Figure - available from: Oxidative Medicine and Cellular Longevity
This content is subject to copyright. Terms and conditions apply.
Gamma irradiation activates MAPK/NF-κB pathways. (a) The activation of MAPK pathway molecules p-p38, p38, p53, p21, and p27 in HUVECs after exposure to gamma irradiation was measured by western blot. (b) Protein levels of p-p65 and p65 were examined by western blot. (c) NF-κB DNA-binding activity by TransAM™ NF-κB Transcription Factor Assay kit. The absorbance at 450 nm was read on a microplate reader. Values were expressed as mean±S.E.M. One-way analysis of variance (ANOVA) was used to determine statistical significance between groups followed by Tukey’s post hoc test. ∗A value of p<0.05 was taken as statistical significance.
Source publication
Ionizing radiation-induced cardiovascular diseases (CVDs) have been well documented. However, the mechanisms of CVD genesis are still not fully understood. In this study, human umbilical vein endothelial cells (HUVECs) were exposed to gamma irradiation at different doses ranging from 0.2 Gy to 5 Gy. Cell viability, migration ability, permeability,...
Citations
... Indeed, irradiation can trigger endothelial dysfunctions, leading to impaired tissue/organ perfusion, exacerbated inflammation, and tissue oedema [1][2][3][4]. The mechanisms involved in irradiation-induced tissue inflammation and oedema include the overexpression of adhesion molecules, endothelial cell apoptosis, and the alteration of inter-endothelial cell junctions [1,[3][4][5][6][7][8][9]. These processes collectively promote the diapedesis of white blood cells in tissues, leading to the release of pro-inflammatory cytokines and oedema development [1,[3][4][5][6][7][8][9]. ...
... The mechanisms involved in irradiation-induced tissue inflammation and oedema include the overexpression of adhesion molecules, endothelial cell apoptosis, and the alteration of inter-endothelial cell junctions [1,[3][4][5][6][7][8][9]. These processes collectively promote the diapedesis of white blood cells in tissues, leading to the release of pro-inflammatory cytokines and oedema development [1,[3][4][5][6][7][8][9]. ...
... At the same time, irradiation can alter the cytoskeleton and cause destabilization and disruption of inter-endothelial adherens junctions made of VE-Cadherin, leading to higher permeability of the endothelial barrier [7,8,[23][24][25][26][27]. This process has been linked to MAP kinases and the NF-kB inflammatory pathway in human umbilical vein endothelial cells [8]. ...
High-dose irradiation can trigger numerous endothelial dysfunctions, including apoptosis, the overexpression of adhesion molecules, and alteration of adherens junctions. Altogether, these endothelial dysfunctions contribute to the development of tissue inflammation and organ damage. The development of endothelial dysfunctions may depend on protein phosphorylation by various protein kinases, but the possible role of protein kinase A (PKA) has not been investigated so far, and efficient compounds able to protect the endothelium from irradiation effects are needed. Here we report the beneficial effects of the PKA inhibitor KT5720 on a panel of irradiation-induced endothelial dysfunctions in human pulmonary microvascular endothelial cells (HPMECs). High-dose X-irradiation (15 Gy) triggered the late apoptosis of HPMECs independent of the ceramide/P38 MAP kinase pathway or p53. In contrast, the treatment of HPMECs with KT5720 completely prevented irradiation-induced apoptosis, whether applied before or after cell irradiation. Immunostainings of irradiated monolayers revealed that KT5720 treatment preserved the overall integrity of endothelial monolayers and adherens junctions linking endothelial cells. Real-time impedance measurements performed in HPMEC monolayers confirmed the overall protective role of KT5720 against irradiation. Treatment with KT5720 before or after irradiation also reduced irradiation-induced ICAM-1 overexpression. Finally, the possible role for PKA in the development of endothelial dysfunctions is discussed, but the potency of KT5720 to inhibit the development of a panel of irradiation-induced endothelial dysfunctions, whether applied before or after irradiation, suggests that this compound could be of great interest for both the prevention and treatment of vascular damages in the event of exposure to a high dose of radiation.
