Objective: To investigate the clinical significance of endothelin A receptor (ETAR) expression in high-grade serous ovarian carcinoma (HGSOC). To design ETAR carboxyl terminal (ETAR-C) amino acids derived polypeptide and to study the inhibitory effect on ovarian epithelial carcinoma cells in vitro. Methods: (1) A total of 126 patients who received surgical treatment and were diagnosed with HGSOC by postoperative pathological examination in Central Hospital of Xuzhou from January 1, 2007 to December 31, 2017 were selected. All patients had completed clinicopathological data and follow-up data. Cancer tissue samples were collected and ETAR mRNA expression in HGSOC tissues was detected by reverse transcript-PCR. The clinical significance was analyzed. (2) ETAR-C fusion polypeptide was designed based on the sequence of carboxyl terminal amino acids of ETAR, expressed and purified in vitro. The effects of ETAR-C fusion polypeptide on migration and invasion ability of ovarian cancer SKOV3 and CAOV3 cells were detected by scratch test and invasion test, respectively. The effect of ETAR-C fusion polypeptide on chemosensitivity of cisplatin-resistant ovarian cancer SKOV3/cDDP and CAOV3/cDDP cells was determined by methyl thiazolyl tetrazolium (MTT) colorimetric assay. The effect of ETAR-C fusion polypeptide on β-arrestin-1 expression in ovarian cancer SKOV3 and CAOV3 cells was detected by western blot. Results: (1) The relative expression level of ETAR mRNA in HGSOC tissues was 18.6±5.1. Patients with HGSOC were divided into high ETAR mRNA expression (n=76) and low ETAR mRNA expression (n=50) with 61.7% as cut-off value analyzed by X-Tile software. High expression of ETAR mRNA was significantly correlated with abdominal water volume, platinum drug resistance, and cancer antigen 125 (CA₁₂₅) value in HGSOC patients (all P<0.05), but was not related to the age of patients with HGSOC and the size of postoperative residual lesions (all P>0.05). The 5-year progression free survival rates were 18.4% and 28.0%, and the 5-year overall survival rates were 38.2% and 52.0% in HGSOC patients with high and low ETAR mRNA expression respectively, there were statistically significant differences (P=0.046, P=0.034). (2) The results of scratch test and invasion test showed that the scratch healing rate and cell invasion rate of SKOV3 or CAOV3 cells treated with endothelin-1 (ET-1) and ET-1+ETAR-C were respectively compared, and the differences were statistically significant (all P<0.05). MTT assay showed that the inhibition rates of ETAR-C fusion polypeptide treated in SKOV3/cDDP and CAOV3/cDDP cells were significantly higher than those of control cells after the addition of 4, 6, 8, 10, 12, and 24 μg/ml cisplatin (all P<0.05). Western blot analysis showed that the relative expression levels of β-arrestin-1 in SKOV3 or CAOV3 cells treated with ET-1 and ET-1+ETAR-C were 1.85±0.09 and 1.13±0.09 (SKOV3 cells), 2.14±0.15 and 1.66±0.12 (CAOV3 cells), respectively. The differences were statistically significant (all P<0.05). Conclusions: The prognosis of HGSOC patients with high expression of ETAR mRNA is significantly worse than those with low expression of ETAR mRNA. ETAR might be a new target for HGSOC treatment. The ETAR-C fusion polypeptide that interferes with the interaction of ETAR and β-arrestin-1 has good inhibitory effect on ovarian cancer cells in vitro, and might have clinical application potential.
Female ; Humans ; Amino Acids/therapeutic use* ; beta-Arrestins/therapeutic use* ; Cell Line, Tumor ; Cisplatin/pharmacology* ; Clinical Relevance ; Ovarian Neoplasms/pathology* ; Receptor, Endothelin A/therapeutic use* ; RNA, Messenger/metabolism*

Antihypertensive Agents ; therapeutic use ; Endothelin Receptor Antagonists ; therapeutic use ; Familial Primary Pulmonary Hypertension ; Humans ; Hypertension ; drug therapy ; Hypertension, Pulmonary ; drug therapy

OBJECTIVETo investigate the long-term effect of bosentan on outcome in patients after Fontan operation.

METHODSPatients after Fontan surgery were randomly divided into bosentan group (B, n = 16) and control group (C, n = 23). Bosentan was applied within 7 days after Fontan surgery as follows: at the first month, 7.8125 mg Bid for patients with body weight ≤ 10 kg; 15.625 mg Bid for patients with body weight between 10-20 kg; 31.25 mg Bid for patients with body weight 20-30 kg and 62.5 mg Bid for patients with body weight > 30 kg. At the second month, the bosentan dose was doubled and Bosentan therapy was continued for more than 1 year. Group C didn't take drugs affecting pulmonary artery pressure. All patients were followed up for 2 years and incidence of mortality, protein losing enteropathy, pulmonary arteriovenous fistulae, 6-minute walk test, heart function were compared between the two groups.

