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Copyright of Herz is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Objective To explore the mechanism of action of urantide in ameliorating renal injury caused by atherosclerosis(AS). Methods The rats were divided into normal group, model group which were treated with ip VitD3 150 U/(kg·d-1) for 3 consecutive days, and fed with high-fat special diet, with an experimental period of 6 weeks], simvastatin group [5 μg/(kg·d-1) for 14 consecutive days] and intervention model group [urantide 30 μg/(kg·d-1),7 d and 14 d]. Microscopy was performed for observing pathological changes in the kidney and evaluation of the degree of renal tissue damage. RT-qPCR and immuno-histochemical staining microscopy was used to detect the expression of related genes and proteins. Results Compared to the normal group, the model group showed glomerular atrophy in the renal tissue and adhesion with surrounding tissues. The experiment found a series of changes in renal tubular epithelial cells, such as edema and degeneration, accompanied by a small area of cell necrosis. Sclerosis was found in the glomerulus; Increased positive expression of genes and proteins related to JAK2 and STAT3 (P＜0.05,P＜0.01)was found . Compared to the model group, urantide groups with prolongated medicine administration and the pathological changes that occur in the kidney tissue showed obvious improvement and upturned. At the same time, the degree of glomerulosclerosis decreased and renal tubulointerstitial injury was improved(P＜0.01); Positive expression of genes and proteins related to JAK2 and STAT3 (P＜0.05, P＜0.01) all decreased. Conclusions Urantide may inhibit JAK2/STAT3 signal pathway and this finding may support the development of clinical strategy for the prevention and treatment of AS related renal injury.

Chronic kidney disease (CKD) is a progressive and long-term condition marked by a gradual decline in kidney function. CKD is prevalent among those with conditions such as diabetes mellitus, hypertension, and glomerulonephritis. Affecting over 10% of the global population, CKD stands as a significant cause of morbidity and mortality. Despite substantial advances in understanding CKD pathophysiology and management, there is still a need to explore novel mechanisms and potential therapeutic targets. Urotensin II (UII), a potent vasoactive peptide, has garnered attention for its possible role in the development and progression of CKD. The UII system consists of endogenous ligands UII and UII-related peptide (URP) and their receptor, UT. URP pathophysiology is understudied, but alterations in tissue expression levels of UII and UT and blood or urinary UII concentrations have been linked to cardiovascular and kidney dysfunctions, including systemic hypertension, chronic heart failure, glomerulonephritis, and diabetes. UII gene polymorphisms are associated with increased risk of diabetes. Pharmacological inhibition or genetic ablation of UT mitigated kidney and cardiovascular disease in rodents, making the UII system a potential target for slowing CKD progression. However, a deeper understanding of the UII system's cellular mechanisms in renal and extrarenal organs is essential for comprehending its role in CKD pathophysiology. This review explores the evolving connections between the UII system and CKD, addressing potential mechanisms, therapeutic implications, controversies, and unexplored concepts.

Objective To explore the mechanism of action of urantide in ameliorating renal injury caused by atherosclerosis (AS). Methods The rats were divided into normal group, model group which were treated with ip VitD3 150 U/(kg·d-1) for 3 consecutive days, and fed with high-fat special diet, with an experimental period of 6 weeks], simvastatin group [5 μg/(kg·d-1) for 14 consecutive days] and intervention model group [urantide 30 μg/(kg·d-1), 7 d and 14 d]. Microscopy was performed for observing pathological changes in the kidney and evaluation of the degree of renal tissue damage. RT-qPCR and immuno-histochemical staining microscopy was used to detect the expression of related genes and proteins. Results Compared to the normal group, the model group showed glomerular atrophy in the renal tissue and adhesion with surrounding tissues. The experiment found a series of changes in renal tubular epithelial cells, such as edema and degeneration, accompanied by a small area of cell necrosis. Sclerosis was found in the glomerulus; Increased positive expression of genes and proteins related to JAK2 and STAT3 (P＜0.05,P＜0.01) was found. Compared to the model group, urantide groups with prolongated medicine administration and the pathological changes that occur in the kidney tissue showed obvious improvement and upturned. At the same time, the degree of glomerulosclerosis decreased and renal tubulointerstitial injury was improved (P＜0.01) ; Positive expression of genes and proteins related to JAK2 and STAT3 (P＜0.05, P＜0.01) all decreased. Conclusions Urantide may inhibit JAK2/STAT3 signal pathway and this finding may support the development of clinical strategy for the prevention and treatment of AS related renal injury. [ABSTRACT FROM AUTHOR]

The effect of urotensin II (U-II), a powerful endogenous vasoconstrictor substance, on the immune system and its mediators is very important. It was herein aimed to demonstrate the possible relationship between the calcineurin/nuclear factor of activated T-cells cytoplasmic 1/interleukin-2 (CaN/NFATc/IL-2) pathway and urotensin receptors (UTRs) in inflammatory response due to lipopolysaccharide (LPS). An LPS-induced inflammation model was used on the human umbilical vein endothelial cells (HUVEC) cell line and drugs were applied accordingly, forming the following groups: Control Group, LPS Group, Agonist Group (10−8 ​M U-II), Antagonist Group (10−6 ​M palosuran), Tacrolimus (TAC) Group (10 ​ng/mL FK-506), Agonist ​+ ​TAC Group, and Antagonist ​+ ​TAC Group. Gene expression analyses were performed using real-time polymerase chain reaction (RT-PCR). In the analysis of the cell viability at 48 and 72 ​h, there was a decrease in the Agonist Group, while in the Agonist ​+ ​TAC Group, the cell viability increased. In the Antagonist Group, cell viability was maintained when compared to the LPS Group, while in the TAC Group, this effect was reduced. The mRNA expression levels of UTR, CaN, NFATc, IL-2 receptor (IL-2R), IL-6 and nuclear factor kappa B (NF-κB) were higher in the LPS Group than in the Control Group, and even the UTR, CaN, NFATc, IL-2R were higher with agonist administration. This effect of the agonist was shown to be completely mitigated in the presence of the CaN inhibitor. U-II and its receptors can perform key functions regarding the endothelial cell damage via the CaN/NFATc/IL-2 pathway. [ABSTRACT FROM AUTHOR]

Objective. To investigate whether Smad2/3 signaling is involved in urotensin II (UII) induced activation of aortic adventitial fibroblasts. Materials and Methods. Growth-arrested adventitial fibroblasts were stimulated with UII in the presence or absence of urotensin II receptor (UT) antagonist SB710411 or transfected with Smad2/3 small inhibitory RNA (siRNA). UII-stimulated Smad2/3 phosphorylation, α-smooth muscle actin (α-SMA), and collagen I expression and migration of adventitial fibroblasts were evaluated by western blot analysis, real-time reverse transcription polymerase chain reaction, immunofluorescence, ELISA, and transwell migration assay, respectively. Results. In cultured adventitial fibroblasts, UII time- and dose-dependently stimulated Smad2/3 protein phosphorylation, with maximal effect at 10-8 mol/l (increased by 147.2%, P<0.001). UII stimulated Smad2/3 upregulation and nuclear translocation. SB710411 significantly inhibited these effects. In addition, UII potently induced α-SMA and procollagen 1 protein or mRNA expression (P<0.01), which were completely blocked by Smad2 (decreased by 75.1%, 54.2% in protein, and by 73.3% and 38.2% in mRNA, respectively, P<0.01) or Smad3 siRNA (decreased by 80.3% and 47.0% in protein, and by 72.3% and 47.7% in mRNA, respectively, P<0.01). Meanwhile, Smad2 or smad3 siRNA significantly inhibited the UII-induced collagen 1 secretion and cell migration. Conclusions. UII may stimulate adventitial-fibroblast phenotype conversion, migration, and collagen I synthesis via phosphorylated-Smad2/3 signal transduction pathways. [ABSTRACT FROM AUTHOR]

