1,915 results on '"Urocortin"'
Search Results
2. The expression of corticotropin-releasing hormone family peptides in premalignant and malignant vulvar lesions.
- Author
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Dimas, Angelos, Goussia, Anna, Papoudou-Bai, Alexandra, Politi, Anastasia, Paschopoulos, Minas, Navrozoglou, Iordanis, Makrigiannakis, Antonis, and Vrekoussis, Thomas
- Abstract
Objectives: To examine the relation of corticotropin-releasing hormone (CRH) family peptides with inflammatory processes and oncogenesis, emphasizing in vulvar inflammatory, premalignant and malignant lesions, as well as to investigate the possibility of lesion cells immunoescaping, utilizing FAS/FAS-L complex. Methods: Immunohistochemical expression of CRH, urocortin (UCN), FasL and their receptors CRHR1, CRHR2 and Fas was studied in vulvar tissue sections obtained from patients with histologically confirmed diagnosis of lichen, vulvar intraepithelial neoplasia (VIN) and vulvar squamous cell carcinoma (VSCC). The patient cohort was selected from a tertiary teaching Hospital in Greece, between 2005 and 2015. For each of the disease categories, immunohistochemical staining was evaluated and the results were statistically compared. Results: A progressive increase of the cytoplasmic immunohistochemical expression of CRH and UCN, from precancerous lesions to VSCC was observed. A similar increase was detected for Fas and FasL expression. Nuclear localization of UCN was demonstrated in both premalignant and VSCC lesions, with staining being significantly intensified in carcinomas, particularly in the less differentiated tumor areas or in the areas at invasive tumor front. Conclusions: Stress response system and CRH family peptides seem to have a role in inflammation maintenance and progression of vulvar premalignant lesions to malignancy. It seems that stress peptides may locally modulate the stroma through Fas/FasL upregulation, possibly contributing to vulvar cancer development. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
3. Urocortin stimulates the ERK1/2 signaling pathway and the proliferation of HeLa cells via CRF receptor 1
- Author
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Bálint Balogh, Mónika Vecsernyés, Alexandra Stayer‐Harci, Gergely Berta, Oktávia Tarjányi, and György Sétáló Jr
- Subjects
cell proliferation ,E2F‐1 ,ERK1/2, MEK ,HeLa ,urocortin ,Biology (General) ,QH301-705.5 - Abstract
Corticotropin‐releasing factor (CRF) stimulates adrenocorticotropic hormone (ACTH) secretion from the pituitary gland and is an essential regulator of the hypothalamic–pituitary–adrenocortical axis. Isoforms of CRF receptor are known to mediate the effects of urocortin stress ligands on the regulation of stress responses, anxiety, and feeding behavior; however, urocortin stress ligands also influence cell proliferation. In view of the tumor‐promoting capacity of prolonged stress, here we investigated (a) the effect of urocortin on cell proliferative signaling via extracellular signal‐regulated kinase 1/2, (b) the expression and cellular distribution of the specific CRF receptor isoforms, and (c) the intracellular localization of phosphorylated ERK1/2 in HeLa cells. Stimulation of cell proliferation was observed in the presence of 10 nm urocortin. Our data also suggest that MAP kinase MEK, the transcription factors E2F‐1 and p53, and PKB/Akt are involved in this process. These findings may have therapeutic relevance for the targeted treatment of various malignancies.
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- 2023
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4. The Role of Corticotropin-Releasing Factor (CRF) and CRF-Related Peptides in the Social Behavior of Rodents.
- Author
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Bagosi, Zsolt, Megyesi, Kíra, Ayman, Jázmin, Rudersdorf, Hanna, Ayaz, Maieda Khan, and Csabafi, Krisztina
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CORTICOTROPIN releasing hormone ,PEPTIDES ,RODENTS ,SOCIAL skills ,SOCIAL interaction - Abstract
Since the corticotropin-releasing factor (CRF) was isolated from an ovine brain, a growing family of CRF-related peptides has been discovered. Today, the mammalian CRF system consists of four ligands (CRF, urocortin 1 (Ucn1), urocortin 2 (Ucn2), and urocortin 3 (Ucn3)); two receptors (CRF receptor type 1 (CRF1) and CRF receptor type 2 (CRF2)); and a CRF-binding protein (CRF-BP). Besides the regulation of the neuroendocrine, autonomic, and behavioral responses to stress, CRF and CRF-related peptides are also involved in different aspects of social behavior. In the present study, we review the experiments that investigated the role of CRF and the urocortins involved in the social behavior of rats, mice, and voles, with a special focus on sociability and preference for social novelty, as well as the ability for social recognition, discrimination, and memory. In general, these experiments demonstrate that CRF, Ucn1, Ucn2, and Ucn3 play important, but distinct roles in the social behavior of rodents, and that they are mediated by CRF1 and/or CRF2. In addition, we suggest the possible brain regions and pathways that express CRF and CRF-related peptides and that might be involved in social interactions. Furthermore, we also emphasize the differences between the species, strains, and sexes that make translation of these roles from rodents to humans difficult. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
5. Urocortin stimulates the ERK1/2 signaling pathway and the proliferation of HeLa cells via CRF receptor 1.
- Author
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Balogh, Bálint, Vecsernyés, Mónika, Stayer‐Harci, Alexandra, Berta, Gergely, Tarjányi, Oktávia, and Sétáló, György
- Subjects
HELA cells ,CELL proliferation ,CELLULAR signal transduction ,EXTRACELLULAR signal-regulated kinases ,CORTICOTROPIN releasing hormone ,MITOGEN-activated protein kinases - Abstract
Corticotropin‐releasing factor (CRF) stimulates adrenocorticotropic hormone (ACTH) secretion from the pituitary gland and is an essential regulator of the hypothalamic–pituitary–adrenocortical axis. Isoforms of CRF receptor are known to mediate the effects of urocortin stress ligands on the regulation of stress responses, anxiety, and feeding behavior; however, urocortin stress ligands also influence cell proliferation. In view of the tumor‐promoting capacity of prolonged stress, here we investigated (a) the effect of urocortin on cell proliferative signaling via extracellular signal‐regulated kinase 1/2, (b) the expression and cellular distribution of the specific CRF receptor isoforms, and (c) the intracellular localization of phosphorylated ERK1/2 in HeLa cells. Stimulation of cell proliferation was observed in the presence of 10 nm urocortin. Our data also suggest that MAP kinase MEK, the transcription factors E2F‐1 and p53, and PKB/Akt are involved in this process. These findings may have therapeutic relevance for the targeted treatment of various malignancies. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
6. The chondroprotective effect of urocortin involves modulation of the mechanosensitive ion channel Piezo1
- Author
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Jones, Rebecca, Richardson, Stephen, and Townsend, Paul
- Subjects
616.7 ,piezo1 ,chondrocyte ,cartilage ,osteoarthritis ,urocortin - Abstract
Osteoarthritis (OA) is one of the leading causes of morbidity worldwide. Single injurious mechanical impact to joints as seen in sports injury is known to be associated with a high risk of later development of OA, known as post-traumatic OA (PTOA). PTOA affects a younger population of patients and significantly increases the socio-economic burden of the disease on society. Breakdown of articular cartilage in the joint is one of the characterising features of OA. Cartilage is populated with chondrocytes responsible for production and turnover of the matrix. Chondrocyte death is known to occur following impact, suggesting a chondroprotective agent might provide a promising candidate as a disease modifying drug. Urocortin (Ucn), a small peptide member of the Corticotrophin- Releasing Factor (CRF) family, has previously been seen to be essential for chondrocyte survival, where depletion of Ucn led to chondrocyte cell death. This thesis sought to elucidate the mechanism of this chondroprotection by Ucn. Initial chondrocyte cell line and monolayer primary cell studies showed a significant increase in calcium influx when cells were deprived of Ucn. A siRNA screen of candidate ion channels highlighted Piezo1 as being involved in this excessive influx. An ex-vivo model of single impact then was developed to study the effect of overloading on cartilage explants over a short timeframe. Both pre-impact and crucially post-impact addition of Ucn to porcine explants significantly increased chondrocyte survival 72 hrs after challenge. This corresponded to a reduction in excessive calcium influx. Further study with specific mechanosensitive ion channel blockers and activators confirmed Piezo1 as the ion channel modulated by Ucn in order to prevent this calcium overload. Observation of these cells on a subcellular level highlighted a distinct programmed cell death response to impact, although molecular biology techniques indicated this was in the absence of caspase-3 activation. This work has detailed a previously unseen chondroprotective role of Ucn in response to single impact. In particular, the protection observed even when Ucn was added postimpact suggests Ucn as an interesting candidate for further study in a post-impact injury context, thereby limiting chondrocyte cell death early after damage and potentially leading to a reduced incidence of PTOA.
- Published
- 2019
7. The Role of Corticotropin-Releasing Factor (CRF) and CRF-Related Peptides in the Social Behavior of Rodents
- Author
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Zsolt Bagosi, Kíra Megyesi, Jázmin Ayman, Hanna Rudersdorf, Maieda Khan Ayaz, and Krisztina Csabafi
- Subjects
CRF ,urocortin ,CRF receptor ,social interaction ,Biology (General) ,QH301-705.5 - Abstract
Since the corticotropin-releasing factor (CRF) was isolated from an ovine brain, a growing family of CRF-related peptides has been discovered. Today, the mammalian CRF system consists of four ligands (CRF, urocortin 1 (Ucn1), urocortin 2 (Ucn2), and urocortin 3 (Ucn3)); two receptors (CRF receptor type 1 (CRF1) and CRF receptor type 2 (CRF2)); and a CRF-binding protein (CRF-BP). Besides the regulation of the neuroendocrine, autonomic, and behavioral responses to stress, CRF and CRF-related peptides are also involved in different aspects of social behavior. In the present study, we review the experiments that investigated the role of CRF and the urocortins involved in the social behavior of rats, mice, and voles, with a special focus on sociability and preference for social novelty, as well as the ability for social recognition, discrimination, and memory. In general, these experiments demonstrate that CRF, Ucn1, Ucn2, and Ucn3 play important, but distinct roles in the social behavior of rodents, and that they are mediated by CRF1 and/or CRF2. In addition, we suggest the possible brain regions and pathways that express CRF and CRF-related peptides and that might be involved in social interactions. Furthermore, we also emphasize the differences between the species, strains, and sexes that make translation of these roles from rodents to humans difficult.
- Published
- 2023
- Full Text
- View/download PDF
8. Neuropeptidergic and Neuroendocrine Systems Underlying Eusociality and the Concomitant Social Regulation of Reproduction in Naked Mole-Rats: A Comparative Approach
- Author
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Coen, Clive W., Bennett, Nigel C., Holmes, Melissa M., Faulkes, Christopher G., Crusio, Wim E., Series Editor, Dong, Haidong, Series Editor, Radeke, Heinfried H., Series Editor, Rezaei, Nima, Series Editor, Xiao, Junjie, Series Editor, Buffenstein, Rochelle, editor, Park, Thomas J., editor, and Holmes, Melissa M., editor
- Published
- 2021
- Full Text
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9. Oxytocin Receptors in the Mouse Centrally-projecting Edinger-Westphal Nucleus and their Potential Functional Significance for Thermoregulation.
