Endothelin-1 Levels Research Articles

Exploring the Endothelin-1 pathway in chronic thromboembolic pulmonary hypertension microvasculopathy.

Targeted vasopeptide therapies have significantly advanced the management of pulmonary arterial hypertension (PAH). However, due to insufficient preclinical evidence regarding the involvement of the endothelin-1 (ET-1) pathway in chronic thromboembolic pulmonary hypertension (CTEPH) pathophysiology, the potential of ET-1 receptor antagonism in treating CTEPH remains uncertain. In this study, we investigated the role of the ET-1 pathway in CTEPH microvasculopathy using a multifaceted approach. Plasma ET-1 levels were measured in a cohort of 59 CTEPH patients and 41 healthy controls. Additionally, we evaluated the expression of key ET-1 pathway members in pulmonary explants from CTEPH, idiopathic PAH, and control patients. We used an in vitro system to test the hypothesis that the turbulent flow, observed near the vascular obstructions pathognomonic of CTEPH, enhances ET-1 expression. Our findings were further validated in vivo using a CTEPH piglet model that contains distinct regions representing pre- and post-thrombus lung territories. We found a twofold increase in circulating ET-1 levels in CTEPH patients compared to healthy subjects. Pulmonary explants from CTEPH patients exhibited pronounced overexpression of ET-1, endothelin receptor A (ETA), and phosphorylated myosin light chain (p-MLC) in muscularized pulmonary microvessels, suggesting heightened vascular contraction. In vitro experiments showed that turbulent flow facilitates ET-1 secretion compared to laminar flow regions. Additionally, in the CTEPH piglet model, elevated plasma ET-1 levels were observed compared to controls. Immunofluorescence and confocal microscopy analyses confirmed increased ETA and p-MLC in remodeled arteries from both pulmonary territories. However, ET-1 protein elevation was exclusively observed in the obstructed territory. These findings collectively indicate impaired vascular tone in microvessels of CTEPH patients and the CTEPH piglet model. Furthermore, our data implicates the ET-1 pathway in microvasculopathy, with turbulent flow playing a pathological role. These insights underscore the potential utility of ET-1 receptor antagonists as a promising therapeutic approach for CTEPH treatment.

CORRECTION OF ENDOTHELIAL DYSFUNCTION WITH SULFAPORIN IN HYPERCHOLESTEROLEMIC RABBITS

In animals with experimental hypercholesterolemia, depending on the time of survey, we observed activation of smooth muscle cells and macrophages, causing development of inflammation in the intima, as evidenced by high levels of C-reactive protein (CRP), endothelin-1, and homocysteine. The aim of the study was to investigate the molecular mechanisms of endothelial dysfunction in HCH and the possibility of their correction with sulfaporin. Material and methods of the study Experiments were conducted on 46 Chinchilla rabbits with an average weight of 2.5–3.0 kg, kept on a standard diet. The model of experimental HCH in animals was reproduced by orally administering cholesterol (CS) dissolved in sunflower oil in a ratio of 0.2 g per 1 kg of body weight daily for 3 months. The development of hypercholesterolemia was assessed by the increase in the level of totalcholesterol (TC), low-density lipoproteins (LDL) and high-density lipoproteins (HDL), which were determined on a biochemical analyzer. Results of the study. In this case, a progressive increase in the homocysteine level was established: an increase of 1.72 (P < 0.01); 2.33 (P < 0.001) and 2.89 (P < 0.001) times, respectively, for the periods of cholesterol administration of 1, 2 and 3 months. Considering that hyperhomocysteinemia enhances the capture of LDL by endothelial cells, it was of interest to study the relationship between these indicators. The studies showed that with a cholesterol level in LDL of 2.38 ± 0.27 mmol / l, the homocysteine content is 3.46 ± 0.25 pg / ml. With a cholesterol level in LDL of 4.08 ± 0.10; 5.97 ± 0.09 and 6.48 ± 0.11 mmol/l, the homocysteine content increases to 5.96 ± 0.05; 8.07 ± 0.43 and 9.99 ± 0.17 pg/ml, respectively. Conclusions. Hypercholesterolemia is manifested by activation of smooth muscle cells and macrophages, causing the development of inflammation in the intima, which is confirmed by high levels of CRP, endothelin-1, homocysteine.

Mechanisms underlying the roles of leukocytes in the progression of cystic fibrosis

Recent advances in cystic fibrosis (CF) treatments have led to improved survival, with life expectancy for Australians living with CF at 57yo. As life expectancy improves, long-term cardiovascular disease risk factors (as for the general population) will become an issue in these patients. We hypothesized that increased leukocyte expression of vasoconstriction and pro-fibrotic mediators may contribute to CF severity in adults with CF. We recruited 13 adult and 24 pediatric healthy controls, and 53 adults and 9 children living with CF. Leukocyte expression/release of endothelin-1 (ET1) and members of the TGF-β/Smad signaling were measured by multifluorescence quantitative confocal microscopy, Western blotting, ELISA, and real-time quantitative polymerase chain reaction. The association between plasma ET1 levels and lung function was assessed. Leukocytes from adults living with CF expressed higher ET1 levels (p = 0.0033), and TGF-β (p = 0.0031); the phosphorylation ratio increased for Smad2/3 (p = 0.0136) but decreased for Smad1/5/8 (p = 0.0007), vs. control subjects. Plasma ET1 levels were significantly increased in adults with CF with FEV1<50% (p = 0.002) vs. controls, and adults with CF with normal lung function. The release of ET1 in adult plasma inversely correlated with CF severity (-0.609, p = 0.046). Our data indicates that upregulated ET1 and TGF-β/Smad signaling in leukocytes may contribute to CF severity, highlighting the need for further investigations into their impact on the clinical outcomes of people living with CF.