... Similar results were also observed in pancreatic ductal cells in caerulein-induced mammary pancreatitis [63,64]. ZO proteins are mainly regulated by nuclear factor kappa B (NF-κB) signaling pathway [59,62,69] and cytokines including tumor necrosis factor-alpha (TNF-α) [60,67], interleukin 1 beta (IL-1β) [60], IL-6 [61], IL-8 [70], IL-9 [68], IL-22 [71] and IL-33 [68]. Zhang et al. found that in patients with inflammatory bowel disease (IBD), the expression level of monocarboxylate transporter 4 (MCT4) increased significantly [61]. ...
Tight junction (TJ) is the barrier of epithelial and endothelial cells to maintain paracellular substrate transport and cell polarity. As one of the TJ cytoplasmic adaptor proteins adjacent to cell membrane, zonula occludens (ZO) proteins are responsible for connecting transmembrane TJ proteins and cytoplasmic cytoskeleton, providing a binding platform for transmembrane TJ proteins to maintain the barrier function. In addition to the basic structural function, ZO proteins play important roles in signal regulation such as cell proliferation and motility, the latter including cell migration, invasion and metastasis, to influence embryonic development, tissue homeostasis, damage repair, inflammation, tumorigenesis, and cancer progression. In this review, we will focus on the signal regulating function of ZO proteins in inflammation and tumorigenesis, and discuss the limitations of previous research and future challenges in ZO protein research.
... Several reports have outlined an absence of negative effects or the presence of positive effects as regards the antioxidant properties and functions of the considered samples after irradiation [57,60]. While relatively low doses of gamma irradiation are used in the food industry (i.e., several kGy), very low doses (i.e., several Gy or even fractions of a Gy) are used for growth-arresting of cell cultures in radiobiology or for the obtention of ancillary cellular materials [61][62][63][64][65]. ...
Cultured primary progenitor tenocytes in lyophilized form were previously shown to possess intrinsic antioxidant properties and hyaluronan-based hydrogel viscosity-modulating effects in vitro. The aim of this study was to prepare and functionally characterize several stabilized (lyophilized) cell-free progenitor tenocyte extracts for inclusion in cytotherapy-inspired complex injectable preparations. Fractionation and sterilization methods were included in specific biotechnological manufacturing workflows of such extracts. Comparative and functional-oriented characterizations of the various extracts were performed using several orthogonal descriptive, colorimetric, rheological, mechanical, and proteomic readouts. Specifically, an optimal sugar-based (saccharose/dextran) excipient formula was retained to produce sterilizable cytotherapeutic derivatives with appropriate functions. It was shown that extracts containing soluble cell-derived fractions possessed conserved and significant antioxidant properties (TEAC) compared to the freshly harvested cellular starting materials. Progenitor tenocyte extracts submitted to sub-micron filtration (0.22 µm) and 60Co gamma irradiation terminal sterilization (5–50 kGy) were shown to retain significant antioxidant properties and hyaluronan-based hydrogel viscosity modulating effects. Hydrogel combination products displayed important efficacy-related characteristics (friction modulation, tendon bioadhesivity) with significant (p < 0.05) protective effects of the cellular extracts in oxidative environments. Overall, the present study sets forth robust control methodologies (antioxidant assays, H2O2-challenged rheological setups) for stabilized cell-free progenitor tenocyte extracts. Importantly, it was shown that highly sensitive phases of cytotherapeutic derivative manufacturing process development (purification, terminal sterilization) allowed for the conservation of critical biological extract attributes.
... Moreover, Wang et al. 29 revealed that IR disrupts the cellular junctions by activating the inflammatory NF-κB signalling pathway, which is manifested by enhanced oxidative stress and increased the levels of cytokines, including IL-6 and TNF-α. Subsequently, it was found that oxidative stress and inflammation down-regulate the expression of SIRT-1 through ROS production and NF-κB activation as reported by Kauppinen et al. 5 SIRT-1 is an NAD + -dependent class III protein deacetylase that regulates many cellular processes, including oxidative stress, metabolism, aging, and apoptosis. ...
Background:
Although ionizing radiation (IR) has been of immense value to human life due to its involvement in several fields, it doesn't eliminate that exposure to IR results in an array of biological consequences, including oxidative stress, inflammation, and death. Thus, this study aimed to explore the curative effect of trans-Resveratrol (t-Res) on hepatic and renal injury in a rat model exposed to single and fractionated doses of γ-rays.
Methods:
Rats exposed to a single dose of IR (6 Gy, as an acute effect) or a fractionated dose of IR (2 Gy/time/3 days, day after day; to imitate a chronic impact) were treated with t-Res. Then, the radio-protective effect of t-Res was investigated via biochemical and histological estimations in the liver and kidney of rats in the different groups.
