Astaxanthin Supplementation Augments the Benefits of CrossFit Workouts on Semaphorin 3C and Other Adipokines in Males with Obesity.

Regular physical activity and the use of nutritional supplements, including antioxidants, are recognized as efficacious approaches for the prevention and mitigation of obesity-related complications. This study investigated the effects of 12 weeks of CrossFit training combined with astaxanthin (ASX) supplementation on some plasma adipokines in males with obesity. Sixty-eight males with obesity (BMI: 33.6 ± 1.4 kg·m-2) were randomly assigned into four groups: the control group (CG; n = 11), ASX supplementation group (SG; n = 11), CrossFit group (TG; n = 11), and training plus supplement group (TSG; n = 11). Participants underwent 12 weeks of supplementation with ASX or placebo (20 mg/day capsule daily), CrossFit training, or a combination of both interventions. Plasma levels of semaphorin 3C (SEMA3C), apelin, chemerin, omentin1, visfatin, resistin, adiponectin, leptin, vaspin, and RBP4 were measured 72 h before the first training session and after the last training session. The plasma levels of all measured adipokines were significantly altered in SG, TG, and TSG groups (p < 0.05). The reduction of resistin was significantly higher in TSG than in SG (p < 0.05). The plasma levels of omentin1 were significantly higher in both training groups of TG and TSG than SG (p < 0.05), although such a meaningful difference was not observed between both training groups (p > 0.05). Significant differences were found in the reductions of plasma levels of vaspin, visfatin, apelin, RBP4, chemerin, and SEMA3C between the SG and TSG groups (p < 0.05). The study found that a 12-week intervention using ASX supplementation and CrossFit exercises resulted in significant improvements in several adipokines among male individuals with obesity. Notably, the combined approach of supplementation and training had the most pronounced results. The findings presented in this study indicate that the supplementation of ASX and participation in CrossFit exercise have the potential to be effective therapies in mitigating complications associated with obesity and enhancing metabolic health.

Quercetin Attenuates Atherosclerosis via Modulating Apelin Signaling Pathway Based on Plasma Metabolomics.

OBJECTIVE: To interpret the pharmacology of quercetin in treatment of atherosclerosis (AS). METHODS: Fourteen apolipoprotein E-deficient (ApoE-/-) mice were divided into 2 groups by a random number table: an AS model (ApoE-/-) group and a quercetin treatment group (7 in each). Seven age-matched C57 mice were used as controls (n=7). Quercetin [20 mg/(kg·d)] was administered to the quercetin group intragastrically for 8 weeks for pharmacodynamic evaluation. Besides morphological observation, the distribution of CD11b, F4/80, sirtuin 1 (Sirt1) and P21 was assayed by immunohistochemistry and immunofluorescence to evaluate macrophage infiltration and tissue senescence. Ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MSC/MS) was performed to study the pharmacology of quercetin against AS. Then, simultaneous administration of an apelin receptor antagonist (ML221) with quercetin was conducted to verify the possible targets of quercetin. Key proteins in apelin signaling pathway, such as angiotensin domain type 1 receptor-associated proteins (APJ), AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), tissue plasminogen activator (TPA), uncoupling protein 1 (UCP1) and angiotensin II receptor 1 (AT1R), were assayed by Western blot. RESULTS: Quercetin administration decreased lipid deposition in arterial lumen and improved the morphology of ApoE-/- aortas in vivo. Quercetin decreased the densities of CD11b, F4/80 and P21 in the aorta and increased the level of serum apelin and the densities of APJ and Sirt1 in the aorta in ApoE-/- mice (all P<0.05). Plasma metabolite profiling identified 118 differential metabolites and showed that quercetin affected mainly glycerophospholipids and fatty acyls. Bioinformatics analysis suggested that the apelin signaling pathway was one of the main pathways. Quercetin treatment increased the protein expressions of APJ, AMPK, PGC-1α, TPA and UCP1, while decreased the AT1R level (all P<0.05). After the apelin pathway was blocked by ML221, the effect of quercetin was abated significantly, confirming that quercetin attenuated AS by modulating the apelin signaling pathway (all P<0.05). CONCLUSION: Quercetin alleviated AS lesions by up-regulation the apelin signaling pathway.

Supplementation with spinach-derived thylakoid augments the benefits of high intensity training on adipokines, insulin resistance and lipid profiles in males with obesity.