The effect of cardiac rehabilitation prescription on medication complications and ET-1, WMSI in elderly patients with coronary heart disease

ObjectiveTo explore the effects of cardiac rehabilitation prescriptions on medication complications, Endothelin 1 (ET-1), and Wall Motion Score Index (WMSI) in elderly patients with coronary heart disease.Methods98 elderly patients with coronary heart disease admitted to the Department of Cardiology of a hospital from January 2020 to June 2022 are selected. According to the red and blue ball method, 98 research subjects are divided into a control group and an observation group. The control group receives routine treatment and exercise intervention, while the observation group receives cardiac rehabilitation prescriptions. After a follow-up of 6 months, the incidence of medication complications between the two groups is compared. The changes in ET-1 and WMSI levels are compared before treatment, 1 month, 3 months, and 6 months after treatment.ResultsThe two groups had no significant difference in ET-1 and WMSI levels before intervention. After intervention, both groups showed significant reductions in ET-1 and WMSI compared with baseline. The ET-1 of the observation group decreased significantly faster than the control group after 1 month, 3 months, and 6 months of intervention. The WMSI decreased more significantly at 6 months. The repeated measurement variance showed that there was a significant difference in the trend of ET-1 changes between the two groups, while the difference between the WMSI groups was not significant. The incidence of medication complications in the observation group was 10.20%, significantly lower than the 26.53% in the control group.ConclusionCardiac rehabilitation prescriptions can reduce the incidence of medication complications in elderly patients with coronary heart disease. It can reduce ET-1 levels faster, improve myocardial motor function, which has better myocardial function and medication safety than conventional treatment.

Fu's subcutaneous needling for non-acute idiopathic facial paralysis : a randomized controlled trial

To observe the effect of Fu's subcutaneous needling in the treatment of non-acute idiopathic facial paralysis and its effect on serum levels of nitric oxide (NO) and endothelin (ET). A total of 76 patients with non-acute idiopathic facial paralysis were randomly divided into an observation group (38 cases, 2 cases dropped out) and a control group (38 cases, 2 cases dropped out). The patients in the control group received basic treatment (mecobalamin tablets orally, specific electromagnetic spectrum irradiation, facial muscle rehabilitation training). The patients in the observation group were treated with Fu's subcutaneous needling on the basis of the control group. The needling points included brachioradialis muscle, sternocleidomastoid muscle, trapezius muscle, etc., and the needling was inserted around the affected muscle, and the reperfusion activity was carried out at the same time, once every other day, 3 times a week. Both groups were treated for 4 weeks. The House-Brackmann (H-B) grade and H-B symptom score were observed before treatment, after 2 and 4 weeks of treatment in the two groups. The facial disability index (FDI) score [including physical function (FDIP) score and social life function (FDIS) score] and the serum levels of NO and ET were compared before and after 4 weeks of treatment in the two groups. The clinical effect and safety of the two groups were assessed. After 2 and 4 weeks of treatment, the H-B grade of the two groups was lower than that before treatment, and the H-B symptom scores were higher than those before treatment (P<0.001, P<0.05); the H-B grade of the observation group was lower than that of the control group, and the H-B symptom score was higher than that of the control group (P<0.01, P<0.05). After 4 weeks of treatment, the FDIP scores of the two groups were higher than those before treatment, and the FDIS scores were lower than those before treatment (P<0.05 ); the FDIP score of the observation group was higher than that of the control group, and the FDIS score was lower than that of the control group (P<0.05). After 4 weeks of treatment, the serum level of NO in the observation group was higher than that before treatment, and the serum level of ET was lower than that before treatment (P<0.05); the increase of serum level of NO and the decrease of serum level of ET in the observation group were greater than those in the control group (P<0.05). The cure rate of the observation group was 55.6% (20/36), which was higher than 22.2% (8/36) of the control group (P<0.05). There were no serious adverse reactions in both groups. Fu's subcutaneous needling combined with basic treatment can effectively improve the motor function of facial muscles in patients with non-acute idiopathic facial paralysis, which may be related to the regulation of serum NO and ET levels.