RESULTSAfter 2 years, mortality tended to be lower in group B compared to group C [6.25% (1/16) vs. 21.8% (5/23), P > 0.05]. Incidence of pulmonary arteriovenous fistulae and protein losing enteropathy were significantly lower in group B than in group C (6.25% vs. 34.78%, P = 0.01;6.25% vs. 39.13%, P = 0.02, respectively) . The results of 6-minute walk test[ (485 ± 44) m vs. (302 ± 183) m] and heart function in group B (3 NYHA III/IV patients in group B vs. 14 NYHA III/IV patients in group C, all P < 0.05) were all better than group C. The concentrations of vasoactive factors such as brain natriuretic peptide (BNP, 279.07 ± 128.17 vs. 457.67 ± 221.30), endothelin (ET, 3.30 ± 0.61 vs. 4.98 ± 1.24) and thromboxane (TXA2, 97.2 ± 24.0 vs. 163.22 ± 24.4) were also significantly lower in group B than in group C (all P < 0.05). Prostacyclin (PGI2) level and incidence of arrhythmias were similar between the two groups. There was no thrombotic event in both groups during follow up.

CONCLUSIONBosentan trerapy in patients post Fontan operation could reduce the incidence of pulmonary arteriovenous fistulae and protein losing enteropathy and improve heart function.

Adolescent ; Child ; Child, Preschool ; Endothelin Receptor Antagonists ; therapeutic use ; Female ; Fontan Procedure ; Humans ; Hypertension, Pulmonary ; drug therapy ; Male ; Prognosis ; Sulfonamides ; therapeutic use ; Treatment Outcome

BACKGROUNDIt has been shown that neurohumoral factors other than mechanical obstruction are involved in the pathophysiology of acute pulmonary thromboembolism (APTE). The aim of this study was to investigate the effects of thrombolytic drugs, a selective endothelin-1 receptor (ET-1R) antagonist alone or their combination on APTE in a canine model.

METHODSTwenty dogs were randomly assigned to five groups: sham, model, urokinase (UK), BQ123, and combination (UK plus BQ123). The dogs in the sham group underwent sham surgery. APTE was induced in the other four groups by intravenous injection of autologous blood clots. Dogs in the UK, BQ123 and combination groups received UK, BQ123 (a selective ET-1R antagonist), or UK plus BQ123, respectively. The dogs in the model group were given saline. Mean pulmonary artery pressure (mPAP), serum concentrations of ET-1, thromboxane (TXB2), and tumor necrosis factor (TNF)-alpha were determined at different time points following the induction of APTE.

RESULTSUK and BQ123 alone markedly decreased mPAP in APTE. By comparison, the reduction was more significant in the combination group. Compared with the sham group ((-0.90 +/- 0.61) mmHg), mPAP increased by (7.44 +/- 1.04), (3.42 +/- 1.12) and (1.14 +/- 0.55) mmHg in the model group, UK alone and BQ123 alone groups, respectively, and decreased by (2.24 +/- 0.67) mmHg in the combination group (P < 0.01). Serum ET-1 concentrations in the BQ123 and combination groups were (52.95 +/- 8.53) and (74.42 +/- 10.27) pg/ml, respectively, and were significantly lower than those in the model and UK groups ((84.56 +/- 7.44) and (97.66 +/- 8.31) pg/ml respectively; P < 0.01). Serum TNF-alpha concentrations were significantly lower in the BQ123 group than in the model, UK and combination groups (P < 0.05).

CONCLUSIONSOur results indicate that the selective ET-1R antagonist BQ123 not only reduces the increase of mPAP and serum ET-1 level, but also inhibits the production of TNF-alpha, and attenuates the local inflammatory response induced by APTE. Selective ET-1R antagonists may be beneficial to the treatment of APTE, particularly when used in combination with a thrombolytic agent.

Animals ; Dogs ; Endothelin A Receptor Antagonists ; Endothelin-1 ; blood ; Fibrinolytic Agents ; therapeutic use ; Peptides, Cyclic ; therapeutic use ; Pulmonary Embolism ; blood ; drug therapy ; pathology ; Random Allocation ; Thromboxanes ; blood ; Tumor Necrosis Factor-alpha ; blood

OBJECTIVETo investigate the effect of sodium ferulate (SF) on diabetic nephropathy (DN).

