Protective Role of Short-term Aerobic Exercise Against Zinc Oxide Nanoparticles-Induced Cardiac Oxidative Stress Via Possible Changes of Apelin, Angiotensin II/Angiotensin II Type I Signalling Pathway.

This study examined the protective role of short-term aerobic exercise on ZnO NPs-induced cardiac oxidative stress and possible changes of apelin, angiotensin II (AngII) and angiotensin II type I receptor (AT1R) signalling pathway. Thirty-five male Wistar rats were randomized into five groups of seven rats, including control, saline, ZnO NPs, exercise and exercise + ZnO NPs groups. The animal in ZnO NPs and exercise + ZnO NPs groups received 1 mg/kg of ZnO NPs. Rats underwent the treadmill exercise program. Treatments lasted four weeks, 5 days/week. After 4 weeks of treatment, superoxide dismutase (SOD) activity, malondialdehyde (MDA), apelin, Ang II and AT1R concentration were measured in heart tissue.Cardiac MDA, Ang II and AT1R levels significantly increased while SOD activity and apelin levels significantly decreased following ZnO NPs administration. The aerobic exercise induced a significant increase in the SOD activity and apelin levels and a significant decrease in the enhanced MDA, Ang II and AT1R levels in the heart of ZnO NPs-exposed rats. These results suggest that the exercise-induced attenuation of the Ang II-AT1R signalling pathway is mediated by reduced lipid peroxidation, augmented antioxidant defence and enhanced apelin synthesis that may be a protective mechanism to prevent and/or treatment ZnO NPs-induced cardiac oxidative stress.

High Hydrostatic Pressure Processing of Human Milk Increases Apelin and GLP-1 Contents to Modulate Gut Contraction and Glucose Metabolism in Mice Compared to Holder Pasteurization.

BACKGROUND: High hydrostatic pressure (HHP) processing is a non-thermal method proposed as an alternative to Holder pasteurization (HoP) for the sterilization of human breast milk (BM). HHP preserves numerous milk bioactive factors that are degraded by HoP, but no data are available for milk apelin and glucagon-like peptide 1 (GLP-1), two hormones implicated in the control of glucose metabolism directly and via the gut-brain axis. This study aims to determine the effects of HoP and HHP processing on apelin and GLP-1 concentrations in BM and to test the effect of oral treatments with HoP- and HHP-BM on intestinal contractions and glucose metabolism in adult mice. METHODS: Mice were treated by daily oral gavages with HoP- or HHP-BM during one week before intestinal contractions, and glucose tolerance was assessed. mRNA expression of enteric neuronal enzymes known to control intestinal contraction was measured. RESULTS: HoP-BM displayed a reduced concentration of apelin and GLP-1, whereas HHP processing preserved these hormones close to their initial levels in raw milk. Chronic HHP-BM administration to mice increased ileal mRNA nNos expression level leading to a decrease in gut contraction associated with improved glucose tolerance. CONCLUSION: In comparison to HoP, HPP processing of BM preserves both apelin and GLP-1 and improves glucose tolerance by acting on gut contractions. This study reinforces previous findings demonstrating that HHP processing provides BM with a higher biological value than BM treated by HoP.

Tumor apelin and obesity are associated with reduced neoadjuvant chemotherapy response in a cohort of breast cancer patients.

Obesity is a known factor increasing the risk of developing breast cancer and reducing disease free survival. In addition to these well-documented effects, recent studies have shown that obesity is also affecting response to chemotherapy. Among the multiple dysregulations associated with obesity, increased level of the apelin adipokine has been recently shown to be directly involved in the association between obesity and increased breast cancer progression. In this study, we analyzed in a retrospective cohort of 62 breast cancer patients the impact of obesity and tumoral apelin expression on response to neoadjuvant chemotherapy. In the multivariate logistic regression, obesity and high tumoral apelin expression were associated with a reduced response to NAC in our cohort. However, obesity and high tumoral apelin expression were not correlated, suggesting that those two parameters could be independently associated with reduced NAC response. These findings should be confirmed in independent cohorts.

Breast milk apelin level increases with maternal obesity and high-fat feeding during lactation.