Endothelial dysfunction in combination of occupational pathology of the respiratory system and atherosclerosis in coal industry workers

Introduction. The increasing prevalence of cardiovascular pathology among industrial workers determines the importance of studying not only occupational diseases, but also their combination with diseases of the circulatory system. Endothelial dysfunction is a key link in the pathogenesis of atherosclerosis. Evaluation of endothelial function indicators in occupational respiratory diseases in combination with atherosclerosis in workers of the coal mining industry is an urgent task. The study aims to consider the indicators of endothelial function in miners with occupational respiratory diseases in combination with atherosclerosis. Materials and methods. The authors have examined 88 miners with previously diagnosed occupational respiratory diseases (chronic dust bronchitis, anthracosilicosis, chronic obstructive pulmonary disease), 45 of them showed signs of atherosclerosis. There were two comparison groups without signs of atherosclerosis: 44 miners who work long-term in harmful working conditions, without lung pathology (control group) and 42 residents of Novokuznetsk who have never worked in harmful working conditions, and without lung pathology (unexposed group). Results. We found that miners with occupational respiratory diseases in combination with atherosclerosis had several forms of endothelial dysfunction: vasomotor (decreased synthesis of nitric oxide, increased endothelin-1 levels), hemostatic (increased levels of Willebrand factor), adhesive (increased levels of endothelial adhesion molecules sVCAM-1). The development of respiratory insufficiency in miners with occupational respiratory diseases increases endothelial dysfunction: miners with respiratory insufficiency have lower levels of nitric oxide (NO), higher levels of endothelin-1 and endothelial adhesion molecules sVCAM-1 than miners without respiratory insufficiency. There are correlations between indicators of endothelial function and production factors: with work experience in harmful working conditions, the level of the average concentration of coal-rock dust in the workplace and the frequency of exceeding the maximum permissible concentration of coal-rock dust. Limitations. The study is limited to a sample of workers in the main professions of coal mines who were examined at the Research Institute of Complex Hygiene Problems and Occupational Diseases, aged 40 to 54 years, with more than 15 years of experience working in underground dust conditions. Conclusion. Miners with occupational respiratory diseases in combination with atherosclerosis develop several forms of endothelial dysfunction: vasomotor, hemostatic, adhesive. The development of respiratory failure increases endothelial dysfunction. Ethics. This medical study involving a human as a subject was carried out in compliance with the Ethical principles presented in the latest version of the Helsinki Declaration, developed by the World Medical Association.

Mid-late gestation leptin infusion induces placental mitochondrial and endoplasmic reticulum unfolded protein responses in a mouse model of preeclampsia

IntroductionPreeclamptic patients, both lean and obese, present with elevated leptin levels which are associated with the development of maternal endothelial dysfunction and adverse fetal outcomes, such as growth restriction, leading to low birth weight. Recent studies in pregnant mice demonstrate that mid-late gestation leptin infusion induces clinical characteristics of preeclampsia, including elevated maternal blood pressure, maternal endothelial dysfunction and fetal growth restriction. However, whether leptin triggers placental stress responses that contribute to adverse fetal outcomes as in preeclampsia is unknown. MethodsIn the current study we measured the expression of proteins involved in the endoplasmic reticulum (UPRer) and mitochondrial (UPRmt) unfolded protein responses in placentas of wild-type sham normal pregnant and leptin-infused preeclamptic mice. ResultsThe data show that mid-late gestation leptin infusion induced activation of indices of placental UPRer and UPRmt, while reducing placental repair mechanisms to UPRmt in preeclamptic mice. Mid-late gestation infusion with leptin upregulated markers of placental oxidative stress, reduced the placental expression levels of mitochondrial electron transport chain complexes I and II and increased the expression of placental endothelin-1 (ET-1) in preeclamptic mice. The leptin-induced activation of several placental UPRmt markers as well as ET-1 levels correlated with fetal growth restriction and impaired maternal endothelial function in preeclamptic mice. DiscussionCollectively, these data indicate that elevated levels of leptin in mid-late pregnancy in mice promote placental stress responses, akin to those in pregnant women with preeclampsia.

Cisplatin-resistance and aggressiveness are enhanced by a highly stable endothelin-converting enzyme-1c in lung cancer cells