Obstructive sleep apnea (OSA) has become major public concern and is continuously investigated in new aspects of pathophysiology and management. Urotensin II (UII) is a powerful vasoconstrictor with a role in cardiovascular diseases. The main goal of this study was to evaluate serum UII levels in OSA patients and matched controls. A total of 89 OSA patients and 89 controls were consecutively enrolled. A medical history review and physical examination of the participants was conducted, with polysomnography performed in the investigated group. UII levels and other biochemical parameters were assessed according to the standard laboratory protocols. The median AHI in the OSA group was 39.0 (31.4–55.2) events/h, and they had higher levels of hsCRP when compared to control group (2.87 ± 0.71 vs. 1.52 ± 0.68 mg/L; p < 0.001). Additionally, serum UII levels were significantly higher in the OSA group (3.41 ± 1.72 vs. 2.18 ± 1.36 ng/mL; p < 0.001), while positive correlation was found between UII levels and hsCRP (r = 0.450; p < 0.001) and systolic blood pressure (SPB) (r = 0.317; p < 0.001). Finally, multiple regression analysis showed significant association of UII levels with AHI (0.017 ± 0.006, p = 0.013), SBP (0.052 ± 0.008, p < 0.001) and hsCRP (0.538 ± 0.164, p = 0.001). As UII levels were associated with blood pressure and markers of inflammation and OSA severity, it might play an important role in the complex pathophysiology of OSA and its cardiometabolic complications. [ABSTRACT FROM AUTHOR]

Abstract Urotensin II (U‐II) and its receptor (UT) are involved in the pathogenesis of various diseases; however, their association with the development of cystitis has not been elucidated. The present study was designed to investigate the functional role of U‐II/UT signaling in cyclophosphamide (CYP)‐induced cystitis. A total of 60 female rats were randomly divided into the control and CYP‐treated groups. Intraperitoneal injection of CYP successfully induced cystitis in rats of the CYP‐treated group. The protein and mRNA expression levels of U‐II and UT were significantly enhanced in rat bladder tissues of the CYP‐treated group. Furthermore, the results of the immunofluorescence staining analysis demonstrated that CYP treatment apparently increased the expression levels of UT in the urothelium layer, detrusor smooth muscle, and bladder interstitial Cajal‐like cells. The selective antagonist of UT, SB657510 (10 μm), significantly suppressed the CYP‐induced increase in the spontaneous contractions of muscle strips and ameliorated the bladder hyperactivity of CYP‐treated rats. Moreover, CYP treatment significantly increased the protein expression levels of Ras homolog family member (Rho) A and Rho‐associated protein kinase 2 in rat bladder tissues. Following pretreatment with the Rho‐kinase inhibitor Y‐27632 (10 μm), the inhibitory effects of SB657510 (10 μm) on the spontaneous contractions of muscle strips were eliminated. In conclusion, the results of the present study suggested that activation of U‐II/UT signaling promoted the development of cystitis‐associated‐bladder hyperactivity by targeting the RhoA/Rho‐kinase pathway, indicating that the U‐II/UT signaling could serve as a novel target for the treatment of interstitial cystitis/bladder pain syndrome.

Introduction. Urotensin II (U II) is a kind of active peptide with a variety of biological effects, such as promoting cell proliferation and endocrine effects. The aim of this study is to investigate the effect of urotensin II on the proliferation and secretion of vascular endothelial growth factor (VEGF) in cultured rat dermal papilla cells (DPCs), and to explore its molecular mechanism. Materials and Methods. We used the DPCs isolated from the thoracic aortas of Wistar-Kyoto rats to run the CCK8 and ELISA assay, RC-PCR and Western blotting techniques to identify the effect of Urotensin II on the proliferation and secretion of VEGF in DPCs, data were analyzed by one-way ANOVA or t-test. Results. U II can increase the mRNA expression of proliferation markers Ki67 and PCNA. In addition, the Wnt/β-catenin pathway was activated by U II, but Wnt inhibitor DKK1 reversed the effect of U II. Conclusions. U II promoted the proliferation and secretion of VEGF in rat DPCs through activation of the Wnt-β-catenin signaling pathway. [ABSTRACT FROM AUTHOR]

Introduction. Urotensin II (U II) is a kind of active peptide with a variety of biological effects, such as promoting cell proliferation and endocrine effects. The aim of this study is to investigate the effect of urotensin II on the proliferation and secretion of vascular endothelial growth factor (VEGF) in cultured rat dermal papilla cells (DPCs), and to explore its molecular mechanism. Materials and Methods. We used the DPCs isolated from the thoracic aortas of Wistar-Kyoto rats to run the CCK8 and ELISA assay, RC-PCR and Western blotting techniques to identify the effect of Urotensin II on the proliferation and secretion of VEGF in DPCs, data were analyzed by one-way ANOVA or t-test. Results. U II can increase the mRNA expression of proliferation markers Ki67 and PCNA. In addition, the Wnt/ß-catenin pathway was activated by U II, but Wnt inhibitor DKK1 reversed the effect of U II. Conclusions. U II promoted the proliferation and secretion of VEGF in rat DPCs through activation of the Wnt-ß-catenin signaling pathway. [ABSTRACT FROM AUTHOR]

Copyright of Firat Universitesi Sağlik Bilimleri Tip Dergisi is the property of Firat Universitesiu, Saglik Bilimleri Enstitusu and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Accumulated evidence shows that elevated urotensin II (UII) levels are associated with cardiovascular diseases. However, the role of UII in the initiation, progression, and regression of atherosclerosis remains to be verified. Different stages of atherosclerosis were induced in rabbits by a 0.3% high cholesterol diet (HCD) feeding, and either UII (5.4 μg/kg/h) or saline was chronically infused via osmotic mini-pumps. UII promoted atherosclerotic fatty streak formation in ovariectomized female rabbits (34% increase in gross lesion and 93% increase in microscopic lesion), and in male rabbits (39% increase in gross lesion). UII infusion significantly increased the plaque size of the carotid and subclavian arteries (69% increase over the control). In addition, UII infusion significantly enhanced the development of coronary lesions by increasing plaque size and lumen stenosis. Histopathological analysis revealed that aortic lesions in the UII group were characterized by increasing lesional macrophages, lipid deposition, and intra-plaque neovessel formation. UII infusion also significantly delayed the regression of atherosclerosis in rabbits by increasing the intra-plaque macrophage ratio. Furthermore, UII treatment led to a significant increase in NOX2 and HIF-1α/VEGF-A expression accompanied by increased reactive oxygen species levels in cultured macrophages. Tubule formation assays showed that UII exerted a pro-angiogenic effect in cultured endothelial cell lines and this effect was partly inhibited by urantide, a UII receptor antagonist. These findings suggest that UII can accelerate aortic and coronary plaque formation and enhance aortic plaque vulnerability, but delay the regression of atherosclerosis. The role of UII on angiogenesis in the lesion may be involved in complex plaque development. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Zhejiang University: Science B is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Urotensin II (UII) could increase blood pressure and heart rate via increased central reactive oxygen species (ROS) levels. We reported previously that hydrogen sulfide (H2S) exerts an antihypertensive effect by suppressing ROS production. The aim of the current study is to further examine the effects of endogenous and exogenous H2S on UII-induced cardiovascular effects by using an integrated physiology approach. We also use cell culture and molecular biological techniques to explore the inhibitory role of H2S on UII-induced cardiovascular effects. In this study, we found that cystathionine-β-synthase (CBS), the main H2S synthesizing enzyme in CNS, was expressed in neuronal cells of the rostral ventrolateral medulla (RVLM) area. Cellular distribution of CBS and urotensin II receptor (UT) in SH-SY5Y cells that are confirmed as glutamatergic were identified by immunofluorescent and Western blots assay. In Sprague–Dawley rats, administration of UII into the RVLM resulted in an increase in mean arterial pressure (MAP), heart rate (HR), ROS production, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, and phosphorylation of p47phox, extracellular signal-regulated protein kinase (ERK)1/2 and p38MAPK, but not stress-activated protein kinase/Jun N-terminal kinase (SAPK/JNK). These effects of UII were attenuated by application into the RVLM of endogenous (L-cysteine, SAM) or exogenous (NaHS) H2S. These results were confirmed in SH-SY5Y cells. UII-induced cardiovascular effects were also significantly abolished by pretreatment with microinjection of Tempol, Apocynin, SB203580, or PD98059 into the RVLM. Preincubated SH-SY5Y cells with Apocynin before administration of UII followed by Western blots assay showed that ROS is in the upstream of p38MAPK/ERK1/2. Gao activation assay in SH-SY5Y cells suggested that H2S may exert an inhibitory role on UII-induced cardiovascular effects by inhibiting the activity of Gαo. These results suggest that both endogenous and exogenous H2S attenuate UII-induced cardiovascular effects via Gαo-ROS-p38MAPK/ERK1/2 pathway. [ABSTRACT FROM AUTHOR]

