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PGE 2 -induced HIF-1 protein stabilization. PC-3ML cells were cultured in serum-free medium and treated with either 1 M PGE 2 , or 1% O 2 , or combination of PGE 2 (1 M) and 1% O 2 for various times as indicated. Proteins in the nuclear and cytosolic fractions were isolated and subjected to Western blot analysis. Twenty g of proteins were loaded in each lane. C, control.
Source publication
Hypoxia-induced up-regulation of vascular endothelial growth factor (VEGF) expression is a critical event leading to tumor
neovascularization. Hypoxia stimulates hypoxia-inducible factor-1α (HIF-1α), a transcriptional activator of VEGF. Cyclooxygenase
(COX)-2, an inducible enzyme that catalyzes the formation of prostaglandins (PGs) from arachidonic...
Citations
... The amount of COX-2's main metabolic product, prostaglandin E2, increases when its expression is deregulated (PGE 2) [25]. PGE 2 generation via the COX-2 catalyzed route is important for hypoxia-inducible factors-1α (HIF-1α) regulation, suggesting that COX-2 inhibitors can prevent hypoxia [26]. COX-2 signaling triggered by COVID-19 has also been suggested to play a function in regulating pulmonary inflammation and injury seen in COVID-19 patients [27]. ...
Cyclooxygenase 2 (COX2) inhibitors have been demonstrated to protect against hypoxia pathogenesis in several investigations. It has also been utilized as an adjuvant therapy in the treatment of COVID-19. COX inhibitors, which have previously been shown to be effective in treating previous viral and malarial infections are strong candidates for improving the COVID-19 therapeutic doctrine. However, another COX inhibitor, ibuprofen, is linked to an increase in the angiotensin-converting enzyme 2 (ACE2), which could increase virus susceptibility. Hence, inhibiting COX2 via therapeutics might not always be protective and we need to investigate the downstream molecules that may be involved in hypoxia environment adaptation. Research has discovered that people who are accustomed to reduced oxygen levels at altitude may be protected against the harmful effects of COVID-19. It is important to highlight that the study’s conclusions only applied to those who regularly lived at high altitudes; they did not apply to those who occasionally moved to higher altitudes but still lived at lower altitudes. COVID-19 appears to be more dangerous to individuals residing at lower altitudes. The downstream molecules in the (COX2) pathway have been shown to adapt in high-altitude dwellers, which may partially explain why these individuals have a lower prevalence of COVID-19 infection. More research is needed, however, to directly address COX2 expression in people living at higher altitudes. It is possible to mimic the gene–environment interaction of higher altitude people by intermittent hypoxia training. COX-2 adaptation resulting from hypoxic exposure at altitude or intermittent hypoxia exercise training (IHT) seems to have an important therapeutic function. Swimming, a type of IHT, was found to lower COX-2 protein production, a pro-inflammatory milieu transcription factor, while increasing the anti-inflammatory microenvironment. Furthermore, Intermittent Hypoxia Preconditioning (IHP) has been demonstrated in numerous clinical investigations to enhance patients’ cardiopulmonary function, raise cardiorespiratory fitness, and increase tissues’ and organs’ tolerance to ischemia. Biochemical activities of IHP have also been reported as a feasible application strategy for IHP for the rehabilitation of COVID-19 patients. In this paper, we aim to highlight some of the most relevant shared genes implicated with COVID-19 pathogenesis and hypoxia. We hypothesize that COVID-19 pathogenesis and hypoxia share a similar mechanism that affects apoptosis, proliferation, the immune system, and metabolism. We also highlight the necessity of studying individuals who live at higher altitudes to emulate their gene–environment interactions and compare the findings with IHT. Finally, we propose COX2 as an upstream target for testing the effectiveness of IHT in preventing or minimizing the effects of COVID-19 and other oxygen-related pathological conditions in the future.