BackgroundLung cancer constitutes the leading cause of cancer mortality. High levels of endothelin-1 (ET-1), its cognate receptor ETAR and its activating enzyme, the endothelin-converting enzyme-1 (ECE-1), have been reported in several cancer types, including lung cancer. ECE-1 comprises four isoforms, which only differ in their cytoplasmic N-terminus. Protein kinase CK2 phosphorylates the N-terminus of isoform ECE-1c, increasing its stability and leading to enhanced invasiveness in glioblastoma and colorectal cancer cells, which is believed to be mediated by the amino acid residue Lys-6, a conserved putative ubiquitination site neighboring the CK2-phosphorylated residues Ser-18 and Ser-20. Whether Lys-6 is linked to the acquisition of a cancer stem cell (CSC)-like phenotype and aggressiveness in human non–small cell lung cancer (NSCLC) cells has not been studied.MethodsIn order to establish the role of Lys-6 in the stability of ECE-1c and its involvement in lung cancer aggressiveness, we mutated this residue to a non-ubiquitinable arginine and constitutively expressed the wild-type (ECE-1cWT) and mutant (ECE-1cK6R) proteins in A549 and H1299 human NSCLC cells by lentiviral transduction. We determined the protein stability of these clones alone or in the presence of the CK2 inhibitor silmitasertib, compared to ECE-1cWT and mock-transduced cells. In addition, the concentration of secreted ET-1 in the growth media was determined by ELISA. Expression of stemness genes were determined by Western blot and RT-qPCR. Chemoresistance to cisplatin was studied by MTS viability assay. Migration and invasion were measured through transwell and Matrigel assays, respectively, and the side-population was determined using flow cytometry.ResultsECE-1cK6R displayed higher stability in NSCLC cells compared to ECE-1cWT-expressing cells, but ET-1 secreted levels showed no difference up to 48 h. Most importantly, ECE-1cK6R promoted expression of the stemness genes c-Myc, Sox-2, Oct-4, CD44 and CD133, which enhance cellular self-renewal capability. Also, the ECE-1cK6R-expressing cells showed higher cisplatin chemoresistance, correlating with an augmented side-population abundance due to the increased expression of the ABCG2 efflux pump. Finally, the ECE-1cK6R-expressing cells showed enhanced invasiveness, which correlated with the regulated expression of known EMT markers.ConclusionsOur findings suggest an important role of ECE-1c in lung cancer. ECE-1c is key in a non-canonical ET-1-independent mechanism which triggers a CSC-like phenotype, leading to enhanced lung cancer aggressiveness. Underlying this mechanism, ECE-1c is stabilized upon phosphorylation by CK2, which is upregulated in many cancers. Thus, phospho-ECE-1c may be considered as a novel prognostic biomarker of recurrence, as well as the CK2 inhibitor silmitasertib as a potential therapy for lung cancer patients.

Clinical significance of HIF-1α, ET-1, and NO as biomarkers in chronic obstructive pulmonary disease patients with pulmonary hypertension.

Pulmonary hypertension (PH) is a common complication of chronic obstructive pulmonary disease (COPD), with repeated infections and airflow limitation leading to endothelial dysfunction. The objective of this study was to retrospectively investigate the clinical significance of serum hypoxia-inducible factor 1-alpha (HIF-1α), plasma endothelin-1 (ET-1), and nitric oxide (NO) as non-invasive blood biomarkers for diagnosing patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). A total of 230 AECOPD patients were assessed for serum HIF-1α, plasma ET-1, and NO levels using Doppler echocardiography and blood tests. Clinical characteristics, including age, COPD duration, and comorbidities, were compared between patients with and without PH. The diagnostic value was determined through ROC analysis. Pearson correlation and multivariate logistic analyses explored the correlation of biomarkers in AECOPD with PH. Serum HIF-1α, plasma ET-1, and NO levels showed significant differences between COPD patients with and without PH. The combination model (0.027 * HIF-1α + 0.028 * ET-1 - 0.049 * NO) demonstrated an AUC of 0.89, indicating superior diagnostic value compared to individual biomarkers. Multivariate logistic analysis identified smoking, higher GOLD grade, hypertension, and elevated levels of HIF-1α, ET-1, and NO as independent risk factors for AECOPD. Positive correlations were observed between serum HIF-1α and plasma ET-1 levels with pulmonary artery systolic pressure (PASP), while NO demonstrated a negative correlation. Serum HIF-1α, plasma ET-1, and NO were associated with AECOPD and PH, and detecting individual or combined levels of these biomarkers in the blood can predict COPD-related PH.

Therapeutic Effects of Proanthocyanidins on Diabetic Erectile Dysfunction in Rats.

The rising occurrence of erectile dysfunction related to diabetes mellitus (DMED) has led to the creation of new medications. Proanthocyanidins (PROs) is a potential agent for DMED. In this study, the DMED rat model was established using streptozotocin (STZ) and erectile function was assessed using apomorphine (APO) in rats. Following this, the rats were subjected to oral treatment with PRO. Then, we evaluated the influence of PROs on DMED rats. The findings suggest that PROs significantly enhance erectile function in DMED rats. PROs modulated glucose and lipid metabolism in DMED rats by decreasing blood glucose and lipid levels while increasing liver glycogen and serum insulin levels. Furthermore, PROs enhanced vascular endothelial function in DMED rats by augmenting nitric oxide (NO) levels and reducing the levels of endothelin-1 (ET-1) and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1). Additionally, PROs have been shown to elevate testosterone (T) levels, mitigate pathological testicular damage, and enhance sperm concentration and survival rates. Finally, the core targets were screened using network pharmacology, followed by validation through molecular docking, enzyme-linked immunoassay (ELISA), and real-time PCR methodologies. Our findings imply that PROs may treat DMED by elevating AKT1 levels while concurrently diminishing CASP3 levels, thereby effectively regulating the PI3K-Akt signaling pathway. Overall, these results support using PROs as a potential candidate for the treatment of DMED.

