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Preeclampsia (PE) is a serious hypertensive pregnancy disorder and a leading cause of maternal and perinatal morbidity and mortality. Despite the prevalence and complications, there are no approved therapeutics to relieve PE symptoms. Inflammation, oxidative stress, and angiogenic imbalance have been shown to contribute to the PE pathophysiology, though there is a lack of understanding in how best to target these pathways in PE. We recently demonstrated that the bioflavonoid luteolin is a potent inhibitor of the anti-angiogenic and pro-hypertensive soluble fms-like tyrosine kinase 1 (sFlt-1), and here we aimed to determine if luteolin was also capable of reducing inflammation and oxidative stress pathways. Tumor necrosis factor (TNF)-α, which is upregulated in PE, was utilized to stimulate these pathways in human placental explants and endothelial cells. Endothelin-1 (ET-1) and interleukin (IL)-6 in the media from explants and cells were measured via ELISA, and NF-κB localization and reactive oxygen species were detected via fluorescence microscopy. Pretreatment with luteolin demonstrated significant reductions in NF-κB activation, reactive oxygen species, superoxide, and IL-6 and ET-1 expression in endothelial cells. We also saw a significant reduction in phosphorylation of NF-κB in human placental explants. These data demonstrate that luteolin inhibits pathways implicated in the development of PE and should be explored further for its potential as a PE therapeutic. [Display omitted] • Inflammation and oxidative stress pathways are activated in preeclampsia. • Luteolin inhibits activation of NF-κB in placental tissue and endothelial cells. • Inflammatory cytokine upregulation in endothelial cells is inhibited by luteolin. • Production of reactive oxygen species and superoxide is ameliorated by luteolin. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate the protective effect and underlying mechanism of orexin A on cerebral ischemia-reperfusion injury, specifically through vasodilation mediated by the hypoxia inducible factor-1α (HIF-1α)-Endothelin-1(ET-1)/endothelial nitric oxide synthase (eNOS) pathway. A model of middle cerebral artery occlusion was established in both wild-type SD rats with exogenous orexin A intervention and in orexin A transgenic rats. Neurological deficit scores and cerebral infarction areas were assessed, and ischemic cortical blood flow was monitored. Gene and protein expression levels of HIF-1α, HIF-2α, ET-1, and three types of NOS were detected using real-time RT-qPCR and Western blot analysis, respectively. Additionally, nitric oxide (NO) levels in the cortex were analyzed through biochemical detection methods. Orexin A demonstrated a protective effect by reducing cerebral infarction and improving neurological deficits, which was achieved by increasing cortical blood flow during reperfusion. This protective mechanism was associated with upregulated HIF-1α expression, downregulated ET-1 expression, upregulated eNOS expression, and increased NO production. This study demonstrates the protective effect of orexin A on cerebral ischemia-reperfusion injury, achieved by regulating the release of vasomotor substances to enhance cortical blood flow during reperfusion. These findings suggest that orexin A may represent a potential therapeutic strategy for ischemic stroke. [Display omitted] • Orexin A alleviates cerebral ischemia-reperfusion injury. • Orexin A elevates blood pressure and enhances reperfusion in ischemic cortex. • Orexin A promotes HIF-1α expression, subsequently suppressing ET-1, upregulating eNOS, and augmenting NO production. [ABSTRACT FROM AUTHOR]

[Display omitted] Receptor tyrosine kinase inhibitors (RTKIs) suppress tumour growth by targeting vascular endothelial growth factor receptor 2 (VEGFR-2) which is an important mediator of angiogenesis. Here, we demonstrate that two potent RTKIs, axitinib and lenvatinib, are associated with hypertensive side effects. Doppler flowmetry was used to evaluate regional haemodynamic profiles of axitinib and lenvatinib. Male Sprague Dawley rats (350–500 g) were instrumented with Doppler flow probes (renal and mesenteric arteries and descending abdominal aorta) and catheters (jugular vein and distal abdominal aorta, via the caudal artery). Rats were dosed daily with axitinib (3 or 6 mg.kg−1) or lenvatinib (1 or 3 mg.kg−1) and regional haemodynamics were recorded over a maximum of 4 days. Both RTKIs caused significant (p < 0.05) increases in mean arterial pressure (MAP), which was accompanied by significant (p < 0.05) vasoconstriction in both the mesenteric and hindquarters vascular beds. To gain insight into the involvement of endothelin-1 (ET-1) in RTKI-mediated hypertension, we also monitored heart rate (HR) and MAP in response to axitinib or lenvatinib in animals treated with the ET A receptor selective antagonist sitaxentan (5 mg.kg−1) or the mixed ET A /ET B receptor antagonist bosentan (15 mg.kg−1) over two days. Co-treatment with bosentan or sitaxentan markedly reduced the MAP effects mediated by both RTKIs (p < 0.05). Bosentan, but not sitaxentan, also attenuated ET-1 mediated increases in HR. These data suggest that selective antagonists of ET A receptors may be appropriate to alleviate the hypertensive effects of axitinib and lenvatinib. [ABSTRACT FROM AUTHOR]

Obesity and insulin resistance are positively correlated with plasma endothelin-1 (ET-1) levels; however, the mechanisms leading to increased ET-1 are not understood. Similarly, the full physiological complexity of ET-1 has yet to be described, especially in obesity. To date, one of the best treatments available for morbid obesity is bariatric surgery to quickly reduce body fat and the factors associated with obesity-related disease; however, the effects of vertical sleeve gastrectomy (SG) on plasma ET-1 have not been described. To determine if SG will reduce plasma ET-1 levels and to determine if plasma ET-1 concentration is associated with weight loss after surgery. The studies were undertaken at a University Hospital. This was tested by measuring plasma ET-1 levels from 12 obese patients before and after SG. All data were collected from clinic visits before SG, 6 weeks after SG, and 6 months after surgery. At 6 weeks after SG, plasma ET-1 levels increased by 24%; however, after 6 months, there was a 27% decrease compared with presurgery. Average weight loss in this cohort was 11.3% ± 2.4% body weight after 6 weeks and 21.4% ± 5.7% body weight after 6 months. Interestingly, we observed an inverse relationship between baseline plasma ET-1 and percent body weight loss (R 2 =.49, P =.01) and change in body mass index 6 months (R 2 =.45, P =.011) post bariatric surgery. Our results indicate that SG reduces plasma ET-1 levels, a possible mechanism for improved metabolic risk in these patients. These data also suggest that ET-1 may serve as a predictor of weight loss after bariatric surgery. • Vertical sleeve gastrectomy reduces plasma endothelin-1 levels. • Plasma endothelin-1 is associated with reduced weight loss following vertical sleeve gastrectomy. • Plasma endothelin-1 is associated with Monocyte Chemoattractant Protein in adipose. [ABSTRACT FROM AUTHOR]

Background: Pulmonary arterial hypertension (PAH) is a chronic fatal disease. The treatment of PAH is less than ideal and the control is far from satisfactory worldwide. Vaccination provides a promising approach for treatment of PAH.Objectives: This study sought to find a vaccine against endothelin-1 (ET-1) receptor type A (ETAR) for treating PAH.Methods: The ETRQβ-002 vaccine was screened and the specific antibodies against epitope ETR-002 belonging to the second extracellular loop of ETAR (including the polyclonal and monoclonal antibody) were produced. The effect of the antibodies on Ca2+-dependent signal transduction events was investigated. In vivo, ETRQβ-002 vaccine was used to vaccinate monocrotaline (MCT)- and Sugen/hypoxia-induced pulmonary hypertension animals. The monoclonal antibody (mAb) against ETR-002 was also injected into the PAH animals. The effect of ETRQβ-002 vaccine on pulmonary hypertension and remodeling of pulmonary arterioles and right ventricle (RV) was carefully evaluated. Further, the possible immune-mediated damage was detected in normal vaccinated animals.Results: ETR-002 peptide has perfect immunogenicity and ETRQβ-002 vaccine could induce strong antibody production. In vitro, the anti-ETR-002 antibody bound to ETAR and inhibited Ca2+-dependent signal transduction events, including extracellular signal-regulated kinase phosphorylation and elevation of intracellular Ca2+ concentration induced by ET-1. In vivo, both ETRQβ-002 vaccine and the mAb significantly decreased the RV systolic pressure up to 20 mm Hg and 10 mm Hg in MCT-exposed rats and Sugen/hypoxia-exposed mice, respectively. Also, ETRQβ-002 vaccine/mAb obviously ameliorated pathological remodeling of pulmonary arterioles and hypertrophy of the RV in PAH animals. Additionally, no significant immune-mediated damage was detected in vaccinated animals.Conclusions: ETRQβ-002 vaccine/mAb attenuated remodeling of pulmonary arterioles and RV in MCT- and Sugen/hypoxia-induced PAH animals and decreased RV systolic pressure effectively through diminishing the pressure response and inhibiting signal transduction initiated by ET-1. ETRQβ-002 vaccine/mAb may provide a novel and promising method for PAH treatment. [ABSTRACT FROM AUTHOR]