Urotensin II (U‐II) and its receptor (UT) are involved in the pathogenesis of various diseases; however, their association with the development of cystitis has not been elucidated. The present study was designed to investigate the functional role of U‐II/UT signaling in cyclophosphamide (CYP)‐induced cystitis. A total of 60 female rats were randomly divided into the control and CYP‐treated groups. Intraperitoneal injection of CYP successfully induced cystitis in rats of the CYP‐treated group. The protein and mRNA expression levels of U‐II and UT were significantly enhanced in rat bladder tissues of the CYP‐treated group. Furthermore, the results of the immunofluorescence staining analysis demonstrated that CYP treatment apparently increased the expression levels of UT in the urothelium layer, detrusor smooth muscle, and bladder interstitial Cajal‐like cells. The selective antagonist of UT, SB657510 (10 μm), significantly suppressed the CYP‐induced increase in the spontaneous contractions of muscle strips and ameliorated the bladder hyperactivity of CYP‐treated rats. Moreover, CYP treatment significantly increased the protein expression levels of Ras homolog family member (Rho) A and Rho‐associated protein kinase 2 in rat bladder tissues. Following pretreatment with the Rho‐kinase inhibitor Y‐27632 (10 μm), the inhibitory effects of SB657510 (10 μm) on the spontaneous contractions of muscle strips were eliminated. In conclusion, the results of the present study suggested that activation of U‐II/UT signaling promoted the development of cystitis‐associated‐bladder hyperactivity by targeting the RhoA/Rho‐kinase pathway, indicating that the U‐II/UT signaling could serve as a novel target for the treatment of interstitial cystitis/bladder pain syndrome. [ABSTRACT FROM AUTHOR]

Both vascular adventitial fibroblasts (VAFs) and urotensin II (UII) play important roles in vascular remodeling diseases, but the mechanism of UII in VAFs is still unclear. UII inhibited miR-124 expression through up-regulating circ0004372 expression, thereby promoting SERTAD4 expression. UII significantly promoted the generation of ROS, MDA and 4-HNE, reduced the activities of SOD, GST and GR, increased Fe2+ concentration and inhibited GPX4 expression through circ0004372/miR-124/SERTAD4. Both UII and ferroptosis inducer Erastin significantly promoted the expression of α-SMA, Collagen I and TGF-β1 in VAFs, but circ0004372 siRNA, miR-124 mimics, SERTAD4 siRNA or Ferrostatin-1 significantly inhibited the effect of UII and Erastin on cell activation. When co-transfected with circ0004372 siRNA and miR-124 inhibitors or miR-124 mimics and SERTAD4 overexpression vector, UII still significantly increased the expression of α-SMA, Collagen I and TGF-β1. After transfection with circ0004372 overexpression vector, miR-124 inhibitors or SERTAD4 overexpression vector and then treating with UII and Ferrostatin-1, the expression of α-SMA, Collagen I and TGF-β1 was still significant; when the circ0004372 overexpression vector and miR-124 mimics or miR-124 inhibitors and SERTAD4 siRNA were co-transfected and then UII and Ferrostatin-1 were added, the expression of α-SMA, Collagen I and TGF-β1 was not significantly increased. Therefore, these results indicate that UII promotes the activation of VAFs through the circ0004372/miR-124/SERTAD4/ferroptosis pathway. [ABSTRACT FROM AUTHOR]

Objective: In this study, it was aimed to investigate Urotensin II in intrauterine growth restriction (IUGR) and its connection to autophagy and/or apoptosis in placenta and umbilical cord by immunohistochemical and biochemical methods., Materials and Methods: The study included 30 healthy pregnant women and 30 pregnant women with IUGR, aged 19-45, at Atatürk University Gynecology Clinic. Samples were collected from placenta, umbilical cord, maternal blood, and umbilical cord blood during delivery. Histopathological examination was carried out on placenta and umbilical cord, and UTII, Beclin 1, and caspase 3 expressions were analyzed in these tissues. Biochemical analysis was performed on maternal and umbilical cord serum samples., Results: In healthy placentas, normal villus formation was seen, but those with IUGR showed accelerated villus maturation, causing inadequate nutrition and development. IUGR placentas had fibrin deposition, villous edema, syncytial nodes increase, and intervillous distance. Umbilical cords of IUGR group had differences in vessel wall thickness, arterial lumens, and vessel number. Higher levels of UTII, Beclin 1, and caspase 3 were found in IUGR placenta and cord. Beclin 1 and caspase 3 levels were significantly higher in IUGR group compared to controls, while UTII levels were not significantly different in maternal and cord serums., Conclusion: As a result of our findings, UTII increase in placenta and umbilical cord may lead to IUGR formation by inducing autophagy and apoptosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Aldosterone is an important hormone in the renin-angiotensin-aldosterone system (RAAS), and playing a pivotal role in the development of hypertension, heart failure, and other cardiovascular diseases. Material and method: In this study, the role of the aldosterone in vascular calcification was underwent in rat model compared with other drugs. Vascular calcification, calcium concentration, activity of alkaline phosphatase (ALP), aldosterone, Urotensin II, mineralocorticoid receptor (MR) and Osteopontin (OPN) were detected or confirmed by the von Kossa staining, colorimetric assays, immunohistochemistry and radioimmunoassay, separately. Result: Results revealed that the aldosterone was significantly increased compared calcification + aldosterone group with calcification group, whereas it was notably decreased in calcification + Spironolactone group in the aortic wall. Compared with control group and aldosterone group, calcium content in vascular tissues was increased in calcification group and calcification + aldosterone group. As the immunoreactivity of the MR, OPN, Urotensin II, IL-6, monocyte chemoattractant protein-1, and deposition of collagen in calcification group and aldosterone group, they all were increased slightly, but were significantly increased in calcification + aldosterone group. Conclusion: It is implied that aldosterone may be involved in the development of vascular calcification, however, the mechanism needs to be further studied.

Objective  Urotensin II (U-II) is a potent vasoconstrictor peptide, and increased U-II levels are associated with atherosclerosis and hypertension in adults. Low birth weight (LBW) infants have higher risks of such diseases in the future. A small number of nephrons is one of possible mechanism underlying these risks in LBW infants, while vascular elasticity and cardiac function might be another important factor. The objective of this study is to evaluate U-II levels in preterm LBW infants at an early stage of life and determine perinatal factors associated with U-II levels. Study Design  The study population consisted of 57 preterm LBW infants (26 males and 31 females), including 49 appropriate for gestational age (AGA) and 8 small for gestational age (SGA) infants, born at a gestational age of ≤34 weeks with a mean birth weight of 1,589 g. Serum U-II levels were measured at term-equivalent age to evaluate perinatal factors related to serum U-II levels. Results  Preterm SGA infants had significantly higher serum U-II levels than preterm AGA infants at term-equivalent age (p  = 0.019). Serum U-II levels in preterm LBW infants at term-equivalent age were inversely correlated with birth weight standard deviation (SD) score in a simple regression analysis (r  =  − 0.395, p  = 0,002) and the correlation was maintained in the multiple regression analysis. Conclusion  Our results indicate that birth weight SD score might be associated with serum U-II levels in preterm LBW infants at term-equivalent age. Further studies are required to determine whether U-II levels at an early stage of life might influence the risk of atherosclerosis and hypertension. Key Points U-II is a potent vasoconstrictor. We evaluated serum U-II levels in preterm infants. Fetal growth is negatively related to serum U-II levels. [ABSTRACT FROM AUTHOR]