... Prostaglandin E2 (PGE2) can increase HIF-1α expression in hematopoietic stem/progenitor cells (HSPCs), thereby increasing CXCR4 expression and promoting the homing of HSPCs [29]. Treatment of human prostate cancer cells with PGE2 enhanced VEGF expression by regulating HIF-1α expression [30]. ...
Background
Pulmonary arterial hypertension (PAH) is associated with oxidative stress and affects the survival and homing of transplanted mesenchymal stem cells (MSCs) as well as cytokine secretion by the MSCs, thereby altering their therapeutic potential. In this study, we preconditioned the MSCs with prostaglandin E1 (PGE1) and performed in vitro and in vivo cell experiments to evaluate the therapeutic effects of MSCs in rats with PAH.
Methods
We studied the relationship between PGE1 and vascular endothelial growth factor (VEGF) secretion, B-cell lymphoma 2 (Bcl-2) expression, and C-X-C chemokine receptor 4 (CXCR4) expression in MSCs and MSC apoptosis as well as migration through the hypoxia-inducible factor (HIF) pathway in vitro. The experimental rats were randomly divided into five groups: (I) control group, (II) monocrotaline (MCT) group, (III) MCT + non-preconditioned (Non-PC) MSC group, (IV) MCT + PGE1-preconditioned (PGE1-PC) MSC group, and (V) MCT +PGE1+YC-1-PC MSC group. We studied methane dicarboxylic aldehyde (MDA) levels, MSC homing to rat lungs, mean pulmonary artery pressure, pulmonary artery systolic pressure, right ventricular hypertrophy index, wall thickness index (%WT), and relative wall area index (%WA) of rat pulmonary arterioles.
Results
Preconditioning with PGE1 increased the protein levels of HIF-1 alpha (HIF-1α) in MSCs, which can reduce MSC apoptosis and increase the protein levels of CXCR4, MSC migration, and vascular endothelial growth factor secretion. Upon injection with PGE1-PC MSCs, the pulmonary artery systolic pressure, mean pulmonary artery pressure, right ventricular hypertrophy index, %WT, and %WA decreased in rats with PAH. PGE1-PC MSCs exhibited better therapeutic effects than non-PC MSCs. Interestingly, lificiguat (YC-1), an inhibitor of the HIF pathway, blocked the effects of PGE1 preconditioning.
Conclusions
Our findings indicate that PGE1 modulates the properties of MSCs by regulating the HIF pathway, providing insights into the mechanism by which PGE1 preconditioning can be used to improve the therapeutic potential of MSCs in PAH.
... Besides anaplerosis, glutamine can be used for energy production, biosynthesis of glutathione, and reductive carboxylation for lipid production [219,221]. Prostanoids mediate angiogenesis through multiple mechanisms, including the induction of VEGF production [222], the stimulation of endothelial cell sprouting, migration, and tube formation [223][224][225]. ...
The endothelium acts as the barrier that prevents circulating lipids such as lipoproteins and fatty acids into the arterial wall; it also regulates normal functioning in the circulatory system by balancing vasodilation and vasoconstriction, modulating the several responses and signals. Plasma lipids can interact with endothelium via different mechanisms and produce different phenotypes. Increased plasma-free fatty acids (FFAs) levels are associated with the pathogenesis of atherosclerosis and cardiovascular diseases (CVD). Because of the multi-dimensional roles of plasma FFAs in mediating endothelial dysfunc-tion, increased FFA level is now considered an essential link in the onset of endothelial dysfunction in CVD. FFA-mediated endothelial dysfunction involves several mechanisms, including dysregulated production of nitric oxide and cytokines, metaflammation, oxidative stress, inflammation, activation of the renin-angiotensin system, and apoptosis. Therefore, modulation of FFA-mediated pathways involved in endothelial dysfunction may prevent the complications associated with CVD risk. This review presents details as to how endothelium is affected by FFAs involving several metabolic pathways.