METHODSForty-eight DN patients of early stage and 54 DN patients of clinical stage were randomly divided into two groups, the conventional treatment group and the SF treatment group. Indexes, including urinary albumin excretion rate (UAER), serum endothelin (ET), blood urea nitrogen (BUN), serum creatinine (Scr) and fasting blood glucose (FBG) were observed.

RESULTSThe levels of UAER, BUN and ET were decreased in all DN patients, either early stage or clinical stage, after treated with SF for 4 weeks (P < 0.05, P < 0.01), but changed insignificantly in those treated with conventional treatment.

CONCLUSIONSF can decrease the levels of UAER and BUN in DN patients, the mechanism may relate with the decreasing of ET production and antagonizing to the binding of ET with its receptors.

Adult ; Aged ; Coumaric Acids ; therapeutic use ; Diabetes Mellitus, Type 2 ; drug therapy ; Diabetic Nephropathies ; drug therapy ; Endothelin Receptor Antagonists ; Female ; Humans ; Male ; Middle Aged ; Phytotherapy

AIMTo investigate the antagonistic effects of the novel compounds on vasoconstriction induced by ET-1 and the effect on the blood pressure of stroke-prone spontaneously hypertensive rats.

METHODSOrgan bath experiment and whole cardiac function experiment were used.

RESULTSThe analogues of o-CPhe-D-Trp-D-Phe(-X)-OH showed good ability against endothelin biological effects. When X was displaced by 3-F, 3-Cl or 4-Cl, the novel compounds inhibit the vascular constriction induced by ET-1 in a concentration-dependent manner, the IC50 +/- L95 were (0.09 +/- 0.05), (0.15 +/- 0.06) or (0.11 +/- 0.03) mumol.L-1 respectively. The blood pressure of stroke-prone spontaneously hypertensive rats was decreased. No significant effect on cardiac function of rats was discovered.

CONCLUSIONThe results demonstrate that among the six kinds of compounds, those with o-CPhe-D-Trp-D-Phe (-X)-OH configuration showed good biological effects.

Animals ; Aorta ; drug effects ; Blood Pressure ; drug effects ; Endothelin Receptor Antagonists ; Endothelins ; pharmacology ; Hypertension ; drug therapy ; physiopathology ; Male ; Molecular Structure ; Peptides ; chemical synthesis ; chemistry ; pharmacology ; therapeutic use ; Rats ; Rats, Inbred SHR ; Rats, Wistar ; Structure-Activity Relationship ; Vasoconstriction ; drug effects

The pathophysiology of diabetes is multifactorial and no single etiology is at the forefront. The proposed mechanisms of erectile dysfunction (ED) in diabetic patients includes elevated advanced glycation end-products (AGEs) and increased levels of oxygen free radicals, impaired nitric oxide (NO) synthesis, increased endothelin B receptor binding sites and ultrastructural changes, upregulated RhoA/Rho-kinase pathway, NO-dependent selective nitrergic nerve degeneration and impaired cyclic guanosine monophosphate (cGMP)-dependent kinase-1 (PKG-1). The treatment of diabetic ED is multimodal. Treatment of the underlying hyperglycemia and comorbidities is of utmost importance to prevent or halt the progression of the disease. The peripherally acting oral phosphodiesterase type 5 (PDE5) inhibitors are the mainstay of oral medical treatment of ED in diabetics. Vacuum erection devices are an additional treatment as a non-invasive treatment option. Local administration of vasoactive medication via urethral suppository or intracorporal injection can be effective with minimal side-effects. Patients with irreversible damage of the erectile mechanism are candidates for penile implantation. Future strategies in the evolution of the treatment of ED are aimed at correcting or treating the underlying mechanisms of ED. With an appropriate vector, researchers have been able to transfect diabetic animals with agents such as neurotrophic factors and nitric oxide synthase (NOS). Further studies in gene therapy are needed to fully ascertain its safety and utility in humans.
Alprostadil ; administration & dosage ; therapeutic use ; Cyclic GMP-Dependent Protein Kinases ; physiology ; Diabetes Complications ; physiopathology ; Diabetic Neuropathies ; physiopathology ; Erectile Dysfunction ; etiology ; physiopathology ; therapy ; Glycation End Products, Advanced ; physiology ; Humans ; Male ; Nitric Oxide ; physiology ; Penile Erection ; Penile Prosthesis ; Penis ; blood supply ; Phosphodiesterase Inhibitors ; therapeutic use ; Receptor, Endothelin B ; physiology ; Suppositories ; Vacuum