Gestational diabetes mellitus is glucose intolerance of varying degree with onset or first detection duringpregnancy, it can causelong and short term morbidities in both the mother and the child, such as shoulder dystocia, preeclampsia, and high blood pressure. The most powerful endogenous vasoconstrictor peptide, urotensin II, and its receptor are involved in the etiology of gestational diabetes mellitus. Aim of the study: The study's goal was to see if there is a link between Urotensin II levels and insulin resistance in pregnant women with gestational diabetes. Patients and method: A case-control study that was conducted in obstetrics and gynecology department at Baghdad Teaching hospital from the first of January 2019 to the end of December 2019. A sample of 80 pregnant women participated in the study fulfilling inclusion criteria. 40 of them diagnosed with gestational diabetes mellitus by (2 hours 75 gm. Oral glucose tolerance test) and 40 women as control group. Results: The mean age of the gestational diabetes mellitus group was 29.8±6.9 years and control was 29.7±6.6 years with no significant differences. The study showed highly significant increase infasting Insulin, fasting blood glucose, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), of the GDM group than that in the group without disease. Significant difference was found regarding high-sensitivity C-reactive protein hs-CRP (p=0.004). The level of Urotensin II in subjects with gestational diabetes was (109±33.22) highly increased than that in healthy subjects (78±22.6). There is a positive correlation between circulating Urotensin II levels with fasting insulin, and HOMA-IR. While negative correlation found with fasting blood glucose. [ABSTRACT FROM AUTHOR]

Obstructive sleep apnea (OSA) has become major public concern and is continuously investigated in new aspects of pathophysiology and management. Urotensin II (UII) is a powerful vasoconstrictor with a role in cardiovascular diseases. The main goal of this study was to evaluate serum UII levels in OSA patients and matched controls. A total of 89 OSA patients and 89 controls were consecutively enrolled. A medical history review and physical examination of the participants was conducted, with polysomnography performed in the investigated group. UII levels and other biochemical parameters were assessed according to the standard laboratory protocols. The median AHI in the OSA group was 39.0 (31.4–55.2) events/h, and they had higher levels of hsCRP when compared to control group (2.87 ± 0.71 vs. 1.52 ± 0.68 mg/L; p < 0.001). Additionally, serum UII levels were significantly higher in the OSA group (3.41 ± 1.72 vs. 2.18 ± 1.36 ng/mL; p < 0.001), while positive correlation was found between UII levels and hsCRP (r = 0.450; p < 0.001) and systolic blood pressure (SPB) (r = 0.317; p < 0.001). Finally, multiple regression analysis showed significant association of UII levels with AHI (0.017 ± 0.006, p = 0.013), SBP (0.052 ± 0.008, p < 0.001) and hsCRP (0.538 ± 0.164, p = 0.001). As UII levels were associated with blood pressure and markers of inflammation and OSA severity, it might play an important role in the complex pathophysiology of OSA and its cardiometabolic complications.

Behçet's disease (BD) is a chronic autoimmune inflammatory disease. Clinical studies revealed that both microRNAs and urotensin II (UTS2) play a significant role in the development of autoinflammatory diseases. The study aimed to determine the association between miR-146a rs2910164 and UTS2 rs228648 genetic variants and BD susceptibility. In addition, the relationship between these gene variants and clinical and laboratory outcomes among Egyptian patients was investigated. The distributions of miR-146a rs2910164 and UTS2 rs228648 (p.Thr21Met) variants were analyzed in 94 patients with BD and 115 healthy control subjects using polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) and Taqman Real-time PCR techniques. Frequencies of the G/G genotype and G allele of miR-146a rs2910164 variant were significantly higher in patients with BD compared with normal controls (p =.042, OR = 2.31; p =.022, OR = 1.58, respectively). The frequencies of the Thr/Thr genotype and the Thr allele of UTS2 rs228648 variant were significantly higher in subjects with BD compared with normal controls (p =.028, OR = 3.35; p =.032, OR = 1.60, respectively). Our results suggest that miR-146a rs2910164 and UTS2 rs228648 variants have significant roles in both the development and clinical modulation of BD in Egyptian patients. [ABSTRACT FROM AUTHOR]

Beyond the CNS, urotensin II (UII) and its receptor (UT) are fu nctionally expressed in peripheral tissues of the endocrine, cardiovascular, and renal systems. The expression levels of UII and UT in the kidney and circulating UII levels a re increased in diabetes. UII also promotes mesangial proliferation and matrix accumulation in vitro. Here, we evaluate the effect of UT deletion on the development of hypergl ycemia and diabetic kidney disease (DKD) in streptozotocin (STZ)-treated mice. Ten-week-old WT and UT knockout (KO) mice were injected with STZ for 5 days to induce diabetes. Blood glucose levels were measured weekly, and necropsy was performed 12 weeks after STZ injection. UT ablation slowed hyperglycemia and glucosuria in STZ-treated mice. UT KO also ameliorated STZ-induced increase in HbA1c, but not STZ-induced decrease in plasma insulin levels. However, STZ-induced increases in plasma glucagon concentration and immunohistochemical staining for glucagon in pancreatic islets were lessened in UT KO mice. UT ablation also protected against STZ-induced kidney derangements, including albuminuria, mesangial expansion, glomerular lesions, and glomerular endoplasmic reticulum stress. UT is expressed in a cultured pancreatic alpha cell line, and its activation by UII triggered membrane depolarization, T- and L-type voltage-gated Ca2+ channeldependent Ca2+ influx, and glucagon secretion. These findings suggest that apart from direct action on the kidneys to cause injury, UT activation by UII may result in DKD by promoting hyperglycemia via induction of glucagon secretion by pancreatic alpha cells. [ABSTRACT FROM AUTHOR]

Accumulated evidence shows that elevated urotensin II (UII) levels are associated with cardiovascular diseases. However, the role of UII in the initiation, progression, and regression of atherosclerosis remains to be verified. Different stages of atherosclerosis were induced in rabbits by a 0.3% high cholesterol diet (HCD) feeding, and either UII (5.4 μg/kg/h) or saline was chronically infused via osmotic mini-pumps. UII promoted atherosclerotic fatty streak formation in ovariectomized female rabbits (34% increase in gross lesion and 93% increase in microscopic lesion), and in male rabbits (39% increase in gross lesion). UII infusion significantly increased the plaque size of the carotid and subclavian arteries (69% increase over the control). In addition, UII infusion significantly enhanced the development of coronary lesions by increasing plaque size and lumen stenosis. Histopathological analysis revealed that aortic lesions in the UII group were characterized by increasing lesional macrophages, lipid deposition, and intra-plaque neovessel formation. UII infusion also significantly delayed the regression of atherosclerosis in rabbits by increasing the intra-plaque macrophage ratio. Furthermore, UII treatment led to a significant increase in NOX2 and HIF-1α/VEGF-A expression accompanied by increased reactive oxygen species levels in cultured macrophages. Tubule formation assays showed that UII exerted a pro-angiogenic effect in cultured endothelial cell lines and this effect was partly inhibited by urantide, a UII receptor antagonist. These findings suggest that UII can accelerate aortic and coronary plaque formation and enhance aortic plaque vulnerability, but delay the regression of atherosclerosis. The role of UII on angiogenesis in the lesion may be involved in complex plaque development.

The Renin Angiotensin System (RAS) is a hormonal system that is responsible for blood pressure hemostasis and electrolyte balance. It is implicated in cancer hallmarks because it is expressed locally in almost all of the body's tissues. In this review, current knowledge on the effect of local RAS in the common types of cancer such as breast, lung, liver, prostate and skin cancer is summarised. The mechanisms by which RAS components could increase or decrease cancer activity are also discussed. In addition to the former, this review explores how the administration of AT1R blockers and ACE inhibitors drugs intervene with cancer therapy and contribute to the outcomes of cancer. [ABSTRACT FROM AUTHOR]

Urp1 and Urp2 are two neuropeptides of the urotensin II family identified in teleost fish and mainly expressed in cerebrospinal fluid (CSF)-contacting neurons. It has been recently proposed that Urp1 and Urp2 are required for correct axis formation and maintenance. Their action is thought to be mediated by the receptor Uts2r3, which is specifically expressed in dorsal somites. In support of this view, it has been demonstrated that the loss of uts2r3 results in severe scoliosis in adult zebrafish. In the present study, we report for the first time the occurrence of urp2, but not of urp1, in two tetrapod species of the Xenopus genus. In X. laevis, we show that urp2 mRNA-containing cells are CSF-contacting neurons. Furthermore, we identified utr4, the X. laevis counterparts of zebrafish uts2r3, and we demonstrate that, as in zebrafish, it is expressed in the dorsal somatic musculature. Finally, we reveal that, in X. laevis, the disruption of utr4 results in an abnormal curvature of the antero-posterior axis of the tadpoles. Taken together, our results suggest that the role of the Utr4 signalling pathway in the control of body straightness is an ancestral feature of bony vertebrates and not just a peculiarity of ray-finned fishes.