Endothelial function in patients after severe or critical acute phase of COVID-19 one year after the disease onset

BACKGROUND. The SARS-CoV-2 virus not only causes respiratory diseases but also significantly impacts endothelial function, which may be one of the mechanisms for developing long-term consequences of coronavirus disease (COVID-19). OBJECTIVE. To determine the levels of endothelial function markers (endothelin-1, thrombomodulin) in the peripheral blood of individuals who experienced non-hospital pneumonia on the background of COVID-19, in the early post-acute phase and one year after the onset of the disease, and to analyze the changes in individual levels of these markers. MATERIALS AND METHODS. The main group consisted of 16 individuals (age – 57.5 (43.8; 64.5) years, 8 (50.0 %) men, 7 (50.0 %) women), who were examined twice: at visit 1 – on day 60.0 (56.3; 62.5) from the onset of the disease; at visit 2 – on day 312.5 (300.0; 365.0) from the onset of the disease. The control group consisted of 10 individuals (age – 58.5 (39.5; 67.8) years, 4 (40.0 %) men, 6 (60.0 %) women). General clinical and laboratory methods were used, as well as an assessment of lung diffusion capacity (DLсо). RESULTS. At visit 1, the clinical status of 16 (100.0 %) individuals in the main group was impaired. At visit 2, the clinical status of 12 (75.0 %) individuals normalized, while 4 (25.0 %) individuals showed improvement; the severity of dyspnea according to the mMRC scale and heart rate decreased, and SpO2 and DLсо levels increased (p&lt;0.01, p&lt;0.01, p&lt;0.01, and p=0.03, respectively). The level of endothelin-1 in the control group was 14.6 (11.7; 17.0) pg/ml, and the thrombomodulin level was 451.7 (403.9; 652.4) pg/ml. The level of endothelin-1 at visit 1 in the main group was 11.1 (6.8; 15.9) pg/ml, and at visit 2 – 14.4 (11.2; 20.0) pg/ml (p=0.02), not differing from the control group (p=0.48 and p=0.61, respectively). The level of thrombomodulin at visit 1 in the main group was 723.1 (689.1; 1012.2) pg/ml, and at visit 2 – 811.5 (713.3; 911.7) pg/ml (p=0.40), which was higher than in the control group (p=0.01 and p=0.01, respectively). CONCLUSIONS. One year after COVID-19, most individuals show normalization of clinical status and improvement in lung diffusion capacity; however, elevated thrombomodulin levels persist, which requires further investigation. In some patients, the level of endothelin-1 also increases, which is why they should be monitored not only by a family doctor or a pulmonologist but also by a cardiologist.

The role of markers of endothelial dysfunction in the pathogenesis of coronary microvascular dysfunction in patients with non-obstructive coronary artery disease

Aim. To study the potential of non-invasive biomarkers in the diagnosis of coronary microvascular dysfunction (CMD) and prediction of the course of heart failure with preserved ejection fraction (HFpEF) in non-obstructive coronary artery disease.Materials and methods. The 12-month observational study included 118 consecutive patients (6 patients dropped out of the study due to contact loss) with non-obstructive coronary artery disease (CAD) and HFpEF (62 [59; 64]%). At the beginning of the study, serum levels of several biomarkers were assessed using the enzyme immunoassay: N-terminal pro-B-type natriuretic peptide (NT-proBNP), vascular endothelial growth factor (VEGF), and endothelin-1. Coronary flow reserve (CFR) was examined using dynamic single photon emission computed tomography. In the absence of obstructive CAD, CMD was defined as a global decrease in CFR ≤ 2. Echocardiography was used to determine parameters of hemodynamics, LV diastolic dysfunction, and myocardial stress. LV global longitudinal strain (GLS) was assessed using 2D speckle tracking.Results. The patients were divided into groups depending on the presence of CMD: group 1 included patients with CMD (n = 43), group 2 included those without it (n = 75). In patients in group 1, serum levels of endothelin-1 were 1.9 times higher (p = 0.012), levels of VEGF were 2.16 times higher (p = 0.008), and the concentration of NT-proBNP was 2.6 times higher (p = 0.004) than in patients in group 2. According to the ROC analysis, the concentrations of endothelin-1 ≥ 6.9 pg / ml (AUC = 0.711; p = 0.040) and VEGF ≥ 346.7 pg / ml (AUC = 0.756; p = 0.002) were considered as markers associated with the presence of CMD in patients with non-obstructive CAD. The multivariate regression analysis showed that only the presence of CMD (odds ratio (OR) 2.42; 95% confidence interval (95% CI) 1.26–5.85; p &lt; 0.001) and an increase in NT-proBNP ≥ 760.5 pg / ml (OR 1.33; 95% CI 1.08–3.19; p = 0.023) were factors associated with adverse events, and their combination increased the risk of HFpEF progression by more than 3 times (OR 3.18; 95% CI 2.76–7.98; p &lt; 0.001), whereas markers of endothelial dysfunction were not independent predictors. Conclusion. Endothelin-1 ≥ 6.9 pg / ml and VEGF ≥ 346.7 pg / ml can be used as non-invasive markers for the diagnosis of CMD. However, markers of endothelial dysfunction were not independent predictors of HFpEF progression in patients with non-obstructive CAD during 12-month follow-up.