... We found that RPL35 positively regulated HIF1α transcriptional activity in a dose-dependent manner, reflecting the positive role of RPL35 in the regulation process of HIF1α ( Figure 7A). The ERK pathway promotes the nuclear translocation of HIF1α [30] or further enhances the transcriptional activity of HIF-1α induced by hypoxia [31]. Therefore, we hypothesized that RPL35 might regulate HIF1α transcriptional activity through activation of the ERK signaling pathway. ...
Neuroblastoma (NB) is an rare type of tumor that almost affects children age 5 or younger due to its rapid proliferation ability. The overall survival rate of patients with advanced NB is not satisfactory. Ribosomal proteins (RPs) play a critical role in the development and progress of cancer. However, the contribution of RPL35 in NB has not been proven. In this study, we reveal that RPL35 is upregulated in NB tissues and the upregulation of RPL35 promotes proliferation and migration of NB while RPL35 knockdown significantly restrained the proliferation of NB cells. In terms of mechanism, glycolysis was decreased and the mitochondrial respiration was increased with knockdown of RPL35 in NB cells, indicating that RPL35 function as a positive regulator in aerobic glycolysis. Importantly, our data indicated that RPL35 deficiency decreased HIF1α expression both in mRNA and protein levels. Western blot analysis showed that RPL35 knockdown has a negative regulatory effect on the ERK pathway, and RPL35 modulated aerobic glycolysis in part through its regulation of the RPL35/ERK/HIF1α axis. Overall, RPL35 functions as a positive regulator of aerobic glycolysis, and the RPL35/ERK/HIF1α axis could be a potential therapeutic target for the therapy of NB.
... NF-κB and HIF-1 mutually up-regulate VEGF expression of inflammatory cytokines and mediators [74][75][76]. Hypoxic microenvironment and inflammation trigger the formation of ROS, causing activation of the COX-2-prostaglandin synthesis pathway [77]. This also activates the IL-1-NFκB-cyclooxygenase-2 (COX-2) axis bidirectionally and can up-regulate HIF-1α and induces VEGF [78]. ...
The hypoxic microenvironment caused by oral pathogens is the most important cause of the disruption of dynamic hemostasis between the oral microbiome and the immune system. Periodontal infection exacerbates the inflammatory response with increased hypoxia and causes vascular changes. The chronicity of inflammation becomes systemic as a link between oral and systemic diseases. The vascular network plays a central role in controlling infection and regulating the immune response. In this review, we focus on the local and systemic vascular network change mechanisms of periodontal inflammation and the pathological processes of inflammatory diseases. Understanding how the vascular network influences the pathology of periodontal diseases and the systemic complication associated with this pathology is essential for the discovery of both local and systemic proactive control mechanisms.
... Several studies have shown that hypoxia and ischemia may be associated with ASD (Kolevzon et al. 2007;Modabbernia et al. 2017). A number of non-hypoxic stimuli have been shown to activate the HIF-1 complex under normoxic conditions beside hypoxia (Feldser et al. 1999;Fukuda et al. 2002;Görlach et al. 2001;Liu et al. 2002;Richard et al. 2000;Sandau et al. 2001;Scharte et al. 2003;Stiehl et al. 2002;Treins et al. 2002), which include proinflammatory cytokines TNF-α and IL-1β (Jung et al. 2003a, b;Jung et al. 2003a, b;Sandau et al. 2001;Zhou et al. 2003). Immunological studies on the etiology of ASD have found changes and irregularities in the cytokine profile in individuals with ASD (Eftekharian et al. 2018;Goines and Ashwood 2013;Xu et al. 2015). ...
... Perinatal hypoxic-ischemic exposure has been shown to lead to a chronic proinflammatory state (Driscoll et al. 2018). There have been a number of non-hypoxic stimuli that activate the HIF-1 complex under normoxic conditions, apart from hypoxia (Feldser et al. 1999;Fukuda et al. 2002;Görlach et al. 2001;Liu et al. 2002;Richard et al. 2000;Sandau et al. 2001;Scharte et al. 2003;Stiehl et al. 2002;Treins et al. 2002). Proinflammatory cytokines TNF-α and IL-1β have been found to increase the accumulation and transcriptional activity of HIF-1α (Jung et al. 2003a, b;Jung et al. 2003a, b;Sandau et al. 2001;Zhou et al. 2003). ...