The system of urotensin II (UII) and its receptor (UT) (or: UII/UT system) mediates hepatic immune inflamed injury in acute liver failure (ALF) with autophagy inhibition. However, it is unknown whether the system has an effect on liver autophagy in ALF. In this study, we attempted to explore hepatic autophagy response in ALF through blocking the UII/UT signal. Autophagy-related genes were examined in the liver tissues of lipopolysaccharide (LPS)/d-galactosamine (D-GalN)-induced ALF after pretreatment of UT receptor specific antagonist urantide. And then, the levels of autophagy- and apoptosis-related genes were assayed in LPS-stimulated KCs via urantide pretreatment. We found that the expressions of hepatic autophagy related genes, including Beclin-1, Atg5, Atg7, LC3 and p62 mRNA, and LC3 II and p62 protein, were significantly downregulated in LPS/D-GalN-induced ALF mice; but they were not affected by pretreatment of urantide, a special UT receptor antagonist. To probe inflammatory mechanisms of the UII/UT system, we further investigated the effect of the system on Kupffer cells (KCs), the innate immune cells in liver. We found that urantide pretreatment significantly inhibited production of inflammatory injury molecules including TRAF6 and ROS in LPS-stimulated KCs. LPS stimulation induced LC3 and p62 mRNA and LC3 II and p62 protein expression in KCs. After urantide pretreatment, LC3 and p62 mRNA and LC3 II protein were downregulated, while p62 protein was upregulated in LPS-stimulated KCs. In addition, antiapoptotic protein Bcl-2 inhibition and proapoptotic protein cleaved caspase-3 increase were observed in LPS-stimulated KCs, and the effects were enhanced after urantide pretreatment in the study. We conclude that liver injury mediated by the UII/UT system is possibly associated with the activation of autophagy-related and apoptosis-resisted pathways of KCs in ALF. [ABSTRACT FROM AUTHOR]

Despite the observation of synergistic interactions between the urotensinergic and angiotensinergic systems, the interplay between the urotensin II receptor (hUT) and the angiotensin II type 1 receptor (hAT1R) in regulating cellular signaling remains incompletely understood. Notably, the putative interaction between hUT and hAT1R could engender reciprocal allosteric modulation of their signaling signatures, defining a unique role for these complexes in cardiovascular physiology and pathophysiology. Using a combination of co-immunoprecipitation, bioluminescence resonance energy transfer (BRET) and FlAsH BRET-based conformational biosensors, we first demonstrated the physical interaction between hUT and hAT1R. Next, to analyze how this functional interaction regulated proximal and distal hUT- and hAT1R-associated signaling pathways, we used BRET-based signaling biosensors and western blots to profile pathway-specific signaling in HEK 293 cells expressing hUT, hAT1R or both. We observed that hUT-hAT1R heterodimers triggered distinct signaling outcomes compared to their respective parent receptors alone. Notably, co-transfection of hUT and hAT1R has no impact on hUII-induced G q activation but significantly reduced the potency and efficacy of Ang II to mediate G q activation. Interestingly, URP, the second hUT endogenous ligand, produce a distinct signaling signature compared to hUII at hUT-hAT1R. Our results therefore suggest that assembly of hUT with hAT1R might be important for allosteric modulation of outcomes associated with specific hardwired signaling complexes in healthy and disease states. Altogether, our work, which potentially explains the interplay observed in native cells and tissues, validates such complexes as potential targets to promote the design of compounds that can modulate heterodimer function selectively. • hUT and AT1R form a heterodimeric complex in HEK 293 cells • Ligand binding stabilizes the hUT-hAT1R heterodimer or promotes formation of new complexes. • The mutual effects of hUT and hAT1R on one another appears to be asymmetric in nature. [ABSTRACT FROM AUTHOR]

Background: Coronary slow-reflow phenomenon (CSFP) and Contrast-Induced Nephropathy (CIN) are associated with an increased risk of major cardiovascular adverse events. This study aimed to evaluate the relationship between serum Urotensin II molecule (U-II) levels and CIN in patients with CSFP undergoing percutaneous coronary intervention (PCI).Methods: We enrolled 227 patients (161 male and 66 female; mean age: 61,44 ± 12,44 years) with angiographically diagnosed CSFP. The patients were divided into two groups according to CIN development (Non-CIN (n=206) and CIN group (n=21)). Results: CIN was observed in 9,25%(n=21) of the CSFP patients. Serum U-II level was significantly higher in CIN group than in non-CIN group (6,79±2,2 vs. 3±1,29, p lt;0.001). One year clinical follow-up findings including all-cause mortality (7(33,3%) vs. 24(11,7%), p=0,013), cardiovascular death(7(33,3%) vs. 18(8,7%), p=0,003) and Major Adverse cardiovascular events (MACE) (10(47,6%) vs. 46(22,4%), p: 0,011) were significantly higher in CIN group. We also performed forward conditional logistic regression analysis and found that U-II (Odds ratio (OR)= 3,983; 95% confidence interval (CI): 2,25 to 7,052; p lt; 0.001) and Mehran score (OR=1,228, 95% CI: 1,083-1,393, p=0,001) were independently predicted CIN development in patients with CSFP. Conclusions: Baseline serum U-II concentrations and higher Mehran scores are independently associated with CIN in CSFP patients. One year clinical follow-up findings including all-cause mortality, cardiovascular death and MACE were significantly higher in CIN group, but stroke and myocardial infarction rates were similar in both groups.

Background/Aims: Skeletal muscle atrophy is one of the main manifestations of protein energy wasting. We hypothesized that urotensin II (UII) can lead to skeletal muscle atrophy through upregulating autophagy and affecting Irisin precursor fibronectin type III domain containing 5 (FNDC5) expressions. Methods: Three animal models (the sham operation, wild-type C57BL/6 mice with 5/6 nephrectomy, UII receptor (UT) gene knockout (UTKO) mice with 5/6 nephrectomy) were designed. Skeletal muscle weight, cross-sectional area (CSA) along with UII, FNDC5, LC3, and p62 expression were investigated. C2C12 cells were differentiated for up to 4 days into myotubes. These cells were then exposed to different UII concentrations (10–5 to 10–7 M) for 6–12 h and analyzed for the expressions of autophagic markers. These cells were also exposed to the same predetermined UII concentrations for 48–72 h and analyzed for the FNDC5 expression. Myotube diameter was measured. Results: Upregulation of UII expression in skeletal muscle tissue was accompanied by reduced muscle weight and skeletal muscle CSA in the 2 posterior limbs, upregulated autophagy markers expression, and downregulated FNDC5 expression in 5/6 nephrectomy mice. The decrease of skeletal muscle weight, skeletal muscle CSA, downregulation of FNDC5 expression, and the upregulation of autophagy markers were inhibited in UTKO with 5/6 nephrectomy mice. Our in vitrostudy showed that UII could directly decrease myotube diameter, induce autophagy markers upregulation, and inhibit expression of FNDC5. When UII receptor gene was interfered by UT-specific siRNA, UII induced autophagy markers upregulation and FNDC5 downregulation were inhibited. Conclusion: We are the first to verify UII induces mice skeletal muscle atrophy associated with enhanced skeletal muscle autophagy and inhibited FNDC5 expression in chronic renal failure.