Abstract Endothelin-1 (ET-1), as it functions as a neuromodulator, has been associated with hypertension in chronic intermittent hypoxia (CIH) which attribute to enhanced carotid body sensibility to hypoxia. However, the molecular mechanism of ET-1 on carotid body sensibility in CIH is still not clear. Here, effect of ET-1 on carotid body chemosensory stimulation in rats exposed to either CIH or room air (Normoxia) was explored. Furthermore, Phospholipase C (PLC), Protein kinase C (PKC) or p38 MAPK antagonists were adopted to clarify the signalling pathways involved. Results showed that ET-1 induced a higher increase of carotid sinus nerve activity (CSNA) in animals exposed to CIH. Both ETA and ETB receptor expression were up-regulated by CIH exposure, but only ETA is responsible for ET-1 induced CSNA increase. Additional, the increase was inhibited by PLC, PKC, p38 MAPK antagonists and calcium channel blocker. Our findings support that ETA receptor mediates ET-1-induced CSNA increase through PLC, PKC and p38 MAPK signalling pathways in chronic intermittent hypoxia. Also, our study indicated that calcium influx was necessary for enhancing effect of ET-1 on CSNA. Highlights • ET-1 increased CSNA in rats exposed to chronic intermittent hypoxia. • ET A -R is mainly responsible for ET-1 induced CSNA increase. • ET-1-induced CSNA increase through PLC, PKC and p38 MAPK signalling pathways. • Calcium influx was necessary for enhancing effect of ET-1. [ABSTRACT FROM AUTHOR]

Bone metastasis is a frequent occurrence in prostate cancer (PCa) that is associated with severe complications such as fracture, bone pain and hypercalcemia. The cross-talk between metastatic cancer cells and bone is critical to the development and progression of bone metastases. In our previous data, we have described how the involvement of the Wnt-induced secreted protein-1/vascular cell adhesion molecule-1 (WISP-1/VCAM-1) system in this tumor-bone interaction contributes to human PCa cell motility. In this study, we found that WISP-1 regulates bone mineralization by inducing bone morphogenetic protein-2 (BMP2), BMP4 and osteopontin (OPN) expression in osteoblasts. We also found that WISP-1 inhibited RANKL-dependent osteoclastogenesis. Moreover, osteoblast-derived WISP-1 enhanced VCAM-1 expression in PCa cells and subsequently promoted the adherence of cancer cells to osteoblasts. Furthermore, endothelin-1 (ET-1) expression in PCa cells was regulated by osteoblast-derived WISP-1, which promoted integrin α4β1 expression in osteoblasts via the MAPK pathway. Pretreatment of PCa cells with VCAM-1 antibody or osteoblasts with integrin α4β1 antibody attenuated the adherence of PCa cells to osteoblasts, suggesting that integrin α4β1 serves as a ligand that captures VCAM-1+ metastatic tumor cells adhering to osteoblasts. Our findings reveal that osteoblast-derived WISP-1 plays a key role in regulating the adhesion of PCa cells to osteoblasts via the VCAM-1/integrin α4β1 system. Osteoblast-derived WISP-1 is a promising target for the prevention and inhibition of PCa-bone interaction. [ABSTRACT FROM AUTHOR]

Abstract Objective To observe the differences in analgesic effect of moxibustion at different intervention times on dysmenorrhea rats and explore its effect mechanism. Methods Forty-five female Wistar rats were randomly divided into blank control group (group A), model group (group B), pre-moxibustion group (group C), instant moxibustion group (group D) and pre-instant moxibustion group (group E), with 9 rats in each group. Cold-damp coagulation and stagnation type dysmenorrhea models were established. In group C, mild moxibustion on “Shénquè (神阙 CV 8) ” and “Guānyuán (关元 CV 4)” was carried out from the time after modeling on the 8th day for 3 consecutive days. In group D, mild moxibustion was given as the same methods with group C after injection with oxytocin on the 11th day. In group E, mild moxibustion was given as the same methods from the time after modeling on the 8th day to that after injection with oxytocin on the 11th day for 4 consecutive days. The writhing behavior and the changes in levels of ET-1 and NO in uterine tissues of rats with dysmenorrhea in each group were observed. Results Comparison of the latent period: compared with (4.38 ± 1.06) min in group B, the latent period of rats in group C (9.67 ± 1.32) min, group D (11.78 ± 1.30) min and group E (15.00 ± 1.22) min obviously prolonged (all p < 0.01). Compared with group C, the latent period of group E obviously prolonged (p < 0.01). Compared with group D, the latent period of group E obviously prolonged (p < 0.01).Comparison of the writhing times: compared with (4.38 ± 1.06) in group B, the writhing times of rats in group C (9.67 ± 1.32), group D (11.78 ± 1.30) and group E (15.00 ± 1.22) reduced (all p < 0.01). Compared with group C, the writhing times of rats in group D and group E reduced (both p < 0.01). Compared with group D, the writhing times in group E reduced (p < 0.05). Comparison of the total writhing score: compared with (4.38 ± 1.06) in group B, the total writhing score of rats in group C (9.67 ± 1.32), group D (11.78 ± 1.30) and group E (15.00 ± 1.22) decreased (all p < 0.01). Compared with group C, the total writhing score of rats in group D and group E decreased (both p < 0.01). Compared with group D, the total writhing score of rats in group E decreased (p < 0.05). Comparison of ET-1 level: compared with (4.80 ± 0.47) in group A, the ET-1 level in uterine tissues of rats in group B (7.57 ± 0.69) significantly increased (P < 0.01). Compared with group B, the ET-1 level in uterine tissues of rats in group C (6.20 ± 0.50), group D (5.67 ± 0.29) and group E (5.16 ± 0.33) obviously decreased (all p < 0.01). Compared with group C, the ET-1 level in uterine tissues of rats in group D and group E obviously decreased (p < 0.05, p < 0.01). Compared with group D, the ET-1 level in uterine tissues of rats in group Eobviously decreased (p < 0.05). Comparison of NO level: compared with (6.63 ± 1.83) in group A, the NO level in uterine tissues of rats in group B (1.62 ± 0.58) significantly decreased (p < 0.01). Compared with group B, the NO level in uterine tissues of rats in group C (3.60 ± 0.59), group D (4.77 ± 0.67) and group E (5.99 ± 0.63) obviously increased (all p < 0.01). Compared with group C, the NO level in uterine tissues of rats in group Dand group E obviously increased (p < 0.05, p < 0.01). Compared with group D, the NO level in uterine tissues of rats in group E obviously increased (p < 0.01). Conclusion The analgesic effect of mild moxibustion at different intervention times on cold-damp coagulation and stagnation type dysmenorrhea rats was different, which was the most significant in pre-instant moxibustion group. One of the mechanisms of action may be related with the adjustment of abnormal levels of ET-1 and NO. [ABSTRACT FROM AUTHOR]

This study investigated the impact of exercise training on major pulmonary vasomotor mediators and receptors including endothelial nitric oxide synthase (eNOS) inducible NOS (iNOS), endothelin-1 (ET-1), ET-1 receptors A (ET A) and-B (ET B) in high-fat-high-carbohydrate (HFHC) induced non-alcoholic fatty liver disease (NAFLD). NAFLD increased iNOS, ET-1 and ET A (p < 0.05) , but not ET B (p > 0.05). Exercise attenuated iNOS, ET-1 and ET A (p < 0.05)., but not ET B (p > 0.05) and eNOS (p > 0.05). Exercise training is beneficial for pulmonary vasculature in NAFLD. • HFHC induced NAFLD increases ET-1 and ET A in the lungs, however, it does not alter ET B. • Exercise training attenuates iNOS in the lungs in HFHC induced NAFLD, however, it does not alter eNOS. • Exercise training attenuates ET-1 and ET A , however, it does not alter ETB. [ABSTRACT FROM AUTHOR]

Purpose Microvascular abnormalities are one of the most important causes of persistent diabetic complications. The aim of our study was to compare microvascular changes examined by nailfold videocapillaroscopy (NVC) examination with serum concentrations of vascular endothelial growth factor (VEGF), soluble thrombomodulin (sTM) and endothelin-1 (ET-1) in people with Type 1 diabetes with and without microangiopathy. Material/methods The study included 106 people with Type 1 diabetes and 40 healthy controls. All participants were evaluated by extensive clinical, laboratory and capillaroscopic studies. NVC was performed using a stereomicroscope SZ 4045 (Olympus, Germany). The intensity of morphological changes was graded from 0 to 3. Serum levels of VEGF, sTM and ET-1 were determined by an enzyme-linked immunosorbent assay (ELISA). Results Morphological changes were observed by NVC in 86 out of 106 (81%) people with Type 1 diabetes mellitus. Severe capillaroscopic changes (score 3) were seen in 32 out of 54 (59%) people with microangiopathy, but in only seven out of 52 (13%) individuals without microangiopathy. Higher serum concentration of VEGF ( p < 0.001), ET-1 ( p < 0.001) and sTM ( p < 0.05) were demonstrated in people with diabetes complicated with microangiopathy compared to healthy controls. Moreover, comparison between people with and without microangiopathic complications showed a significantly higher capillaroscopic score and sTM serum concentration in the group with retinopathy ( p < 0.001) nephropathy ( p < 0.001) and neuropathy ( p < 0.01). Conclusions Our results suggest that abnormalities in NVC may reflect the extent of microvascular involvement and associated with higher VEGF, sTM and ET-1 serum levels, as well as with microangiopathic complications in diabetic people. [ABSTRACT FROM AUTHOR]