Introduction: This study investigated the effects of 12 weeks of high-intensity functional training (HIFT) combined with spinach-derived thylakoid supplementation on some selected Adipokines and insulin resistance in males with obesity. Method: Sixty-eight participants (mean age: 27.6 ± 8.4 yrs.; mean height: 168.4 ± 2.6 cm; mean weight: 95.7 ± 3.8 kg, mean BMI: 32.6 ± 2.6 kg/m2) were randomly divided into four groups of 17 per group: Control group (CG), Supplement group (SG), Training group (TG), and Training + supplement group (TSG). Following baseline measurements, the two training groups (TG and TSG) started the 12 weeks of exercise training program (3 sessions per week). A total of 36 sessions lasting up to 60 min were included in the HIFT program using the CrossFit program. The eligible participants received 5 g/day of thylakoid-rich spinach extract or matching placebo as 5 g/day of raw corn starch (one sachet, 30 min before lunch) for 12 weeks. Baseline assessments were obtained 48 hours before the start of the training protocols and 48 hours after the last training session in all groups. Results: There were significant interactions (p<0.001 for all) between exercise and time for adiponectin (ES:0.48), leptin (ES:0.46), resistin (ES:0.3), omentin (ES:0.65), vaspin (ES:0.46), visfatin (ES:0.62), apelin (ES:0.42), RBP4 (ES:0.63), chemrin (0.36) and semaphorin3c (ES: 0.5). Plasma levels of semaphorin3c were significantly correlated (p<0.05) with body weight (r= 0.57), BMI (r= 0.43), FFM (r= -0.612), FAT (r= 0.768), VO2peak (r=-0.53), insulin (r= 0.756), glucose (r= 0.623), and HOMA-IR (r= 0.727). There were also significant group differences in insulin (ES: 0.77), glucose (ES: 0.21), and HOM-IR (ES: 0.44) (p<0.05). Discussion: Our findings indicate that 12 weeks of HIFT supplemented with spinach-derived thylakoid reduced levels of leptin, resistin, vaspin, visfatin, apelin, RBP4, chemrin, semaphorin3c and insulin resistance while increasing adiponectin and omentin levels in men with obesity.

7ß-Hydroxycholesterol and 7-ketocholesterol: New oxidative stress biomarkers of sarcopenia inducing cytotoxic effects on myoblasts and myotubes.

Aging is a complex biological process which can be associated with skeletal muscle degradation leading to sarcopenia. The aim of this study consisted i) to determine the oxidative and inflammatory status of sarcopenic patients and ii) to clarify the impact of oxidative stress on myoblasts and myotubes. To this end, various biomarkers of inflammation (C-reactive protein (CRP), TNF-α, IL-6, IL-8, leukotriene B4 (LTB4)) and oxidative stress (malondialdehyde, conjugated dienes, carbonylated proteins and antioxidant enzymes: catalase, superoxide dismutase, glutathione peroxidase) as well as oxidized derivatives of cholesterol formed by cholesterol autoxidation (7-ketocholesterol, 7ß-hydroxycholesterol), were analyzed. Apelin, a myokine which contributes to muscle strength, was also quantified. To this end, a case-control study was conducted to evaluate the RedOx and inflammatory status in 45 elderly subjects (23 non-sarcopenic; 22 sarcopenic) from 65 years old and higher. SARCopenia-Formular (SARC-F) and Timed Up and Go (TUG) tests were used to distinguish between sarcopenic and non-sarcopenic subjects. By using red blood cells, plasma and/or serum, we observed in sarcopenic patients an increased activity of major antioxidant enzymes (superoxide dismutase, glutathione peroxidase, catalase) associated with lipid peroxidation and protein carbonylation (increased level of malondialdehyde, conjugated dienes and carbonylated proteins). Higher levels of 7-ketocholesterol and 7ß-hydroxycholesterol were also observed in the plasma of sarcopenic patients. Significant differences were only observed with 7ß-hydroxycholesterol. In sarcopenic patients comparatively to non-sarcopenic subjects, significant increase of CRP, LTB4 and apelin were observed whereas similar levels of TNF-α, IL-6 and IL-8 were found. The increased plasma level of 7-ketocholesterol and 7ß-hydroxycholesterol in sarcopenic patients led us to study the cytotoxic effect of these oxysterols on undifferentiated (myoblasts) and differentiated (myotubes) murine C2C12 cells. With the fluorescein diacetate and sulforhodamine 101 assays, an induction of cell death was observed both on undifferentiated and differentiated cells: the cytotoxic effects were less pronounced with 7-ketocholesterol. In addition, IL-6 secretion was never detected whatever the culture conditions, TNF-α secretion was significantly increased on undifferentiated and differentiated C2C12 cells treated with 7-ketocholesterol- and 7ß-hydroxycholesterol, and IL-8 secretion was increased on differentiated cells. 7-ketocholesterol- and 7ß-hydroxycholesterol-induced cell death was strongly attenuated by α-tocopherol and Pistacia lentiscus L. seed oil both on myoblasts and/or myotubes. TNF-α and/or IL-8 secretions were reduced by α-tocopherol and Pistacia lentiscus L. seed oil. Our data support the hypothesis that the enhancement of oxidative stress observed in sarcopenic patients could contribute, especially via 7ß-hydroxycholesterol, to skeletal muscle atrophy and inflammation via cytotoxic effects on myoblasts and myotubes. These data bring new elements to understand the pathophysiology of sarcopenia and open new perspectives for the treatment of this frequent age-related disease.