OBJECTIVE: Recent evidence indicates that levels of breast milk (BM) hormones such as leptin can fluctuate with maternal adiposity, suggesting that BM hormones may signal maternal metabolic and nutritional environments to offspring during postnatal development. The hormone apelin is highly abundant in BM but its regulation during lactation is completely unknown. Here, we evaluated whether maternal obesity and overnutrition impacted BM apelin and leptin levels in clinical cohorts and lactating rats. METHODS: BM and plasma samples were collected from normal-weight and obese breastfeeding women, and from lactating rats fed a control or a high fat (HF) diet during lactation. Apelin and leptin levels were assayed by ELISA. Mammary gland (MG) apelin expression and its cellular localization in lactating rats was measured by quantitative RT-PCR and immunofluorescence, respectively. RESULTS: BM apelin levels increased with maternal BMI, whereas plasma apelin levels decreased. BM apelin was also positively correlated with maternal insulin and C-peptide levels. In rats, maternal HF feeding exclusively during lactation was sufficient to increase BM apelin levels and decrease its plasma concentration without changing body weight. In contrast, BM leptin levels increased with maternal BMI in humans, but did not change with maternal HF feeding during lactation in rats. Apelin is highly expressed in the rat MG during lactation and was mainly localized to mammary myoepithelial cells. We found that MG apelin gene expression was up-regulated by maternal HF diet and positively correlated with BM apelin content and maternal insulinemia. CONCLUSIONS: Our study indicates that BM apelin levels increase with long- and short-term overnutrition, possibly via maternal hyperinsulinemia and transcriptional upregulation of MG apelin expression in myoepithelial cells. Apelin regulates many physiological processes, including energy metabolism, digestive function, and development. Further studies are needed to unravel the consequences of such changes in offspring development.

Apelin and apelin receptor in human placenta: Expression, signalling pathway and regulation of trophoblast JEG­3 and BeWo cells proliferation and cell cycle.

Placentation requires the production of numerous growth factors, hormones and transcription factors. Many of them, like the adipose tissue­derived leptin or adiponectin, have been identified in the placenta and their role has been established in the proliferation and subsequent development of the placenta. Apelin is another adipokine known for proliferative effects in different cell types. PCR, immunoblotting and immunocytochemistry were used to study mRNA and protein expression of apelin and its receptor (APJ) in syncytiotrophoblast (BeWo) and cytotrophoblast (JEG­3) cells as well in immunohistochemistry in human normal placenta slides. The effect of apelin on cell proliferation study was investigated by alamarBlue® and Cell Counting Kit­8 assays, the cell cycle by the flow cytometry method and the protein expression of cyclins and phosphorylation level of extracellular signal­regulated kinases (ERK)1/2, phosphatidylinositol 3'­kinase/protein kinase B (Akt), signal transducer and activator of transcription 3 (Stat3) and 5'­monophosphate­activated protein kinase (AMPKα) were studied by western blotting. Apelin was increased in JEG­3 compared with in BeWo cells, while APJ was the same in both placenta cell lines. Immunocytochemical analyses revealed high cytoplasmic and/or membrane apelin localisation in JEG­3, while BeWo cells exhibited markedly weaker apelin signal in the cytoplasm. Apelin increased cell proliferation as well as the percentage of cells in the G2/M phase of the cell cycle, cyclin proteins and the expression of all kinases mentioned above. In conclusion, apelin by promotion of trophoblast cell proliferation by APJ and ERK1/2, Stat3 and AMPKα signalling could be a new important adipokine in the regulation of early placental development.

Plasma apelin levels in overweight/obese adults following a single bout of exhaustive exercise: A preliminary cross-sectional study / Niveles plasmáticos de apelina en adultos con sobrepeso/obesidad tras una sola sesión de ejercicio exhaustivo: estudio transversal preliminar

Introduction: Physical activity is beneficial for preventing metabolic diseases. Here, the circulatory level of apelin, one of the myokines, was assessed in patients with obesity to examine the effects of body composition, metabolic parameters, and physical fitness on apelin secretion following an exercise program. Methods: A total 60 subjects [34 women (21 lean and 13 overweight/obese) and 26 men (8 lean and 18 overweight/obese)], age 30-59 years, with body mass index (BMI) of 18-30kg/m2 were recruited based on the guidelines for Korean obesity therapy in a clinical trial. Body composition, biochemical parameters, and physical fitness test were conducted. A single bout of exhaustive exercise was performed following Bruce protocol. Relationships among exercise-induced apelin, metabolic factors, and physical capacity were then analyzed. Independent/paired t-test between groups/time points and Pearson correlations were performed. Results: There were significant positive correlations in post-exercise apelin and lean mass (P=0.006), homeostatic model assessment of insulin resistance (HOMA-IR; P=0.004), HOMA insulin secretion (HOMA-%B; P=0.005), lactate dehydrogenase (LDH; P=0.002), grip strength (P=0.004), and isokinetic knee flexion and extension tests in 60° and 240°/s (all variables, P<0.05), but these parameters were not correlated with pre-exercise apelin. Exercise was more effective in increasing apelin level in men compared to women. Conclusion: Acute exercise increased circulating apelin, which was more effective in obese compared to healthy men, while no effect in women regardless of obesity status. Thus, apelin secretion after a single exercise is dependent on gender and metabolic status of subjects

