019–2022 (ED431G 2019/02), the European Union European Regional Development Fund (ERDF), and National Institute of Health Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III (ISCIII) Madrid, Spain (PI18/00821, CIBERCV CB16/11/00226 and FAISCA Intramural Project 2019)S

Treatment of Diabetes and Long-Term Survival After Insulin and Glucokinase Gene Therapy

Diabetes is associated with severe secondary complications, largely caused by poor glycemic control. Treatment with exogenous insulin fails to prevent these complications completely, leading to significant morbidity and mortality. We previously demonstrated that it is possible to generate a "glucose sensor" in skeletal muscle through coexpression of glucokinase and insulin, increasing glucose uptake and correcting hyperglycemia in diabetic mice. Here, we demonstrate long-term efficacy of this approach in a large animal model of diabetes. A one-time intramuscular administration of adeno-associated viral vectors of serotype 1 encoding for glucokinase and insulin in diabetic dogs resulted in normalization of fasting glycemia, accelerated disposal of glucose after oral challenge, and no episodes of hypoglycemia during exercise for >4 years after gene transfer. This was associated with recovery of body weight, reduced glycosylated plasma proteins levels, and long-term survival without secondary complications. Conversely, exogenous insulin or gene transfer for insulin or glucokinase alone failed to achieve complete correction of diabetes, indicating that the synergistic action of insulin and glucokinase is needed for full therapeutic effect. This study provides the first proof-of-concept in a large animal model for a gene transfer approach to treat diabetes

Gradual reduction of testosterone using a gonadotropin-releasing hormone vaccination delays castration resistance in a prostate cancer model

In a previous study aimed to design a novel prostate cancer vaccine, the authors of the present study demonstrated the advantage of combining the adjuvants Montanide ISA 51 with very small size proteoliposomes (VSSP) to promote a significant humoral immune response to gonadotropin‑releasing hormone (GnRH) in healthy animals. The present study compared the efficacy of this vaccine formulation versus the standard treatment currently available in terms of preventing the development of tumors in DD/S mice injected with Shionogi carcinoma (SC) 115 cells. The results demonstrated that 5 non‑vaccinated control mice exhibited a fast tumor growth, and succumbed to the disease within 19‑31 days. Mice immunized with the GnRH/Montanide ISA 51/VSSP vaccine exhibited a moderate decline in testosterone levels that was associated with a decrease in anti‑GnRH antibody titers, which lead to a sustained tumor growth inhibition. In total, 2 mice in the immunized group exhibited complete remission of the tumor for the duration of the present study. In addition, castrated mice, which were used as a control for standard hormonal therapy, exhibited an accelerated decrease in tumor size. However, tumor relapse was observed between days 50 and 54, and between days 65 and 85, following the injection of SC 155 cells. Therefore, these mice were sacrificed at day 90. The present study concludes that the slow and moderate reduction of testosterone levels observed using the GnRH‑based vaccine may delay the appearance of castration resistance in a Shionogi prostate cancer model. These findings suggest that this vaccine may be used to delay castration resistance in patients with prostate cancer.The authors would like to thank the Union for International Cancer Control (Geneva, Switzerland; grant no., YY1/09/008/2009) for the fellowship received to support the present study. The authors would also like to thank the researchers at the Trev and Joyce Deeley Research Centre (Victoria, Canada), British Columbia Cancer Research Centre (Vancouver, Canada) and University of Victoria (Victoria, Canada), particularly Professor Brad Nelson, Dr Julian Lum and Dr John Webb, for purchasing the mice and providing the laboratory facilities required to conduct the present study.http://www.spandidos-publications.com/or/2017-02-27am2016Mammal Research Institut