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Li, Ju and Ryabinin, Andrey E
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OXYTOCIN receptors , *BODY temperature regulation , *GLUTAMATE transporters , *BODY temperature , *PEPTIDES - Abstract
• The centrally-projecting Edinger-Westphal nucleus expresses oxytocin receptors. • We confirm that urocortin neurons of EWcp are not glutamatergic. • Exogenous oxytocin administration induces FOS in EWcp neurons. • Oxytocin doses inducing FOS in EWcp lead to hypothermia. The centrally-projecting Edinger-Westphal nucleus (EWcp) has been shown to contribute to regulation of multiple functions, including responses to stress and fear, attention, food consumption, addiction, body temperature and maternal behaviors. However, receptors involved in regulation of these behaviors through EWcp remain poorly characterized. On the other hand, the oxytocin peptide (OXT) is also known to regulate a substantial number of physiological responses and behaviors. Here we show that mRNA encoding OXT receptors (Oxtr) is expressed in EWcp of male and female C57BL/6J mice. These receptors are present on urocortin 1 (Ucn) mRNA-containing neurons and, to a lesser extent, on neurons in EWcp expressing the vesicular glutamate transporter 2 (Vglut2) mRNA of EWcp. Using RNAscope in situ hybridization, we show that neurons containing Ucn and Vglut2 mRNAs are two intermingled, but independent subpopulations in EWcp and characterize their relationship with other populations of neurons in the vicinity of this nucleus. Using immunohistochemistry, we show that intraperitoneal (IP) administration of OXT can induce FOS in Oxtr-containing neurons, suggesting that these receptors on EWcp neurons are functional. A follow up study showed that injection of OXT (2.3 or 7.7 mg/kg, IP) is accompanied by a decrease in body temperature. Since EWcp is known to be involved in regulation of body temperature, we hypothesize that OXT's effects on body temperature could be mediated through the EWcp. The contribution of OXTR in EWcp to regulation of various functions of EWcp and OXT needs to be deciphered. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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10. Crinecerfont in a First Clinical Application of a CRH Antagonist: Further Potential Uses Are Still an Open Chapter!
- Author
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Chrousos, George P
- Abstract
The article comments on a study which evaluated the use of crinecerfont in a first clinical application of a corticotropin-releasing hormone (CRH) antagonist in the treatment of congenital adrenal hyperplasia. It cautions potential changes in the function of systems and organs when administering a nonpeptidic CRH antagonist such as crinecerfont. It discusses alterations in the production of adrenocortical hormones in classic CAH due to deficiency in the enzyme 21-hydroxylase.
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- 2024
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11. Urocortin-1 Is Chondroprotective in Response to Acute Cartilage Injury via Modulation of Piezo1.
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Jones, Rebecca C., Lawrence, Kevin M., Higgins, Scott M., Richardson, Stephen M., and Townsend, Paul A.
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CARTILAGE , *INTRACELLULAR calcium , *IMPACT loads , *CRASH injuries , *CELL death , *ENDOCHONDRAL ossification - Abstract
Post-traumatic OA (PTOA) is often triggered by injurious, high-impact loading events which result in rapid, excessive chondrocyte cell death and a phenotypic shift in residual cells toward a more catabolic state. As such, the identification of a disease-modifying OA drug (DMOAD) that can protect chondrocytes from death following impact injury, and thereby prevent cartilage degradation and progression to PTOA, would offer a novel intervention. We have previously shown that urocortin-1 (Ucn) is an essential endogenous pro-survival factor that protects chondrocytes from OA-associated pro-apoptotic stimuli. Here, using a drop tower PTOA-induction model, we demonstrate the extent of Ucn's chondroprotective role in cartilage explants exposed to excessive impact load. Using pathway-specific agonists and antagonists, we show that Ucn acts to block load-induced intracellular calcium accumulation through blockade of the non-selective cation channel Piezo1 rather than TRPV4. This protective effect is mediated primarily through the Ucn receptor CRF-R1 rather than CRF-R2. Crucially, we demonstrate that the chondroprotective effect of Ucn is maintained whether it is applied pre-impact or post-impact, highlighting the potential of Ucn as a novel DMOAD for the prevention of injurious impact overload-induced PTOA. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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12. Urocortin3 in the Posterodorsal Medial Amygdala Mediates Stress-induced Suppression of LH Pulsatility in Female Mice.
- Author
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Ivanova, Deyana, Li, Xiao-Feng, McIntyre, Caitlin, Liu, Yali, Kong, Lingsi, and O'Byrne, Kevin T
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UROCORTIN ,AMYGDALOID body ,ADRENOCORTICOTROPIC hormone - Abstract
Psychosocial stress disrupts reproduction and interferes with pulsatile LH secretion. The posterodorsal medial amygdala (MePD) is an upstream modulator of the reproductive axis and stress. Corticotropin-releasing factor type 2 receptors (CRFR2s) are activated in the presence of psychosocial stress together with increased expression of the CRFR2 ligand Urocortin3 (Ucn3) in the MePD of rodents. We investigate whether Ucn3 signalling in the MePD is involved in mediating the suppressive effect of psychosocial stress on LH pulsatility. First, we administered Ucn3 into the MePD and monitored the effect on LH pulses in ovariectomized mice. Next, we delivered Astressin2B, a selective CRFR2 antagonist, intra-MePD in the presence of predator odor, 2,4,5-trimethylthiazole (TMT) and examined the effect on LH pulses. Subsequently, we virally infected Ucn3-cre-tdTomato mice with inhibitory designer receptor exclusively activated by designer drugs (DREADDs) targeting MePD Ucn3 neurons while exposing mice to TMT or restraint stress and examined the effect on LH pulsatility as well as corticosterone release. Administration of Ucn3 into the MePD dose-dependently inhibited LH pulses and administration of Astressin2B blocked the suppressive effect of TMT on LH pulsatility. Additionally, DREADDs inhibition of MePD Ucn3 neurons blocked TMT and restraint stress-induced inhibition of LH pulses and corticosterone release. These results demonstrate for the first time that Ucn3 neurons in the MePD mediate psychosocial stress-induced suppression of the GnRH pulse generator and corticosterone secretion. Ucn3 signalling in the MePD plays a role in modulating the hypothalamic-pituitary-gonadal and hypothalamic-pituitary-adrenal axes, and this brain locus may represent a nodal center in the interaction between the reproductive and stress axes. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
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13. Expression Patterns of the Neuropeptide Urocortin 3 and Its Receptor CRFR2 in the Mouse Central Auditory System.
- Author
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Pagella, Sara, Deussing, Jan M., and Kopp-Scheinpflug, Conny
- Subjects
AUDITORY pathways ,CORTICOTROPIN releasing hormone ,SENSE organs ,HYPOTHALAMIC-pituitary-adrenal axis ,MICE ,NEUROMODULATION - Abstract
Sensory systems have to be malleable to context-dependent modulations occurring over different time scales, in order to serve their evolutionary function of informing about the external world while also eliciting survival-promoting behaviors. Stress is a major context-dependent signal that can have fast and delayed effects on sensory systems, especially on the auditory system. Urocortin 3 (UCN3) is a member of the corticotropin-releasing factor family. As a neuropeptide, UCN3 regulates synaptic activity much faster than the classic steroid hormones of the hypothalamic-pituitary-adrenal axis. Moreover, due to the lack of synaptic re-uptake mechanisms, UCN3 can have more long-lasting and far-reaching effects. To date, a modest number of studies have reported the presence of UCN3 or its receptor CRFR2 in the auditory system, particularly in the cochlea and the superior olivary complex, and have highlighted the importance of this stress neuropeptide for protecting auditory function. However, a comprehensive map of all neurons synthesizing UCN3 or CRFR2 within the auditory pathway is lacking. Here, we utilize two reporter mouse lines to elucidate the expression patterns of UCN3 and CRFR2 in the auditory system. Additional immunolabelling enables further characterization of the neurons that synthesize UCN3 or CRFR2. Surprisingly, our results indicate that within the auditory system, UCN3 is expressed predominantly in principal cells, whereas CRFR2 expression is strongest in non-principal, presumably multisensory, cell types. Based on the presence or absence of overlap between UCN3 and CRFR2 labeling, our data suggest unusual modes of neuromodulation by UCN3, involving volume transmission and autocrine signaling. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
14. Expression Patterns of the Neuropeptide Urocortin 3 and Its Receptor CRFR2 in the Mouse Central Auditory System
- Author
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Sara Pagella, Jan M. Deussing, and Conny Kopp-Scheinpflug
- Subjects
urocortin ,CRFR2 ,auditory ,stress signaling ,multimodal ,volume transmission ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Sensory systems have to be malleable to context-dependent modulations occurring over different time scales, in order to serve their evolutionary function of informing about the external world while also eliciting survival-promoting behaviors. Stress is a major context-dependent signal that can have fast and delayed effects on sensory systems, especially on the auditory system. Urocortin 3 (UCN3) is a member of the corticotropin-releasing factor family. As a neuropeptide, UCN3 regulates synaptic activity much faster than the classic steroid hormones of the hypothalamic-pituitary-adrenal axis. Moreover, due to the lack of synaptic re-uptake mechanisms, UCN3 can have more long-lasting and far-reaching effects. To date, a modest number of studies have reported the presence of UCN3 or its receptor CRFR2 in the auditory system, particularly in the cochlea and the superior olivary complex, and have highlighted the importance of this stress neuropeptide for protecting auditory function. However, a comprehensive map of all neurons synthesizing UCN3 or CRFR2 within the auditory pathway is lacking. Here, we utilize two reporter mouse lines to elucidate the expression patterns of UCN3 and CRFR2 in the auditory system. Additional immunolabelling enables further characterization of the neurons that synthesize UCN3 or CRFR2. Surprisingly, our results indicate that within the auditory system, UCN3 is expressed predominantly in principal cells, whereas CRFR2 expression is strongest in non-principal, presumably multisensory, cell types. Based on the presence or absence of overlap between UCN3 and CRFR2 labeling, our data suggest unusual modes of neuromodulation by UCN3, involving volume transmission and autocrine signaling.
- Published
- 2021
- Full Text
- View/download PDF
15. Urocortin 3 overexpression reduces ER stress and heat shock response in 3T3-L1 adipocytes.
- Author
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Kavalakatt, Sina, Khadir, Abdelkrim, Madhu, Dhanya, Koistinen, Heikki A., Al-Mulla, Fahd, Tuomilehto, Jaakko, Abubaker, Jehad, and Tiss, Ali
- Subjects
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FAT cells , *UROCORTIN , *PROTEIN expression , *ENDOPLASMIC reticulum , *METABOLIC disorders - Abstract
The neuropeptide urocortin 3 (UCN3) has a beneficial effect on metabolic disorders, such as obesity, diabetes, and cardiovascular disease. It has been reported that UCN3 regulates insulin secretion and is dysregulated with increasing severity of obesity and diabetes. However, its function in the adipose tissue is unclear. We investigated the overexpression of UCN3 in 3T3-L1 preadipocytes and differentiated adipocytes and its effects on heat shock response, ER stress, inflammatory markers, and glucose uptake in the presence of stress-inducing concentrations of palmitic acid (PA). UCN3 overexpression significantly downregulated heat shock proteins (HSP60, HSP72 and HSP90) and ER stress response markers (GRP78, PERK, ATF6, and IRE1α) and attenuated inflammation (TNFα) and apoptosis (CHOP). Moreover, enhanced glucose uptake was observed in both preadipocytes and mature adipocytes, which is associated with upregulated phosphorylation of AKT and ERK but reduced p-JNK. Moderate effects of UCN3 overexpression were also observed in the presence of 400 μM of PA, and macrophage conditioned medium dramatically decreased the UCN3 mRNA levels in differentiated 3T3-L1 cells. In conclusion, the beneficial effects of UCN3 in adipocytes are reflected, at least partially, by the improvement in cellular stress response and glucose uptake and attenuation of inflammation and apoptosis. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
16. Corticotropin Releasing Hormone and Urocortin 3 Stimulate Vascular Endothelial Growth Factor Expression through the cAMP/CREB Pathway.