Elabela-apelin-12, 17, 36/APJ system promotes platelet aggregation and thrombosis via activating the PANX1-P2X7 signaling pathway.

The elabela-apelin/angiotensin domain type 1 receptor-associated protein (APJ) system is an important regulator in certain thrombosis-related diseases such as atherosclerosis, myocardial infarction, and cerebral infarction. Our previous reports have revealed that apelin exacerbates atherosclerotic lesions. However, the relationship between the elabela-apelin/APJ system and platelet aggregation and atherothrombosis is unclear. The results of the present study demonstrate that elabela and other endogenous ligands such as apelin-12, -17, and -36 induce platelet aggregation and thrombosis by activating the pannexin1(PANX1)-P2X7 signaling pathway. Interestingly, the diuretic, spironolactone, a novel PANX1 inhibitor, alleviated elabela- and apelin isoforms-induced platelet aggregation and thrombosis. Significantly, two potential antithrombotic drugs were screened out by targeting APJ receptors, including the anti-HIV ancillary drug cobicistat and the traditional Chinese medicine monomer Schisandrin A. Both cobicistat and Schisandrin A abolished the effects of elabela and apelin isoforms on platelet aggregation, thrombosis, and cerebral infarction. In addition, cobicistat significantly attenuated thrombosis in a ponatinib-induced zebrafish trunk model. Overall, the elabela-apelin/APJ axis mediated platelet aggregation and thrombosis via the PANX1-P2X7 signaling pathway in vitro and in vivo. Blocking the APJ receptor with cobicistat/Schisandrin A or inhibiting PANX1 with spironolactone may provide novel therapeutic strategies against thrombosis.

The Yin and Yang Effect of the Apelinergic System in Oxidative Stress.

Apelin is an endogenous ligand for the G protein-coupled receptor APJ and has multiple biological activities in human tissues and organs, including the heart, blood vessels, adipose tissue, central nervous system, lungs, kidneys, and liver. This article reviews the crucial role of apelin in regulating oxidative stress-related processes by promoting prooxidant or antioxidant mechanisms. Following the binding of APJ to different active apelin isoforms and the interaction with several G proteins according to cell types, the apelin/APJ system is able to modulate different intracellular signaling pathways and biological functions, such as vascular tone, platelet aggregation and leukocytes adhesion, myocardial activity, ischemia/reperfusion injury, insulin resistance, inflammation, and cell proliferation and invasion. As a consequence of these multifaceted properties, the role of the apelinergic axis in the pathogenesis of degenerative and proliferative conditions (e.g., Alzheimer's and Parkinson's diseases, osteoporosis, and cancer) is currently investigated. In this view, the dual effect of the apelin/APJ system in the regulation of oxidative stress needs to be more extensively clarified, in order to identify new potential strategies and tools able to selectively modulate this axis according to the tissue-specific profile.

Alleviation of liver cirrhosis and associated portal-hypertension by Astragalus species in relation to their UPLC-MS/MS metabolic profiles: a mechanistic study.