Aims Determine the subacute time course of mitochondria disruption, cell death, and inflammation in a rat model of unilateral motor cortical ischemic stroke. Main methods Rats received unilateral ischemia of the motor cortex and were tested on behavioral tasks to determine impairments. Animals were euthanized at 24 h, 72 h and 144 h and mRNA expression of key mitochondria proteins and indicators of inflammation, apoptosis and potential regenerative processes in ipsilesion cortex and striatum, using RT-qPCR. Mitochondrial proteins were examined at 144 h using immunoblot analysis. Key findings Rats with stroke induced-behavioral deficits had sustained, 144 h post-lesion, decreases in mitochondrial-encoded electron transport chain proteins NADH dehydrogenase subunit-1 and cytochrome c oxidase subunit-1 (mRNA and protein) and mitochondrial DNA content in perilesion motor and sensory cortex. Uncoupling-protein-2 gene expression, but not superoxide dismutase-2, remained elevated in ipsilateral cortex and striatum at this time. Cortical inflammatory cytokine, interleukin-6, was increased early and was followed by increased macrophage marker F 4/80 after stroke. Cleaved caspase-3 activation was elevated in cortex and growth associated protein-43 was elevated in the cortex and striatum six days post-lesion. Significance We identified a relationship between three disrupted pathways, (1) sustained loss of mitochondrial proteins and mitochondrial DNA copy number in the cortex linked to decreased mitochondrial gene transcription; (2) early inflammatory response mediated by interleukin- 6 followed by macrophages; (3) apoptosis in conjunction with the activation of regenerative pathways. The stroke-induced spatial and temporal profiles lay the foundation to target pharmacological therapeutics to these three pathways. [ABSTRACT FROM AUTHOR]

Brain–blood barrier (BBB) disruption results in vasogenic edema, which is involved in the pathogenesis of epilepsy. Following status epilepticus (SE), up-regulated transient receptor potential canonical channel-3 (TRPC3), a Ca 2+ -permeable cation channels in endothelial cells, is relevant to vasogenic edema formation in the rat piriform cortex. In addition, pyrazole-3 (Pyr-3, a TRPC3 inhibitor) attenuated SE-induced vasogenic edema. However, the upstream regulators of TRPC3 expression in vasogenic edema formation have been unclear. In the present study, soluble tumor necrosis factor p55 receptor (sTNFp55R, a TNF-α inhibitor), SN50 (a nuclear factor-κB (NFκB) inhibitor), BQ-788 (an endothelin B (ET B ) receptor inhibitor) and Pyr-3 effectively prevented vasogenic edema following SE. sTNFp55R and SN50 (but not BQ-788) attenuated SE-induced up-regulation of endothelial TRPC3 expression. Pyr-3 ameliorated SE-induced NFκB p65-Thr435 phosphorylation and ET B receptor expression. In addition, Pyr-3 mitigated NFκB p65-Thr435 phosphorylation induced by recombinant TNF-α. These findings indicate that TNF-α-mediated NFκB p65-Thr435 phosphorylation may up-regulate TRPC3 expression, which participates in vasogenic edema formation via increasing endothelial nitric oxide synthase expression following SE, independent of ET B receptor activation. Therefore, we suggest that TRPC3 may be involved in a positive feedback loop of NFκB/ET B receptor signaling pathway. [ABSTRACT FROM AUTHOR]

Aims Cardiac aging is associated with progressive structural changes and functional impairment, such as left ventricular hypertrophy, fibrosis and diastolic dysfunction. Aging also increases myocardial activity of endothelin-1 (ET-1), a multifunctional peptide with growth-promoting and pro-fibrotic activity. Because the G protein-coupled estrogen receptor (GPER) regulates vascular responsiveness to ET-1, we investigated whether GPER also plays a role in the regulation of the myocardial endothelin system with aging. Main methods Young (4 month-old) and aged (24 month-old) wild-type and Gper -deficient ( Gper − / − ) mice were studied. Gene expression levels of prepro-ET-1, endothelin converting enzymes ECE-1 and ECE-2, and endothelin ET A and ET B receptors were determined by qPCR in left ventricular myocardium. Key findings Aging markedly increased steady-state mRNA expression levels of ECE-1, ECE-2, ET A and ET B receptors (each p < 0.001 vs. young mice). Deletion of Gper inhibited the age-dependent increase in ECE-2 and ET B receptor mRNA levels (57% and 40% reduction, respectively, each p < 0.01 vs. wild-type mice), whereas gene expression of prepro-ET-1, ECE-1, and the ET A receptor was unaffected in Gper − / − mice. Significance We identified a novel regulatory mechanism through which the endogenous Gper facilitates the age-dependent increase in myocardial expression of ECE-2 and the ET B receptor, which is compatible with an activating role of GPER for the local endothelin system with aging. Targeting GPER signaling by selective antagonists may therefore be considered a new therapeutic approach to reduce age-dependent increased ET-1 activity and the associated development of left ventricular hypertrophy, fibrosis and heart failure. [ABSTRACT FROM AUTHOR]

The Pregnancy Prevention Program (PPP) is in place to prevent drug-induced developmental malformations. Remarkably, among the ten PPP-enlisted drugs are three endothelin-1 (ET-1) receptor antagonists (ERA's: ambrisentan, bosentan and macitentan), which are approved for the treatment of Pulmonary Arterial Hypertension (PAH). This review describes the effects of ERA's in PAH pathobiology and cardiopulmonary fetal development. While ERA's hamper pathological remodeling of the pulmonary vasculature and as such exert beneficial effects in PAH, they disturb fetal development of cardiopulmonary tissues. By blocking ET-1-mediated positive inotropic effects and myocardial fetal gene induction, ERA's may affect right ventricular adaptation to the increased pulmonary vascular resistance in both the fetus and the adult PAH patient. [ABSTRACT FROM AUTHOR]

Background Normothermic ex vivo lung perfusion (EVLP) is a preservation technique that allows reassessment of donor lungs before transplantation. We hypothesized that the endothelin-1 (ET-1) axis would be associated with donor lung performance during EVLP and recipient outcomes after transplantation. Methods ET-1, Big ET-1, endothelin-converting enzyme (ECE), and nitric oxide (NO) metabolites were quantified in the perfusates of donor lungs enrolled in a clinical EVLP trial. Lungs were divided into 3 groups: (I) Control: bilateral transplantation with good early outcomes defined as absence of primary graft dysfunction (PGD) Grade 3 (PGD3) ; (II) PGD3: bilateral lung transplantation with PGD3 any time within 72 hours; and (III) Declined: lungs rejected after EVLP. Results There were 25 lungs in Group I, 7 in Group II, and 16 in Group III. At 1 and 4 hours of EVLP, the perfusates of Declined lungs had significantly higher levels of ET-1 (3.1 ± 2.1 vs 1.8±2.3 pg/ml, p = 0.01; 2.7 ± 2.2 vs 1.3 ± 1.1 pg/ml, p = 0.007) and Big ET-1 (15.8 ± 14.2 vs 7.0 ± 6.5 pg/ml, p = 0.001; 31.7 ± 17.4 vs 19.4 ± 9.5 pg/ml, p = 0.007) compared with Controls. Nitric oxide metabolite concentrations were significantly higher in Declined and PGD3 lungs than in Controls. For cases of donation after cardiac death, PGD3 and Declined lungs had higher ET-1 and Big ET-1 levels at 4 hours of perfusion compared with Controls. At this time point, Big ET-1 had excellent accuracy to distinguish PGD3 (96%) and Declined (92%) from Control lungs. Conclusions In donation after cardiac death lungs, perfusate ET-1 and Big ET-1 are potential predictors of lung function during EVLP and after lung transplantation. They were also associated with non-use of lungs after EVLP and thus could represent useful biomarkers to improve the accuracy of donor lungs selection. [ABSTRACT FROM AUTHOR]

Pain is the most disruptive influence on the quality of prognosis among head and neck squamous cell carcinoma (HNSCC) patients. The development of pain is closely associated with tumor growth and inflammation in the cancer patients. Notably, cyclooxygenase-2 (COX-2) is an important mediator during inflammation. Celecoxib, a selective inhibitor of COX-2, was hailed as a promising chemopreventive agent for HNSCC. Dose-dependent cardiac toxicity limits long-term use of celecoxib. However, the toxicity can be diminished by lowering the dosage. In this study, we hypothesized that a combinatory strategy to reduce cancer pain via two distinct pathways, tumor grown inhibition and inflammation blockade, which would enhance analgesia effect induced by HNSCC. We found that treatment of cetuximab (C225), a monoclonal anti-epidermal growth factor receptor (EGFR) antibody, with low-dose celecoxib results in a more pronounced anticancer effect in HNSCC than either agent alone. More noticeably, the combination could downregulate the phosphorylation of constitutively active extracellular signal regulated kinase (ERK) in CAL-27 and Fadu cells. Furthermore, combination therapy enhancing S phase arrest and downregulating cyclin D1 was observed in Fadu cells. The COX-2 expression was significantly blocked by celecoxib combined with C225, and other cancer pain related factors, such as ET-1 and NGF, was also downregulated by combination treatment. Taken together, these results strongly suggest that combination of celecoxib with C225 holds potential as a new therapy strategy in developing cancer pain treatment in HNSCC. [ABSTRACT FROM AUTHOR]

Physiological concentrations (1 μM) of 15 flavonoids were evaluated in human umbilical vein endothelial cells in the presence of hydrogen peroxide (H 2 O 2 ) for their ability to affect endothelial nitric oxide synthase (eNOS) and endothelin-1 (ET-1) expression in order to establish the structural basis of their bioactivity. Flavonoid effects on eNOS transcription factor Krüpple like factor-2 (KLF-2) expression were also evaluated. All studied flavonoids appeared to be effective compounds for counteracting the oxidative stress-induced effects on vascular gene expression, indicating that flavonoids are an excellent source of functional endothelial regulator products. Notably, the more effective flavonoids for KLF-2 up-regulation resulted in the highest values for eNOS expression, showing that the increment of eNOS expression would take place through KLF-2 induction. Structure–activity relationship studies showed that the combinations of substructures on flavonoid skeleton that regulate eNOS expression are made up of the following elements: glycosylation and hydroxylation of C-ring, double bond C2 C3 at C-ring, methoxylation and hydroxylation of B-ring, ketone group in C4 at C-ring and glycosylation in C7 of A-ring, while flavonoid features involved in the reduction of vasoconstrictor ET-1 expression are as follows: double bond C2 C3 at C-ring glycosylation in C7 of A-ring and ketone group in C4 of C-ring. [ABSTRACT FROM AUTHOR]