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Rhee, Sang Hoon, Ma, Elise L, Lee, Yunna, Taché, Yvette, Pothoulakis, Charalabos, and Im, Eunok
- Subjects
Intestinal Mucosa ,Cells ,Cultured ,Animals ,Mice ,Transgenic ,Humans ,Mice ,Corticotropin-Releasing Hormone ,Vascular Endothelial Growth Factor A ,Cyclic AMP ,Cyclic AMP Response Element-Binding Protein ,Urocortins ,Promoter Regions ,Genetic ,angiogenesis ,cAMP response element-binding protein ,colitis ,corticotropin-releasing hormone ,inflammatory bowel disease ,urocortin ,vascular endothelial growth factor ,Cells ,Cultured ,Transgenic ,Promoter Regions ,Genetic ,Biochemistry & Molecular Biology ,Biological Sciences ,Medical and Health Sciences ,Chemical Sciences - Abstract
Colonic epithelium is the first line of defense against various pathological offenses in the gut. Previous studies have shown that the peptides of the corticotropin-releasing hormone (CRH) family modulate vascular endothelial growth factor (VEGF)-A production in other cells. Here we sought to investigate whether CRH and urocortin (Ucn) 3 regulate VEGF-A secretion in colonocytes through CRH receptors and to elucidate the underlying mechanism of action. CRH and Ucn 3 significantly increased the expression levels of VEGF-A mRNA and protein through CRH receptor 1 and 2, respectively, in human colonic epithelial cells and primary mouse intestinal epithelial cells. Underlying mechanisms involve activation of adenylyl cyclase with subsequent increase of intracellular cAMP level and increased DNA binding activity of transcription factor CREB on VEGF-A promoter region. Finally, genetic deficiency of CREB decreased intestinal inflammation and VEGF-A expression in a dextran sodium sulfate-induced colitis model. These results show that activation of CRH receptors by CRH ligands stimulates VEGF-A expression in intestinal epithelial cells through the cAMP/CREB pathway. Since VEGF-A boosts inflammatory responses through angiogenesis, these data suggest that CREB may be a key effector of CRH and Ucn 3-dependent inflammatory angiogenesis.
- Published
- 2015
17. Corticotropin-Releasing Factor (CRF) Neurocircuitry and Neuropharmacology in Alcohol Drinking
- Author
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Schreiber, Allyson L., Gilpin, Nicholas W., Barrett, James E., Editor-in-Chief, Flockerzi, Veit, Editorial Board Member, Frohman, Michael A., Editorial Board Member, Geppetti, Pierangelo, Editorial Board Member, Hofmann, Franz B., Editorial Board Member, Michel, Martin C., Editorial Board Member, Page, Clive P., Editorial Board Member, Rosenthal, Walter, Editorial Board Member, Wang, KeWei, Editorial Board Member, Grant, Kathleen A., editor, and Lovinger, David M., editor
- Published
- 2018
- Full Text
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18. CRF and urocortin peptides as modulators of energy balance and feeding behavior during stress
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Stengel, Andreas and Taché, Yvette
- Subjects
Basic Behavioral and Social Science ,Neurosciences ,Behavioral and Social Science ,body weight ,CRF ,food intake ,stress ,urocortin ,Psychology ,Cognitive Sciences - Abstract
Early on, corticotropin-releasing factor (CRF), a hallmark brain peptide mediating many components of the stress response, was shown to affect food intake inducing a robust anorexigenic response when injected into the rodent brain. Subsequently, other members of the CRF signaling family have been identified, namely urocortin (Ucn) 1, Ucn 2, and Ucn 3 which were also shown to decrease food intake upon central or peripheral injection. However, the kinetics of feeding suppression was different with an early decrease following intracerebroventricular injection of CRF and a delayed action of Ucns contrasting with the early onset after systemic injection. CRF and Ucns bind to two distinct G-protein coupled membrane receptors, the CRF1 and CRF2. New pharmacological tools such as highly selective peptide CRF1 or CRF2 agonists or antagonists along with genetic knock-in or knock-out models have allowed delineating the primary role of CRF2 involved in the anorexic response to exogenous administration of CRF and Ucns. Several stressors trigger behavioral changes including suppression of feeding behavior which are mediated by brain CRF receptor activation. The present review will highlight the state-of-knowledge on the effects and mechanisms of action of CRF/Ucns-CRF1/2 signaling under basal conditions and the role in the alterations of food intake in response to stress.
- Published
- 2014
19. Urocortins in the mammalian endocrine system
- Author
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Caterina Squillacioti, Alessandra Pelagalli, Giovanna Liguori, and Nicola Mirabella
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Corticotropin-releasing hormone receptors ,Endocrine system ,Mammals ,Urocortin ,Veterinary medicine ,SF600-1100 - Abstract
Abstract Urocortins (Ucns), peptides belonging to the corticotropin-releasing hormone (CRH) family, are classified into Ucn1, Ucn2, and Ucn3. They are involved in regulating several body functions by binding to two G protein-coupled receptors: receptor type 1 (CRHR1) and type 2 (CRHR2). In this review, we provide a historical overview of research on Ucns and their receptors in the mammalian endocrine system. Although the literature on the topic is limited, we focused our attention particularly on the main role of Ucns and their receptors in regulating the hypothalamic–pituitary–adrenal and thyroid axes, reproductive organs, pancreas, gastrointestinal tract, and other tissues characterized by “diffuse” endocrine cells in mammals. The prominent function of these peptides in health conditions led us to also hypothesize an action of Ucn agonists/antagonists in stress and in various diseases with its critical consequences on behavior and physiology. The potential role of the urocortinergic system is an intriguing topic that deserves further in-depth investigations to develop novel strategies for preventing stress-related conditions and treating endocrine diseases.
- Published
- 2019
- Full Text
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20. Urocortin Expression in Endometriosis: A Systematic Review
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Vasilios Pergialiotis, Nikoletta Maria Tagkou, Athina Tsimpiktsioglou, Olga Klavdianou, Antonia Neonaki, and Pantelis Trompoukis
- Subjects
endometrioma ,endometriosis ,urocortin ,Medicine (General) ,R5-920 - Abstract
Urocortin (UCN) is a neuropeptide that belongs to the corticotrophin-releasing hormone family and is expressed by eutopic and ectopic human endometria. The past years, this expression has been thoroughly investigated in the field of endometriosis. The objective of this systematic review is to accumulate current evidence related to the expression of UCN in tissue and blood samples of patients suffering from endometriosis. Literature search was designed accord- ing to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and primarily conducted using the Medline (1966-2018), Scopus (2004-2018), EMBASE (1947-2018) and Clinicaltrials.gov (2008- 2018) databases, along with the reference lists of electronically retrieved full-text papers. Overall, eight studies were retrieved. Current evidence suggests that the expression of UCN is increased in patients with ovarian endometriomas and that its levels may correlate with the severity of the disease. The diagnostic efficacy of UCN1 plasma levels was evaluated in three studies. Two of them suggested that the sensitivity and specificity of the method may reach, and even exceed, 80%. However, the wide variation in outcome reporting and outcome reporting measures in endome- triosis among the included studies precludes meta-analysis of available data. Therefore, although UCN seems to be a promising biomarker for the identification and follow-up of patients that suffer from endometriosis, more studies are needed to reach firm conclusions with respect to its predictive accuracy.
- Published
- 2019
- Full Text
- View/download PDF
21. Identification of epigenetic memory candidates associated with gestational age at birth through analysis of methylome and transcriptional data.
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Kashima, Kohei, Kawai, Tomoko, Nishimura, Riki, Shiwa, Yuh, Urayama, Kevin Y., Kamura, Hiromi, Takeda, Kazue, Aoto, Saki, Ito, Atsushi, Matsubara, Keiko, Nagamatsu, Takeshi, Fujii, Tomoyuki, Omori, Isaku, Shimizu, Mitsumasa, Hyodo, Hironobu, Kugu, Koji, Matsumoto, Kenji, Shimizu, Atsushi, Oka, Akira, and Mizuguchi, Masashi
- Subjects
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PREMATURE labor , *DISEASE risk factors , *EPIGENETICS , *DISEASE susceptibility , *GESTATIONAL age , *DNA methylation , *UROCORTIN - Abstract
Preterm birth is known to be associated with chronic disease risk in adulthood whereby epigenetic memory may play a mechanistic role in disease susceptibility. Gestational age (GA) is the most important prognostic factor for preterm infants, and numerous DNA methylation alterations associated with GA have been revealed by epigenome-wide association studies. However, in human preterm infants, whether the methylation changes relate to transcription in the fetal state and persist after birth remains to be elucidated. Here, we identified 461 transcripts associated with GA (range 23–41 weeks) and 2093 candidate CpG sites for GA-involved epigenetic memory through analysis of methylome (110 cord blood and 47 postnatal blood) and transcriptional data (55 cord blood). Moreover, we discovered the trends of chromatin state, such as polycomb-binding, among these candidate sites. Fifty-four memory candidate sites showed correlation between methylation and transcription, and the representative corresponding gene was UCN, which encodes urocortin. [ABSTRACT FROM AUTHOR]
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- 2021
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22. Urocortin
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Smani, Tarik and Choi, Sangdun, editor
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- 2018
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23. Study of the central corticotrophin-releasing factor system using the 2-deoxyglucose method for measurement of local cerebral glucose utilisation
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Warnock, Geoffrey Iain and Jones, Roland
- Subjects
615.19 ,glucose metabolism ,LCGU ,urocortin ,CRF - Abstract
Stress is defined as a challenge to homeostatic equilibrium by physical or psychological events, generating a coping response consisting of central and peripheral changes, with the aim of exerting control over the threatening events. Corticotropin-releasing factor (CRF) is well known as a hypothalamic factor which controls the hypothalamic-pituitary-adrenocortical (HPA) axis during basal activity and stress. CRF also serves a neurotransmitter function in the brain, where it is implicated in a range of stress-related behaviours. The measurement of local cerebral glucose utilisation (LCGU) using radiolabelled 2-deoxy-D-glucose (2DG) provides an estimate of cellular activity in the brain. 2DG competes with glucose in its metabolic pathway, but is not fully metabolised, instead accumulating within astrocytes where it can be quantified. After consideration of available modifications to the LCGU technique, the effect of manipulating the CRF system on LCGU was studied, in order to test the hypothesis that CRF and other endogenously expressed CRF-related peptides would induce different patterns of LCGU, and to examine the involvement of CRF receptors in any response. The CRF1 receptor has been implicated in the mediation of stress- and anxiety-related behaviour, while recent evidence has suggested a role for CRF2 in mediating the delayed effects of stress, although it has previously been postulated that CRF2 may be involved in the attenuation of stress-related behaviour. CRF and the endogenous CRF-related peptide Urocortin 1 both induced increases in LCGU in a number of brain regions associated with the CRF system, with concomitant activation of the HPA axis. CRF induced increases in LCGU in the dissected hypothalamus, thalamus, cerebellum and hippocampus, while Urocortin 1 induced a significant increase in LCGU in a dissected hindbrain region, with trend-like effects in frontal cortex and hippocampus. These regions contain components of the CRF system, or receive projections from regions involved in the CRF system, and have been implicated in stress-related function. The effects of CRF on LCGU appear to be mediated by the CRF2 receptor, as they were abolished by the selective CRF2 antagonist antisauvagine-30, but persisted in mice lacking CRF1 and were unaffected by a selective CRF1 antagonist. However, neither of the endogenous CRF-related peptides selective for CRF2, Urocortin 2 and Stresscopin, affected LCGU, which may indicate ligand-specific effects within the CRF system. In contrast to the effects of CRF, restraint stress reduced LCGU, while activating the HPA axis, and this response was unaffected by a selective CRF1 antagonist. This data suggests that the role of CRF receptors in restraint-induced LCGU changes may be overshadowed by effects on other neurotransmitter systems. These studies support the hypothesis that CRF and other endogenously expressed CRF-related peptides would induce different patterns of LCGU, and highlight the involvement of particular brain regions in the response to CRF receptor stimulation. Furthermore, these studies provide evidence suggesting ligand-specific effects within the CRF system.