Liver cirrhosis is a late-stage liver disease characterized by excessive fibrous deposition triggering portal-hypertension (PH); the prime restrainer for cirrhosis-related complications. Remedies that can dually oppose hepatic fibrosis and lower PH, may prevent progression into decompensated-cirrhosis. Different Astragalus-species members have shown antifibrotic and diuretic actions with possible subsequent PH reduction. However, A.spinosus and A.trigonus were poorly tested for eliciting these actions. Herein, A.spinosus and A.trigonus roots and aerial parts extracts were subjected to comprehensive metabolic-fingerprinting using UHPLC-MS/MS resulting in 56 identified phytoconstituents, followed by chemometric untargeted analysis that revealed variable metabolic profiles exemplified by different species and organ types. Consequently, tested extracts were in-vivo evaluated for potential antifibrotic/anticirrhotic activity by assessing specific markers. The mechanistic prospective to induce diuresis was investigated by analyzing plasma aldosterone and renal-transporters gene-expression. Serum apelin and dimethylarginine-dimethylaminohydrolase-1 were measured to indicate the overall effect on PH. All extracts amended cirrhosis and PH to varying extents and induced diuresis via different mechanisms. Further, An OPLS model was built to generate a comprehensive metabolic-profiling of A.spinosus and A.trigonus secondary-metabolites providing a chemical-based evidence for their efficacious consistency. In conclusion, A.spinosus and A.trigonus organs comprised myriad pharmacologically-active constituents that act synergistically to ameliorate cirrhosis and associated PH.

The Combinatory Effect of Spirulina Supplementation and Resistance Exercise on Plasma Contents of Adipolin, Apelin, Ghrelin, and Glucose in Overweight and Obese Men.

Methods: The current investigation was conducted in a single-blind and quasiexperimental fashion. Sixty overweight and obese men (BMI > 25) ranging in age from 30 to 55 years were purposefully selected and randomly assigned to one of four groups: training plus spirulina (T+S), training plus placebo (T+P), spirulina (S), or placebo (P). For eight weeks, the (S) and (P) groups consumed two 500 mg spirulina and placebo capsules daily, respectively. Resistance training was performed three sessions a week over eight weeks, consisting of 12 movements with 1-, 2-, 3-, and 4-minute rest intervals and 40-90 percent maximal repetition. Adipolin, apelin, and ghrelin indices were measured before and after exercise using special kits. Results: All variables changed significantly between groups except for apelin. Within-group comparisons revealed a substantial increase in adipolin levels in the (T+S) and (T+P) groups (P < 0.05). Apelin levels were decreased in the (T+S) and (T+P) groups. Additionally, FBS levels reduced significantly in (T+S) (P = 0.01). Conclusion: It seems that eight weeks of circuit resistance training and spirulina supplementation can lead to reduced weight and apelin and FBS levels as well as increased concentrations of adipolin and ghrelin contents in overweight and obese men.

The Effect of Six-Week Aerobic Exercise Combined with ease max Incr2Green Tea Consumption on PON1 and VOand Apelin, Blood Pressure, and Blood Lipids Reduction in Young Obese Men.

Obesity is among the major health problems; therefore, the present study aimed to investigate six-week aerobic training with green tea supplementation on some cardiovascular markers in young obese men. After measuring physiological markers, 57 overweight men in the age range of 28-35 years old were randomly divided into four groups: aerobic exercise + green tea consumption (AE+GE; n=10), aerobic exercise (AE; n=10), green tea consumption (GE; n=10), control group (C; n=10) in which members of this group neither participated in aerobic exercise nor consumed green tea. Eighteen sessions of aerobic exercises were held over the six-week study period (three 45-minute training sessions per week). The variables were examined before the intervention and 48 hours after the last training session and tea consumption. Body Mass Index and fat percentage significantly decreased in AE+GE, AE, and GE groups (P=0.001 for all). Aerobic power significantly increased in AE+GE (P=0.001) and AE (P=0.001) groups. Systolic blood pressure significantly decreased in AE+GE (P=0.006) and AE (P=0.002) groups. Diastolic blood pressure significantly decreased in AE+GE (P=0.001) and AE (P=0.015) groups. Total cholesterol and low-density lipoprotein decreased in AE+GE (P=0.001), AE (P=0.004, P=0.002) and GE groups (P=0.02; P=0.012). High-density lipoprotein significantly increased in AE+GE (P=0.001) and AE groups (P=0.04). Apelin levels decreased in AE+GE (P=0.001) and AE groups (P=0.001). Paraoxonase-1 significantly increased in AE+GE (P=0.001), AE (P=0,001), and GE (P=0.30) groups. Aerobic exercise and green tea consumption effectively controlled cardiovascular risk factors in obese or overweight people. However, combining aerobic exercise and green tea consumption led to better results.

