RESUMEN
Frequent screening for thyroid cancer has been suggested as a probable explanation for the observed high risk of thyroid cancer in nuclear power plant (NPP) areas. We aimed to compare thyroid cancer screening rates of residents living near NPPs to those of the general population. This study utilized data from two national survey-based studies in 2016 and in 2014, respectively, for residents (n = 1,200) living in administrative districts within 5 km of NPP sites as the interest group, and the general population (n = 228,712) including distant-living residents (n = 19,100) in administrative districts within 30 km of NPP sites as reference groups. We observed an increase in screening rates in residents near NPPs, which may lead to a higher possibility of thyroid cancer detection. Therefore, further epidemiological studies investigating radiation-induced thyroid cancer risk among residents near NPPs should be carefully designed and interpreted considering possible detection bias.
Asunto(s)
Neoplasias Inducidas por Radiación , Neoplasias de la Tiroides , Humanos , Plantas de Energía Nuclear , Detección Precoz del Cáncer , Neoplasias de la Tiroides/diagnóstico , Neoplasias de la Tiroides/epidemiología , Neoplasias Inducidas por Radiación/diagnóstico , Neoplasias Inducidas por Radiación/epidemiologíaRESUMEN
Radiation-induced cutaneous ulcers are a challenging medical problem for patients receiving radiation therapy. The inhibition of cell senescence has been suggested as a prospective strategy to prevent radiation ulcers. However, there is no effective treatment for senescent cells in radiation ulcers. In this study, we investigated whether zileuton alleviated radiation-induced cutaneous ulcer by focusing on cell senescence. We demonstrate increased cell senescence and senescence-associated secretory phenotype (SASP) in irradiated dermal fibroblasts and skin tissue. The SASP secreted from senescent cells induces senescence in adjacent cells. In addition, 5-lipoxygenase (5-LO) expression increased in irradiated dermal fibroblasts and skin tissue, and SASP and cell senescence were regulated by 5-LO through p38 phosphorylation. Finally, the inhibition of 5-LO following treatment with zileuton inhibited SASP and mitigated radiation ulcers in animal models. Our results demonstrate that inhibition of SASP from senescent cells by zileuton can effectively mitigate radiation-induced cutaneous ulcers, indicating that inhibition of 5-LO might be a viable strategy for patients with this condition.
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Fibroblastos , Úlcera , Animales , Senescencia Celular , Fibroblastos/metabolismo , Hidroxiurea/análogos & derivados , Fenotipo , Roedores , Fenotipo Secretor Asociado a la Senescencia , Úlcera/metabolismoRESUMEN
Radiation-induced gastrointestinal (GI) damage is one of the critical factors that serve as basis for the lethality of nuclear accidents or terrorism. Further, there are no Food and Drug Administration-approved agents available to mitigate radiation-induced intestinal injury. Although pravastatin (PS) has been shown to exhibit anti-inflammatory and epithelial reconstructive effects following radiation exposure using mouse and minipig models, the treatment failed to improve the survival rate of high-dose irradiated intestinal injury. Moreover, we previously found that metformin (MF), a common drug used for treating type 2 diabetes mellitus, has a mitigating effect on radiation-induced enteropathy by promoting stem cell properties. In this study, we investigated whether the combined administration of PS and MF could achieve therapeutic effects on acute radiation-induced intestinal injury in mouse and minipig models. We found that the combined treatment markedly increased the survival rate and attenuated histological damage in a radiation-induced intestinal injury mouse model, in addition to epithelial barrier recovery, anti-inflammatory effects, and improved epithelial proliferation with stem cell properties. Furthermore, in minipig models, combined treatment with PS and MF ameliorates gross pathological damage in abdominal organs and attenuated radiation-induced intestinal histological damage. Therefore, the combination of PS and MF effectively alleviated radiation-induced intestinal injury in the mouse and minipig models. We believe that the combined use of PS and MF is a promising therapeutic approach for treating radiation-induced intestinal injury.