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- 2007
24. Urocortin Neuropeptide Levels Are Impaired in the PBMCs of Overweight Children
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Sina Kavalakatt, Abdelkrim Khadir, Shihab Kochumon, Dhanya Madhu, Sriraman Devarajan, Maha Hammad, Nada Alam-Eldin, Samia Warsame, Hessa Al-Kandari, Maria AlMahdi, Rasheed Ahmad, Heikki A. Koistinen, Jaakko Tuomilehto, Fahd Al-Mulla, Jehad Abubaker, and Ali Tiss
- Subjects
urocortin ,UCN3 ,CRH ,obesity ,children ,Nutrition. Foods and food supply ,TX341-641 - Abstract
The corticotropin-releasing hormone (CRH) and urocortins (UCNs) have been implicated in energy homeostasis and the cellular stress response. However, the expression of these neuropeptides in children remains unclear. Therefore, we determined the impact of obesity on their expression in 40 children who were normal weight, overweight, and had obesity. Peripheral blood mononuclear cells (PBMCs) and plasma were used to assess the expression of neuropeptides. THP1 cells were treated with 25 mM glucose and 200 µM palmitate, and gene expression was measured by real-time polymerase chain reaction (RT-PCR). Transcript levels of neuropeptides were decreased in PBMCs from children with increased body mass index as indicated by a significant decrease in UCN1, UCN3, and CRH mRNA in overweight and obese children. UCN3 mRNA expression was strongly correlated with UCN1, UCN2, and CRH. Exposure of THP1 cells to palmitate or a combination of high glucose and palmitate for 24 h increased CRH, UCN2, and UCN3 mRNA expression with concomitant increased levels of inflammatory and endoplasmic reticulum stress markers, suggesting a crosstalk between these neuropeptides and the cellular stress response. The differential impairment of the transcript levels of CRH and UCNs in PBMCs from overweight and obese children highlights their involvement in obesity-related metabolic and cellular stress.
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- 2022
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25. Urocortin 3 Levels Are Impaired in Overweight Humans With and Without Type 2 Diabetes and Modulated by Exercise
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Sina Kavalakatt, Abdelkrim Khadir, Dhanya Madhu, Maha Hammad, Sriraman Devarajan, Jehad Abubaker, Fahd Al-Mulla, Jaakko Tuomilehto, and Ali Tiss
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urocortin ,UCN3 ,CRF ,obesity ,diabetes ,exercise ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
Urocortin3 (UCN3) regulates metabolic functions and is involved in cellular stress response. Although UCN3 is expressed in human adipose tissue, the association of UCN3 with obesity and diabetes remains unclear. This study investigated the effects of Type 2 diabetes (T2D) and increased body weight on the circulatory and subcutaneous adipose tissue (SAT) levels of UCN3 and assessed UCN3 modulation by a regular physical exercise. Normal-weight (n = 37) and overweight adults with and without T2D (n = 98 and n = 107, respectively) were enrolled in the study. A subset of the overweight subjects (n = 39 for each group) underwent a supervised 3-month exercise program combining both moderate intensity aerobic exercise and resistance training with treadmill. UCN3 levels in SAT were measured by immunofluorescence and RT-PCR. Circulatory UCN3 in plasma was assessed by ELISA and was correlated with various clinical and metabolic markers. Our data revealed that plasma UCN3 levels decreased in overweight subjects without T2D compared with normal-weight controls [median; 11.99 (0.78–86.07) and 6.27 (0.64–77.04), respectively; p < 0.001], whereas plasma UCN3 levels increased with concomitant T2D [median; 9.03 (0.77–104.92) p < 0.001]. UCN3 plasma levels were independently associated with glycemic index; fasting plasma glucose and hemoglobin A1c (r = 0.16 and r = 0.20, p < 0.05, respectively) and were significantly different between both overweight, with and without T2D, and normal-weight individuals (OR = 2.11 [1.84–4.11, 95% CI] and OR = 2.12 [1.59–3.10, 95% CI], p < 0.01, respectively). Conversely, the UCN3 patterns observed in SAT were opposite to those in circulation; UCN3 levels were significantly increased with body weight and decreased with T2D. After a 3-month supervised exercise protocol, UCN3 expression showed a significant reduction in SAT of both overweight groups (2.3 and 1.6-fold change; p < 0.01, respectively). In conclusion, UCN levels are differentially dysregulated in obesity in a tissue-dependent manner and can be mitigated by regular moderate physical exercise.
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- 2019
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26. Urocortin Role in Ischemia Cardioprotection and the Adverse Cardiac Remodeling
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Eva M. Calderón-Sánchez, Débora Falcón, Marta Martín-Bórnez, Antonio Ordoñez, and Tarik Smani
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urocortin ,adverse cardiac remodeling ,cardioprotection ,ischemia and reperfusion ,heart failure ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Despite the considerable progress in strategies of myocardial protection, ischemic heart diseases (IHD) and consequent heart failure (HF) remain the main cause of mortality worldwide. Several procedures are used routinely to guarantee the prompt and successful reestablishment of blood flow to preserve the myocardial viability of infarcted hearts from ischemia injuries. However, ischemic heart reperfusion/revascularization triggers additional damages that occur when oxygen-rich blood re-enters the vulnerable myocardial tissue, which is a phenomenon known as ischemia and reperfusion (I/R) syndrome. Complications of I/R injuries provoke the adverse cardiac remodeling, involving inflammation, mishandling of Ca2+ homeostasis, apoptotic genes activation, cardiac myocytes loss, etc., which often progress toward HF. Therefore, there is an urgent need to develop new cardioprotective therapies for IHD and HF. Compelling evidence from animal studies and pilot clinical trials in HF patients suggest that urocortin (Ucn) isoforms, which are peptides associated with stress and belonging to the corticotropin releasing factor family, have promising potential to improve cardiovascular functions by targeting many signaling pathways at different molecular levels. This review highlights the current knowledge on the role of urocortin isoforms in cardioprotection, focusing on its acute and long-term effects.
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- 2021
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27. UCN2: a new candidate influencing pancreatic ß-cell adaptations in pregnancy.
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Simpson, Sian J. S., Smith, Lorna I. F., Jones, Peter M., and Bowe, James E.
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PREGNANCY , *ISLANDS of Langerhans , *INSULIN resistance , *CATABOLITE repression , *PHYSIOLOGICAL adaptation - Abstract
The corticotropin-releasing hormone (CRH) family of peptides, including urocortin (UCN) 1, 2 and 3, are established hypothalamic neuroendocrine peptides, regulating the physiological and behaviour responses to stress indirectly, via the hypothalamicpituitary- adrenal (HPA) axis. More recently, these peptides have been implicated in diverse roles in peripheral organs through direct signalling, including in placental and pancreatic islet physiology. CRH has been shown to stimulate insulin release through activation of its cognate receptors, CRH receptor 1 (CRHR1) and 2. However, the physiological significance of this is unknown. We have previousl y reported that during mouse pregnancy, expression of CRH peptides increase in mouse placenta suggesting that these peptides may play a role in various biological functions associated with pregnancy, particularly the pancreatic islet adaptations that occur in the pregnant state to compensate for the physiological increase in maternal insulin resistance. In the current study, we show that mouse pregnancy is associated with increased circulating levels of UCN2 and that when we pharmacologically block endogen ous CRHR signalling in pregnant mice, impairment of glucose tolerance is observed. This effect on glucose tolerance was comparable to that displayed with specific CRHR2 b lockade and not with specific CRHR1 blockade. No effects on insulin sensitivity or the proliferative capacity of ß-cells were detected. Thus, CRHR2 signalling appears to be involved in ß-cell adaptive responses to pregnancy in the mouse, with endogenous placental UCN2 being the likely signal mediating this. [ABSTRACT FROM AUTHOR]
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- 2020
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28. The Role of Urocortins in Intracerebral Hemorrhage.
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Ker Woon Choy, Tsai, Andy Po-Yi, Lin, Peter Bor-Chian, Meng-Yu Wu, Chihyi Lee, Alias, Aspalilah, Cheng-Yoong Pang, and Hock-Kean Liew
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- *
CEREBRAL hemorrhage , *G protein coupled receptors , *CEREBRAL edema , *BLOOD-brain barrier - Abstract
Intracerebral hemorrhage (ICH) causes an accumulation of blood in the brain parenchyma that disrupts the normal neurological function of the brain. Despite extensive clinical trials, no medical or surgical therapy has shown to be effective in managing ICH, resulting in a poor prognosis for the patients. Urocortin (UCN) is a 40-amino-acid endogenous neuropeptide that belongs to the corticotropin-releasing hormone (CRH) family. The effect of UCN is activated by binding to two G-protein coupled receptors, CRH-R1 and CRH-R2, which are expressed in brain neurons and glial cells in various brain regions. Current research has shown that UCN exerts neuroprotective effects in ICH models via anti-inflammatory effects, which generally reduced brain edema and reduced blood-brain barrier disruption. These effects gradually help in the improvement of the neurological outcome, and thus, UCN may be a potential therapeutic target in the treatment of ICH. This review summarizes the data published to date on the role of UCN in ICH and the possible protective mechanisms underlined. [ABSTRACT FROM AUTHOR]
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- 2020
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29. Cancer-Specific Loss of Urocortin 3 in Human Renal Cancer.
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Faraj Tabrizi, Pouriya, Mohebbi Tafrechi, Anahit, Peters, Inga, Atschekzei, Faranaz, Kuczyk, Markus Antonius, Serth, Jürgen, and Tezval, Hossein
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RNA metabolism ,RENAL cell carcinoma ,CORTICOTROPIN releasing hormone ,WESTERN immunoblotting ,IMMUNOHISTOCHEMISTRY ,CELL receptors ,KIDNEY tumors ,CARRIER proteins - Abstract
Introduction: The corticotropin-releasing hormone (CRH) system, its receptors corticotropin-releasing hormone receptor 1 (CRHR1) and 2 (CRHR2), and its corresponding binding protein corticotropin-releasing hormone-binding protein (CRHBP) as well as the urocortin proteins-structural homologues to CRH, which are included in this peptide family-have become interesting oncological targets recently. Carcinogenesis of various human tumors has been reported with an altered presence of members of this system. The aim of the present study was to examine the role of urocortin 3 (UCN3) in renal cell carcinoma (RCC).Methods: Therefore, tumoral tissues of 106 patients with RCC and available corresponding normal tissues were analyzed using qPCR for quantitative mRNA expression analysis. Tissue localization and protein signals of UCN3 in normal and tumoral renal specimens were evaluated using western blot and immunohistochemistry. In addition, correlation studies of UCN3 mRNA expression with clinicopathological parameters of patients with RCC and different histological subtypes were evaluated.Results: UCN3 mRNA was significantly downregulated in nearly all tumoral tissues (p = 7.92 × 10-13). The same effect was observed at protein level using immunohistochemistry. Level of UCN3 mRNA expression was not directly correlated with clinicopathological parameters.Conclusion: We report for the first time the significant downregulation of UCN3 in RCC. These results demonstrate a possible involvement of the CRH system and its significance in carcinogenesis of RCC. [ABSTRACT FROM AUTHOR]- Published
- 2020
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30. Activation of CRF2 receptor increases gastric vagal afferent mechanosensitivity.