Results:
The data displayed a significant amelioration in biochemical and histological indices in the liver and kidney of rats exposed to IR doses and treated with t-Res. Particularly, t-Res reduced the oxidative stress milieu through decreasing HIF-1α, ROS, and MDA levels associated with increased CAT activity and Nrf-2 gene expression. Also, t-Res improved the inflammatory status via a decrease in TNF-α, NF-κB, SOCS-3, and HSP-70 genes expression linked with elevations in SIRT-1 and P53 genes expression.
Conclusion:
It could be concluded that t-Res had hepatoprotective and renoprotective effects against the deleterious consequences of γ-rays exposure due to its antioxidant and anti-inflammatory properties.
... Human umbilical vein endothelial cells (HUVECs) have been mostly used to study the effects and mechanisms of radiation on blood vessels at the cellular level in vitro. In addition to the canonical nuclear genomic DNA damage response and proliferation inhibition [20,25,26], other various forms of radiation effects on HUVECs were observed, which include senescence-associated secretory phenotype (SASP) and premature senescence [27][28][29], increased intrinsic ROS and NO 2 − production and release of pro-inflammatory cytokines [30][31][32][33], decreasing mitochondrial membrane potential [31], suppression of the autophagic flux [34], endothelial-to-mesenchymal transition (EndMT) [35], decreasing the capacity of forming capillary-like network [36,37], and increased permeability and disruption of cellular junctions [33]. The types of cell death of HUVECs induced by radiation include apoptosis [38], pyroptosis [39], and ferroptosis [40]. ...
... Human umbilical vein endothelial cells (HUVECs) have been mostly used to study the effects and mechanisms of radiation on blood vessels at the cellular level in vitro. In addition to the canonical nuclear genomic DNA damage response and proliferation inhibition [20,25,26], other various forms of radiation effects on HUVECs were observed, which include senescence-associated secretory phenotype (SASP) and premature senescence [27][28][29], increased intrinsic ROS and NO 2 − production and release of pro-inflammatory cytokines [30][31][32][33], decreasing mitochondrial membrane potential [31], suppression of the autophagic flux [34], endothelial-to-mesenchymal transition (EndMT) [35], decreasing the capacity of forming capillary-like network [36,37], and increased permeability and disruption of cellular junctions [33]. The types of cell death of HUVECs induced by radiation include apoptosis [38], pyroptosis [39], and ferroptosis [40]. ...
The long-term survival rate of cancer patients has been increasing as a result of advances in treatments and precise medical management. The evidence has accumulated that the incidence and mortality of non-cancer diseases have increased along with the increase in survival time and long-term survival rate of cancer patients after radiotherapy. The risk of cardiovascular disease as a radiation late effect of tissue damage reactions is becoming a critical challenge and attracts great concern. Epidemiological research and clinical trials have clearly shown the close association between the development of cardiovascular disease in long-term cancer survivors and radiation exposure. Experimental biological data also strongly supports the above statement. Cardiovascular diseases can occur decades post-irradiation, and from initiation and development to illness, there is a complicated process, including direct and indirect damage of endothelial cells by radiation, acute vasculitis with neutrophil invasion, endothelial dysfunction, altered permeability, tissue reactions, capillary-like network loss, and activation of coagulator mechanisms, fibrosis, and atherosclerosis. We summarize the most recent literature on the tissue reactions and mechanisms that contribute to the development of radiation-induced cardiovascular diseases (RICVD) and provide biological knowledge for building preventative strategies.