Summary All components of the endothelin (ET) system are present in renal tubular cells. In this review, we summarize current knowledge about ET and the most common tubular diseases: acute kidney injury (AKI) and polycystic kidney disease. AKI originally was called acute tubular necrosis , pointing to the most prominent morphologic findings. Similarly, cysts in polycystic kidney disease, and especially in autosomal-dominant polycystic kidney disease, are of tubular origin. Preclinical studies have indicated that the ET system and particularly ET A receptors are involved in the pathogenesis of ischemia-reperfusion injury, although these findings have not been translated to clinical studies. The ET system also has been implicated in radiocontrast-dye–induced AKI, however, ET-receptor blockade in a large human study was not successful. The ET system is activated in sepsis models of AKI; the effectiveness of ET blocking agents in preclinical studies is variable depending on the model and the ET-receptor antagonist used. Numerous studies have shown that the ET system plays an important role in the complex pathophysiology associated with cyst formation and disease progression in polycystic kidney disease. However, results from selective targeting of ET-receptor subtypes in animal models of polycystic kidney disease have proved disappointing and do not support clinical trials. These studies have shown that a critical balance between ET A and ET B receptor action is necessary to maintain structure and function in the cystic kidney. In summary, ETs have been implicated in the pathogenesis of several renal tubulointerstitial diseases, however, experimental animal findings have not yet led to use of ET blockers in human beings. [ABSTRACT FROM AUTHOR]

[Display omitted] • GDM patients had more family members than the ones in NGT family who developed T2DM. • Endothelial function was impaired in GDM patients. • Endothelial dysfunction was correlated with FPG in GDM patients. • Endothelial dysfunction was correlated with plasma glucose after 1 h of OGTT in GDM patients. • Endothelial dysfunction was correlated with plasma glucose after 2 h of OGTT in GDM patients. Gestational diabetes mellitus (GDM) is a common pregnancy-related disorder that pregnant women without diabetes develop glucose tolerance during pregnancy. Endothelial dysfunction is the early event of vascular complications of diabetes. However, the role of endothelial dysfunction in GDM remains unknown. In this study, we hypothesize that there is a correlation between endothelial dysfunction and GDM indexes in the patients. 96 GDM patients and 96 gestational week-matched healthy pregnancies with normal glucose tolerance were recruited in our study. The expressions of endothelial function markers, including nitride oxidase (NO) and endothelin-1 (ET-1), as well as flow-mediated dilatation (FMD), were measured. In addition, their correlation in GDM patients were also analyzed using Pearson's correlation analysis. GDM patients displayed decrease on FMD and serum NO levels with an increase on serum ET-1 secretion in comparison with normal glucose tolerance group. ROC analysis identified the predictive value of FMD, ET-1 and NO for GDM. Furthermore, endothelial dysfunction was correlated with both fasting plasma glucose and plasma glucose levels after 1 h or 2 h of oral glucose tolerance test in GDM patients. Our data indicated that endothelial dysfunction was associated with GDM, and these markers might serve as potential biomarkers for GDM. [ABSTRACT FROM AUTHOR]

[Display omitted] • The role of G protein-coupled estrogen receptor 1 (GPER) was evaluate in vascular reactivity of middle-aged female and male rats. • Endothelial dysfunction occurs in young adult males, but is delayed until middle-age in female rats. • Activation of GPER mitigates the downregulation of the vascular reactivity in middle-aged female rats, not male rats. Hormone replacement therapy was found to be effective in cardiovascular protection only in younger women, not in older women. In this study, we tested whether G protein-coupled estrogen receptor 1 (GPER) activation improves vascular activities in response to ET-1 and ACh in aging rats. Isometric tension study was applied on aortic rings isolated from young adult (5–7 months) and reproductive senescent middle-aged (10–12 months) female Sprague Dawley rats and age matched males. The aortic contractile response to ET-1 and the relaxation response to ACh were reduced in the female middle-aged rats compared to the female young adult rats. The presence of G-1, the GPER agonist, normalized the reduced vascular activities. Cyclooxygenase inhibitor, meclofenamate, blocked the increased constriction effect of G-1, but further enhanced relaxation effect of G-1. There was no significant difference in aortic reactivity to either ET-1 or ACh between the male middle-aged and young adult rats. The contractile response to ET-1 was not different within the same age of the two sex groups, but there was a remarkable difference in relaxation response to ACh between young adult females and males with better response in females. GPER activation greatly improved the aortic relaxation of both young adult and middle-aged females, but not the males. Endothelial dysfunction occurs earlier in males, but in females, dysfunction delays until middle age. GPER activation improves the vascular activities in females, but not males. It is promising to employ GPER as a potential drug target in cardiovascular disease in women. [ABSTRACT FROM AUTHOR]

Aim To assess the relationship between both photoreceptor function and choroidal thickness and endothelin-1 (ET-1) plasma levels in patients with early stage retinitis pigmentosa (RP). Main methods We compared 24 RP patients (14 males and 10 females), 25 to 42 years of age (mean age: 34 ± 7 years) with 24 healthy controls (12 males and 12 females) aged between 28 and 45 years (mean 36 ± 6.8 years). All patients underwent visual field test, electroretinogram and multifocal-electroretinogram and choroidal thickness measurement by using spectral domain optical coherence tomography. Key findings RP patients had a visual acuity of 0.95, a mean defect of the visual field of − 7.90 ± 1.75 dB, a pattern standard deviation index of 6.09 ± 4.22 dB and a b-wave ERG amplitude of 45.08 ± 8.24 μV. Notably RP subjects showed significantly increased ET-1 plasma levels and reduced choroidal thickness compared with controls: respectively, 2.143 ± 0.258 pg/ml vs. 1.219 ± 0.236 pg/ml; p < 0.002 and 226.75 ± 76.37 μm vs. 303.9 ± 39.87 μm; p < 0.03. Spearman's correlation test highlighted that the increase of ET-1 plasma levels was related with the decrease of choroidal thickness ( r = − 0.702; p < 0.023) and the increase of implicit time in both ring 2 ( r = − 0.669; p < 0.034) and ring 3 ( r = − 0.883; p < 0.007) of mfERG. Significance Increased ET-1 plasma levels may play a key role in the impairment of retinal and choroidal blood flow due to the vasoconstriction induced by ET-1. This could lead to worsening of the abiotrophic process of the macular photoreceptors. [ABSTRACT FROM AUTHOR]

The rising epidemic of diabetes worldwide is of significant concern. Although the ultimate objective is to prevent the development and find a cure for the disease, prevention and treatment of diabetic complications is very important. Vascular complications in diabetes, or diabetic vasculopathy, include macro- and microvascular dysfunction and represent the principal cause of morbidity and mortality in diabetic patients. Endothelial dysfunction plays a pivotal role in the development and progression of diabetic vasculopathy. Endothelin-1 (ET-1), an endothelial cell-derived peptide, is a potent vasoconstrictor with mitogenic, pro-oxidative and pro-inflammatory properties that are particularly relevant to the pathophysiology of diabetic vasculopathy. Overproduction of ET-1 is reported in patients and animal models of diabetes and the functional effects of ET-1 and its receptors are also greatly altered in diabetic conditions. The current therapeutic approaches in diabetes include glucose lowering, sensitization to insulin, reduction of fatty acids and vasculoprotective therapies. However, whether and how these therapeutic approaches affect the ET-1 system remain poorly understood. Accordingly, in the present review, we will focus on experimental and clinical evidence that indicates a role for ET-1 in diabetic vasculopathy and on the effects of current therapeutic approaches in diabetes on the vascular ET-1 system. [ABSTRACT FROM AUTHOR]

Aims There is a growing body of evidence suggesting that epigallocatechin gallate (EGCG), a major catechin isolated from green tea, has several beneficial effects, such as anti-oxidant and anti-inflammatory activities. However, whether treatment with EGCG can suppress the endothelin-1 (ET-1)-induced contraction in carotid arteries from type 2 diabetic rats is unknown, especially at the chronic stage of the disease. We hypothesized that long-term treatment with EGCG would attenuate ET-1-induced contractions in type 2 diabetic arteries. Main methods Otsuka Long–Evans Tokushima fatty (OLETF) rats (43 weeks old) were treated with EGCG (200 mg/kg/day for 2 months, p.o.), and the responsiveness to ET-1, phenylephrine (PE), acetylcholine (ACh) and sodium nitroprusside (SNP) was measured in common carotid artery (CA) from EGCG-treated and -untreated OLETF rats and control Long–Evans Tokushima Otsuka (LETO) rats. Key findings In OLETF rats, EGCG attenuated responsiveness to ET-1 in CA compared to untreated groups. However, EGCG did not alter PE-induced contractions in CA from OLETF rats. In endothelium-denuded arteries, EGCG did not affect ET-1-induced contractions in either the OLETF or LETO group. Acetylcholine-induced relaxation was increased by EGCG treatment in CA from the OLETF group. The expressions of ET receptors, endothelial nitric oxide synthase, superoxide dismutases, and gp91 phox [an NAD(P)H oxidase component] in CA were not altered by EGCG treatment in either group. Significance Our data suggest that, within the timescale investigated here, EGCG attenuates ET-1-induced contractions in CA from type 2 diabetic rats, and one of the mechanisms may involve normalizing endothelial function. [ABSTRACT FROM AUTHOR]