Efficacy of combined use of octreotide and sodium tanshinone IIA sulfonate in patients with cirrhosis complicated with severe acute pancreatitis

Purpose: To assess the prognosis of liver cirrhosis complicated with severe acute pancreatitis (SAP) after treatment with octreotide in combination with sodium tanshinone IIA sulfonate. Methods: A total of 164 patients with cirrhosis complicated with SAP were randomly assigned to two groups, each with 82 patients. Serum levels of inflammatory factors, as well as vascular endothelial function and liver function indices were determined. Treatment outcomes in the patients were recorded in terms of abdominal pain relief time, gastrointestinal function recovery time, hospital stay duration, and incidence of complications. Results: Relative to the control group, there were decreases in concentrations of inflammatory indices in the study cohort. Endothelial function index levels increased in the two groups, but the levels of endothelin (ET) and von Willebrand Factor (vWF) decreased more in the study group of patients, when compared to the control group, while nitric oxide (NO) level was raised (p &lt; 0.05). Liver function improved in both groups. There were marked reductions in serum ALT, AST and total bilirubin (TBIL) in study cohort, relative to the control cohort (p &lt; 0.05). However, albumin (ALB) levels were comparable in the two groups. Abdominal pain relief time, duration of hospitalization and time taken for normal digestive system function were shorter in the study cohort (p &lt; 005). Receiver operating characteristic (ROC) curve analysis revealed that after treatment with octreotide and sodium tanshinone IIA sulfonate, values of area under the curve (AUC) for abdominal pain relief time, gastrointestinal function recovery time and hospital stay were 0.886, 0.918 and 0.794, respectively. Conclusion: The combined use of octreotide and sodium tanshinone IIA sulfonate inhibits the release of inflammatory factors in cirrhotic patients with SAP, and improves vascular endothelial and liver functions, thereby improving disease prognosis. These data constitute a good scientific basis for the use of octreotide and sodium tanshinone IIA sulfonate in the treatment of liver cirrhosis complicated with SAP.

Complex regulation of tau phosphorylation by the endothelin system in brain microvascular endothelial cells (BMVECs): link to barrier function.

Endothelin-1 (ET-1), the most potent vasoconstrictor identified to date, contributes to cerebrovascular dysfunction. ET-1 levels in postmortem brain specimens from individuals diagnosed with Alzheimer's disease (AD) and related dementias (ADRD) were shown to be related to cerebral hypoxia and disease severity. ET-1-mediated vascular dysfunction and ensuing cognitive deficits have also been reported in experimental models of AD and ADRD. Moreover, studies also showed that ET-1 secreted from brain microvascular endothelial cells (BMVECs) can affect neurovascular unit integrity in an autocrine and paracrine manner. Vascular contributions to cognitive impairment and dementia (VCID) is a leading ADRD cause known to be free of neuronal tau pathology, a hallmark of AD. However, a recent study reported cytotoxic hyperphosphorylated tau (p-tau) accumulation, which fails to bind or stabilize microtubules in BMVECs in VCID. Thus, the study aimed to determine the impact of ET-1 on tau pathology, microtubule organization, and barrier function in BMVECs. Cells were stimulated with 1 μM ET-1 for 24 h in the presence/absence of ETA (BQ123; 20 μM) or ETB (BQ788; 20 μM) receptor antagonists. Cell lysates were assayed for an array of phosphorylation site-specific antibodies and microtubule organization/stabilization markers. ET-1 stimulation increased p-tau Thr231 but decreased p-tau Ser199, Ser262, Ser396, and Ser214 levels only in the presence of ETA or ETB antagonism. ET-1 also impaired barrier function in the presence of ETA antagonism. These novel findings suggest that (1) dysregulation of endothelial tau phosphorylation may contribute to cerebral microvascular dysfunction and (2) the ET system may be an early intervention target to prevent hyperphosphorylated tau-mediated disruption of BMVEC barrier function.

Transpulmonary Plasma Endothelin-1 Arterial:Venous Ratio Differentiates Survivors from Non-Survivors in Critically Ill Patients with COVID-19-Induced Acute Respiratory Distress Syndrome.