Asunto(s)
Diabetes Mellitus Tipo 2 , Enfermedades Intestinales , Metformina , Traumatismos por Radiación , Ratones , Animales , Porcinos , Porcinos Enanos , Pravastatina/farmacología , Pravastatina/uso terapéutico , Metformina/farmacología , Metformina/uso terapéutico , IntestinosRESUMEN
Radiotherapy or accidental exposure to high-dose radiation can cause severe damage to healthy organs. The gastrointestinal (GI) tract is a radiation-sensitive organ of the body. The intestinal barrier is the first line of defense in the GI tract, and consists of mucus secreted by goblet cells and a monolayer of epithelium. Intestinal stem cells (ISCs) help in barrier maintenance and intestinal function after injury by regulating efficient regeneration of the epithelium. The Wnt/ß-catenin pathway plays a critical role in maintaining the intestinal epithelium and regulates ISC self-renewal. Metformin is the most widely used antidiabetic drug in clinical practice, and its anti-inflammatory, antioxidative, and antiapoptotic effects have also been widely studied. In this study, we investigated whether metformin alleviated radiation-induced enteropathy by focusing on its role in protecting the epithelial barrier. We found that metformin alleviated radiation-induced enteropathy, with increased villi length and crypt numbers, and restored the intestinal barrier function in the irradiated intestine. In a radiation-induced enteropathy mouse model, metformin treatment increased tight-junction expression in the epithelium and inhibited bacterial translocation to mesenteric lymph nodes. Metformin increased the number of ISCs from radiation toxicity and enhanced epithelial repair by activating Wnt/ß-catenin signaling. These data suggested that metformin may be a potential therapeutic agent for radiation-induced enteropathy.
Asunto(s)
Enfermedades Intestinales , Metformina , Animales , Proliferación Celular , Células Caliciformes/metabolismo , Enfermedades Intestinales/metabolismo , Mucosa Intestinal/metabolismo , Intestinos , Metformina/metabolismo , Metformina/farmacología , Ratones , Ratones Endogámicos C57BL , beta Catenina/metabolismoRESUMEN
Colorectal cancer (CRC) is a recurring cancer that is often resistant to conventional therapies and therefore requires the development of molecular-based therapeutic approaches. Dopamine receptor D2 (DRD2) is associated with the growth of many types of tumors, but its oncogenic role in CRC is unclear. Here, we observed that elevated DRD2 expression was associated with a poor survival rate among patients with CRC. Depletion of DRD2 suppressed CRC cell growth and motility by downregulating ß-catenin/ZEB signaling in vitro and in vivo, whereas overexpression of DRD2 promoted CRC cell progression. Inhibition of DRD2 by the antagonist pimozide inhibited tumor growth and lymph node metastasis in vivo and enhanced the cytotoxic effects of conventional agents in vitro. Taken together, our findings indicate that targeting the DRD2/ß-catenin/ZEB1 signaling axis is a potentially promising therapeutic strategy for patients with CRC.
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Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/mortalidad , Progresión de la Enfermedad , Receptores de Dopamina D2/metabolismo , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/metabolismo , beta Catenina/metabolismo , Anciano , Animales , Movimiento Celular/genética , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Antagonistas de Dopamina/farmacología , Femenino , Células HCT116 , Células HT29 , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Pimozida/farmacología , Interferencia de ARN , Receptores de Dopamina D2/genética , Transducción de Señal , Tasa de Supervivencia , Transfección , Carga Tumoral/efectos de los fármacos , Carga Tumoral/genética , Regulación hacia Arriba , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Intestinal injury is observed in cancer patients after radiotherapy and in individuals exposed to radiation after a nuclear accident. Radiation disrupts normal vascular homeostasis in the gastrointestinal system by inducing endothelial damage and senescence. Despite advances in medical technology, the toxicity of radiation to healthy tissue remains an issue. To address this issue, we investigated the effect of atorvastatin, a commonly prescribed hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor of cholesterol synthesis, on radiation-induced enteropathy and inflammatory responses. We selected atorvastatin based on its pleiotropic anti-fibrotic and anti-inflammatory effects. We found that atorvastatin mitigated radiation-induced endothelial damage by regulating plasminogen activator inhibitor-1 (PAI-1) using human umbilical vein endothelial cells (HUVECs) and mouse model. PAI-1 secreted by HUVECs contributed to endothelial dysfunction and trans-endothelial monocyte migration after radiation exposure. We observed that PAI-1 production and secretion was inhibited by atorvastatin in irradiated HUVECs and radiation-induced enteropathy mouse model. More specifically, atorvastatin inhibited PAI-1 production following radiation through the JNK/c-Jun signaling pathway. Together, our findings suggest that atorvastatin alleviates radiation-induced enteropathy and supports the investigation of atorvastatin as a radio-mitigator in patients receiving radiotherapy.