Aims Levels of the endothelium-derived peptide endothelin-1 (ET-1) are elevated in obese humans, and ET-1 mediated vascular tone is increased. Renal arterial smooth muscle is highly responsive to ET-1. Whether or not endothelium-derived ET-1 affects contractions of the renal artery under normal conditions or in obesity is unknown. The present study was designed to investigate whether or not overexpression of endogenous ET-1 in the endothelium affects the responsiveness of the main and segmental renal arteries differently in obesity. Main methods Mice with tie - 1 promoter-driven endothelium-restricted heterozygous overexpression of preproendothelin-1 were used (TET het ). Obesity was induced in TET het mice and wild-type (WT) littermates by feeding a high fat diet for 30 weeks; lean controls were kept on standard chow. The renal arteries were studied in wire myographs testing contractions (in the presence of l -NAME) to ET-1, serotonin, and U46619. Key findings Contractions to ET-1 were comparable between groups in main renal arteries, but augmented in segmental preparations from obese mice. Serotonin-induced responses were enhanced in obese TET het mice renal arteries compared to lean controls. Concentration–contraction curves to U46619 were shifted significantly to the left in main renal arteries of obese animals, and the maximal response was significantly increased between lean and obese TET het mice. Significance These results indicate an augmented responsiveness of main renal arteries in obesity particularly to TP receptor activation. When combined with endothelial ET-1 overexpression this effect is even more pronounced, which may help to gain further insights into the mechanisms of hypertension in obesity. [ABSTRACT FROM AUTHOR]

Aims Although endothelin (ET) is known to play pleiotropic roles in various pathological conditions, its relation to autoimmune disease has not been elucidated. Here, we focused on interleukin (IL)-17, which is closely related to the pathogenesis of multiple sclerosis, and investigated the effect of ET receptor blockers on the production of IL-17 by T lymphocytes. Main methods Lymph node cells from mice at 8 days post-immunization with MOG 35–55 were stimulated in vitro with MOG 35–55 in the presence or absence of an ET receptor blocker (BQ123 for ET A or BQ788 for ET B ). Naïve T cells from mice were subjected to an in vitro model of Th17 differentiation, and ET-mediated IL-17 production was investigated under the states of Th17 differentiation and activation. Key findings ELISA revealed that MOG 35–55 -induced IL-17 production was significantly inhibited by BQ123 but not BQ788. Consistent with the ELISA results for IL-17, the frequency of CD4 + T cells producing IL-17 but not IFN-γ was reduced by BQ123. Under the differentiating state from naïve T cells to Th17 cells, the spontaneous release of IL-17 from CD4 + T cells was increased, which was insensitive to BQ123, indicating that ET/ET A signaling did not affect Th17 differentiation. After the time period of Th17 differentiation, however, the increase in IL-17 production by restimulation of the cells with anti-CD3 plus anti-CD28 antibodies was significantly inhibited by BQ123. Significance We demonstrated that ET/ET A signaling plays a crucial role in IL-17 production by Th17. BQ123 might be expected to be a future therapeutic drug for multiple sclerosis. [ABSTRACT FROM AUTHOR]

Abstract: The endothelin axis is a group of signaling molecules and their receptors that have been implicated in vascularization of cancers, with their expression being observed to change in different cancer types. In this research, we examined the expression of endothelin 1 and endothelin receptor A at the protein and messenger RNA (mRNA) levels in 123 papillary thyroid carcinomas and 40 matched lymph nodes with metastatic papillary thyroid carcinomas. We found altered endothelin axis mRNA expression in several clinicopathologic parameters with increased endothelin 1 expression in thyroid papillary carcinoma showing stromal calcification, cancers in men, and primary cancers with lymph node metastases. Increased endothelin receptor A mRNA expression was noted in the larger cancers. There is a significant correlation between expression of endothelin receptor A and endothelin 1 in papillary thyroid carcinoma. Both endothelin receptor A and endothelin 1 mRNA expressions were significantly higher in metastatic carcinoma in the lymph node than in primary thyroid cancer. The metastatic carcinoma in the lymph node had increased expression compared with matched primary thyroid carcinoma. Expressions of endothelin 1 and endothelin receptor A were also documented as being high at the protein level. Our results indicate that in thyroid cancer, endothelin 1 and endothelin receptor A are associated with growth in advanced stages and lymph node metastases, likely through known angiogenic linkages. Targeting the endothelin axis may be useful in planning angiogenesis therapy for thyroid cancer. [Copyright &y& Elsevier]

Abstract: Paracetamol is one of the first rank drugs which cause hepatic damage during drug intoxications. Endothelin (ET) which is known as one of the most potent vasoactive agent has been shown to contribute in the pathophysiology of various diseases. We hypothesized that bosentan, which is a non-selective ET-1 receptor antagonist, can prevent liver damage. This study included 49 female rats. Groups; I: Healthy group, II: Paracetamol (2g/kg orally). Groups 3, 4 and 5 received NAC 140mg/kg (2 doses), BOS 45mg/kg and BOS 90mg/kg orally, respectively. 1h after administration of pretreatment drugs, Groups 3, 4, 5 were given paracetamol. VI: received BOS 90mg/kg. VII: received 140mg/kg NAC (2 doses). According to biochemical results, TNF-α, ALT and AST levels were statistically increased in the paracetamol group, these parameters were improved in the bosentan groups. Paracetamol administration decreased SOD activity, GSH level and increased level of MDA in the liver, while bosentan administration significantly improved these parameters. In immunohistochemical staining ET-1 receptor expression was excessively increased in paracetamol group, but not in bosentan groups when compared to healthy control. All these results suggest that bosentan exerted protective effects against experimentally induced paracetamol toxicity in liver. [Copyright &y& Elsevier]

Highlights: [•] In cardiomyocytes, ET-1 treatment resulted in significant upregulation of COX-2 expression and activity. [•] Both COX-2 inhibitors and COX-2 RNA interference suppressed cardiomyocyte hypertrophy induced by ET-1. [•] Calcineurin/NFATc3 signaling pathway participated in the transcriptional regulation of COX-2 by ET-1. [ABSTRACT FROM AUTHOR]

Abstract: In this study, the relationships between high water fluoride exposure and essential hypertension as well as plasma ET-1 levels were investigated. A total of 487 residents aged 40 to 75 were randomly recruited from eight villages in Zhaozhou County from Heilongjiang Province in China and were divided into 4 groups according to the concentrations of fluoride in their water. Consumption levels of drinking water fluoride for normal, mild, moderate, and high exposure groups were 0.84±0.26mg/L, 1.55±0.22mg/L, 2.49±0.30mg/L, and 4.06±1.15mg/L, respectively. The prevalence of hypertension in each group was 20.16%, 24.54%, 32.30%, and 49.23%, respectively. There were significant differences between all the groups; namely, with the increase in water fluoride concentrations, the risk of essential hypertension in adults grows in a concentration-dependent manner. Significant differences were observed in the plasma ET-1 levels between the different groups (P<0.0001). In the multivariable logistic regression model, high water fluoride concentrations (F− ≥3.01mg/L, OR4/1 =2.84), age (OR3/1 =2.63), and BMI (OR2/1 =2.40, OR3/1 =6.03) were closely associated with essential hypertension. In other words, the study not only confirmed the relationship between excess fluoride intake and essential hypertension in adults, but it also demonstrated that high levels of fluoride exposure in drinking water could increase plasma ET-1 levels in subjects living in fluoride endemic areas. [Copyright &y& Elsevier]

Abstract: Aims: We have compared the endothelin receptor subtype affinity (KD) and selectivity of four structural classes of antagonists (peptide, sulphonamide-based, carboxylic acid-based, myceric acid-based) in human cardiovascular tissues to determine whether these are predicted by values reported for human cloned receptors. Additionally, affinities (KB) for these antagonists, determined in ET-1-mediated vasoconstriction assays in human blood vessels, were used to identify discrepancies between KB and KD determined in the same tissues. Main methods: Competition binding experiments were carried out in sections of human left ventricle, coronary artery and homogenates of saphenous vein to determine KD values for structurally different ETA-selective (FR139317, BMS 182874, S97-139, sitaxentan, ambrisentan) and mixed (PD142893, Ro462005, bosentan, L-749329, SB209670) antagonists. Schild-derived values of antagonist affinity were obtained in vascular functional studies. Key findings: When compared with previously reported data in human cloned endothelin receptors, those antagonists reported to be ETA-selective exhibited even greater ETA selectivity in human ventricle (BMS 182874, sitaxentan, ambrisentan) that expressed both receptor subtypes. Those antagonists reported to have <100 fold selectivity in cloned receptors (PD142893, Ro-462005, bosentan, SB209670, L-749329) did not distinguish between receptor subtypes in human left ventricle. For antagonists where we determined affinity in vascular functional and binding assays (Ro462005, bosentan, BMS 182874, L-749329, SB209670) there was no correlation between the degree of discrepancy in KB and KD and structural class. Significance: For an antagonist to retain ETA-selectivity in vivo it may be necessary to identify those compounds that have at least 1000 fold ETA:ETB selectivity in in vitro assays. [Copyright &y& Elsevier]

Abstract: The ovary is a dynamic organ that undergoes cyclic structural and functional changes. Structurally, the internal architecture of the ovary constantly changes as follicles grow, rupture and transform into corpora lutea in a cyclical manner. Functionally, a variety of regulatory ovarian hormones are sequentially produced, and eggs are periodically released. As a highly vascularized organ, the ovarian structures and functions change in response to external stimuli that include but are not limited to pituitary gonadotropins. Following stimulation, the ovary synthesizes and releases autocrine and paracrine signals that play unique roles in regulating its function. Recent studies have identified endothelins as local regulators in the ovary that modulate multiple cyclic events, such as follicle growth, steroidogenesis, oocyte maturation, ovulation, corpus luteum formation and luteolysis. Interestingly, in all mammalian species examined to date, a common observation has been made: the ovary produces two pharmacologically similar endothelins (ET-1 and ET-2) but expresses two functionally different endothelin receptors (ETA and ETB) that often give rise to opposite physiological outcomes following activation by an endothelin. In this review, the physiological significance of the presence of the two ligand-two receptor endothelin system in the ovary will be discussed. [Copyright &y& Elsevier]