Glioblastomas (GBMs) are the most common primary brain tumors characterized by strong invasiveness and angiogenesis. GBM cells and microenvironment secrete angiogenic factors and also express chemoattractant G protein-coupled receptors (GPCRs) to their advantage. We investigated the role of the vasoactive peptide urotensin II (UII) and its receptor UT on GBM angiogenesis and tested potential ligand/therapeutic options based on this system. On glioma patient samples, the expression of UII and UT increased with the grade with marked expression in the vascular and peri-necrotic mesenchymal hypoxic areas being correlated with vascular density. In vitro human UII stimulated human endothelial HUV-EC-C and hCMEC/D3 cell motility and tubulogenesis. In mouse-transplanted Matrigel sponges, mouse (mUII) and human UII markedly stimulated invasion by macrophages, endothelial, and smooth muscle cells. In U87 GBM xenografts expressing UII and UT in the glial and vascular compartments, UII accelerated tumor development, favored hypoxia and necrosis associated with increased proliferation (Ki67), and induced metalloproteinase (MMP)-2 and -9 expression in Nude mice. UII also promoted a “tortuous” vascular collagen-IV expressing network and integrin expression mainly in the vascular compartment. GBM angiogenesis and integrin αvβ3 were confirmed by in vivo99mTc-RGD tracer imaging and tumoral capture in the non-necrotic area of U87 xenografts in Nude mice. Peptide analogs of UII and UT antagonist were also tested as potential tumor repressor. Urotensin II-related peptide URP inhibited angiogenesis in vitro and failed to attract vascular and inflammatory components in Matrigel in vivo. Interestingly, the UT antagonist/biased ligand urantide and the non-peptide UT antagonist palosuran prevented UII-induced tubulogenesis in vitro and significantly delayed tumor growth in vivo. Urantide drastically prevented endogenous and UII-induced GBM angiogenesis, MMP, and integrin activations, associated with GBM tumoral growth. These findings show that UII induces GBM aggressiveness with necrosis and angiogenesis through integrin activation, a mesenchymal behavior that can be targeted by UT biased ligands/antagonists.

Chronic kidney disease (CKD) is a progressive and long-term condition marked by a gradual decline in kidney function. CKD is prevalent among those with conditions such as diabetes mellitus, hypertension, and glomerulonephritis. Affecting over 10% of the global population, CKD stands as a significant cause of morbidity and mortality. Despite substantial advances in understanding CKD pathophysiology and management, there is still a need to explore novel mechanisms and potential therapeutic targets. Urotensin II (UII), a potent vasoactive peptide, has garnered attention for its possible role in the development and progression of CKD. The UII system consists of endogenous ligands UII and UII-related peptide (URP) and their receptor, UT. URP pathophysiology is understudied, but alterations in tissue expression levels of UII and UT and blood or urinary UII concentrations have been linked to cardiovascular and kidney dysfunctions, including systemic hypertension, chronic heart failure, glomerulonephritis, and diabetes. UII gene polymorphisms are associated with increased risk of diabetes. Pharmacological inhibition or genetic ablation of UT mitigated kidney and cardiovascular disease in rodents, making the UII system a potential target for slowing CKD progression. However, a deeper understanding of the UII system's cellular mechanisms in renal and extrarenal organs is essential for comprehending its role in CKD pathophysiology. This review explores the evolving connections between the UII system and CKD, addressing potential mechanisms, therapeutic implications, controversies, and unexplored concepts., Competing Interests: The authors declared that they have no conflicts of interest in this work., (© 2024 The Authors.)

This study was designed to evaluate the effects of DS37001789, a novel and highly potent urotensin II (U-II) receptor (GPR14) antagonist, against mortality, hypertrophy, and cardiac dysfunction in pressure-overload hypertrophy by transverse aortic constriction (TAC) in mice. In addition, we analyzed the phenotype of GPR14 knockout (KO) mice after TAC induction to confirm the contribution of the U-II/GPR14 system. The oral administration of 0.2% DS37001789 to TAC mice for 12 weeks significantly ameliorated the mortality rate and 0.2% DS37001789 for 4 weeks significantly improved cardiac function by pressure-volume analysis. GPR14 expression was significantly upregulated in the left ventricle in the TAC mice treated with 0.2% DS37001789. Moreover, we confirmed that the significant amelioration of mortality was accomplished by the inhibition of cardiac enlargement and the improvement of cardiac function in GPR14 KO mice after TAC surgery. These results suggest that the U-II/GPR14 system contributes to the progression of heart failure and its blockade ameliorates the mortality via improved cardiac function. The U-II/GPR14 system may thus be an attractive target for treating heart failure with pathological cardiac hypertrophy and DS37001789 may be a novel therapeutic agent for heart failure in patients with pressure-overload conditions such as hypertension and aortic valve stenosis.

Temperature is a critical environmental factor that affect most biological and physiological processes in fish. The caudal neurosecretory system (CNSS) is unique to fish and is proved to maintain homeostasis during seasonal alterations. However, the dynamic expression and secretion pattern of its major hormones, corticotrophin-releasing hormone (CRH), urotensin I (UI), and urotensin II (UII), and their response to thermal stress has not been studied. CRH, UII and cortisol in plasma, gene expression levels of CRH, UI, and UII in the CNSS of olive flounder (Paralichthys olivaceus) were therefore characterized. UI- and UII-positive Dahlgren cells, as well as cell proliferation in the CNSS, were also quantified. The results showed that plasma cortisol and CRH were increased in both low temperature (LT) and high temperature (HT) groups. However, there was no difference in plasma UI and UII during thermal stress. In CNSS, CRH, UI, and UII mRNA levels were all significantly elevated in response to acute hypothermal stress and recovered back to the control (normal) level after 8 days of adaptation. During hyperthermal challenge, gene expression of CRH and UI only significantly increased after 8-days of transfer but no change in UII was observed. We also demonstrated an increasing percent of UI-positive Dahlgren cells in the CNSS of 8-days hyperthermal stressed fish. However, no BrdU-labeled Dahlgren cells were found among the three treatment groups. Collectively, our results demonstrate that the CNSS is subjected to dynamic responses under thermal stress and expands upon the role of the CNSS in thermoregulation. The dynamic responses of hormone levels and the gene expression of CRH, UI and UII in CNSS are all involved in the process of hyper- or hypo-thermal stress and adaptation.

Maternal insulin resistance (IR) can be associated with a significant increased risk of subsequent preeclampsia, therefore finding biomarkers thatgive anearly diagnosis of insulin resistance during pregnancy can predict preeclampsia. The objective of this study is toevaluate the use of irisin and urotensin II (UII) as potential biomarkers for insulin resistance, which may assist in the early prediction of preeclampsia. This study is a case-control study conducted at maternity section in ALEmamain AL-Kadhemain medical city hospital, Baghdad, Iraq from June 2019 to January2020. A total of 90 pregnant women in their third trimester were included in this study and were divided into three groups according to the obtained results from all participant of laboratory investigations including fasting serum insulin and blood glucose and Homeostatic model assessment (HOMA) in which; 30 preeclamptic women with insulin resistance, 30 preeclamptic women without insulin resistance and 30 healthy pregnant women served as a control group participated in this study. Serum irisin, urotensin II (UII) and serum insulin levels were measured in all participants by enzyme linked immunosorbent assay method (ELISA). Irisin levels in preeclamptic patients with insulin resistance were significantly lower than its level in the other groups i.e., preeclamptic patients without insulin resistance and normal controls. On the other hand, serum UII was significantly higher in preeclamptic women in both groups than controls. There was no relationship between serum urotensin II UII and irisin levels. In preeclamptic patients with insulin resistance, serum irisin has shown three significant inverse correlations: with BMI (r= -0.482, p= 0.007), FBS (r= - 0.375, p= 0.041) and HOMA-IR (r= -0.374, p= 0.042). While, serum UII had only one significant positive correlation with HOMA-IR (r= 0.347, p= 0.047)).The current study concluded that serum irisin'sassociations with insulin resistance make it an excellentcandidate biomarker for insulin resistance in preeclamptic pregnant women. Serum urotensin II(UII)could be used as a biomarker for preeclampsia. [ABSTRACT FROM AUTHOR]