The aim of this study was to determine whether serum VEGF, IGF-1, and HIF-1α levels differed between Autism Spectrum Disorder (ASD) patients and healthy controls. A total of 40 children with ASD and 40 healthy controls aged 4–12 years were included. Serum levels of VEGF, IGF-1, and HIF-1α were measured using commercial enzyme-linked immunosorbent assay kits. Serum IGF-1 levels were found to be statistically significantly higher in the ASD group than in the control group. Serum HIF-1α levels were borderline significantly lower in the ASD group. There was no statistically significant difference in serum VEGF levels between the two groups. IGF-1 and HIF-1α may play a potential role in the etiopathogenesis of ASD.
... Prostaglandin E2 (PGE2) stabilizes HIF-1α proteins and facilitates their nuclear translocation [143]. In this study, pharmacological inhibition of the ERK pathway using PD98059 abolishes the effect of PGE2 on HIF-1α. ...
Hypoxia-inducible factor-1 alpha (HIF-1α) is overexpressed in cancer, leading to a poor prognosis in patients. Diverse cellular factors are able to regulate HIF-1α expression in hypoxia and even in non-hypoxic conditions, affecting its progression and malignant characteristics by regulating the expression of the HIF-1α target genes that are involved in cell survival, angiogenesis, metabolism, therapeutic resistance, et cetera. Numerous studies have exhibited the anti-cancer effect of HIF-1α inhibition itself and the augmentation of anti-cancer treatment efficacy by interfering with HIF-1α-mediated signaling. The anti-cancer effect of plant-derived phytochemicals has been evaluated, and they have been found to possess significant therapeutic potentials against numerous cancer types. A better understanding of phytochemicals is indispensable for establishing advanced strategies for cancer therapy. This article reviews the anti-cancer effect of phytochemicals in connection with HIF-1α regulation.
... MELOX has been reported to suppress the growth and induced apoptosis of HCC-cells [18], as well as to hinder the growth of different types of cancers such as prostate [19], breast [20] and lung [21] cancers. ...
The present study investigates the anti-inflammatory and cytoprotective potentials of a selective COX-II inhibitor, Meloxicam (MELOX) from solid-dispersions (SDs), using lipopolysaccharide (LPS)–stimulated RAW 264.7 macrophages cell line. MELOX/SDs were prepared by fusion (FM) & hot-melt-extrusion (HME) techniques using Soluplus/Lutrol F127 as mixed-polymers. SDs were physicochemically evaluated by SEM, XRD and solubility-testing. Viability of cell-growth was determined by MTT assay. Evaluation of inflammation was based on production of nitric oxide (NO), tumor necrosis factor-α (TNF-α) and prostaglandin E2 (PGE2). MELOX Solubility increased by 3- and 4- folds from SDs prepared by FM and HME, respectively, compared to pure drug. XRD/SEM analyses confirmed drug-dispersion within mixed-polymers. Exposure of normal-cells to different MELOX-treatments maintained the integrity of cell-growth. LPS-stimulated cells treated with MELOX/SDs exhibited higher viabilities compared to cells treated with pure MELOX. The prepared MELOX/SDs showed statistically stronger inhibition of inflammatory-mediators with respect to pure drug. Only, MELOX/SDs prepared by HME, successfully restored LPS-induced TNF-α level to that of normal-cells. SDs prepared by HME provided superior reduction of NO, TNF-α and PGE2, while maintaing normal cell-growth. The present study highlights the effect of SDs preparation techniques, on MELOX treatment performance.