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Hui Li and Page, Amanda J.
- Abstract
Gastric vagal afferent (GVA) sensing of food-related mechanical stimuli is a crucial mechanism in the control of feeding behavior and gastric function. Stress is an important factor contributing to eating disorders and gastric diseases. Chronic stress has been shown to increase the mechanosensitivity of GVAs in mice and to reduce food intake and body weight. Whether the mechanosensitivity of GVAs is modulated by stress hormones is not known. This study aimed to determine the effect of stress hormones on GVA mechanosensitivity. The expression of stress hormone receptors in GVA cell bodies was determined in 8-wk-old male C57BL/6 mice using quantitative RT-PCR combined with laser capture microdissection. The mechanosensitivity of GVAs was determined in the absence and presence of stress hormones using an in vitro single-fiber recording preparation. NR3C1 and CRHR2 (mRNA isoforms of glucocorticoid receptor and CRF2 receptor, respectively) were expressed in GVA neurons. The glucocorticoid receptor agonist corticosterone had no effect on the mechanosensitivity of either tension or mucosal GVAs. Activation of CRF2 receptor by its specific analog, urocortin 3, significantly increased the mechanosensitivity of both tension and mucosal GVAs, an effect prevented by the CRF2 receptor antagonist astressin 2B. In conclusion, activation of CRF2 receptor increases the mechanosensitivity of GVAs. This may contribute to the stress- and CRF2 receptor-associated changes in feeding behavior and gastric function, possibly contributing to the hypersensitivity of GVAs in chronic stress conditions.NEW & NOTEWORTHY Gastric vagal afferents (GVAs) relay food-related signals to the central nervous system, where they are processed, eventually leading to modulation of food intake and gastric function. GVA signaling can be modulated by an array of hormones. Stress has been shown to induce GVA hypersensitivity. This study demonstrates that GVA neurons express subtypes of stress hormone receptors, specifically CRF2. Furthermore, activation of CRF2 receptor increases GVA mechanosensitivity, which could have implications for food intake and gastric function. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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31. mRNA expression of CRF family members in urothelial bladder cancer.
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Mavridis, Charalampos, Venihaki, Maria, Dermitzaki, Eirini, Deiktakis, Michail, Liapakis, Georgios, and Mamoulakis, Charalampos
- Subjects
- *
BLADDER cancer , *GENE expression , *TRANSITIONAL cell carcinoma , *REVERSE transcriptase polymerase chain reaction , *CORTICOTROPIN releasing hormone - Abstract
The corticotropin-releasing factor (CRF) gene family includes the three urocortins (UCN1, 2 and 3) and the two receptors (CRFR1 and 2), which play a significant role in the physiology of various organs. The expression of the CRF family of genes and its receptors are shown to participate in the pathogenesis of inflammation and even tumorigenesis. However, data regarding the human urinary tract, especially the bladder, are scarce. To the best of our knowledge, no studies are currently available on the CRF system and bladder cancer. The primary goal of the present study was to investigate the mRNA expression of the CRF family members in bladder cancer. The secondary aim was to analyze the differences with the expression of the same mRNAs in normal bladders. From August 2018 to July 2021, 43 recruited patients were divided into three groups. Group A included healthy patients, group B included patients with bladder cancer and group C included patients with a history of cancer from whom samples were taken from the normal bladder mucosa. Detection of mRNA of the CRF family of genes was performed using reverse transcription-quantitative PCR. The mRNA of the three urocortins, CRF and the two receptors were predominantly expressed in all three groups of patients. Statistical analysis using the Kruskal-Wallis test showed that UCN1 was downregulated in patients with bladder cancer and those with possible cancer compared with the healthy group (mean rank group A=24.3 vs. mean rank group B=12.58; P=0.006) and (mean rank group A=24.3 vs. mean rank group C=8.88; P=0.001). The present experiments showed that mRNA of the CRF family of genes was amplified in normal and cancer bladder tissues. Downregulation of the UCN1 gene may be associated with bladder cancer, contributing to the prognosis, diagnosis or therapy of urothelial malignancies. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
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32. Changes in Musculoskeletal System and Metabolism in Osteoporotic Rats Treated With Urocortin
- Author
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Dominik Saul, Laura Katharina Geisberg, Torben Gehle, Daniel Bernd Hoffmann, Mohammad Tezval, Stephan Sehmisch, and Marina Komrakova
- Subjects
osteoporosis ,urocortin ,muscle ,bone ,metabolism ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
Objective: In aging population, postmenopausal osteoporosis and decline of musculoskeletal function, referred to as “frailty syndrome” lead to loss of bone and muscle, causing falls, and fall-related injuries. To limit the impact of this portentous duo, simultaneous treatment of both is needed. Urocortin (UCN) has been reported to improve osteoporotic bone properties while its effect on muscle has not been addressed yet.Design and Methods: We aimed to investigate the effect of urocortin in vivo on skeletal muscle structure in osteopenic rats. Sixty Sprague-Dawley rats were divided into five groups: four were ovariectomized (OVX) and one underwent sham operation (SHAM). One ovariectomized group was left untreated (OVX), while one was treated with urocortin s.c. in 3 μg/kg body weight (bw) (OVX+UCN low), one with 30 μg/kg (OVX+UCN high), while one group was treated with estradiol orally (OVX+E: 0.2 mg/kg bw), each for 35 days. Mm. gastrocnemius, longissimus, and soleus were isolated and capillary density as well as diameters of type I and II fibers were measured. In addition, we examined the effect of UCN on tibia using biomechanical, micro-CT and ashing analysis and investigated the blood serum.Results: We demonstrated a positive effect of UCN on M. soleus, in which fiber diameter was positively influenced. The biomechanical and structural parameters of bone were not changed in UCN treated rats. The higher cholesterol, glucose and triglyceride levels in the “UCN high” group raise concern about this treatment.Conclusions: Our results portray urocortin as a substance that can be assessed for future therapeutic treatments of estrogen deficiency.New and Noteworthy: Urocortin has a positive effect on M. soleus (diameter). Urocortin raises serum cholesterol and triglyceride levels. Bone tissue was not affected by UCN.
- Published
- 2019
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33. Linking stress with urocortin in rats.
- Author
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Balraj M, Sarvepalli A, Chatterjee B, Ekambaram G, Rajapandian N, Nisha K, and Mani V
- Abstract
The corticotropin-releasing factor neuropeptides (CRH and UCN-1,2,3), as well as spexin, contribute to the control of energy balance and limit food intake in mammals. However, the role of these neuropeptides in chronic variable stress remains unknown. The effect of chronic varied stress on circulating corticosterone levels and urocortin expression levels in the brains of experimental rats was studied in this study. Rats were subjected with 28 days long term stress protocol, end of stress protocol experimental and control animal organs isolated, brain urocorcortin-1,2,3 expression by RT-PCR and serum corticosterone by ELISA method. UCN levels in the brain were altered in rats subjected to prolonged varied stress. Furthermore, corticosterone levels were elevated as a result of the same urocortin expression pattern, indicating that urocortin expression is controlled by glucocorticoids via a glucocorticoid-responsive element (GRE). Thus, data shows that hypothalamus-pituitary-adrenal (HPA) axis, also known as the LHPA axis, and limbic system are both stimulated by stress, which is reflected in the form of elevated corticosterone levels, according to the genes UCN1, 2, and 3., Competing Interests: The authors report no conflicts of interest., (© 2023 Biomedical Informatics.)
- Published
- 2023
- Full Text
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34. mRNA expression of CRF family members in urothelial bladder cancer.
- Author
-
Mavridis C, Venihaki M, Dermitzaki E, Deiktakis M, Liapakis G, and Mamoulakis C
- Abstract
The corticotropin-releasing factor (CRF) gene family includes the three urocortins (UCN1, 2 and 3) and the two receptors (CRFR1 and 2), which play a significant role in the physiology of various organs. The expression of the CRF family of genes and its receptors are shown to participate in the pathogenesis of inflammation and even tumorigenesis. However, data regarding the human urinary tract, especially the bladder, are scarce. To the best of our knowledge, no studies are currently available on the CRF system and bladder cancer. The primary goal of the present study was to investigate the mRNA expression of the CRF family members in bladder cancer. The secondary aim was to analyze the differences with the expression of the same mRNAs in normal bladders. From August 2018 to July 2021, 43 recruited patients were divided into three groups. Group A included healthy patients, group B included patients with bladder cancer and group C included patients with a history of cancer from whom samples were taken from the normal bladder mucosa. Detection of mRNA of the CRF family of genes was performed using reverse transcription-quantitative PCR. The mRNA of the three urocortins, CRF and the two receptors were predominantly expressed in all three groups of patients. Statistical analysis using the Kruskal-Wallis test showed that UCN1 was downregulated in patients with bladder cancer and those with possible cancer compared with the healthy group (mean rank group A=24.3 vs. mean rank group B=12.58; P=0.006) and (mean rank group A=24.3 vs. mean rank group C=8.88; P = 0.001). The present experiments showed that mRNA of the CRF family of genes was amplified in normal and cancer bladder tissues. Downregulation of the UCN1 gene may be associated with bladder cancer, contributing to the prognosis, diagnosis or therapy of urothelial malignancies., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2023, Spandidos Publications.)
- Published
- 2023
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35. Urocortin 3 signalling in the auditory brainstem aids recovery of hearing after reversible noise‐induced threshold shift.
