Search

Growth hormone releasing hormone is a hypothalamic neuropeptide, which regulates the release of growth hormone from the anterior pituitary gland. Growth hormone releasing hormone antagonists are anticancer agents, associated with strong anti-inflammatory activities. In the present study, we investigated the effects of the GHRH antagonist MIA-602 in the integrity of the brain microvascular endothelium in vitro. Our observations suggest that MIA-602 protects against the H 2 O 2 -induced breakdown of the brain endothelium and enhances its integrity by inducing P53, deactivating cofilin, and suppressing the RhoA inflammatory pathway. Thus, GHRH antagonists may offer an exciting possibility for the treatment of pathologies related to the blood brain barrier dysfunction, including the Parkinson's and Alzheimer's diseases., Competing Interests: The authors declare that they have no conflict of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

The endothelium constitutes the innermost lining of the blood vessels and controls blood fluidity, vessel permeability, platelet aggregation, and vascular tone. Endothelial dysfunction plays a key role in initiating a vascular inflammatory cascade and is the pivotal cause of various devastating diseases in multiple organs including the heart, lung, kidney, and brain. Glucocorticoids have traditionally been used to combat vascular inflammation. Endothelial cells express glucocorticoid receptors (GRs), and recent studies have demonstrated that endothelial GR negatively regulates vascular inflammation in different pathological conditions such as sepsis, diabetes, and atherosclerosis. Mechanistically, the anti-inflammatory effects of GR are mediated, in part, through the suppression of Wnt signaling. Moreover, GR modulates the fatty acid oxidation (FAO) pathway in endothelial cells and hence can influence FAO-mediated fibrosis in several organs including the kidneys. This review summarizes the relationship between GR and Wnt signaling in endothelial cells and the effects of the Wnt pathway in different cardiac and renal diseases. Available data suggest that GR plays a significant role in restoring endothelial integrity, and research on endothelial GR–Wnt interactions could facilitate the development of novel therapies for many cardiorenal conditions. [ABSTRACT FROM AUTHOR]

The discovery of hypothalamic hormones propelled exciting advances in pharmacotherapy and improved life quality worldwide. Growth hormone–releasing hormone (GHRH) is a crucial element in homeostasis maintenance, and regulates the release of growth hormone from the anterior pituitary gland. Accumulating evidence suggests that this neuropeptide can also promote malignancies, as well as inflammation. Our review is focused on the role of that 44 - amino acid peptide (GHRH) and its antagonists in inflammation and vascular function, summarizing recent findings in the corresponding field. Preclinical studies demonstrate the protective role of GHRH antagonists against endothelial barrier dysfunction, suggesting that the development of those peptides may lead to new therapies against pathologies related to vascular remodeling (eg, sepsis, acute respiratory distress syndrome). Targeted therapies for those diseases do not exist. [ABSTRACT FROM AUTHOR]

Growth hormone-releasing hormone (GHRH) and its receptors are expressed in a variety of human cancers, and have been involved in malignancies. GHRH antagonists (GHRHAnt) were developed to suppress tumor progression and metastasis. Previous studies demonstrate the involvement of reactive oxygen species (ROS) in cancer progression. Herein, we investigate the effect of a commercially available GHRH antagonist, namely JV-1-36, in the redox status of the A549 human cancer cell line. Our results suggest that this peptide significantly reduces ROS production in those cells in a time-dependent manner and counteracts H2O2-induced ROS. Our study supports the anti-oxidative effects of JV-1-36 and contributes in our knowledge towards the in vitro effects of GHRHAnt in cancers. [ABSTRACT FROM AUTHOR]

Endothelial barrier dysfunction (EBD) is the hallmark of Acute Respiratory Distress Syndrome (ARDS), a potentially lethal respiratory disorder associated with the COVID-19 – related deaths. Herein, we employed a cecal ligation and puncture (CLP) murine model of sepsis, to evaluate the effects of sepsis-induced EBD in the expression of the never in mitosis A (NIMA)-related kinases (NEKs). Members of that family of kinases regulate the activity and expression of the tumor suppressor P53, previously shown to modulate the actin cytoskeleton remodeling. Our results introduce the induction of NEK2, NEK3, NEK4, NEK7, and NEK9 in a CLP model of sepsis. Hence, we suggest that NEKs are involved in inflammatory processes and are holding the potential to serve as novel therapeutic targets for pathologies related to EBD, including ARDS and sepsis. Further studies will delineate the underlying molecular events and their interrelations with P53. [ABSTRACT FROM AUTHOR]