Endothelin-1 (ET-1) is a potent vasoconstrictor produced by endothelial cells and cleared from circulating blood mainly in the pulmonary vasculature. In a healthy pulmonary circulation, the rate of local production of ET-1 is less than its rate of clearance. In the present study, we aimed to investigate whether the abnormal pulmonary circulatory handling of ET-1 relates to poor clinical outcomes in patients with coronavirus disease 2019 (COVID-19)-induced acute respiratory distress syndrome (ARDS). To this end, central venous and systemic arterial ET-1 plasma levels were simultaneously measured on Days 1 and 3 following ICU admission in mechanically ventilated COVID-19 patients with ARDS (COVID-19 ARDS, N = 18). Central venous and systemic arterial ET-1 plasma levels were also measured in two distinct SARS-CoV-2-negative mechanically ventilated critically ill patient groups, matched for age, sex, and critical illness severity, with ARDS (non-COVID-19 ARDS, N = 14) or without ARDS (non-COVID-19 non-ARDS, N = 20). Upon ICU admission, COVID-19-induced ARDS patients had higher systemic arterial and central venous ET-1 levels compared to the non-COVID-19 ARDS and non-COVID-19 non-ARDS patients (p < 0.05), yet a normal systemic arterial:central venous (A:V) ET-1 ratio [0.63 (0.49-1.02)], suggesting that pulmonary ET-1 clearance is intact in these patients. On the other hand, the non-COVID-19 ARDS patients demonstrated abnormal ET-1 handling [A:V ET-1 ratio 1.06 (0.93-1.20)], while the non-COVID-19 non-ARDS group showed normal ET-1 handling [0.79 (0.52-1.11)]. On Day 3, the A:V ratio in all three groups was <1. When the COVID-19 ARDS patients were divided based on 28-day ICU mortality, while their systemic arterial and central venous levels did not differ, the A:V ET-1 ratio was statistically significantly higher upon ICU admission in the non-survivors [0.95 (0.78-1.34)] compared to the survivors [0.57 (0.48-0.92), p = 0.027]. Our results highlight the potential importance of ET-1 as both a biomarker and a therapeutic target in critically ill COVID-19 patients. The elevated A:V ET-1 ratio in non-survivors suggests that the early disruption of pulmonary ET-1 handling may be a key marker of poor prognosis.

Melatonin Inhibits ET-1 Production to Break Crosstalk Between Prostate Cancer and Bone Cells: Implication for Osteoblastic Bone Metastasis Treatment.

Bone metastasis is the primary cause of death among patients with advanced prostate cancer (PCa). PCa tends to spread to bones and acquire the bone-like phenotype, causing osteoblastic bone metastasis. Unfortunately, there is no effective treatment for this condition. However, melatonin, which regulates our circadian rhythm, has been found to have anti-tumor properties. It has yet to be established whether it is effective in treating osteoblastic PCa metastasis. Our findings show that melatonin inhibits the production of endothelin-1 (ET-1) in osteoblastic PCa cells, suppressing osteoblast differentiation. Clinical results indicate that bone metastatic PCa patients have higher levels of ET-1 compared to nonmetastatic PCa patients. Furthermore, melatonin-induced miR-let-7f-5p inhibits ET-1-promoted osteoblast differentiation in osteoblastic PCa. Melatonin also suppresses the property of osteomimicry in osteoblastic PCa cells. Importantly, in the intratibia injection PCa metastasis model, melatonin decreased osteoblastic PCa tumor growth, inhibiting ET-1 production and osteoblast differentiation in vivo. Taken together, melatonin inhibits osteoblastic PCa-regulated osteoblastogenesis by reducing ET-1 production through upregulation of miR-let-7f-5p, while suppressing the property of osteomimicry in osteoblastic PCa. Melatonin therapy could be a promising approach to treating bone metastasis in osteoblastic PCa.

The Relationship between Vascular Biomarkers (Serum Endocan and Endothelin-1), NT-proBNP, and Renal Function in Chronic Kidney Disease, IgA Nephropathy: A Cross-Sectional Study

IgA nephropathy (IgAN) is the most common primary glomerular disease. Endothelin-1 (ET-1) is one of the strongest vasoconstrictor materials in the blood. The N-terminal prohormone of brain natriuretic peptide (NT-proBNP) is associated with renal function and poor outcomes in chronic kidney disease (CKD). Serum endocan is a biomarker associated with proinflammatory cytokines, and the increase in the serum level plays a critical role in inflammatory, proliferative, and neovascularization processes and is associated with poor cardiovascular outcomes in patients with CKD too. Identifying high-risk patients using biomarkers could help to optimize their treatment. Ninety patients with biopsy-confirmed IgAN were included in the study (50 males/40 females, mean age: 54.9 ± 14.4 years). Serum endocan, ET-1, and NT-proBNP were measured by enzyme-linked immunosorbent assay kits. Echocardiography was performed, and carotid-femoral pulse wave velocity (cfPWV) was measured by SphygmoCor in this cross-sectional study. Patients were divided into two groups based on serum endocan median level (cut-off: 44 ug/L). There was significantly higher aorta systolic blood pressure (SBPao) (p = 0.013), NT-proBNP (p = 0.028), albumin/creatinine ratio (p = 0.036), and uric acid (p = 0.045) in the case of the higher endocan group compared to the lower. There was also significantly higher SBPao (p = 0.037) and NT-proBNP (p = 0.038) in the case of higher endothelin-1 (ET-1) levels compared to the lower (cut-off: 231 pg/mL) group by the two-sample t-test. Then, we divided the patients into two groups based on the eGFR (CKD 1–2 vs. CKD 3–5). The levels of serum endocan, NT-proBNP, cfPWV, SBPao, left ventricular mass index (LVMI), uric acid, and albuminuria were significantly higher in the CKD 3–5 group compared to the CKD 1–2 group. The serum endocan and NT-proBNP levels were significantly higher in the diastolic dysfunction group (p = 0.047, p = 0.015). There was a significant increase in serum endocan levels (CKD 1 vs. CKD 5; p = 0.008) with decreasing renal function. In IgAN, vascular biomarkers (endocan, ET-1) may play a role in endothelial dysfunction through vascular damage and elevation of SBPao. Serum endocan, ET-1, and NT-proBNP biomarkers may help to identify IgAN patients at high risk.