- Author
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Fischl, Matthew J., Ueberfuhr, Margarete A., Drexl, Markus, Pagella, Sara, Sinclair, James L., Alexandrova, Olga, Deussing, Jan M., and Kopp‐Scheinpflug, Conny
- Subjects
- *
UROCORTIN , *HEARING aids , *NOISE-induced deafness , *AUDITORY pathways , *HAIR cells , *CELL physiology - Abstract
Key points: Ongoing, moderate noise exposure does not instantly damage the auditory system but may cause lasting deficits, such as elevated thresholds and accelerated ageing of the auditory system.The neuromodulatory peptide urocortin‐3 (UCN3) is involved in the body's recovery from a stress response, and is also expressed in the cochlea and the auditory brainstem.Lack of UCN3 facilitates age‐induced hearing loss and causes permanently elevated auditory thresholds following a single 2 h noise exposure at moderate intensities.Outer hair cell function in mice lacking UCN3 is unaffected, so that the observed auditory deficits are most likely due to inner hair cell function or central mechanisms.Highly specific, rather than ubiquitous, expression of UCN3 in the brain renders it a promising candidate for designing drugs to ameliorate stress‐related auditory deficits, including recovery from acoustic trauma. Environmental acoustic noise is omnipresent in our modern society, with sound levels that are considered non‐damaging still causing long‐lasting or permanent changes in the auditory system. The small neuromodulatory peptide urocortin‐3 (UCN3) is the endogenous ligand for corticotropin‐releasing factor receptor type 2 and together they are known to play an important role in stress recovery. UCN3 expression has been observed in the auditory brainstem, but its role remains unclear. Here we describe the detailed distribution of UCN3 expression in the murine auditory brainstem and provide evidence that UCN3 is expressed in the synaptic region of inner hair cells in the cochlea. We also show that mice with deficient UCN3 signalling experience premature ageing of the auditory system starting at an age of 4.7 months with significantly elevated thresholds of auditory brainstem responses (ABRs) compared to age‐matched wild‐type mice. Following a single, 2 h exposure to moderate (84 or 94 dB SPL) noise, UCN3‐deficient mice exhibited significantly larger shifts in ABR thresholds combined with maladaptive recovery. In wild‐type mice, the same noise exposure did not cause lasting changes to auditory thresholds. The presence of UCN3‐expressing neurons throughout the auditory brainstem and the predisposition to hearing loss caused by preventing its normal expression suggests UCN3 as an important neuromodulatory peptide in the auditory system's response to loud sounds. Key points: Ongoing, moderate noise exposure does not instantly damage the auditory system but may cause lasting deficits, such as elevated thresholds and accelerated ageing of the auditory system.The neuromodulatory peptide urocortin‐3 (UCN3) is involved in the body's recovery from a stress response, and is also expressed in the cochlea and the auditory brainstem.Lack of UCN3 facilitates age‐induced hearing loss and causes permanently elevated auditory thresholds following a single 2 h noise exposure at moderate intensities.Outer hair cell function in mice lacking UCN3 is unaffected, so that the observed auditory deficits are most likely due to inner hair cell function or central mechanisms.Highly specific, rather than ubiquitous, expression of UCN3 in the brain renders it a promising candidate for designing drugs to ameliorate stress‐related auditory deficits, including recovery from acoustic trauma. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
36. Urocortinergic system in the epididymis of the normal and cryptorchid dogs.
- Author
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Squillacioti, Caterina, Pelagalli, Alessandra, De Luca, Adriana, Liguori, Giovanna, Ali, Sabrina, and Mirabella, Nicola
- Subjects
- *
MALE reproductive organs , *REVERSE transcriptase polymerase chain reaction , *EPIDIDYMIS , *GENITALIA , *VASCULAR smooth muscle , *DOGS - Abstract
Cryptorchidism is associated with changes in the gonads and the spermatic duct system, which may cause infertility problems. Urocortin (UCN) is a corticotrophin‐releasing hormone (CRH)‐related peptide, which affects several functions of male genital organs. The aim of the present study was to investigate the expression of UCN and its receptors CRHR1 and CRHR2 using immunohistochemistry, western blotting and real‐time reverse transcription polymerase chain reaction in tissues collected from the epididymis of normal and cryptorchid dogs. The lumen of the cryptic epididymal duct was found to be relatively smaller than that of the normal one, and interstitial tissue was abundant in the cryptic epididymis. In addition, only a few spermatids were observed in the lumen of the epididymal duct. Results showed that UCN, CRHR2 and CRHR1 were expressed in tissues collected from normal and cryptic epididymal ducts. Urocortin‐ and CRHR2‐immunoreactivities (IRs) were detected in the principal cells of the caput, corpus and cauda of the normal and cryptic epididymides. CRHR1‐IR was detected in vascular smooth muscles and fibromuscular cells surrounding epididymal tubules of the normal and cryptorchid dogs. Expression levels of UCN and CRHR2 mRNA were higher in cryptic epididymal ducts than that in normal epididymal ducts. These results suggest that UCN and its receptors might play a role in regulating the maturation and storage of spermatozoa. These findings indicated that the expression of these proteins could be modulated by the cryptorchidism condition. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
37. Changes in Musculoskeletal System and Metabolism in Osteoporotic Rats Treated With Urocortin.
- Author
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Saul, Dominik, Geisberg, Laura Katharina, Gehle, Torben, Hoffmann, Daniel Bernd, Tezval, Mohammad, Sehmisch, Stephan, and Komrakova, Marina
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MUSCULOSKELETAL system ,SERUM ,BLOOD serum analysis ,METABOLIC clearance rate ,BLOOD cholesterol ,OSTEOPOROSIS in women ,RATS ,SKELETAL muscle - Abstract
Objective: In aging population, postmenopausal osteoporosis and decline of musculoskeletal function, referred to as "frailty syndrome" lead to loss of bone and muscle, causing falls, and fall-related injuries. To limit the impact of this portentous duo, simultaneous treatment of both is needed. Urocortin (UCN) has been reported to improve osteoporotic bone properties while its effect on muscle has not been addressed yet. Design and Methods: We aimed to investigate the effect of urocortin in vivo on skeletal muscle structure in osteopenic rats. Sixty Sprague-Dawley rats were divided into five groups: four were ovariectomized (OVX) and one underwent sham operation (SHAM). One ovariectomized group was left untreated (OVX), while one was treated with urocortin s.c. in 3 μg/kg body weight (bw) (OVX+UCN low), one with 30 μg/kg (OVX+UCN high), while one group was treated with estradiol orally (OVX+E: 0.2 mg/kg bw), each for 35 days. Mm. gastrocnemius, longissimus , and soleus were isolated and capillary density as well as diameters of type I and II fibers were measured. In addition, we examined the effect of UCN on tibia using biomechanical, micro-CT and ashing analysis and investigated the blood serum. Results: We demonstrated a positive effect of UCN on M. soleus , in which fiber diameter was positively influenced. The biomechanical and structural parameters of bone were not changed in UCN treated rats. The higher cholesterol, glucose and triglyceride levels in the "UCN high" group raise concern about this treatment. Conclusions: Our results portray urocortin as a substance that can be assessed for future therapeutic treatments of estrogen deficiency. New and Noteworthy: Urocortin has a positive effect on M. soleus (diameter). Urocortin raises serum cholesterol and triglyceride levels. Bone tissue was not affected by UCN. [ABSTRACT FROM AUTHOR]
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- 2019
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38. Polydatin protects against ovalbumin-induced bronchial asthma in rats; involvement of urocortin and surfactant-D expression.
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Hanna, Dina A., Khalaf, Marwa M., and Abo-Saif, Ali A.
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OVALBUMINS , *ASTHMA , *NITRIC-oxide synthases , *WESTERN immunoblotting , *IMMUNOGLOBULIN E , *INFLAMMATORY mediators - Abstract
Context: Prevalence of bronchial asthma massively increases worldwide, while the frequent therapies are still not sufficient. Polydatin, a naturally occurring glycoside, was known as to have anti-inflammatory and anti-oxidant effects. Objective: The current study aimed to investigate the possible protective effect of polydatin against experimental bronchial asthma in rats. Material and methods: Bronchial asthma was induced by ovalbumin (OVA) sensitization and challenge. Rats were randomly allocated into five groups; Group I (normal control group); Group II (asthma control group) received OVA; Group III (reference standard treatment group) received dexamethasone (1 mg/kg/day); Group IV (treatment group) received polydatin (200/mg/kg); and Group V (polydatin control group). The inflammatory biomarkers interleukin-4 (IL-4), IL-5, IL-13, tumor necrosis factor-alpha, interferon-gamma and absolute eosinophil count in bronchoalveolar lavage fluid (BALF), as well as serum immunoglobulin E were assessed, coupled with the oxido-nitrative stress biomarkers malondialdehyde and glutathione reduced levels and superoxide dismutase activity in the lung tissue, besides inducible nitric oxide synthase level in BALF. Western blot analysis of surfactant-D and immunohistochemical assay of urocortin (UCN) expression in the lung was performed. Results: Polydatin significantly reduced the inflammatory mediators and restored the normal values of oxidative and nitrosative stress biomarkers. It also significantly reduced the expression of surfactant-D and UCN as compared to asthma control. The histopathological study strongly augmented the biochemical results. Discussion and conclusions: Polydatin may be a promising protective agent against experimentally induced bronchial asthma. Modulation of SP-D and UCN expressions seems to mediate such protective effects. [ABSTRACT FROM AUTHOR]
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- 2019
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39. Urocortin Expression in Endometriosis: A Systematic Review.
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Pergialiotis, Vasilios, Tagkou, Nikoletta Maria, Tsimpiktsioglou, Athina, Klavdianou, Olga, Neonaki, Antonia, and Trompoukis, Pantelis
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DIAGNOSIS of endometriosis , *CORTICOTROPIN releasing hormone , *GENE expression , *MEDICAL information storage & retrieval systems , *MEDLINE , *SYSTEMATIC reviews , *SEVERITY of illness index - Abstract
Urocortin (UCN) is a neuropeptide that belongs to the corticotrophin-releasing hormone family and is expressed by eutopic and ectopic human endometria. The past years, this expression has been thoroughly investigated in the field of endometriosis. The objective of this systematic review is to accumulate current evidence related to the expression of UCN in tissue and blood samples of patients suffering from endometriosis. Literature search was designed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and primarily conducted using the Medline (1966-2018), Scopus (2004-2018), EMBASE (1947-2018) and Clinicaltrials.gov (2008- 2018) databases, along with the reference lists of electronically retrieved full-text papers. Overall, eight studies were retrieved. Current evidence suggests that the expression of UCN is increased in patients with ovarian endometriomas and that its levels may correlate with the severity of the disease. The diagnostic efficacy of UCN1 plasma levels was evaluated in three studies. Two of them suggested that the sensitivity and specificity of the method may reach, and even exceed, 80%. However, the wide variation in outcome reporting and outcome reporting measures in endometriosis among the included studies precludes meta-analysis of available data. Therefore, although UCN seems to be a promising biomarker for the identification and follow-up of patients that suffer from endometriosis, more studies are needed to reach firm conclusions with respect to its predictive accuracy. [ABSTRACT FROM AUTHOR]
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- 2019
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40. The effects of the urocortins on the hypothalamic-pituitary-adrenal axis - similarities and discordancies between rats and mice.
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Bagosi, Zsolt, Csabafi, Krisztina, Karasz, Gergely, Jászberényi, Miklós, Földesi, Imre, Siska, Andrea, Szabó, Gyula, and Telegdy, Gyula
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UROCORTIN , *HYPOTHALAMIC-pituitary-thyroid axis , *VASOPRESSIN , *ENZYME-linked immunosorbent assay , *RATS - Abstract
Highlights • Ucn I increased the hypothalamic CRF and AVP concentrations in rats and mice. • Ucn II and Ucn III influenced only the hypothalamic CRF concentration in rats. • Ucn II and Ucn III increased only the hypothalamic AVP concentration in mice. • The hypothalamic changes were reflected by changes of plasma ACTH and CORT levels. • Ucns regulate the HPA axis via modulation of ACTH secretagogues in both species. Abstract The urocortins (Ucn I, Ucn II and Ucn III) are structural analogues of corticotropin-releasing factor (CRF). The aim of our present experiments was to compare the effects of the urocortins on the hypothalamic-pituitary-adrenal (HPA) axis in rats and mice, including the hypothalamic adrenocorticotropic hormone (ACTH) secretagogues, such as CRF and arginine vasopressin (AVP). Therefore, male CFLP mice and male Wistar rats were injected intracerebroventricularly (icv) with 0.5, 1, 2 and 5 μg/2 μl of Ucn I, Ucn II or Ucn III. After 30 min the animals were decapitated, and then, hypothalamic CRF and AVP concentrations and plasma ACTH and corticosterone (CORT) levels were measured. All measurements were performed by enzyme-linked immunosorbent assays (ELISA), except that of the plasma CORT level, which was determined by chemofluorescent assay. Ucn I increased significantly the hypothalamic CRF and AVP concentrations in both rats and mice. Ucn II and Ucn III influenced significantly only the hypothalamic CRF concentration in rats, without affecting the hypothalamic AVP concentration. In contrast, Ucn II and Ucn III increased significantly only the hypothalamic AVP concentration in mice, without affecting the hypothalamic CRF concentration. The hypothalamic changes were reflected more or less accurately by changes of the plasma ACTH and CORT levels. The present experiments demonstrate that the urocortins regulate the HPA axis centrally via modulation of the hypothalamic ACTH secretagogues and that there are some similarities and discordancies between rats and mice regarding this regulation. [ABSTRACT FROM AUTHOR]
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- 2019
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41. Urocortins and their unfolding role in mammalian social behavior.