The anti-inflammatory activities of P53 in the vasculature have been associated with the enhancement of the endothelial barrier function. In the present study, we employed human and bovine lung endothelial cells, to investigate whether P53 expression levels affect the redox status of pulmonary cells. Moreover, we tested the possibility that those events affect the endothelial integrity of the lung microvascular monolayers. Our observations suggest that P53 suppression by LPS, pifithrin, or small interfering RNA increased the expression of the redox marker malondialdehyde. In contrast, P53 induction by Nutlin or the Hsp90 inhibitor AUY922 exerted the opposite effects, namely, suppressed that lipid oxidation marker. The direct measurement of the reactive oxygen species by 2,7-Dichlorodihydrofluorescein diacetate confirmed the antioxidant activity of P53 in the vasculature. Furthermore, the increased reactive oxygen species production due to P53 suppression was associated with lung hyperpermeability responses. In conclusion, P53 supports endothelial barrier function, at least in part, via the modulation of the reactive oxygen species. [ABSTRACT FROM AUTHOR]

• Hsp90 inhibition induces P53 expression. • P53 negatively regulate APE1/Ref1 expression. • APE1/Ref1 increased endothelial permeability. • Suppression of Ape1/Ref1 potentiates P53-mediated vascular barrier enhancement. The tumor suppressor protein P53 is strongly involved in orchestrating cellular defenses in the diverse variety of human tissues. Anomalies to lung endothelium permeability are streaming severe consequences towards human health, often associated with fatal outcomes. Ongoing investigations suggest that P53 exerts a prominent strategic role in crucial signaling cascades, in charge of both the maintenance and defense of pulmonary endothelium against toxic intruders. The current study employs human and bovine lung microvascular cells, as well as pharmacologic and genetic P53 modulators to demonstrate the negative regulation of APE1/Ref1 by P53. Moreover, it includes real time measurements of endothelial permeability, to reveal the disruptive role of APE1/Ref1 towards endothelial integrity. Those findings supports our efforts to elucidate the highly sophisticated regulatory network that enact endothelial adaptations under the plethora of challenging environmental factors. [ABSTRACT FROM AUTHOR]

Etiologies of human pathophysiology have been associated with states of severe inflammation. The endothelium defender P53 supports cellular functions, by orchestrating anti-inflammatory responses. The purpose of the present article is to provide an update on the mechanisms enforcing the protective actions of P53 in human homeostasis, and to discuss current efforts on the development of new therapies against inflammatory abnormalities. [ABSTRACT FROM AUTHOR]

Growth Hormone-Releasing Hormone (GHRH) is a hypothalamic peptide which regulates the release of Growth Hormone from the anterior pituitary gland, and has been involved in inflammatory processes. On the other hand, GHRH antagonists (GHRHAnt) were developed to counteract those effects. Herein we demonstrate for the first time that GHRHAnt can suppress hydrogen peroxide (H 2 O 2) - induced paracellular hyperpermeability in bovine pulmonary artery endothelial cells. Increased production of reactive oxygen species (ROS) and barrier dysfunction have been associated with the development of potentially lethal disorders, including sepsis and acute respiratory distress syndrome (ARDS). Our study supports the protective actions of GHRHAnt in the impaired endothelium, and suggests that those compounds represent an exciting therapeutic possibility towards lung inflammatory disease. • Growth Hormone-Releasing Hormone antagonists support barrier integrity. • Hydrogen peroxide induces endothelial paracellular permeability. • Barrier dysfunction is the hallmark of ARDS. • Growth Hormone-Releasing Hormone antagonists represent an exciting therapeutic possibility towards lung inflammatory disease. [ABSTRACT FROM AUTHOR]