BACKGROUND: The aim of our study is to investigate the effects of urotensin-II (U-II) on the left internal mammary artery (LIMA) wall and role of U-II in atherosclerotic processes affecting the long-term patency of LIMA. METHOD: Patients were divided into 2 groups, namely Group I: patients with coronary artery disease (CAD) and Group II: DM + CAD. The patients were evaluated by Gencini scoring before coronary artery bypass grafting (CABG). Routine tissue follow-up, hemotoxylin-eosin staining and immunoreactivity with U-II were observed. Then, vessel damage score, H-Score and LIMA layer thickness were calculated and evaluated statistically. RESULTS: On light microscopic examination, the LIMA total damage score in DM + CAD group was significantly higher compared to the control group. The assessment of H score revealed that U-II was more intense in tunica intima and tunica media in the DM+CAD group as compared to the control group (p < 0.05). Furthermore, tunica intima and tunica media in the DM + CAD group were thicker than in the control group (p < 0.05). CONCLUSIONS: We found that U-II is effective in atherosclerotic processes of arterial grafts. The DM + CAD group has high U-II density with high total damage score in intima and media layers of LIMA. U-II may be effective in late survival results after CABG (Tab. 3, Fig. 2, Ref. 19). Text in PDF www.elis.sk [ABSTRACT FROM AUTHOR]

Temperature is a critical environmental factor that affect most biological and physiological processes in fish. The caudal neurosecretory system (CNSS) is unique to fish and is proved to maintain homeostasis during seasonal alterations. However, the dynamic expression and secretion pattern of its major hormones, corticotrophin-releasing hormone (CRH), urotensin I (UI), and urotensin II (UII), and their response to thermal stress has not been studied. CRH, UII and cortisol in plasma, gene expression levels of CRH, UI, and UII in the CNSS of olive flounder (Paralichthys olivaceus) were therefore characterized. UI- and UII-positive Dahlgren cells, as well as cell proliferation in the CNSS, were also quantified. The results showed that plasma cortisol and CRH were increased in both low temperature (LT) and high temperature (HT) groups. However, there was no difference in plasma UI and UII during thermal stress. In CNSS, CRH, UI, and UII mRNA levels were all significantly elevated in response to acute hypothermal stress and recovered back to the control (normal) level after 8 days of adaptation. During hyperthermal challenge, gene expression of CRH and UI only significantly increased after 8-days of transfer but no change in UII was observed. We also demonstrated an increasing percent of UI-positive Dahlgren cells in the CNSS of 8-days hyperthermal stressed fish. However, no BrdU-labeled Dahlgren cells were found among the three treatment groups. Collectively, our results demonstrate that the CNSS is subjected to dynamic responses under thermal stress and expands upon the role of the CNSS in thermoregulation. The dynamic responses of hormone levels and the gene expression of CRH, UI and UII in CNSS are all involved in the process of hyper- or hypo-thermal stress and adaptation. [ABSTRACT FROM AUTHOR]

The aims of this study are to observe irisin and urotensin II (UII) levels in serum and placenta in normal pregnant and preeclamptic women and investigate the relationship between expressions irisin and UII, and their association with blood pressure. A total of 67 pregnant subjects were recruited, including 31 healthy and 36 preeclamptic pregnant women. Serum irisin and UII concentrations were measured. Expressions of fibronectin type III domain-containing protein 5 (FNDC5) (irisin precursor) and UII in placenta specimens were performed. There was no significant difference of serum irisin levels between severe preeclamptic (SPE)) patients, mild preeclamptic (MPE) patients and normal controls, while serum UII was significantly higher in preeclamptic women than normal pregnancy. There was no relationship between serum UII and irisin levels. In patients with preeclampsia, serum irisin was negatively associated with systolic and diastolic blood pressure(r = −0.350, P = 0.004, r = −0.307, P = 0.011), while serum UII was positively associated with systolic blood pressure (r = 0.291, P = 0.031). Serum irisin, UII, urinary protein level, BMI and serum creatinine were the independent determinants of blood pressure in preeclampsia by multiple regression analysis. Protein expression of FNDC5 and UII was upregulated in placenta of patients with SPE and positively correlated with systolic blood pressure and urinary protein level. We firstly verify that serum irisin and placental irisin precursor expressions have differently correlated with blood pressure. Expressions of irisin and urotensin II have relationships with blood pressure in patients with preeclampsia

Aims: Rheumatic valve diseases are most common etiological valve diseases in developing countries. Urotensin II is cardiovascular autacoid/hormone and may be associated with patients of heart valve diseases. The present study was to measure plasma urotensin II concentrations in patients with left-sided rheumatic valve diseases such as mitral regurgitation (MR) and aortic regurgitation (AR), and to examine its correlation with severity of valve impairment, function (New York Heart association, NYHA) class and pulmonary artery pressure (PAP). Methods and results: Sixty patients with moderate to severe rheumatic left-sided valve regurgitation and 20 healthy controls were selected after performing the echocardiography. Plasma urotensin II level was measured in all subjects. The patients with MR and AR were significantly increased of left ventricular end diastolic dimension (LVEDD), left ventricular end systolic dimension (LVESD), left atrial diameter, PAP, but decreased of EF% versus the controls. Urotensin II level was highly significant in patients with MR (1.83 ± 0.92 ng/ml, P

The urotensinergic system, comprised of a G protein-coupled receptor (UT) and two endogenous ligands named urotensin II (UII) and urotensin II-related peptide (URP), has garnered significant attention due to its involvement in the initiation and/or the evolution of various diseases. Accordingly, multiple studies using animal models have demonstrated that UT antagonists may have utility as potential therapeutic agents for treating atherosclerosis, pulmonary arterial hypertension, heart failure, and cancer. Unfortunately, clinical investigations of UT antagonist candidates showed limited efficacy in humans. This system, which has yet to be effectively targeted, therefore remains to be therapeutically exploited. Here, we discuss various hypotheses that could explain the in vivo failure of UT antagonists. Structural and sequence differences between rat and human urotensinergic system introduce pharmacological diversity through selection/stabilization of particular UT active conformations that may be ligand- and species-specific. Several reports indicated that UII and URP can exert distinct and separate actions, thereby highlighting the possibility that altered UT signaling in response to UII or URP could lead to distinct roles for each peptide in the pathogenesis and progression of UT-associated diseases. Despite the discovery of URP more than 10 years ago, only a small numbers of UT antagonists have been systematically assessed for their ability to block URP-mediated action. Such studies led to identification of several molecules, both peptidic and nonpeptidic, exerting probe-dependent action with a wide range of activity against UII- and URP-mediated functions. Analysis of currently available UT antagonists may reveal their propensity to trigger the activation of certain subsets of UT-associated signaling as well as exert probe-dependent action upon UII or URP binding. A better understanding of the molecular and cellular pharmacology of the urotensinergic system, including the functional selectivity of its endogenous ligands and its interspecies variability, should facilitate the design of innovative (bias agonists and allosteric modulators) and therapeutically relevant compounds for the treatment of UT-associated diseases. [ABSTRACT FROM AUTHOR]

Background/Aims: Skeletal muscle atrophy is one of the main manifestations of protein energy wasting. We hypothesized that urotensin II (UII) can lead to skeletal muscle atrophy through upregulating autophagy and affecting Irisin precursor fibronectin type III domain containing 5 (FNDC5) expressions. Methods: Three animal models (the sham operation, wild-type C57BL/6 mice with 5/6 nephrectomy, UII receptor (UT) gene knockout (UTKO) mice with 5/6 nephrectomy) were designed. Skeletal muscle weight, cross-sectional area (CSA) along with UII, FNDC5, LC3, and p62 expression were investigated. C2C12 cells were differentiated for up to 4 days into myotubes. These cells were then exposed to different UII concentrations (10–5 to 10–7 M) for 6–12 h and analyzed for the expressions of autophagic markers. These cells were also exposed to the same predetermined UII concentrations for 48–72 h and analyzed for the FNDC5 expression. Myotube diameter was measured. Results: Upregulation of UII expression in skeletal muscle tissue was accompanied by reduced muscle weight and skeletal muscle CSA in the 2 posterior limbs, upregulated autophagy markers expression, and downregulated FNDC5 expression in 5/6 nephrectomy mice. The decrease of skeletal muscle weight, skeletal muscle CSA, downregulation of FNDC5 expression, and the upregulation of autophagy markers were inhibited in UTKO with 5/6 nephrectomy mice. Our in vitrostudy showed that UII could directly decrease myotube diameter, induce autophagy markers upregulation, and inhibit expression of FNDC5. When UII receptor gene was interfered by UT-specific siRNA, UII induced autophagy markers upregulation and FNDC5 downregulation were inhibited. Conclusion: We are the first to verify UII induces mice skeletal muscle atrophy associated with enhanced skeletal muscle autophagy and inhibited FNDC5 expression in chronic renal failure. [ABSTRACT FROM AUTHOR]