Effects of Dezocine and Propofol Combination on Plasma 5-HT and ET Levels in Stroke Patients Undergoing Thrombolysis

Objective: To investigate the effect of dezocine combined with propofol on brain metabolism in patients undergoing cerebral thrombosis thrombolysis. Methods: A total of 86 stroke patients admitted between July 2022 and December 2023 were randomly divided into two groups: Group A (study group) and Group B (control group), with 43 patients in each group. Both groups underwent intra-arterial thrombolysis therapy. Group B received dezocine for anesthesia, while Group A received a combination of dezocine and propofol. Plasma concentrations of 5-hydroxytryptamine and endothelin, as well as brain metabolic indicators, were compared between the two groups immediately after anesthesia, at 1 hour post-reperfusion, and 3 hours post-reperfusion. Results: There were no significant differences in the levels of 5-hydroxytryptamine and endothelin between the two groups immediately after anesthesia and at 1 hour post-reperfusion (P &gt; 0.05). However, at 3 hours post-reperfusion, the levels of 5-hydroxytryptamine and endothelin in Group A were significantly lower than those in Group B. Furthermore, in Group A, the levels of 5-hydroxytryptamine and endothelin at 3 hours post-reperfusion were lower compared to the levels at 1 hour post-reperfusion (P &lt; 0.05). Conclusion: Dezocine combined with propofol can effectively improve the quality of anesthesia and has a minimal effect on brain metabolic indices, suggesting reduced damage to brain metabolism.

Research on the Improvement of Endothelial Cell Function and Trophoblast Apoptosis in Rats with Preeclampsia by Tanshinone IIA

Background Preeclampsia is a pregnancy complication characterized by high blood pressure and signs of damage to another organ system, often the kidneys. Recent studies suggest that endothelial dysfunction and trophoblast apoptosis are involved in the pathogenesis of preeclampsia. Purpose To investigate the effects of tanshinone IIA (TIIA) on clinical symptoms, vascular endothelial function, and placental trophoblast apoptosis in preeclampsia rats. Materials and Methods Twenty-four pregnant Sprague-Dawley rats, between 8 and 10 weeks old, were randomly divided and allocated into three groups: Control, model, and treatment, with each group consisting of 8 rats. The control group received normal saline injections via the tail vein; the model group received NG-nitro-l-arginine methyl ester (l-NAME) to induce preeclampsia, followed by normal saline injections; and the treatment group received TIIA (10 mg/kg) via tail vein injection after preeclampsia induction with l-NAME. Various parameters were measured, including tail artery systolic pressure, 24-hour proteinuria, offspring and placental weight, levels of endothelial nitric oxide synthase (eNOS), endothelin-1 (ET-1), placental growth factor (PLGF), and soluble FMS-like tyrosine kinase 1 (sFlt-1) in serum, and expression of B-cell lymphoma-2 (Bcl-2) and Bcl-2-related X protein (Bax) in placental trophoblasts. Results TIIA treatment led to decreased tail artery systolic pressure and 24-hour urine protein levels, increased body and placental weights of offspring, and favorable changes in serum levels of ET-1, sFlt-1, eNOS, and PLGF. Moreover, TIIA treatment resulted in decreased Bax levels and apoptosis in placental trophoblasts, along with increased Bcl-2 levels. Conclusion TIIA can improve the clinical symptoms of preeclampsia in rats induced by l-NAME, alleviate the apoptosis of placental trophoblast cells, and improve vascular endothelial function.

Evaluation of some nonroutine cardiac biomarkers among adults and children with beta-thalassemia major.

Cardiac injury caused by iron overload is the leading cause of mortality and morbidity in patients with beta-thalassemia, owing to frequent blood transfusion, increased iron overload, and blood hemolysis. This research aimed to assess several novel cardiac biomarkers in the blood samples of children and adult patients with beta-thalassemia major (βTM), along with their respective control groups. These biomarkers included endothelin 1 (ET-1), N-terminal pro-brain natriuretic peptide (NT-proBNP), atrial natriuretic peptide (ANP), growth differentiation factor-15 (GDF-15), and renalase (RNLS). This case-control study was done on 46 patients with βTM (23 children <18 years, and 23 adults ≥18 years) from the Genetic Hematology Center in Thi-Qar province, Iraq, and 42 comparable controls in 2 groups (21 for each group) in the period from February to April 2023. Levels of ET-1, NT-proBNP, ANP, GDF-15, RNLS, and ferritin were higher in the children and adults with βTM than in the control subjects. Elevations of the novel cardiac biomarkers ET-1, NT-proBNP, ANP, GDF-15, and RNLS in the sera of children and adult patients with βTM when compared with comparable control subjects confirm that the majority of patients with βTM are at risk of cardiac and cardiovascular complications even when there are no obvious symptoms, especially in children, which gives suitable predictive biomarkers.