Endothelial hyperpermeability is associated with sepsis and acute respiratory distress syndrome (ARDS). The identification of molecular pathways involved in barrier dysfunction; may reveal promising therapeutic targets to combat ARDS. Unfolded protein response (UPR) is a highly conserved molecular pathway, which ameliorates endoplasmic reticulum stress. The present work focuses on the effects of ATF6, which is a UPR sensor, in lipopolysaccharides (LPS)-induced endothelial hyperpermeability. The in vitro effects of AA147 and Ceapin-A7 in LPS-induced endothelial barrier dysfunction were investigated in bovine pulmonary artery endothelial cells (BPAEC). Small interfering (si) RNA was utilized to "silence" ATF6, and electric cell-substrate impedance sensing (ECIS) measured transendothelial resistance. Fluorescein isothiocyanate (FITC)-dextran assay was utilized to assess paracellular permeability. Protein expression levels were evaluated with Western blotting, and cell viability with MTT assay. We demonstrated that AA147 prevents LPS-induced barrier disruption by counteracting Cofilin and myosin light chain 2 (MLC2) activation, as well as VE-Cadherin phosphorylation. Moreover, this ATF6 inducer opposed LPS-triggered decrease in transendothelial resistance (TEER), as well as LPS-induced paracellular hyperpermeability. On the other hand, ATF6 suppression due to Ceapin-A7 or small interfering RNA exerted the opposite effects, and potentiated LPS-induced endothelial barrier disruption. Moderate concentrations of both ATF6 modulators did not affect cell viability. ATF6 activation protects against endothelial barrier function, suggesting that this UPR sensor may serve as a therapeutic target for sepsis and ARDS. • Endothelial barrier dysfunction is associated with sepsis and Acute Respiratory Distress Syndrome. • Unfolded protein response protects against endoplasmic reticulum stress. • Activating transcription factor-6 is an unfolded protein response sensor. • Activating transcription factor-6 activation due to AA147 enhances barrier integrity and protects against vascular leak. • ATF6 may represent a therapeutic target towards disorders related to endothelial dysregulation. [ABSTRACT FROM AUTHOR]

Growth hormone‐releasing hormone (GHRH) regulates the synthesis of growth hormone from the anterior pituitary gland, and it is involved in inflammatory responses. On the other hand, GHRH antagonists (GHRHAnt) exhibit the opposite effects, resulting in endothelial barrier enhancement. Exposure to hydrochloric acid (HCL) is associated with acute and chronic lung injury. In this study, we investigate the effects of GHRHAnt in HCL-induced endothelial barrier dysfunction, utilizing commercially available bovine pulmonary artery endothelial cells (BPAEC). Cell viability was measured by utilizing 3-(4,5-dimethylthiazol2-yl)− 2,5-diphenyltetrazolium bromide (MTT) assay. Moreover, fluorescein isothiocyanate (FITC)-dextran was used to assess barrier function. Our observations suggest that GHRHAnt exert protective effects against HCL-induced endothelial breakdown, since those peptides counteract HCL-triggered paracellular hyperpermeability. Based on those findings, we propose that GHRHAnt represent a new therapeutic approach towards HCL-induced endothelial injury. [ABSTRACT FROM AUTHOR]

• Metformin protects against LPS-induced endothelial barrier dysfunction. • P53 mediates the beneficial effects of metformin towards the microvasculature. • The P53 suppressor pifithrin enhances endothelial paracellular permeability. • Metformin prevents the deteriorating effects of pifithrin in the lungs. The endothelial barrier regulates interstitial fluid homeostasis by transcellular and paracellular means. Dysregulation of this semipermeable barrier may lead to vascular leakage, edema, and accumulation of pro-inflammatory cytokines, inducing microvascular hyperpermeability. Investigating the molecular pathways involved in those events will most probably provide novel therapeutic possibilities in pathologies related to endothelial barrier dysfunction. Metformin (MET) is an anti-diabetic drug, opposes malignancies, inhibits cellular transformation, and promotes cardiovascular protection. In the current study, we assess the protective effects of MET in LPS-induced lung endothelial barrier dysfunction and evaluate the role of P53 in mediating the beneficial effects of MET in the vasculature. We revealed that this biguanide (MET) opposes the LPS-induced dysregulation of the lung microvasculature, since it suppressed the formation of filamentous actin stress fibers, and deactivated cofilin. To investigate whether P53 is involved in those phenomena, we employed the fluorescein isothiocyanate (FITC) – dextran permeability assay, to measure paracellular permeability. Our observations suggest that P53 inhibition increases paracellular permeability, and MET prevents those effects. Our results contribute towards the understanding of the lung endothelium and reveal the significant role of P53 in the MET-induced barrier enhancement. [ABSTRACT FROM AUTHOR]