ABSTRACTPurposeThe aim of this study was to investigate the function and mechanisms of ELABELA (ELA) in the aerobic exercise-induced antiapoptosis and angiogenesis of ischemic heart.MethodsThe myocardial infarction (MI) model of Sprague–Dawley rat was established by the ligation of the left anterior descending coronary artery. MI rats underwent 5 wk of Fc-ELA-21 subcutaneous injection and aerobic exercise training using a motorized rodent treadmill. Heart function was evaluated by hemodynamic measures. Cardiac pathological remodeling was evaluated by Masson’s staining and the calculation of left ventricular weight index. Cell proliferation, angiogenesis, and Yes-associated protein (YAP) translocation were observed by immunofluorescence staining. Cell apoptosis was analyzed by TUNEL. Cell culture and treatment were used to elucidate the molecular mechanism of ELA. Protein expression was detected by Western blotting. Angiogenesis was observed by tubule formation test. One-way or two-way ANOVA and Student’s t-test were used for statistical analysis.ResultsAerobic exercise stimulated the endogenous ELA expression. Exercise and Fc-ELA-21 intervention significantly activated APJ-Akt-mTOR-P70S6K signaling pathway, kept more cardiomyocytes alive, and increased angiogenesis, so as to inhibit the cardiac pathological remodeling and improved the heart function of MI rats. Fc-ELA-32 also had the cellular and functional cardioprotective activities in vivo. In vitro, ELA-14 peptide regulated the phosphorylation and nucleoplasmic translocation of YAP and activated the APJ-Akt signaling pathway so as to increase the proliferation of H9C2 cells. Moreover, the antiapoptosis and the tubule formation of HUVECs were also enhanced by ELA-14, whereas the inhibition of Akt activity weakened such effects.ConclusionsELA is a potential therapeutic member that plays a key role through APJ-Akt/YAP signaling axis in aerobic exercise-induced cardioprotection of MI rats.

2023-04-12·International journal of molecular sciences

A Causal Treatment for X-Linked Hypohidrotic Ectodermal Dysplasia: Long-Term Results of Short-Term Perinatal Ectodysplasin A1 Replacement.

Article

作者: Faschingbauer, Florian ; Schneider, Holm ; Schneider, Pascal ; Hadj-Rabia, Smail ; Schweikl, Christine

X-linked hypohidrotic ectodermal dysplasia (XLHED), caused by a genetic deficiency of ectodysplasin A1 (EDA1), is a rare developmental disorder of ectodermal derivatives such as hair, sweat glands, and teeth. The absence of sweat glands and perspiration can evoke life-threatening hyperthermia. As molecular genetic findings are not always conclusive, the concentrations of circulating EDA1 may help to distinguish between total and partial EDA1 deficiencies. We previously treated nine male patients with obvious signs of XLHED with a recombinant EDA1 replacement protein, Fc-EDA, either shortly after birth (n = 3) or by prenatal administration in gestational week 26 and beyond (n = 6). Here, we present the long-term follow-up for up to six years. In patients who had received Fc-EDA after birth, neither sweat glands nor sweating ability were detected at the age of 12-60 months. In contrast, prenatal EDA1 replacement resulted in ample sweat gland development and pilocarpine-inducible sweating in all treated subjects, who also attained more permanent teeth than their untreated affected relatives. Normal perspiration has persisted for six years in the two oldest boys treated repeatedly with Fc-EDA in utero. When they had a sauna, adequate thermoregulation was evidenced. Lower sweat production after single prenatal dosing may indicate a dose-response relationship. The absence of circulating EDA1 in five prenatally treated subjects proved that these children would have been unable to perspire if they had been left untreated. The sixth infant was shown to produce an EDA1 molecule that, albeit interacting with its cognate receptor, cannot activate EDA1 signaling. In conclusion, a causal treatment of XLHED before birth is feasible.

2022-01-01·Peptides3区 · 医学

Effect of Fc-Elabela-21 on renal ischemia/reperfusion injury in mice: Mediation of anti-apoptotic effect via Akt phosphorylation

3区 · 医学

Article

作者: Zhou, Huifen ; Cui, Wenpeng ; Xu, Feng ; Miao, Lining ; Wu, Man ; Lu, Xuehong ; Xi, Yue ; Gong, Da-Wei ; Shi, Lin ; Wang, Junhong ; Zhang, Hong

INTRODUCTIONRenal ischemia/reperfusion injury (IRI) is the most common cause of acute kidney injury (AKI), and patients with AKI have a high rate of mortality. Apelin is a therapeutic candidate for treatment of IRI and Elabela (ELA) is a recently discovered hormone that also activates the apelin receptor (APJ). We examined the use of ELA as a preventive treatment for IRI using in vitro and in vivo models.METHODSMale mice were subjected to renal IRI, with or without administration of a stabilized form of ELA (Fc-ELA-21) for 4 days. Renal tubular lesions were measured using H&E staining, reactive oxygen species (ROS) were measured using a dihydroethidium stain assay, and renal cell apoptosis was measured using the TUNEL assay and flow cytometry. Immortalized human proximal tubular epithelial (HK-2) cells were pretreated with or without LY294002 and/or ELA-32, maintained at normoxic or hypoxic conditions, and then returned to normal culture conditions to mimic IRI. Cell apoptosis was determined using the TUNEL assay and cell proliferation was determined using the MTT assay. The levels of Akt, p-Akt, ERK1/2, p- ERK1/2, Bcl-2, Bax, caspase-3 and cleaved caspase-3 were measured using western blotting.RESULTSFc-ELA-21 administration reduced renal tissue damage, ROS production, and apoptosis in mice that had renal IRI. ELA-32 reduced HK-2 cell apoptosis and restored the proliferation of cells subjected to IRI. Akt phosphorylation had a role in the anti-apoptotic effect of ELA.CONCLUSIONThis study of in vitro and in vivo models of IRI indicated that the preventive and anti-apoptotic effects of ELA were mediated via the PI3K/Akt signaling pathway.

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适应症	最高研发状态	国家/地区	公司	日期
心脏衰竭	临床前	中国	陕西师范大学	2019-10-01
心脏衰竭	临床前	美国	University of Maryland School of Medicine	2019-10-01
心肌梗塞	临床前	美国	Accufusion Therapeutics, Inc.	-
肾脏损伤	临床前	美国	University of Maryland School of Medicine	-