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Atorvastatina/farmacología , Rayos gamma/efectos adversos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Enfermedades Intestinales/metabolismo , Monocitos/metabolismo , Inhibidor 1 de Activador Plasminogénico/metabolismo , Traumatismos Experimentales por Radiación/metabolismo , Migración Transendotelial y Transepitelial , Animales , Células Endoteliales de la Vena Umbilical Humana/patología , Humanos , Enfermedades Intestinales/patología , Ratones , Monocitos/patología , Traumatismos Experimentales por Radiación/patología , Migración Transendotelial y Transepitelial/efectos de los fármacos , Migración Transendotelial y Transepitelial/efectos de la radiaciónRESUMEN
Accurate dosimetry plays a key role in evaluating the radiation-induced health risks of radiation workers. The National Dose Registry in Korea contains the dose records of radiation workers in nuclear-related occupations since 1984. Thus, radiation doses for workers before 1984 are often sparse or missing. This study aimed to estimate the historical radiation dose before 1984 for radiation workers in Korea based on dose reconstruction models. The dose reconstruction models were derived from the nationwide self-administered questionnaire survey and the personal badge doses for workers in the cohort of the Korean Radiation Worker Study. The mean estimated annual doses between 1984 and 2016 from the dose reconstruction model were 4.67-0.6 mSv, which closely matched the reported doses of 4.51-0.43 mSv. The mean estimated annual doses between 1961 and 1983 based on the exposure scenarios developed by factors associated with radiation doses ranged from 11.08 to 4.82 mSv. The mean estimated annual doses of individuals in the cohort from 1961 to 1983 ranged from 11.15 to 4.88 mSv. Although caution needs to be exercised in the interpretation of these estimations due to uncertainty owed to the nature of extrapolation beyond the range of observed data, this study offers a sense of the radiation doses for workers during Korea's early period of radiation-related activities, which can be a useful piece of information for radiation-induced health risk assessments.
Asunto(s)
Exposición Profesional , Estudios de Cohortes , Humanos , Exposición Profesional/análisis , Dosis de Radiación , Radiometría , República de CoreaRESUMEN
Delayed wound healing after radiation exposure can cause serious cutaneous damage, and its treatment is a major clinical challenge. Although mesenchymal stem cells (MSCs) have emerged as a promising therapeutic agent in regenerative medicine, they alone do not produce satisfactory effects in a combined radiation and wound injury (CRWI) model. Here, we investigated the therapeutic effect of combined umbilical cord blood-derived (UCB)-MSCs and platelet-rich plasma (PRP) treatment on wound healing in a CRWI mouse model. First, we assessed the release of cytokines from UCB-MSCs cultured with PRP and observed changes in the expression of angiogenic factors. The angiogenic paracrine factors from UCB-MSCs cultured with PRP were assessed in human umbilical vein endothelial cells (HUVECs). To assess therapeutic efficacy, UCB-MSCs and PRP were topically implanted into a CRWT mouse model. Vascular endothelial growth factor (VEGF), a pro-angiogenic growth factor, urokinase-type plasminogen activator and contributor to VEGF-induced signalling were more highly expressed in conditioned media of UCB-MSCs cultured with PRP than in that of UCB-MSCs alone. Furthermore, conditioned media of UCB-MSCs cultured with PRP increased the formation of tube-like structures in HUVECs. Co-treatment of UCB-MSCs and PRP in a CRWI mouse model increased the wound closure rate and angiogenesis compared with an untreated irradiated group. Moreover, increased expression of VEGF and CD31 were observed in the wound tissue of co-treated mice compared with untreated irradiated mice. PRP stimulates the release of angiogenic factors from UCB-MSCs, and combined therapy of UCB-MSCs and PRP improves regeneration efficacy by enhancing angiogenesis in a CRWI model.