... MAPK kinase is an important intracellular signal transduction that regulates various intracellular functions. Many studies have found that MAPK pathway activation can affect endothelial cell occludin expression and modification in physiological and pathological conditions: (1) Exposure of cerebral microvascular endothelial cells to lipopolysaccharide can affect the p38MAPK/JNK signaling pathway and MMP2 expression, thereby regulating the level of occludin protein in endothelial cells and leading to central nervous system inflammation and brain edema [34]; (2) ERK1/2 inhibits the activation of the NF-κB signaling pathway resulting in the increase of occludin and decrease of endothelial barrier permeability to protect the TJ barrier in human lung microvascular endothelial cells [35]; (3) after lipopolysaccharide stimulates human umbilical vein endothelial cells, it can promote the mRNA and protein expression of CXCL4 and its receptor CXCR3 activates the downstream p38 signaling pathway, thereby inhibiting the expression of occludin in endothelial cells, promoting endothelial cell apoptosis, and increasing endothelial cell permeability [36]; (4) exposure of human umbilical vein endothelial cells to γ-rays can promote the expression of MAPK pathway molecules p38, p53, p21, and p27, induce the activation of NF-κB signaling pathway, and inhibit the expression of occludin in endothelial cells, resulting in the increase of cell permeability, oxidative stress, nitrification, and inflammatory [37]; (5) in human brain microvascular endothelial cells, reduction of occludin can upregulate PI3K/AKT and ERK signaling pathways, and promote cytokine secretion, inflammatory factor activation, and apoptosis protein expression. However, overexpression of occludin can inhibit endothelial cell apoptosis and inflammation [25]. ...
Endothelial tight junction proteins play an important role in maintaining the integrity of vascular endothelial structure and physiological function. In recent years, studies have found that alterations in the expression, distribution, and structure of endothelial tight junction proteins may lead to many related vascular diseases and pathologies (such as diabetes, atherosclerosis, neurodegenerative diseases, and hypertension). Therefore, related strategies to prevent and/or tight junction proteins dysfunction may be an important therapeutic target. Occludin, as the most representative one among tight junction proteins, is mainly responsible for sealing intercellular junctions, maintaining cell permeability and the integrity of vascular endothelium. Here, we review the published biological information of occludin. We highlight the relationship between occludin and vascular endothelial injury-related disease. At the same time, we show our current knowledge of how vascular endothelial occludin exerts the protective effect and possible clinical applications in the future.
... MAPKs phosphorylate themselves or their binding partners or activate or inhibit them (4,5). In the classical signaling cascade, three classes of MAPKs (such as MAP3K, MAP2K, and MAPK) are involved in transducing signals from transmembrane receptors to the nucleus (6,7). Upon receiving the signal from extracellular ligands, MAP3K undergoes phosphorylation, which in turn phosphorylates MAP2K and subsequently, MAP2K phosphorylates MAPK to complete the upstream events of the MAPK signaling cascade (8)(9)(10). ...
Mitogen‑activated protein kinase (MAPK) pathway is a prominent signaling cascade that modulates cell proliferation, apoptosis, stress response, drug resistance, immune response, and cell motility. Activation of MAPK by various small molecules/natural compounds has been demonstrated to induce apoptosis in cancer cells. Herein, the effect of leelamine (LEE, a triterpene derived from bark of pine trees) on the activation of MAPK in hepatocellular carcinoma (HCC) and breast cancer (BC) cells was investigated. LEE induced potent cytotoxicity of HCC (HepG2 and HCCLM3) and BC (MDA-MB-231 and MCF7) cells over normal counterparts (MCF10A). LEE significantly enhanced the phosphorylation of p38 and JNK MAPKs in a dose-dependent fashion and it did not affect the phosphorylation of ERK in HCC and BC cells. The apoptosis-driving effect of LEE was further demonstrated by cleavage of procaspase-3/Bid and suppression of prosurvival proteins (Bcl-xL and XIAP). Furthermore, LEE also reduced the SDF1-induced-migration and -invasion of HCC and BC cells. Taken together, the data demonstrated that LEE promotes apoptosis and induces an anti-motility effect by activating p38 and JNK MAPKs in HCC and BC cells.
... Many researchers have reported that endothelial cells undergo changes in their molecular pathways and cell phenotypes after they are exposed to gamma irradiation 21-24 . In particular, the reorganization and reduction of cell-cell junctions between endothelial cells are major problems because they increase cell permeability and weaken barrier functions [25][26][27] . However, most of these studies were conducted on 2-D in vitro culture systems, in which the endothelial cells grow as a homogenous monolayer. ...