Introduction: Urotensin II (UII) is an important vasoactive peptide involved in the pathogenesis of atherosclerosis. Monocytes/macrophages play important roles in every step of atherosclerosis. Although UII has a chemoattractant effect on monocytes, it is unclear whether UII regulates inflammatory responses in macrophages. The present study sought to explore whether UII can promote leukotriene B4 (LTB4) production by macrophages.Material and Methods: The mRNA expression level of LTB4 and 5-lipoxygenase were determined by real-time polymerase chain reaction. The protein level of LTB4 and 5-lipoxygenase expression was assayed by enzyme-linked immunosorbent assay and Western blot, respectively. Western blot analysis was also employed to determine the phosphorylated forms of Akt. Reactive oxygen species (ROS) level was detected by the fluorescent probe 2',7'-dichlorofluorescin diacetate and fluorescence intensity was measured with a multiwell fluorescence plate reader.Results: Urotensin II promoted LTB4 release and increased 5-lipoxygenase expression in a concentration- and time-dependent manner in RAW264.7 cells. Leukotriene B4 production and 5-lipoxygenase expression were decreased by blocking the UII receptor (UT) with urantide, eliminating ROS with N-acetylcysteine and diphenyliodonium, and inhibiting Akt phosphorylation with LY294002. UII significantly elevated ROS production, whereas urantide, N-acetylcysteine and diphenyliodonium substantially attenuated this effect. UII also enhanced Akt phosphorylation significantly, and this effect was potently inhibited by urantide, N-acetylcysteine, diphenyliodonium and LY294002.Conclusions: Urotensin II may promote 5-lipoxygenase expression and LTB4 release in RAW264.7 macrophages via UT-ROS-Akt pathways. These results indicate that UII may participate in macrophage activation and suggest a potential new mechanism underlying atherosclerosis. [ABSTRACT FROM AUTHOR]

Increased serum urotensin II (UII) levels in human cirrhotic populations have been recently shown, but the long-term effects of UII receptor antagonist on the cirrhosis have not been investigated. To investigate the therapeutic effects of urotensin II receptor (UT) antagonist palosuran on rats with carbon tetrachloride (CCl4)-induced cirrhosis, the hepatic and systemic hemodynamics, liver fibrosis, the metalloproteinase-13 (MMP-13)/tissue inhibitor of metalloproteinase-1 (TIMP-1) ratio, hepatic Rho-kinase activity, and the endothelial nitric oxide synthase (eNOS) activity are measured in CCl4-cirrhotic rats treated with palosuran or vehicle for 4 weeks. Primary hepatic stellate cells (HSCs) are used to investigate the changes in UII/UT expression and the in vitro effect of palosuran. Compared with the vehicle-treated cirrhotic rats, treatment with palosuran can reduce the portal pressure (PP), decrease the risk of liver fibrosis and the level of α smooth muscle actin, collagen-I (COL-I), and transforming growth factor β expression. However, treatment with palosuran can increase MMP-13/TIMP-1, pvasodilator-stimulated phosphoprotein (p-VASP), and p-eNOS expression. Moreover, in vitro UII/UT mRNA expression increases during HSC activation. MMP-13/TIMP-1, COL-I, and p-VASP are inhibited after palosuran treatment. Our data indicate that long-term administration of palosuran can decrease PP in cirrhosis, which results from decreased hepatic fibrosis and enhanced eNOS-dependent HSC vasodilatation. [ABSTRACT FROM AUTHOR]

Through population-based studies, associations have been found between coffee drinking and numerous health benefits, including a reduced risk of cardiovascular disease. Active ingredients in coffee have therefore received considerable attention from researchers. A wide variety of effects have been attributed to cafestol, one of the major compounds in coffee beans. Because cardiac hypertrophy is an independent risk factor for cardiovascular events, this study examined whether cafestol inhibits urotensin II (U-II)-induced cardiomyocyte hypertrophy. Neonatal rat cardiomyocytes were exposed only to U-II (1 nM) or to U-II (1 nM) following 12-h pretreatment with cafestol (1–10 μ M). Cafestol (3–10 μ M) pretreatment significantly inhibited U-II-induced cardiomyocyte hypertrophy with an accompanying decrease in U-II-induced reactive oxygen species (ROS) production. Cafestol also inhibited U-II-induced phosphorylation of redox-sensitive extracellular signal-regulated kinase (ERK) and epidermal growth factor receptor transactivation. In addition, cafestol pretreatment increased Src homology region 2 domains-containing phosphatase-2 (SHP-2) activity, suggesting that cafestol prevents ROS-induced SHP-2 inactivation. Moreover, nuclear factor erythroid-2-related factor 2 (Nrf2) translocation and heme oxygenase-1 (HO-1) expression were enhanced by cafestol. Addition of brusatol (a specific inhibitor of Nrf2) or Nrf2 siRNA significantly attenuated cafestol-mediated inhibitory effects on U-II-stimulated ROS production and cardiomyocyte hypertrophy. In summary, our data indicate that cafestol prevented U-II-induced cardiomycyte hypertrophy through Nrf2/HO-1 activation and inhibition of redox signaling, resulting in cardioprotective effects. These novel findings suggest that cafestol could be applied in pharmacological therapy for cardiac diseases. [ABSTRACT FROM AUTHOR]

Urotensin II (UII) is a polypeptide molecule with neurohormone- like activity. It has been confirmed that UII is widely distributed in numerous organs of d ifferent animal species from fish to mammals, including humans. The UII receptor is orph an G-protein-coupled receptor 14, also known as UT. The tissue distribution of UII a nd UT is highly consistent, and their expression may be regulated by autocrine and paracrin e mechanisms. In the body, UII has many physiological and pathophysiological activities, such as vasoconstrictor and vasodilatory actions, cell proliferation, pro-fibrosis, neuroendocrine activity, insulin resistance and carcinogenic and inflammatory e ffects, which have been recognized only in recent years. In fact, UII is involved in th e process of inflammatory injury and plays a key role in the onset and development of infl ammatory diseases. In this paper, we will review the roles UII plays in inflammatory d iseases. [ABSTRACT FROM AUTHOR]

New Findings: What is the central question of this study?Urotensin II is upregulated in patients in the later stages of chronic kidney disease (CKD), particularly in individuals requiring dialysis. Could treatment with a urotensin II receptor antagonist slow progression of renal disease?What is the main finding and its importance?In the rat, expression of urotensin II and its receptor increased, extending into cortical structures as CKD progressed towards end‐stage renal failure. Subchronic treatment with a urotensin receptor antagonist slowed but did not prevent progression of CKD. This suggests that urotensin II contributes to the decline in renal function in CKD. Elevated serum and urine urotensin II (UII) concentrations have been reported in patients with end‐stage chronic kidney disease (CKD). Similar increases in UII and its receptor, UT, have been reported in animal models of CKD, but only at much earlier stages of renal dysfunction. The aim of this study was to characterize urotensin system expression as renal disease progresses to end‐stage failure in a ⅚ subtotal nephrectomy (SNx) rat model. Male Sprague–Dawley rats underwent SNx or sham surgery and were killed at 8 weeks postsurgery [early (E)] or immediately before end‐stage renal failure [30 ± 3 weeks postsurgery; late (L)]. Systolic blood pressure, urinary albumin:creatinine ratio and glomerulosclerosis index were all increased in SNx‐E rats compared with sham‐E by 8 weeks postsurgery. These changes were associated with an increase in renal immunoreactive UII staining but little change in UT expression. As CKD progressed to end‐stage disease in the SNx‐L group, markers of renal function deteriorated further, in association with a marked increase in immunoreactive UII and UT staining. Subchronic administration of a UT antagonist, SB‐611812, at 30 mg kg−1 day−1 for 13 weeks, in a separate group of SNx rats resulted in a 2 week delay in the increase in both systolic blood pressure and urinary albumin:creatinine ratio observed in vehicle‐treated SNx but did not prevent the progression of renal dysfunction. The urotensin system is upregulated as renal function deteriorates in the rat; UT antagonism can slow but not prevent disease progression, suggesting that UII plays a role in CKD. [ABSTRACT FROM AUTHOR]