Apelin and Vasopressin: The Yin and Yang of Water Balance.

Apelin, a (neuro)vasoactive peptide, plays a prominent role in controlling body fluid homeostasis and cardiovascular functions. Experimental data performed in rodents have shown that apelin has an aquaretic effect via its central and renal actions. In the brain, apelin inhibits the phasic electrical activity of vasopressinergic neurons and the release of vasopressin from the posterior pituitary into the bloodstream and in the kidney, apelin regulates renal microcirculation and counteracts in the collecting duct, the antidiuretic effect of vasopressin occurring via the vasopressin receptor type 2. In humans and rodents, if plasma osmolality is increased by hypertonic saline infusion/water deprivation or decreased by water loading, plasma vasopressin and apelin are conversely regulated to maintain body fluid homeostasis. In patients with the syndrome of inappropriate antidiuresis, in which vasopressin hypersecretion leads to hyponatremia, the balance between apelin and vasopressin is significantly altered. In order to re-establish the correct balance, a metabolically stable apelin-17 analog, LIT01-196, was developed, to overcome the problem of the very short half-life (in the minute range) of apelin in vivo. In a rat experimental model of vasopressin-induced hyponatremia, subcutaneously (s.c.) administered LIT01-196 blocks the antidiuretic effect of vasopressin and the vasopressin-induced increase in urinary osmolality, and induces a progressive improvement in hyponatremia, suggesting that apelin receptor activation constitutes an original approach for hyponatremia treatment.

Acetone Ingestion Mimics a Fasting State to Improve Glucose Tolerance in a Mouse Model of Gestational Hyperglycemia.

Gestational diabetes mellitus results, in part, from a sub-optimal ß-cell mass (BCM) during pregnancy. Artemisinins were reported to increase BCM in models of diabetes by α- to ß-cell conversion leading to enhanced glucose tolerance. We used a mouse model of gestational glucose intolerance to compare the effects of an artemisinin (artesunate) on glycemia of pregnant mice with vehicle treatment (acetone) or no treatment. Animals were treated daily from gestational days (GD) 0.5 to 6.5. An intraperitoneal glucose tolerance test was performed prior to euthanasia at GD18.5 or post-partum. Glucose tolerance was significantly improved in both pregnant and non-pregnant mice with both artesunate and vehicle-alone treatment, suggesting the outcome was primarily due to the acetone vehicle. In non-pregnant, acetone-treated animals, improved glucose tolerance was associated with a higher BCM and a significant increase in bihormonal insulin and glucagon-containing pancreatic islet cells, suggesting α- to ß-cell conversion. BCM did not differ with treatment during pregnancy or post-partum. However, placental weight was higher in acetone-treated animals and was associated with an upregulation of apelinergic genes. Acetone-treated animals had reduced weight gain during treatment despite comparable food consumption to non-treated mice, suggesting transient effects on nutrient uptake. The mean duodenal and ileum villus height was reduced following exposure to acetone. We conclude that acetone treatment may mimic transient fasting, resulting in a subsequent improvement in glucose tolerance during pregnancy.

Andrographolide, a novel inducer of apelin gene expression.

ETHNOPHARMACOLOGICAL RELEVANCE: Andrographis paniculata (A. paniculata) has been used as a traditional medicine in Asia and Scandinavia for centuries to remedy several illnesses. It has since been shown to possess antibacterial, antifungal, antiviral, anti-neoplasm, hepatoprotective, hypoglycemic, hypocholesterolemic, and energetic effects. AIMS OF THE STUDY: This study sought to investigate the effect of Andrographolide on apelin gene expression and serum levels of glucose. MATERIALS AND METHODS: In this study, 18 male rats were used. They were divided into three groups of six, including i) negative control group, ii) 3.5 mg/kg Andrographolide group, and iii) 7 mg/kg Andrographolide group. Apelin gene expression was investigated by real-time PCR method. Serum levels of glucose were measured by the photometric method. RESULTS: The results of this study revealed that 3.5 and 7 mg doses per kg of body weight of andrographolide, for six days, significantly increased hepatic expression of apelin gene in male Wistar rats, as compared with the control group (p < 0.05). Serum levels of glucose at doses of 3.5 and 7 mg/kg of andrographolide, and in the control group, were 71.5 ± 8.96, 51.5 ± 2.64, and 93.87 ± 14.27 mg/dl, respectively. Andrographolide induced a decrease in serum levels of HDL-c and an increase in LDL-c/HDL-c ratio. CONCLUSIONS: Our results suggest that Andrographolide can elicit an increase of hepatic apelin gene expression and a decrease in serum levels of blood glucose.