During radiotherapy, microenvironments neighboring the tumor are also exposed to gamma irradiation; this results in unexpected side effects. Blood vessels can serve as microenvironments for tumors and they play an important role in providing nutrients to tumors. This is mostly related to tumor progression, metastasis, and relapse after therapy. Many studies have been performed to obtain a better understanding of tumor vasculature after radiotherapy with in vitro models. However, compared to 3-D models, 2-D in vitro endothelial monolayers cannot physiologically reflect in vivo blood vessels. We previously remodeled the extracellular matrix (ECM) hydrogel that enhanced the tight barrier formation of 3-D blood vessels and the vascular endothelial growth factor (VEGF) gradient induced angiogenesis in a microfluidic device. In this study, the blood vessel model is further introduced to understand how gamma irradiation affects the endothelial monolayer. After the gamma irradiation exposure, we observed a collapsed endothelial barrier and a reduced angiogenic potential. Changes in the cell behaviors of the tip and stalk cells were also detected in the angiogenesis model after irradiation, which is difficult to observe in 2-D monolayer models. Therefore, the 3-D in vitro blood vessel model can be used to understand radiation-induced endothelial injuries.
... In vitro study of γ-irradiation-induced endothelial cell DNA damage, apoptosis, senescence and relevant molecular mechanisms have been well documented [32][33][34][35][36][37][38]. However, in vivo investigation of radiationinduced age-dependent DNA damages in endothelial cells of brain capillary is scarce, in particular, irradiation at different early postnatal days. ...
Gamma H2A histone family member X (γH2AX) is a molecular marker of aging and disease. However, radiosensitivity of the different brain cells, including neurons, glial cells, cells in cerebrovascular system, epithelial cells in pia mater, ependymal cells lining the ventricles of the brain in immature animals at different postnatal days remains unknown. Whether radiation-induced γH2AX foci in immature brain persist in adult animals still needs to be investigated. Hence, using a mouse model, we showed an extensive postnatal age-dependent induction of γH2AX foci in different brain regions at 1 day after whole body gamma irradiation with 5Gy at postnatal day 3 (P3), P10 and P21. P3 mouse brain epithelial cells in pia mater, glial cells in white matter and cells in cerebrovascular system were more radiosensitive at one day after radiation exposure than those from P10 and P21 mice. Persistent DNA damage foci (PDDF) were consistently demonstrated in the brain at 120 days and 15 months after irradiation at P3, P10 and P21, and these mice had shortened lifespan compared to the age-matched control. Our results suggest that early life irradiation-induced PDDF at later stages of animal life may be related to the brain aging and shortened life expectancy of irradiated animals.
... The down-regulation of splenic α-7nAchR in the RAD group might be related to cumulative pro-inflammatory and diminished anti-inflammatory cytokine release through the NF-κB pathway [38]. Further, Wang et al. [39] revealed that exposure of human umbilical vein endothelial cells to γ -radiation disrupts the Fig. 8. Histopathological examination of the kidney in different animal groups. All tissues sections are stained with haematoxylin and eosin, magnification ×400 (H&E ×400). ...
Apelin-13 and APJ are implicated in different key physiological processes. This work aims at exploring the radioprotective effect of fucoxanthin (FX) on γ-radiation (RAD)-induced changes in the apelin-13/APJ pathway, which causes damage in the liver, kidney, lung and spleen of mice. Mice were administered FX (10 mg kg–1 day–1, i.p) and exposed to γ-radiation (2.5 Gy week–1) for four consecutive weeks. The treatment of irradiated mice by FX resulted in a significant amendment in protein expression of the apelin-13/APJ/NF-κB signalling pathway concurrently with reduced hypoxia (hypoxia-inducible factor-1α), suppressed oxidative stress marker (malondialdehyde), enhanced antioxidant defence mechanisms (reduced glutathione and glutathione peroxidase), a modulated inflammatory response [interleukin-6 (IL-6), monocyte chemoattractant protein-1, IL-10 and α-7-nicotinic acetylcholine receptor) and ameliorated angiogenic regulators [matrix metalloproteinase (MMP-2), MMP-9 and tissue inhibitor of metalloproteinase-1), as well as the tissue damage indicator (lactate dehydrogenase) in organ tissues. In addition, there were significant improvement in serum inflammatory markers tumour necrosis factor-α, IL-10, IL-1β and C-reactive protein compared with irradiated mice. The histopathological investigation of the FX + RAD organ tissues support the biochemical findings where the improvements in the tissues’ architecture were obvious when compared with those of RAD. FX was thus shown to have a noticeable radioprotective action mediated through its regulatory effect on the apelin-13/APJ/NF-κB signalling pathway attributed to its antioxidant and anti-inflammatory activity that was reflected in different physiological processes. It could be recommended to use FX in cases of radiation exposure to protect normal tissues.