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Wagner, Shlomo
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UROCORTIN , *SOCIAL behavior in mammals , *CORTICOTROPIN releasing hormone , *AMYGDALOID body , *NEUROPEPTIDES - Abstract
The corticotropin-releasing factor (CRF) system is well known for its major role in coordinating the endocrine, autonomic and behavioral responses to stress. These functions have been shown to be mediated mainly by the binding of the CRF neuropeptide to its specific receptor CRFR1. Yet, the CRF system comprises several more neuropeptides, including the three urocortins, UCN1, UCN2 and UCN3, of which the latter two bind specifically to a distinct receptor—CRFR2. Unlike the brain-wide abundant expression of CRF and CRFR1, the brain expression of the urocortins and CRFR2 is rather restricted and seems to be focused in limbic areas associated with social behavior. Here, we will review accumulating evidence from recent studies that unfold the role of UCN2 and UCN3 in regulating mammalian social behavior, via activation of CRFR2. [ABSTRACT FROM AUTHOR]
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- 2019
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42. The Effect of Metformin on the Endometrium of Women with Polycystic Ovary Syndrome.
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Dragamestianos, Christos, Messini, Christina I., Antonakis, Pantelis T., Zacharouli, Konstantina, Kostopoulou, Evanthia, Makrigiannakis, Antonis, Georgoulias, Panagiotis, Anifandis, George, Dafopoulos, Konstantinos, Garas, Antonios, Daponte, Alexandros, Messinis, Ioannis E., Messini, Christina I, Antonakis, Pantelis T, and Messinis, Ioannis E
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POLYCYSTIC ovary syndrome , *METFORMIN , *ENDOMETRIUM , *CORTICOTROPIN releasing hormone , *MENSTRUAL cycle , *ESTROGEN replacement therapy , *THERAPEUTIC use of progestational hormones , *COMBINATION drug therapy , *ESTRADIOL , *HYPOGLYCEMIC agents , *LONGITUDINAL method , *OLIGOMENORRHEA , *PROGESTERONE , *IMPACT of Event Scale , *DISEASE complications , *PHARMACODYNAMICS - Abstract
Objectives: To investigate the effect of metformin on endometrial receptivity in women with polycystic ovary syndrome (PCOS).Methods: Twenty volunteer women with polycystic ovaries and oligomenorrhea were prospectively investigated. All women were treated with exogenous estradiol and progesterone to simulate a normal menstrual cycle (28-day duration) after GnRH-induced pituitary desensitization. Ten of the women received no other medication (group A, control), while the remaining 10 received metformin (group B, metformin). Endometrial biopsy was performed in all women on day 21 of the 2 simulated cycles.Results: The expression of corticotropin - releasing hormone and urocortin in the endometrium was investigated. There was no significant difference between the 2 groups. A 3-day delay in the secretory maturation of the glandular epithelium relatively to the stroma was observed in 7 out of 10 women of group B (70%) as compared to only 1 out of 10 women of group A (10%, p = 0.02).Conclusions: It is shown for the first time that metformin administration to women with PCOS did not affect the expression of endometrial receptivity markers but delayed histological glandular maturation. It is suggested that metformin may have an impact on the function of the endometrium in PCOS. [ABSTRACT FROM AUTHOR]- Published
- 2019
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43. Urocortin 3 Gene Transfer Increases Function of the Failing Murine Heart.
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Giamouridis, Dimosthenis, Gao, Mei Hua, Lai, N. Chin, Tan, Zhen, Kim, Young Chul, Guo, Tracy, Miyanohara, Atsushi, Blankesteijn, Matthijs W., Biessen, Erik A. L., and Hammond, H. Kirk
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GENETIC transformation , *UROCORTIN , *PEPTIDES , *CORTICOTROPIN releasing hormone , *HEART failure , *GENE therapy - Abstract
Peptide infusions of peptides the corticotropin releasing factor family, including urocortin 2, stresscopin, and urocortin 3 (UCn3), have favorable acute effects in clinical heart failure (HF), but their short half-lives make them unsuitable for chronic therapy. This study asked whether UCn3 gene transfer, which provides sustained elevation of plasma UCn3 levels, increases the function of the failing heart. HF was induced by transmural left ventricular (LV) cryoinjury in mice. LV function was assessed 3 weeks later by echocardiography. Those with ejection fractions (EF) <40% received intravenous saline or intravenous adeno-associated virus type-8 encoding murine UCn3 (AAV8.mUCn3; 1.9 × 1013 genome copies/kg). Five weeks after randomization, repeat echocardiography, assessment of LV function (+dP/dt, −dP/dt), and quantification of Ca2+ transients and sarcomere shortening in isolated cardiac myocytes were conducted, and assessment of LV Ca2+ handling and stress proteins was performed. Three weeks after myocardial infarction, prior to treatment, EFs were reduced (mean 31%, from 63% in sham-operated animals). Mice randomized to receive UCn3 gene transfer showed increased plasma UCn3 (from 0.1 ± 0.01 ng/mL in the saline group to 5.6 ± 1.1 ng/mL; n = 12 each group; p < 0.0001). Compared to mice that received saline, UCn3 gene transfer was associated with higher values for EF (p = 0.0006); LV +dP/dt (p < 0.0001), and LV −dP/dt (p < 0.0001). Cardiac myocytes from mice that received UCn3 gene transfer showed higher peak Ca2+ transients (p = 0.0005), lower time constant of cytosolic Ca2+ decline (tau, p < 0.0001), and higher rates of sarcomere shortening (+dL/dt, p = 0.03) and lengthening (–dL/dt, p = 0.04). LV samples from mice that received UCn3 gene transfer contained higher levels of SERCA2a (p = 0.0004 vs. HF) and increased amounts of phosphorylated troponin I (p = 0.04 vs. HF). UCn3 gene transfer is associated with improved Ca2+ handling and LV function in mice with HF and reduced EF. [ABSTRACT FROM AUTHOR]
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- 2019
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44. Do urocortins have a role in treating cardiovascular disease?
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Chatzaki, Ekaterini, Kefala, Nikoleta, Drosos, Ioannis, Lalidou, Fani, and Baritaki, Stavroula
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UROCORTIN , *CARDIOVASCULAR disease treatment , *NEUROPEPTIDES , *CLINICAL trials , *CONGESTIVE heart failure treatment - Abstract
Highlights • Urocortins could serve as alternative/adjunct therapies for cardiovascular disease. • Pre-clinical and clinical data for such uses of urocortins are promising. • Urocortins may play a role in the treatment of ischemic heart disease, hypertension and heart failure. Corticotropin-releasing factor (CRF) and the three homolog neuropeptides, urocortin (UCN) 1, 2 and 3, are the major neuroendocrine factors implicated in the response of the body to stress. Recent evidence suggests that UCNs have a significant role in the pathogenesis and management of cardiovascular disease, such as congestive heart failure, ischemic heart disease, and hypertension. These data led to the initiation of clinical trials testing a possible role of UCNs in the diagnosis and therapy of cardiovascular disease, with encouraging results. Here, we summarize the available literature concerning the role of UCNs in the cardiovascular system, focusing on the emerging data creating a potential for clinical applications. [ABSTRACT FROM AUTHOR]
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- 2019
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45. Tranexamic acid inhibits the plasma and non-irradiated skin markers of photoaging induced by long-term UVA eye irradiation in female mice.