Introducción: La actividad física es beneficiosa para prevenir las enfermedades metabólicas. Se evaluaron los niveles circulantes de apelina, una mioquina, en pacientes obesos para investigar los efectos de la composición corporal, los parámetros metabólicos y el estado físico en la secreción de apelina después de un programa de ejercicio. Métodos: Sesenta sujetos [34 mujeres (21 delgadas y 13 con sobrepeso/obesidad) y 26 varones (8 delgados y 18 con sobrepeso/obesidad)], de 30-59 años, con un índice de masa corporal (IMC) de 18-30kg/m2 fueron incluidos en un ensayo clínico basado en las directrices coreanas para el tratamiento de la obesidad. Se evaluaron la composición corporal, los parámetros bioquímicos y el estado físico. Se realizó una sola sesión de ejercicio exhaustivo siguiendo el protocolo de Bruce. A continuación se analizaron las relaciones entre la apelina inducida por el ejercicio, los factores metabólicos y el estado físico. Se realizaron pruebas de la t independientes/por parejas entre grupos/puntos temporales y correlaciones de Pearson. Resultados: Se observaron correlaciones positivas y significativas entre los niveles de apelina después del ejercicio y la masa magra (P=0,006), modelo homeostático de resistencia a la insulina (HOMA-IR; P=0,004), la secreción de insulina según el HOMA (HOMA-%B; P=0,005), el nivel de lactato deshidrogenasa (LDH; P=0,002), la fuerza de prensión (P=0,004) y las pruebas isocinéticas de flexión y extensión de la rodilla en 60° y 240°/s (todas las variables, P<0,05), pero estos parámetros no se correlacionaron con la apelina previa al ejercicio. El ejercicio fue más eficaz para aumentar los niveles de apelina en los varones que en las mujeres. Conclusión: El ejercicio agudo incrementó los niveles de apelina circulante y fue más eficaz en los varones obesos que en los sanos, mientras que no se observó ningún efecto en las mujeres, independientemente del estado de obesidad. Por tanto, la secreción de apelina tras una única sesión de ejercicio depende del sexo y del estado metabólico de los sujetos

Comparative evaluation of cannabinoid receptors, apelin and S100A6 protein in the heart of women of different age groups.

BACKGROUND: Recent studies have shown a significant role of the endocannabinoid system, apelin and S100A6 protein in the regulation of cardiovascular system functioning. The aim of the study was to compare and evaluate the distribution of cannabinoid receptors (CB1 and CB2), apelin and S100A6 protein in the heart of healthy women in different age groups. METHODS: The study was conducted on the hearts of 10 women (organ donors) without a history of cardiovascular disease, who were divided into two age groups: women older than 50 years and women under 50 years of age. Paraffin heart sections were processed by immunohistochemistry for detection of cannabinoids receptors (CB1 and CB2), apelin and S100A6 protein. RESULTS: CB1 and CB2 immunoreactivity in the cytoplasm of cardiomyocytes in the heart of women over 50 was weaker than in younger individuals. There was also strong immunoreactivity of CB1 in intercalated discs (ICDs) of the heart, only in women over 50. The presence of this receptor in this location was not found in women under 50. Apelin- and S100A6-immunoreactivity in the cardiomyocytes was stronger in older women compared to women under 50.The CB1, apelin and S100A6 immunostaining in the endothelium of myocardial vessels was weaker in women over 50 than in younger women, while intensity of CB2- immunoreaction in coronary endothelium was similar in both groups of women. The results of the study indicate the important role of endocannabinoids, apelin, and S100A6 protein in cardiac muscle function. CONCLUSION: This report might contribute to a better understanding of the role of endocannabinoid system, apelin and S100 proteins in heart function as well as shed new light on processes involved in age-related cardiomyopathy.