Abstract: Purpose: This study investigated the role and mechanism of Cdc42 in Endothelin-1 (ET-1)-induced trophoblast cell migration. Methods: We examined ET-1-mediated stimulation of trophoblast migration with HTR-8/SVneo cells. Cdc42 activation was measured after ET-1 treatment of HTR-8/SVneo cells. To determine the ET receptor subtype involved in ET-1-mediated Cdc42 activation, experiments were performed in the presence of ETA and ETB receptor antagonists. Finally, using siRNA we knocked down the expression of Cdc42 to examine the involvement of Cdc42 in the regulation of ET-1-stimulated trophoblast cell migration. Results: ET-1 was shown to have a dose-dependent effect on trophoblast migration. At low concentrations of ET-1 (0.1 nmol/L) ET-1 had a stimulatory effect on cell migration. ET-1 (10 nmol/L) increased HTR-8/svneo cell migration index by 2.5 fold. ET-1 (10 nmol/L) elevated protein level and activity of Cdc42. ET-1 induced activation of Cdc42 GTPase was mediated by both ETA and ETB. ET-1-induced cell migration was shown to be inhibited by Cdc42 siRNA.The inhibition was not mitigated by the addition of ET-1, suggesting that Cdc42 plays an important role in trophoblast migration and is obligatory for ET-1 action. Conclusions: ET-1 stimulates EVT migration through Cdc42 activation. [Copyright &y& Elsevier]

Abstract: Aim: To investigate the effect of angiotensin II AT1 receptor blocker valsartan on hypoxia-inducible factor (HIF)-1α-mediated gene activation and its association with renal interstitial fibrosis (RIF) in diabetic nephropathy rats. Methods: Sprague-Dawley rats were randomly divided into 3 groups: control (C group), streptozocin-induced diabetic nephropathy (D group), and valsartan-treated D rats (T group). At end of the 4th, 8th and 12th week 6 rats from each group were sacrificed and blood, urine and kidneys were collected. Blood glucose, serum creatinine (Scr) and 24-h urinary protein were measured and kidneys were processed for Masson-stain as well as immunohistochemistry and real time-PCR analyses of the expressions of HIF-1α, and its target genes tissue inhibitor of metalloproteinase (TIMP)-1 and endothelin (ET)-1 in the kidney. Result: (1) At the 4th, 8th and 12th week, the areas of RIF were significantly increased in D and T groups, which was accompanied by higher levels of 24-h urinary protein, Scr, HIF-1α, ET-1 and TIMP-1 compared with C group. (2) At the 8th and 12th week, the above changes were significantly attenuated in T group compared with D group. Conclusions: Valsartan may reduce HIF-1α-mediated gene activation and consequently improve kidney damage in diabetic nephropathy rats. [Copyright &y& Elsevier]

Summary: Endothelin-1 (ET-1) is a potent vasoconstrictor involved not only in vascular biology but also in carcinogenesis. Results of a study in 2007 suggested salivary ET-1 as a potential biomarker for oral squamous cell carcinoma (OSCC), but a later study showed conflicting results. The purpose of our pilot study was to investigate feasibility of using salivary ET-1 as a biomarker for OSCC in two groups: oral lichen planus (OLP) patients and patients with OSCC in remission. Saliva samples were collected from five groups of subjects: patients with newly diagnosed, active OSCC (Group A); patients with OSCC in remission (Group B); patients with active OLP lesions (Group C); patients with OLP in remission (Group D); and normal controls (Group E). Salivary ET-1 levels were determined by enzyme-linked immunosorbent assay, and the results were analyzed by the Mann–Whitney U test. The mean salivary ET-1 level in Group A was significantly higher than that found in Group C (p =0.001), Group D (p =0.015) or Group E (p =0.004). There were no significant differences (p >0.05) in the mean salivary ET-1 levels between Groups A and B; Groups B and C; Groups B and D; Groups B and E; Groups C and D; Groups C and E; or Groups D and E. Salivary ET-1 could be a good biomarker for OSCC development in OLP patients regardless of the degree of OLP disease activity. However, it appeared not to be a good biomarker for detecting recurrence of OSCC in patients in remission. [Copyright &y& Elsevier]

Abstract: Ethnopharmacological relevance: We investigated the antiproliferative effects of baicalein, isolated from Scutellaria baicalensis (Huang-qin), on ET-1-mediated pulmonary artery smooth muscle cells (PASMCs) proliferation and the mechanisms underlying these effects. Materials and methods: Intrapulmonary artery smooth muscle cells were isolated and cultured from female Sprague-Dawley rats and used during passages 3–6. The proliferation of PASMCs was quantified by cell counting and XTT assay. The protein expression of TRPC1 and PKCα were determined by western blotting. The cell cycle pattern was assayed by flow cytometry. The intracellular calcium concentrations ([Ca2+]i) were measured using the fluorescent indicator fura-2-AM and flow cytometry. Results: Baicalein (0.3–3μM) inhibited PASMCs proliferation, promoted cell cycle progression, enhanced [Ca2+]i levels, increased capacitative Ca2+ entry (CCE), upregulated the canonical transient receptor potential 1 (TRPC1) channel and membrane protein kinase Cα (PKCα) expression induced by ET-1 (0.1μM). The PKC activator PMA (1μM) reversed the inhibitory effects of baicalein on ET-1-induced upregulation of TRPC1 expression and S phase accumulation, while the PKC inhibitor chelerythrine (1μM) potentiated baicalein-mediated G2/M phase arrest and TRPC1 channel inhibition. Conclusion: Our findings suggest that baicalein protects against ET-1-induced PASMCs proliferation via modulation of the PKC-mediated TRPC channel. [Copyright &y& Elsevier]

Abstract: When comparing a cumulative dose–response curve for endothelin-1 (ET-1)-induced mechanical hyperalgesia to the effect of individual doses (1 ng, 10 ng, 100 ng, and 1 μg) administered in separate groups of rats, a marked difference was observed in the peak magnitude of hyperalgesia. Hyperalgesia was measured as decrease in the threshold for mechanically-induced withdrawal of the hind paw. The cumulative dosing protocol produced markedly greater maximum hyperalgesia. To determine whether this was due to the cumulative dosing protocol or to the repeated exposure to the mechanical test stimulus, we evaluated the impact of repeated testing on ET-1-induced mechanical hyperalgesia. While ET-1-induced mechanical hyperalgesia was dose- and time-dependent, repeated testing of nociceptive threshold, at 5 min intervals, following a single dose of ET-1, produced further decrease in nociceptive threshold. This mechanical stimulation-induced enhancement of ET-1 hyperalgesia lasted only 3–4 h, while the hyperalgesia lasted in excess of 5 days. The stimulation-enhanced hyperalgesia also occurred after a second injection of ET-1, administered 24 h after the initial dose. That this phenomenon is unique to ET-1 is suggested by the observation that while five additional, direct-acting hyperalgesic agents—prostaglandin E2 (PGE2), nerve growth factor (NGF), glia-derived neurotrophic factor (GDNF), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFα)—induced robust mechanical hyperalgesia, none produced mechanical stimulation-enhanced hyperalgesia. [Copyright &y& Elsevier]

Abstract: Ovarian cancer is a highly metastatic disease and the leading cause of death from gynecologic malignancy. Hence, and understanding of the molecular changes associated with ovarian cancer metastasis could lead to the identification of targets for novel therapeutic interventions. The conversion of an epithelial cell to a mesenchymal cell plays a key role both in the embryonic development and cancer invasion and metastasis. Cells undergoing epithelial–mesenchymal transition (EMT) lose their epithelial morphology, reorganize their cytoskeleton and acquire a motile phenotype through the up- and down-regulation of several molecules including tight and adherent junctions proteins and mesenchymal markers. EMT is believed to be governed by signals from the neoplastic microenvironment including a variety of cytokines and growth factors. In ovarian cancer EMT is induced by transforming growth factor-β (TGF-β), epidermal growth factor (EGF), hepatocyte growth factor (HGF) and endothelin-1 (ET-1). Alterations in these cellular pathways candidate them as useful target for ovarian cancer treatment. [Copyright &y& Elsevier]

Abstract: Background: Diabetes mellitus (DM) is associated with increased risk for complications following coronary artery bypass graft (CABG) surgery, in which tissue damage involves leukocyte–endothelial interactions mediated by endothelin-1 (ET-1) and adhesion molecules (AMs). Aim: This study compared lipids and their peroxidation product, malondialdehyde (MDA), high-sensitivity C-reactive protein (hsCRP), ET-1, platelet-selectin (P-selectin), intercellular AM-1 (ICAM-1), and vascular cell AM-1 (VCAM-1) between healthy controls and type 2 DM subjects who did not receive CABG surgery as well as those who did. Vitamin E as an adjunctive therapy in subjects who underwent CABG was evaluated. Methods: ELISA was used to measure hsCRP, ET-1, and AMs. For all subjects, glycosylated hemoglobin (HbA1c) and lipid profile were estimated. Results: Percentage of HbA1c, lipids, MDA, hsCRP, ET-1, P-selectin, ICAM-1, and VCAM-1 levels were significantly higher in the diabetic groups than in healthy controls. Vitamin E supplementation for 3 successive months significantly lowered MDA, hsCRP, ET-1, ICAM-1, and VCAM-1 levels by 64%, 47%, 12%, 74%, and 25%, respectively. However, high-density lipoprotein cholesterol (HDL-C) and vitamin E serum levels were increased by 65% and 90.55%, respectively (P≤.05). Vitamin E cosupplementations correlated restored ET-1, P-selectin, and ICAM-1 levels, which have been functionally damaged by decreased HDL-C, hypercholesterolemia, and hypertriacylglycerolemia, respectively. Conclusion: This study indicates that increased levels of the proinflammatory markers and AMs occur in type 2 DM. Vitamin E administration appears beneficial in lowering proinflammatory markers and their downstream effectors that played an important role in diabetic complications following CABG. [Copyright &y& Elsevier]