Evodiamine alleviates lipopolysaccharide-induced pulmonary inflammation and fibrosis by activating apelin pathway.

Inflammation can cause a series of inflammatory lung disease, which seriously endangers human health. Pulmonary fibrosis is a kind of inflammatory disease with end-stage lung pathological changes. It has complicated and unknown pathogenesis and is still lack of effective therapeutic drugs. LPS-induced inflammation is a common feature of many infectious inflammations such as pneumonia, bacteremia, glomerulonephritis, etc. Evodiamine, one of the main components of Evodia rutaecarpa, is an alkaloid with excellent antiinflammatory effects. In this study, we evaluated the protective capacities of evodiamine on LPS-induced inflammatory damages in vitro and in vivo. MTT method, flow cytometry, immunofluorescence, and other methods were used for in vitro study to determine the protective capacities of evodiamine. The results suggest that evodiamine can protect murine macrophages from the LPS-nigericin-induced damages by (a) inhibiting cellular apoptosis, (b) inhibiting inflammatory cytokines releasing, and (c) activating the apelin pathway. We also used the exogenous apelin-13 peptide co-cultured with LPS-nigericin in RAW264.7 cells and found that apelin-13 contributes to protecting the effects of evodiamine. In vivo, the ELISA method and immunohistochemistry were used to examine inflammatory cytokines, apelin, and histological changes. BALB/c mice were exposed to LPS and subsequent administration of evodiamine （p.o.）for some time, the results of the alveolar lavage fluid and the tissue slices showed that evodiamine treatment alleviated the pulmonary inflammation and fibrosis, stimulated apelin expression and inhibited the inflammatory cytokines. These results provide a basis for the protective effect and mechanism of evodiamine in LPS-induced inflammation and suggest that it might be potential therapeutics in human pulmonary infections.

Cardioprotective effect of electroacupuncture in cardiopulmonary bypass through apelin/APJ signaling.

Aim Acupuncture, particularly electroacupuncture (EA), can improve the clinical outcomes of cardiopulmonary bypass (CPB) patients; however, the mechanisms remain unclear. This study aimed to examine the effects of EA pre-treatment on myocardial injury after CPB and investigate its potential mechanisms. MAIN METHODS: Male Sprague-Dawley rats were subjected to CPB and divided into Control (sham-operated), CPB, and EA (CPB + EA) groups. In the EA group, rats were treated with EA at the "PC6" acupoint for 30 min before being subjected to CPB. At 0.5, 1, and 2 h after CPB, the expression levels of plasma cardiac troponin I (cTnI) and lactate dehydrogenase (LDH), and myeloperoxidase (MPO) activity, TNFα, IL-1ß, reduced glutathione (GSH), oxidized glutathione (GSSH), and the ratio of GSH/GSSH in the myocardial tissue were measured. Apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL) staining. The expression of cleaved caspase-3 was detected by immunofluorescence. The expression of apelin, APJ, AKT, p-Akt, ERK1/2, and p-ERK1/2 was determined using western blotting. KEY FINDINGS: Decreased myocardial injury marker levels, myocardial apoptosis, oxidative stress, and the inflammatory response were found in the EA group compared with the CPB group. The expression levels of apelin, APJ, and p-Akt/AKT were increased in the EA group, and the p-ERK1/2/ERK1/2 level was decreased. SIGNIFICANCE: This study showed that EA pre-treatment can protect the heart from damage following CPB, which might be mainly mediated by restoring the apelin/APJ signaling pathway.

Role of apelin/APJ system in hypothalamic-pituitary axis.

Apelin and its G protein-coupled receptor APJ are specifically expressed in endocrine organs. As well known, the hypothalamus is the regulatory center of endocrine activity, which combined with the pituitary and other gonads form regulatory axes involved in endocrine function. Evidence to date has shown that the apelin/APJ system plays an important role in mediating these axes, such as food intake, acute stress, steroid release, as well as, an anti-depressant-like activity. Here we review the effect of the apelin/APJ system on hypothalamic-pituitary-thyroid, hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes. Although the apelinergic system exerts a positive effect on these axes, there are contradictory reports on the role of apelin in endocrine disease caused by hypothalamic-pituitary disorders. Thus, as research continues to evolve we expect that apelin-related drugs can be used as a treatment for clinical diseases resulting from hypothalamic-pituitary dysfunction.