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Hiramoto, Keiichi, Yamate, Yurika, Sugiyama, Daijiro, Matsuda, Kazunari, Iizuka, Yasutaka, and Yamaguchi, Tomohiko
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TRANEXAMIC acid , *UROCORTIN , *ENDORPHINS , *METHIONINE , *HISTAMINE , *ESTROGEN receptors - Abstract
Graphical abstract Highlights • The levels of urocortin 2, β-endorphin, OGF, histamine, CRHR type 2, μ-opioid receptor, OGFR, T-bet and GATA3 was increased by UVA eye irradiation. • Increase in the levels of urocortin 2, methionine enkephalin, histamine, OGFR, T-bet and GATA3 were suppressed by tranexamic acid treatment. • Tranexamic acid increased β-endorphin and μ-opioid receptor levels. • Tranexamic acid increased estrogen receptor-β on the surface of mast cell. • Photoaging induced by UVA eye irradiation is ameliorated by tranexamic acid. Abstract Photoaging can be induced by long-term ultraviolet (UV)A eye irradiation, but an ameliorating method for such photoaging is not known. In this study, we examined the effects of tranexamic acid (trans-4-aminomethylcyclohexanecarboxylic acid) on photoaging of the skin induced by UVA eye irradiation. We used the C57BL/6 j female mice and locally exposed their eyes to UVA at a dose of 110 kJ/m2 using an FL20SBLB-A lamp multiple times a week for one year. The plasma urocortin 2, β-endorphin, methionine enkephalin (OGF), and histamine content, as well as the expression of the corticotropin-releasing hormone receptor (CRHR) type 2, μ-opioid receptor, opioid growth factor receptor (OGFR), T-bet, and GATA3 increased in the mice subjected to UVA eye irradiation. However, the increased levels of urocortin 2, methionine enkephalin, histamine, OGFR, T-bet, and GATA3 were suppressed by tranexamic acid treatment. Conversely, the levels of β-endorphin and μ-opioid receptor increased with tranexamic acid treatment. In addition, the expression of the estrogen receptor-β on the surface of mast cells was increased by tranexamic acid. These results indicate that photoaging induced by UVA eye irradiation can be ameliorated by tranexamic acid through the regulation of hypothalamo-pituitary hormones. Furthermore, this ameliorative effect on photoaging may be due to an increase in estrogen receptor-β after tranexamic acid treatment. [ABSTRACT FROM AUTHOR]
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- 2018
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46. Assessment of clinical data on urocortins and their therapeutic potential in cardiovascular diseases: A systematic review and meta‐analysis
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Dora K. Kovacs, Szimonetta Eitmann, Alexandra Soós, Péter Hegyi, Zsolt Molnár, Nelli Farkas, Bálint Erőss, Anna Schekk, Leonardo Kelava, and Márta Balaskó
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medicine.medical_specialty ,endocrine system ,RM1-950 ,General Biochemistry, Genetics and Molecular Biology ,Article ,Internal medicine ,Heart rate ,medicine ,Humans ,General Pharmacology, Toxicology and Pharmaceutics ,Urocortins ,Urocortin ,Ejection fraction ,business.industry ,General Neuroscience ,Research ,General Medicine ,Articles ,medicine.disease ,Confidence interval ,Blood pressure ,Treatment Outcome ,Cardiovascular Diseases ,Heart failure ,Meta-analysis ,Cardiology ,Therapeutics. Pharmacology ,Public aspects of medicine ,RA1-1270 ,business ,hormones, hormone substitutes, and hormone antagonists - Abstract
Heart failure (HF) and cardiovascular diseases present public health challenges. Although great progress was achieved in their treatment, there is continuous need for new therapies. Urocortins of the corticotropin neuropeptide family were reported to exert beneficial effects in animal models of HF and cardiovascular diseases. We aimed to assess the available clinical evidence on the potential role of urocortins in HF and other cardiovascular diseases. We explored MEDLINE, Embase, CENTRAL, and Scopus databases. Twenty‐seven studies were included in the qualitative and 15 studies (2005 patients) in the quantitative syntheses. Available data allowed us to meta‐analyze the blood pressure (BP) lowering and heart rate (HR) increasing effects of urocortin 2 in HF with reduced ejection fraction. We applied meta‐regression to explore the association between left ventricular ejection fraction and serum urocortin 1 and urocortin 2 levels. Short‐term urocortin 2 infusion decreased mean arterial pressure in chronic HF with reduced ejection fraction (mean difference = −9.161 mmHg, 95% confidence interval [CI] −12.661 to −5.660 mmHg, p
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- 2021
47. Corticotropin-Releasing Factor Receptors Modulate Oxytocin Release in the Dorsolateral Bed Nucleus of the Stria Terminalis (BNST) in Male Rats
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Daisy Martinon and Joanna Dabrowska
- Subjects
oxytocin ,CRF ,urocortin ,BNST ,bed nucleus of the stria terminalis ,release ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
The neuropeptide oxytocin (OT) plays an important role in the regulation of social and anxiety-like behavior. Our previous studies have shown that OT neurons send projections from the hypothalamus to the dorsolateral bed nucleus of the stria terminalis (BNSTdl), a forebrain region critically involved in the modulation of anxiety-like behavior. Importantly, these OT terminals in the BNSTdl express presynaptic corticotropin releasing factor (CRF) receptor type 2 (CRFR2). This suggests that CRFR2 might be involved in the modulation of OT release. To test this hypothesis, we measured OT content in microdialysates collected from the BNSTdl of freely-moving male Sprague-Dawley rats following the administration of a selective CRFR2 agonist (Urocortin 3) or antagonist (Astressin 2B, As2B). To determine if type 1 CRF receptors (CRFR1) are also involved, we used selective CRFR1 antagonist (NBI35965) as well as CRF, a putative ligand of both CRFR1 and CRFR2. All compounds were delivered directly into the BNSTdl via reverse dialysis. OT content in the microdialysates was measured with highly sensitive and selective radioimmunoassay. Blocking CRFR2 with As2B caused an increase in OT content in BNSTdl microdialysates, whereas CRFR2 activation by Urocortin 3 did not have an effect. The As2B-induced increase in OT release was blocked by application of the CRFR1 antagonist demonstrating that the effect was dependent on CRFR1 transmission. Interestingly, CRF alone caused a delayed increase in OT content in BNSTdl microdialysates, which was dependent on CRF2 but not CRF1 receptors. Our results suggest that members of the CRF peptide family modulate OT release in the BNSTdl via a fine-tuned mechanism that involves both CRFR1 and CRFR2. Further exploration of mechanisms by which endogenous OT system is modulated by CRF peptide family is needed to better understand the role of these neuropeptides in the regulation of anxiety and the stress response.
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- 2018
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48. Urocortin 3 overexpression reduces ER stress and heat shock response in 3T3-L1 adipocytes
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Jehad Abubaker, Heikki A. Koistinen, Ali Tiss, Jaakko Tuomilehto, Fahd Al-Mulla, Sina Kavalakatt, Abdelkrim Khadir, Dhanya Madhu, HUS Internal Medicine and Rehabilitation, Department of Medicine, University of Helsinki, Clinicum, and Department of Public Health
- Subjects
0301 basic medicine ,INCREASES ,Glucose uptake ,PROTEIN ,Adipose tissue ,Diseases ,Biochemistry ,Mice ,0302 clinical medicine ,Endocrinology ,OBESE HUMANS ,Adipocytes ,PEPTIDE ,Endoplasmic Reticulum Chaperone BiP ,Urocortins ,Urocortin ,Multidisciplinary ,Chemistry ,Cell Differentiation ,Endoplasmic Reticulum Stress ,ADIPOSE-TISSUE ,FACTOR RECEPTOR ,SKELETAL-MUSCLE ,Medicine ,HSP60 ,EXPRESSION ,medicine.medical_specialty ,Science ,030209 endocrinology & metabolism ,Protein Serine-Threonine Kinases ,Article ,03 medical and health sciences ,Insulin resistance ,INFLAMMATION ,Heat shock protein ,Internal medicine ,3T3-L1 Cells ,Endoribonucleases ,medicine ,Animals ,Heat shock ,medicine.disease ,GENE ,030104 developmental biology ,3121 General medicine, internal medicine and other clinical medicine ,Unfolded protein response ,Insulin Resistance - Abstract
The neuropeptide urocortin 3 (UCN3) has a beneficial effect on metabolic disorders, such as obesity, diabetes, and cardiovascular disease. It has been reported that UCN3 regulates insulin secretion and is dysregulated with increasing severity of obesity and diabetes. However, its function in the adipose tissue is unclear. We investigated the overexpression of UCN3 in 3T3-L1 preadipocytes and differentiated adipocytes and its effects on heat shock response, ER stress, inflammatory markers, and glucose uptake in the presence of stress-inducing concentrations of palmitic acid (PA). UCN3 overexpression significantly downregulated heat shock proteins (HSP60, HSP72 and HSP90) and ER stress response markers (GRP78, PERK, ATF6, and IRE1α) and attenuated inflammation (TNFα) and apoptosis (CHOP). Moreover, enhanced glucose uptake was observed in both preadipocytes and mature adipocytes, which is associated with upregulated phosphorylation of AKT and ERK but reduced p-JNK. Moderate effects of UCN3 overexpression were also observed in the presence of 400 μM of PA, and macrophage conditioned medium dramatically decreased the UCN3 mRNA levels in differentiated 3T3-L1 cells. In conclusion, the beneficial effects of UCN3 in adipocytes are reflected, at least partially, by the improvement in cellular stress response and glucose uptake and attenuation of inflammation and apoptosis.
- Published
- 2021
49. Urocortin-2 improves right ventricular function and attenuates pulmonary arterial hypertension.
- Author
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Adão, Rui, Mendes-Ferreira, Pedro, Santos-Ribeiro, Diana, Maia-Rocha, Carolina, Pimentel, Luís D., Monteiro-Pinto, Cláudia, Mulvaney, Eamon P., Reid, Helen M., Kinsella, B. Therese, Potus, François, Breuils-Bonnet, Sandra, Rademaker, Miriam T., Provencher, Steeve, Bonnet, Sébastien, Leite-Moreira, Adelino F., and Brás-Silva, Carmen
- Subjects
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PULMONARY hypertension , *UROCORTIN , *HEART failure treatment , *CARDIAC hypertrophy , *VENTRICULAR remodeling - Abstract
Aims Pulmonary arterial hypertension (PAH) is a devastating disease and treatment options are limited. Urocortin-2 (Ucn-2) has shown promising therapeutic effects in experimental and clinical left ventricular heart failure (HF). Our aim was to analyse the expression of Ucn-2 in human and experimental PAH, and to investigate the effects of human Ucn-2 (hUcn-2) administration in rats with monocrotaline (MCT)-induced pulmonary hypertension (PH). Methods and results Tissue samples were collected from patients with and without PAH and from rats with MCT-induced PH. hUcn-2 (5 lg/kg, bi-daily, i.p., for 10 days) or vehicle was administered to male wistar rats subjected to MCT injection or to pulmonary artery banding (PAB) to induce right ventricular (RV) overload without PAH. Expression of Ucn-2 and its receptor was increased in the RV of patients and rats with PAH. hUcn-2 treatment reduced PAH in MCT rats, resulting in decreased morbidity, improved exercise capacity and attenuated pulmonary arterial and RV remodelling and dysfunction. Additionally, RV gene expression of hypertrophy and failure signalling pathways were attenuated. hUcn-2 treatment also attenuated PAB-induced RV hypertrophy. Conclusions Ucn-2 levels are altered in human and experimental PAH. hUcn-2 treatment attenuates PAH and RV dysfunction in MCT-induced PH, has direct anti-remodelling effects on the pressure-overloaded RV, and improves pulmonary vascular function. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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50. Urocortin-2 Prevents Dysregulation of Ca2+ Homeostasis and Improves Early Cardiac Remodeling After Ischemia and Reperfusion.
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Domínguez-Rodríguez, Alejandro, Mayoral-Gonzalez, Isabel, Avila-Medina, Javier, de Rojas-de Pedro, Eva S., Calderón-Sánchez, Eva, Díaz, Ignacio, Hmadcha, Abdelkrim, Castellano, Antonio, Rosado, Juan A., Benitah, Jean-Pierre, Gomez, Ana M., Ordoñez, Antonio, and Smani, Tarik
- Subjects
UROCORTIN ,ISCHEMIA ,HOMEOSTASIS ,REPERFUSION ,INTRACELLULAR pathogens - Abstract
Aims: Urocortin-2 (Ucn-2) is a potent cardioprotector against Ischemia and Reperfusion (I/R) injuries. However, little is known about its role in the regulation of intracellular Ca2+ concentration ([Ca2+ ]i ) under I/R. Here, we examined whether the addition of Ucn-2 in reperfusion promotes cardioprotection focusing on ([Ca2+ ]i handling.Methods and Results: Cardiac Wistar rat model of I/R was induced by transient ligation of the left coronary artery and experiments were conducted 1 week after surgery in tissue and adult cardiomyocytes isolated from risk and remote zones. We observed that I/R promoted significant alteration in cardiac contractility as well as an increase in hypertrophy and fibrosis in both zones. The study of confocal [Ca2+ ]i imaging in adult cardiomyocytes revealed that I/R decreased the amplitude of [Ca2+ ]i transient and cardiomyocytes contraction in risk and remote zones. Interestingly, intravenous infusion of Ucn-2 before heart’s reperfusion recovered significantly cardiac contractility and prevented fibrosis, but it didn’t affect cardiac hypertrophy. Moreover, Ucn-2 recovered the amplitude of [Ca2+ ]i transient and modulated the expression of several proteins related to [Ca2+ ]i homeostasis, such as TRPC5 and Orai1 channels. Using Neonatal Rat Ventricular Myocytes (NRVM) we demonstrated that Ucn-2 blunted I/R-induced Store Operated Ca2+ Entry (SOCE), decreased the expression of TRPC5 and Orai1 as well as their interaction in reperfusion.Conclusion: Our study provides the first evidences demonstrating that Ucn-2 addition at the onset of reperfusion attenuates I/R-induced adverse cardiac remodeling, involving the [Ca2+ ]i handling and inhibiting the expression and interaction between TRPC5 and Orai1. [ABSTRACT FROM AUTHOR]- Published
- 2018
- Full Text
- View/download PDF
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