Abstract: Glutaredoxins utilize the reducing power of glutathione to maintain and regulate the cellular redox state and redox-dependent signaling pathways, for instance, by catalyzing reversible protein S-glutathionylation. Due to the general importance of these processes, glutaredoxins have been implied in various physiological and disease-related conditions, such as immune defense, cardiac hypertrophy, hypoxia-reoxygenation insult, neurodegeneration and cancer development, progression as well as treatment. The past years have seen an impressive gain of knowledge regarding new glutaredoxin systems and functions. This is true both with respect to new functions in redox regulation and also with respect to unexpected new ties to iron metabolism and iron–sulfur cluster biosynthesis. The aim of this review is to provide a state-of-the-art overview over these recent discoveries with a focus on aspects related to human health. [Copyright &y& Elsevier]

Abstract: Aim: Liuwei Dihuang (Rehmannia complex, RC) decoction, a classic prescription of Traditional Chinese Medicine (TCM), has been used in treating diabetic nephropathy (DN). Among the 6 crude medicines which contains Corni fructus is recognized as the active fraction for its effectiveness. We aimed to investigate, first, if without Corni fructus a modified RC could be still effective, second, if the ethanol extracts could be better than that of water extract and third, the beneficial effect is mainly stemmed from suppressing the endothelin (ET-1) pathway associated with a moderate hypoglycemic effect. Methods and materials: Diabetes for 8 weeks was induced by a single dose of streptozotocin (STZ, 65mg/kg, i.p.) in rats and treated with RC extracts in either 95%, 70% ethanol or water separately during 5–8th week. The efficacy of extracts was compared with aminoguanidine (AMG). Results: An increase in albumin and creatinine in 24h urine, blood urea nitrogen (BUN) was found in STZ rats. Oxidative stress was found in renal cortex in association with upregulated plasma ET-1 and mRNA of ETA, decreased MMP2,9 (matrix matelloproteinases) and increased hydroxyproline. Conclusions: The RC without Corni fructus was very effective in alleviating DN and ethanol extracts provided greater effects against water extracts. The efficacy in alleviating DN is attributed to normalizing the activated ET system, oxidative stress and MMP2,9 in combination with a moderate hypoglycemic activity. [Copyright &y& Elsevier]

Abstract: α-Zearalanol (α-ZAL), a phytochemical with both antioxidant and estrogen-like properties, has been shown to retard progression of atherosclerosis and regulate cardiovascular function in part through suppression of endothelin-1 (ET-1) secretion. However, the precise nature behind α-ZAL-elicited inhibition on ET-1 cascade is not largely known. Oxidized low density lipoprotein (oxLDL) plays a critical role in the expression and secretion of ET-1 as well as the onset and progression of atherosclerosis through accumulation of reactive oxygen species (ROS) and activation of mitogen-activated protein kinase stress signaling cascade. Therefore, this study was designed to examine the effect of α-ZAL on oxLDL-induced extracellular signal-regulated kinase (ERK) phosphorylation, ROS generation, activation of the transcriptional factor activator protein-1 (AP-1), expression, secretion and promoter activity of ET-1 in human umbilical vein endothelial cells (HUVEC). ROS generation was monitored using 2,7-dichlorofluorescin fluorescence. ET-1 expression and promoter activity were evaluated by RT-PCR and luciferase assays, respectively. oxLDL (35μg/ml) significantly enhanced ERK phosphorylation, ROS generation, AP-1 activity, mRNA expression, secretion and promoter activity of ET-1 in HUVECs, all of which were abrogated by α-ZAL and the antioxidant N-acetyl-l-cysteine. Collectively, these data favor the notion that α-ZAL antagonizes oxLDL-induced upregulation of ET-1 gene expression and secretion via suppression of oxLDL-induced ROS accumulation, ERK phosphorylation, and activation of the endothelial transcriptional factor AP-1. [Copyright &y& Elsevier]

Abstract: Fibrosis is believed to occur through the failure to terminate the normal tissue remodeling program. Tissue repair intimately involves the ability of fibroblasts to attach to extracellular matrix (ECM), resulting in cell migration and ECM contraction. Elevated, activated adhesive signaling is a key phenotypic hallmark of fibrotic cells. The precise contribution of adhesion to tissue remodeling and repair and fibrotic responses in fibroblasts is unclear, but involves focal adhesion kinase (FAK). FAK signals downstream of integrin-mediates attachment of fibroblasts to extracellular matrix. In this report, we show that FAK is required for the expression of a cohort of mRNAs encoding ECM and matrix remodeling genes including CCN2, α-smooth muscle actin (SMA) and type I collagen. Adhesion of fibroblasts to fibronectin, a component of the provisional matrix deposited in the initial phases of tissue repair, also resulted in the induction of CCN2, α-SMA and type I collagen mRNAs. Endothelin-1 (ET-1), a key inducer of pro-fibrotic gene expression, was also induced upon fibroblast attachment to ECM, and antagonism of the ET-1 receptors significantly reduced the ability of adhesion to induce expression of CCN2, α-SMA and type I collagen mRNAs. These results suggest that adhesion of fibroblasts to matrix during the initial phases of tissue remodeling and repair may actively contribute to the tissue repair program through the induction of pro-fibrotic gene expression. [Copyright &y& Elsevier]

Summary: The CDC25 phosphatases are cell cycle regulators known to play an important role in cancer cell growth. Increased expression of CDC25B has been reported in tumors of different tissue origins, including non–small cell lung carcinoma (NSCLC). We analyzed primary tumors and corresponding healthy lung tissues from 177 patients with NSCLC for relative expression levels of CDC25B by reverse transcription-polymerase chain reaction, with the dual aims of investigating the relationships between CDC25B expression and angiogenesis as well as prognosis. Eighty-one (45.76%) of the 177 patients with NSCLC overexpressed the CDC25B gene; there was no significant difference in CDC25B expression among sex, age, T or N status, or clinical stages of NSCLC. Concerning the possible involvement of CDC25B in angiogenesis, high expression of CDC25B correlated with positive expression of endothelin-1 (χ 2 test; P = .0002), one of the major angiogenic factors in NSCLC. A significant association was also found with the number of intratumoral microvessels (χ 2 test; P = .03). Statistical analysis of survival data revealed that elevated CDC25B expression was significantly associated with shorter survival in terms of both overall survival and disease-free interval (P = .04 for both), maintaining its independent prognostic role in a Cox proportional hazards model (P = .009). A rich and varied engagement of many cellular pathways could cause or maintain a cancer; our study may offer insights into these mechanisms in lung cancer, suggesting that CDC25B might play an important role in the angiogenic process and in determining the prognosis of patients with NSCLC. [Copyright &y& Elsevier]

Summary: The analysis of saliva has been proposed as a potentially rapid, non-invasive method to monitor and diagnose patients with oral disease. In this study we measured salivary endothelin-1 (ET-1) levels in patients diagnosed with oral squamous cell carcinoma (SCC) prior to treatment. We demonstrate significantly elevated salivary ET-1 levels in the oral SCC group (4.37±1.35pg/ml), relative to the control group (1.16±0.29pg/ml). ET-1 and ET-1 mRNA were also measured in oral SCC tissue specimens and compared to normal oral epithelial controls. The concentration of ET-1 in the oral SCC specimens was 17.87±4.0pg/ml and in the normal epithelial controls the concentration of ET-1 was 5.43±2.5pg/ml. ET-1 mRNA was significantly overexpressed in 80% (8/10) of the oral SCC specimens. Our results demonstrate the potential utility of salivary analysis for ET-1 levels to monitor patients at risk for oral SCC. [Copyright &y& Elsevier]

Abstract: Objective: We sought to examine the effect of trimetazidine (TMZ) on heart rate variability (HRV), endothelin-1 (ET-1), NO, and anginal symptoms in patients with slow coronary artery flow (SCAF). Methods: The 48 patients with SCAF (29 women and 19 men; mean age, 52 ± 9 years) were included in the study. Twenty milligrams TMZ 3 times a day or matched placebo were given randomly in a double-blinded fashion for 4 weeks. Patients were divided into 4 groups as follows: exercise-positive, TMZ-given group (group A, n = 12); exercise-positive, placebo-given group (group B, n = 12); exercise-negative, TMZ-given group (group C, n = 12); and exercise-negative, placebo-given group (group D, n = 12). Results: After TMZ treatment, HRV parameters, including SD of the all R-R intervals, SD of the averages of R-R intervals in all 5-minute segments of the entire recording, percentage of R-R intervals with more than 50-millisecond variation, and the square root of the mean of the sum of the squares of differences between adjacent R-R intervals, significantly improved both in exercise-positive and exercise-negative groups when compared with baseline. After TMZ treatment, ET-1 and NO levels significantly altered both in exercise-positive and exercise-negative groups when compared with baseline (17.7 ± 2.7 vs 13.9 ± 2.8 pg/mL [P = .01] and 18.1 ± 3.8 vs 14.2 ± 2.6 pg/mL [P = .01], respectively). After TMZ treatment, NO levels significantly increased in both exercise-positive and exercise-negative groups when compared with baseline (36.4 ± 5.4 vs 43.3 ± 6.8 μmol/L [P = .01] and 36.8 ± 7.8 vs 43.3 ± 4.8 μmol/L [P = .01], respectively). However, in placebo group, neither HRV parameters nor ET-1 and NO levels altered when compared with baseline. Also, after treatment, a significant correlation was detected between HRV parameters, including SD of the averages of R-R intervals in all 5-minute segments of the entire recording, SD of the all R-R intervals, percentage of R-R intervals with more than 50-millisecond variation, and the square root of the mean of the sum of the squares of differences between adjacent R-R intervals, and NO and ET-1 levels in TMZ group but not placebo. Conclusion: Short-term TMZ therapy improved HRV parameters and endothelial products such as ET-1 and NO as well as anginal symptom in patients with SCAF. Improvement in HRV parameters was correlated with ET-1 and NO levels. [Copyright &y& Elsevier]