The anti-angiogenic effect of tryptanthrin is mediated by the inhibition of apelin promoter activity and shortened mRNA half-life in human vascular endothelial cells.

BACKGROUND: Anti-angiogenesis is an important strategy of psoriasis treatment, but the side effects of systemic agents remain difficult to overcome. Topical use of indigo naturalis ointment has been proved to improve the skin lesion of psoriasis effectively and safely and one of its major components, tryptanthrin, has been demonstrated to have anti-angiogenic effect. Apelin, which has been reported to act as an angiogenic factor that could stimulate the proliferation and migration of vascular endothelial cells and proved to be elevated in psoriasis patients, is a potential target of anti-angiogenic therapy. PURPOSE: We aim to find out if tryptanthrin works on the apelin pathway and study its anti-angiogenic mechanism. STUDY DESIGN: Human umbilical vein endothelial cells (HUVECs) were used as the in vitro model. METHODS: The effect of tryptanthrin on the expression of apelin and its receptor, APJ, was examined. The mRNA stability, promoter activity, and bioactivity of apelin, were also investigated. Migration and tube formation assay were used to evaluate the relationship between tryptanthrin and apelin. PD98059 and wortmannin were used to study the role of ERK1/2 MAPK and PI3K in apelin signaling pathway. RESULTS: We demonstrated that tryptanthrin could inhibit the expression of apelin, attenuated the stability of apelin mRNA, and significantly inhibited the apelin promoter activity. The addition of apelin-13 restored the suppression of tube formation and migration by tryptanthrin. Both PD98059 and wortmannin could down-regulate the apelin mRNA expression suggesting the important signaling role of ERK1/2 MAPK and PI3K in the gene expression of apelin. CONCLUSION: The anti-angiogenic effect of tryptanthrin was mediated by down-regulating apelin gene expression through suppression of promoter activity and decrease of mRNA stability in human vascular endothelial cells.

Diet-induced obesity and associated disorders are prevented by natural bioactive type 1 fish collagen peptides (Naticol®) treatment.

To fight against metabolic disorders such as insulin resistance, new alimentary behaviors are developed. For instance, hyperproteined, gluten-free, or collagen-enriched diets could be preconized in order to reduce the consequences of obesity. In this aim, this study evaluates the potential effects of warm sea fish collagen peptides (Naticol®) on representative metabolic and inflammatory parameters. For that, male C57Bl6/J mice fed with either a chow- (CD) or high-fat diet (HFD) were submitted or not to specific collagen peptides in drinking water (4 g/kg bw/d) for 20 weeks. Weight, body composition, glucose tolerance, and insulin sensitivity were followed up. Effects of fish collagen peptides on various blood parameters reflecting the metabolism status were also measured (free fatty acids, triglycerides, cholesterol, hormones) together with adipocyte inflammation. Results showed that HFD-fed mice supplemented by fish collagen peptides exhibited a significant lower increase in body weight as soon as the twelfth week of treatment whereas no effect of the peptide was observed in CD fed mice. In line with this result, a weaker increase in fat mass in HFD-fed mice supplemented with Naticol® at both 9 and 18 weeks of treatment was also observed. In spite of this resistance to obesity promoted by fish collagen peptides treatment, no difference in glucose tolerance was found between groups whereas mice treated with Naticol® exhibited a lower basal glycemia. Also, even if no effect of the treatment on adipocyte lipolysis was found, a decrease of inflammatory cytokines was retrieved in collagen-supplemented group arguing for a potential better insulin sensitivity. Altogether, these results need to be completed but are the first describing a benefic role of warm sea fish collagen peptides in a context of metabolic disease paving the route for a potential utilization in human obesity-associated disorders.

Apelin-13 Upregulates BDNF Against Chronic Stress-induced Depression-like Phenotypes by Ameliorating HPA Axis and Hippocampal Glucocorticoid Receptor Dysfunctions.