... COX inhibition might affect angiogenesis through a number of different mechanisms. Because HIF-1α is considered to be a master regulator in tissue response to hypoxia including angiogenesis (Dvorak, 2005;Madrigal-Martínez et al., 2018;Sharp & Bernaudin, 2004), and was shown to be COX-dependent in some angiogenesis models (Jung et al., 2003;Kaidi et al., 2006;Liu et al., 2002;Zhong et al., 2004), we first determined HIF-1α alterations under hypoxia and ketorolac treatment. Consistent with previous studies (Benderro & LaManna, 2014;Ward et al., 2007), we detected a slight but significant increase in HIF-1α upon 24-hr and 10-day hypoxia ( Figure 5a). ...
... In different cancer cell lines, non-selective COX inhibitors reduce HIF-1α and − 2α levels in response to hypoxia (Jung et al., 2003) (Zhong et al., 2004) (Kaidi et al., 2006). It is possible that COX products, prostaglandins (PG), regulate HIF-1α stabilization and nuclear localization as has been demonstrated for PGE 2 in a human prostate cancer cell line (Liu et al., 2002). However, the relation between HIF levels and COX activity is not completely established in all models and in some cases the effect of COX inhibition on angiogenesis might be independent from HIF pathway. ...
Although cyclooxygenase (COX) role in cancer angiogenesis has been studied, little is known about its role in brain angioplasticity. In the present study, we chronically infused mice with ketorolac, a non‐specific COX inhibitor that does not cross the blood–brain barrier (BBB), under normoxia or 50% isobaric hypoxia (10% O2 by volume). Ketorolac increased mortality rate under hypoxia in a dose‐dependent manner. Using in vivo multiphoton microscopy, we demonstrated that chronic COX inhibition completely attenuated brain angiogenic response to hypoxia. Alterations in a number of angiogenic factors that were reported to be COX‐dependent in other models were assayed at 24‐hr and 10‐day hypoxia. Intriguingly, hypoxia‐inducible factor 1 was unaffected under COX inhibition, and vascular endothelial growth factor receptor type 2 (VEGFR2) and C‐X‐C chemokine receptor type 4 (CXCR4) were significantly but slightly decreased. However, a number of mitogen‐activated protein kinases (MAPKs) were significantly reduced upon COX inhibition. We conclude that additional, angiogenic factor‐independent mechanism might contribute to COX role in brain angioplasticity, probably including mitogenic COX effect on endothelium. Our data indicate that COX activity is critical for systemic adaptation to chronic hypoxia, and BBB COX is essential for hypoxia‐induced brain angioplasticity. These data also indicate a potential risk for using COX inhibitors under hypoxia conditions in clinics. Further studies are required to elucidate a complete mechanism for brain long‐term angiogenesis regulation through COX activity.
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... [4] Generally, secretion of PGE2 results in the production of Hypoxia-Inducible Factor (HIF)-1alpha that in turn leads to sequential responses to hypoxia. [5] Correspondingly, HIF-1alpha seems to reduce the expansion of ACE2 indirectly. [6] Therefore, on the one hand, PGE2 may play a cytoprotective role against SARS-COV-2. ...
The outbreak of a new, potentially fatal virus, SARS‐COV‐2, which started in December 2019 in Wuhan, China, and since developed into a pandemic has stimulated research for an effective treatment and vaccine. For this research to be successful, it is necessary to understand the pathology of the virus. So far, we know that this virus can harm different organs of the body. Although the exact mechanisms are still unknown, this phenomenon may result from the body's secretion of prostaglandin E2 (PGE2), which is involved in several inflammation and immunity pathways. Noticeably, the expression of this molecule can lead to a cytokine storm causing a variety of side effects. In this paper, we discuss those side effects in SARS‐COV‐2 infection separately to determine whether PGE2 is, indeed, an important causative factor. Lastly, we propose a mechanism by which PGE2 production increases in response to COVID‐19 disease and suggest the possible direct relation between PGE2 levels and the severity of this disease. Also see the video abstract here: https://youtu.be/SnPFAcjxxKw.