Abstract: We characterized vascular reactivity to endothelin-1 (ET-1) in mesenteric vessels from DOCA-salt hypertensive and SHAM control mice and assessed the effect that endothelial-derived vasodilators have on ET-1-induced vasoconstriction. Changes in the diameter of unpressurized small mesenteric arteries and veins (100- to 300-μm outside diameter) were measured in vitro using computer-assisted video microscopy. Veins were more sensitive than arteries to the contractile effects of ET-1. There was a decrease in arterial maximal responses (E max) compared to veins, this effect was larger in DOCA-salt arteries. The selective ETB receptor agonist, sarafotoxin 6c (S6c), contracted DOCA-salt and SHAM veins but did not contract arteries. The ETB receptor antagonist, BQ-788 (100 nM), but not the ETA receptor antagonist, BQ-610 (100 nM), blocked S6c responses. BQ-610 partially inhibited responses to ET-1 in mesenteric veins from DOCA-salt and SHAM mice while BQ-788 did not affect responses to ET-1. Co-administration of both antagonists inhibited responses to ET-1 to a greater extent than BQ-610 alone suggesting a possible functional interaction between ETA and ETB receptors. Responses to ET-1 in mesenteric arteries were completely inhibited by BQ-610 while BQ-788 did not affect arterial responses. Nitric oxide synthase inhibition potentiated ET-1 responses in veins from SHAM but not DOCA-salt mice. There was a prominent role for ET-mediated nitric oxide release in DOCA-salt but not SHAM arteries. In summary, these studies showed a differential regulation of ET-1 contractile mechanisms between murine mesenteric arteries and veins. [Copyright &y& Elsevier]

Abstract: Angiotensin II and endothelin-1 (ET) are two hormones involved in cardiovascular diseases and well known for their capacity to induce free radical generation in vascular and cardiac tissues. In addition to its prooxidative effect, angiotensin II can increase the synthesis of ET-1 in vascular smooth muscle cells (VSMC). Our objective was to determine whether the ET-1 synthesis in VSMC is involved in angiotensin II-induced superoxide anion production in rats. Our results show that treatments of isolated VSMC with angiotensin II and ET increased superoxide. However, this increase occurred in a bimodal fashion for angiotensin II with a fast transient production (10 min) and a late sustained production (6 h), while ET-1 induced superoxide formation after a delay of 6 h. LU302872 and BQ-123, a nonselective and a selective ETA receptor antagonists, respectively, prevented angiotensin II-induced superoxide anion production only during the late phase. In contrast, BQ-3020, a selective ETB receptor antagonist, had no effect. In vivo, LU302872 reduced the aortic superoxide production induced by angiotensin II administered for 12 days. In conclusion, our results suggest that the superoxide generation induced by chronic angiotensin II infusion may be mediated by ET-1 acting on ETA receptors in VSMC in vitro. Furthermore, this effect appears to contribute to the excess superoxide production during the chronic activation of the renin-angiotensin system in vivo. [Copyright &y& Elsevier]

Abstract: Objectives:: To investigate the status of lipid peroxidation and serum levels of several vasoactive substances in preeclamptic (PE) pregnant women before and during treatment with magnesium sulfate (MgSO4). Design and methods:: The study population included 16 PE women. Circulating levels of malondialdehyde (MDA), endothelin 1 (ET-1), nitric oxide (NO) metabolites, and calcitonin gene-related peptide (CGRP) were measured before (at admission) and during MgSO4 treatment (at delivery and 24 h postpartum). Results:: At admission systolic and diastolic blood pressures were 157 ± 3 mm Hg and 106 ± 2 mm Hg, respectively, and decreased significantly during treatment at delivery and 24 h postpartum (P < 0.0001). Before treatment, serum MDA concentrations were 0.383 ± 0.037 μmol/L, and decreased significantly during MgSO4 administration at delivery and 24 h postpartum (P < 0.0001). In contrast, serum ET-1 levels at 24 h postpartum were significantly higher as compared with those observed before treatment (79 ± 3 versus 65 ± 2 pg/mL, P = 0.002). Serum NO metabolite concentrations were 26 ± 3 μmol/L, and no significant changes were observed during treatment. Serum levels of CGRP were 50 ± 3 pg/mL at admission, and increased significantly at partum (P < 0.001). Serum ET-1 correlated negatively with NO metabolites before treatment (r = −0.69, P = 0.002), but not during treatment. In contrast, ET-1 correlated positively with serum CGRP levels during treatment (r = 0.73, P = 0.002 and r = 0.71, P = 0.002, at delivery and 24 h postpartum, respectively), but not before treatment. Conclusions:: This study demonstrates that MgSO4 administration to PE pregnant women induced significant changes in lipid peroxidation, production of ET-1 and CGRP. [Copyright &y& Elsevier]

Vasopeptidase inhibitor restores the balance of vasoactive hormones in progressive nephropathy.Background.The mechanism(s) underlying greater renoprotection of combined blockade of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) by vasopeptidase over ACE inhibitors are ill defined. We previously found that progressive renal disease is associated with increased renal synthesis of endothelin-1 (ET-1) in the face of reduced generation of renal nitric oxide (NO) in the remnant kidney model. Here we compared changes in urinary excretion of ET-1 and nitrite/nitrate, markers of renal ET-1, and NO synthesis, respectively, and urinary cGMP, an indirect index of renal atrial natriuretic peptide (ANP) synthesis, after administration of vasopeptidase or ACE inhibitor in rats with renal mass reduction (RMR).Methods.Twenty-one days after 5/6 nephrectomy, after the onset of hypertension and overt proteinuria, rats were divided in 3 groups (N= 7–8) and given daily by gavage: vehicle, the vasopeptidase inhibitor AVE7688 (3 mg/kg bid), or enalapril (5 mg/kg bid) until day 90. Normal rats (N= 5) served as control rats.Results.Systolic blood pressure in RMR rats was equally controlled by AVE7688 and enalapril. AVE7688 resulted in a significant antiproteinuric effect, with urinary protein levels being reduced on average by 83% in respect to vehicle (88± 28 vs. 518± 27 mg/day,P<0.0001). Enalapril achieved a 47% reduction in proteinuria (277± 81 mg/day,P<0.01 vs. vehicle) to levels that remained higher (P<0.01), however, than those after AVE7688. Renal function impairment and glomerular and tubular changes were significantly (P<0.05 vs. vehicle) ameliorated by AVE7688, and partially affected by enalapril. AVE7688 reduced the abnormal urinary excretion of ET-1 of RMR animals (98± 8 vs. vehicle: 302± 50 pg/24h,P<0.001) more than enalapril (159± 14 pg/24h,P<0.05 vs. AVE7688). Consistently, AVE7688 was more effective than enalapril in augmenting renal synthesis of NO (2487± 267 and 1519± 217 vs. vehicle: 678± 71 nmol/15 h;P<0.001, AVE7688 vs. vehicle,P<0.01 AVE7688 vs. enalapril). AVE7688 significantly increased urinary cGMP (78± 6 vs. vehicle 45± 9 nmol/24h;P<0.01).Conclusion.The superior renoprotection achieved by AVE7688 over enalapril in progressive renal injury is due to the correction of the altered balance of vasoconstrictor/vasodilator mediators in the kidney. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to determine plasma malondialdehyde (MDA), superoxide dismutase (SOD), soluble E-selectin (sE-selectin), fibronectin, endothelin-1 (ET-1) and nitric oxide (NO) levels in women with preeclampsia and to find out the relations of diastolic blood pressure with these variables. Study design: We performed a case-control study consisting of randomly selected 34 healthy pregnant women and 35 patients diagnosed as preeclampsia. Lipoperoxidation was ascertained by the formation of MDA. SOD activity was determined by the method of Sun et al. Plasma concentration of NO was estimated using colorimetric assay. Plasma ET-1 and sE-selectin were measured by enzyme-linked immunosorbent assay (ELISA). A nephelometric method for fibronectin quantitation was used. Results: The mean plasma level of MDA was significantly higher and SOD was significantly lower in preeclamptic pregnancies (P<0.001). Plasma concentrations of fibronectin, sE-selectin and ET-1 were significantly increased, whereas NO was significantly decreased in women with preeclampsia than normotensive women (P<0.001) Conclusion: Increased plasma levels of MDA, fibronectin, sE-selectin, ET-1, and decreased plasma levels of NO and SOD in preeclamptic patients suggest that poorly perfused fetoplacental unit is the origin of oxygen free radicals and lipid peroxides. [Copyright &y& Elsevier]