Localization of apelin and its receptor APJ in limbic structures such as the hippocampus suggests potential involvement of apelin/APJ signaling in stress-related emotional responses. We have recently reported that apelin-13 exerts antidepressant-like actions in acute stressed rats, and that the hippocampus is a critical brain region mediating its actions. However, the neural mechanism underling antidepressant-like actions of apelin-13 is still largely unknown. The aim of the present study is to determine whether apelin-13 ameliorates chronic water-immersion restraint stress (CWIRS)-induced depression-like phenotypes and its neural mechanism in rats. Here, we report that CWIRS exposure leaded to upregulation of apelin/APJ signaling in the hippocampus. Apelin-13 ameliorated CWIRS-induced depression-like phenotypes including hedonic-like deficit and behavioral despairs. Moreover, apelin-13 ameliorated hypothalamic-pituitary-adrenal (HPA) axis hyperactivity, and hippocampal BDNF expression deficit and glucocorticoid receptor (GR) nucleus translocation hypoactivity in chronic stressed rats. Finally, apelin-13-mediated effects were blocked by the selective TrkB receptor antagonist ANA-12. These results suggest that apelin-13 upregulates BDNF against chronic stress-induced depression-like phenotypes by ameliorating HPA axis and hippocampal GR dysfunctions.

Central apelin administration and restraint stress induce hypothalamic cholecystokinin release via the APJ receptor.

Exposure to an acute stressor induces up-regulation of apelin and cholecystokinin (CCK) in the hypothalamic paraventricular nucleus (PVN), which is the key brain centre integrating the stress-induced alterations in neuroendocrine, autonomic and behavioural functions. We tested the hypothesis that the release of CCK from the PVN is increased by centrally administered or stress-induced up-regulated endogenous apelin via the APJ receptor. Additionally, the effect of hypothalamic CCK on autonomic outflow was investigated under basal and stressed conditions. In vivo brain microdialysis was performed in rats that received (i) intra-PVN administration of apelin-13 or (ii) acute restraint stress (ARS). For chemical stimulation of the neurones in the PVN, a high concentration of KCl was applied by reverse microdialysis. CCK-8 levels in microdialysates were quantified by an enzyme immunoassay. The immunoreactivity of the APJ receptor and CCK was detected by immunofluorescence in hypothalamic sections. Heart rate variability was assessed in rats that received PVN stimulation or ARS following pre-administration of vehicle or CCK1 receptor antagonist lorglumide. Both intra-PVN exogenous apelin-13 and ARS increased the CCK-8 levels in dialysates significantly. The ARS-induced elevations in CCK levels were reversed by intra-PVN pre-administration of the APJ receptor antagonist F13A. Within the PVN, robust APJ receptor expression was detected on the CCK-producing mediocellular cells, in addition to the parvocellular neurones in the periventricular region. Dual immunoreactivity of APJ/CCK was observed in magnocellular cells to a lesser degree. Both exogenous apelin and ARS increased the CCK immunoreactivity markedly within the PVN, which was diminished significantly by F13A. Sympathetic tonus was increased markedly both by PVN stimulation and ARS, which was attenuated by lorglumide. These results revealed the interaction between apelin and CCK in the brain, suggesting that hypothalamic CCK may contribute to the apelin-induced alterations in autonomic outflow under stressed conditions.

Effects of Bisphenol S on hypothalamic neuropeptides regulating feeding behavior and apelin/APJ system in mice.

Since 2010, Bisphenol A (BPA), an endocrine disruptor has been restricted and replaced by analogues like Bisphenol S (BPS). However, little is known about BPS effects and growing concern have suspected the "BPA-free" Label. Several recent studies suggest that BPS is associated with increased risk of diabetes and obesity. However, the underlying mechanisms remain unidentified. The current study investigates investigate BPS effects on hypothalamic neuropeptides regulating feeding behavior, either orexigenic or anorexigenic in Swiss Albino mice. We also studied the effect of BPS on the apelinergic system (apelin/apelin receptor (APJ)) as an original physiological system with pleiotropic actions. Bisphenol S at 25, 50, 100 µg/kg was administered to mice in water drink for 10 weeks started after weaning. Our results showed that BPS exposure alters orexigenic hypothalamic neuropeptide (AgRP) regulating feeding behavior but not anorexigenic neuropeptides (POMC, CART). Such orexigenic alterations may underlay appetite disorders leading to a concomitant food intake and body weight gain increase. In addition, data show that BPS affects the hypothalamic apelinergic system. We found a significant decrease in APJ mRNA but not in apelin expression. Based on hypothalamic APJ distribution, we suggested a potent specific physiological alteration of this receptor in mediating neuroendocrine responses in hypothalamus. Thus, our findings provide that BPS exposure could contribute to the development of obesity and metabolic disorders.