Asunto(s)
Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/fisiología , Neovascularización Fisiológica , Comunicación Paracrina/fisiología , Plasma Rico en Plaquetas , Cicatrización de Heridas/fisiología , Animales , Medios de Cultivo Condicionados/farmacología , Modelos Animales de Enfermedad , Endotelina-1/genética , Endotelina-1/metabolismo , Sangre Fetal/citología , Células Endoteliales de la Vena Umbilical Humana , Humanos , Masculino , Células Madre Mesenquimatosas/metabolismo , Ratones , Transducción de Señal/efectos de los fármacos , Activador de Plasminógeno de Tipo Uroquinasa/genética , Activador de Plasminógeno de Tipo Uroquinasa/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo , Cicatrización de Heridas/efectos de la radiaciónRESUMEN
Intestinal organoids have recently emerged as an in vitro model relevant to the gut system owing to their recapitulation of the native intestinal epithelium with crypt-villus architecture. However, it is unclear whether intestinal organoids reflect the physiology of the in vivo stress response. Here, we systemically investigated the radiation response in organoids and animal models using mesenchymal stem cell-conditioned medium (MSC-CM), which contains secreted paracrine factors. Irradiated organoids exhibited sequential induction of viability loss and regrowth after irradiation (within 12 days), similar to the response of the native intestinal epithelium. Notably, treatment with MSC-CM facilitated the reproliferation of intestinal stem cells (ISCs) and restoration of damaged crypt-villus structures in both models. Furthermore, Wnt/Notch signaling pathways were commonly upregulated by MSC-CM, but not radiation, and pharmacologically selective inhibition of Wnt or Notch signaling attenuated the enhanced recovery of irradiated organoids, with increases in ISCs, following MSC-CM treatment. Interestingly, the expression of Wnt4, Wnt7a, and active ß-catenin was increased, but not notch family members, in MSC-CM-treated organoid after irradiation. Treatment of recombinant mouse Wnt4 and Wnt7a after irradiation improved to some extent intestinal epithelial regeneration both in vitro and in vivo. Overall, these results suggested that intestinal organoids recapitulated the physiological stress response of the intestinal epithelium in vivo. Thus, our findings provided important insights into the physiology of intestinal organoids and may contribute to the development of strategies to enhance the functional maturation of engineered organoids.
Asunto(s)
Mucosa Intestinal/metabolismo , Células Madre Mesenquimatosas/metabolismo , Organoides/metabolismo , Regeneración/efectos de los fármacos , Rayos X/efectos adversos , Animales , Medios de Cultivo Condicionados , Humanos , Masculino , Ratones , Regeneración/efectos de la radiaciónRESUMEN
Radiation-induced multiorgan dysfunction is thought to result primarily from damage to the endothelial system, leading to a systemic inflammatory response that is mediated by the recruitment of leukocytes. The Eph-ephrin signaling pathway in the vascular system participates in various disease developmental processes, including cancer and inflammation. In this study, we demonstrate that radiation exposure increased intestinal inflammation via endothelial dysfunction, caused by the radiation-induced activation of EphA2, an Eph receptor tyrosine kinase, and its ligand ephrinA1. Barrier dysfunction in endothelial and epithelial cells was aggravated by vascular endothelial-cadherin disruption and leukocyte adhesion in radiation-induced inflammation both in vitro and in vivo. Among all Eph receptors and their ligands, EphA2 and ephrinA1 were required for barrier destabilization and leukocyte adhesion. Knockdown of EphA2 in endothelial cells reduced radiation-induced endothelial dysfunction. Furthermore, pharmacological inhibition of EphA2-ephrinA1 by the tyrosine kinase inhibitor dasatinib attenuated the loss of vascular integrity and leukocyte adhesion in vitro. Mice administered dasatinib exhibited resistance to radiation injury characterized by reduced barrier leakage and decreased leukocyte infiltration into the intestine. Taken together, these data suggest that dasatinib therapy represents a potential approach for the protection of radiation-mediated intestinal damage by targeting the EphA2-ephrinA1 complex.
Asunto(s)
Dasatinib/uso terapéutico , Intestinos/lesiones , Intestinos/efectos de la radiación , Traumatismos por Radiación/tratamiento farmacológico , Receptor EphA2/antagonistas & inhibidores , Animales , Adhesión Celular/efectos de los fármacos , Adhesión Celular/efectos de la radiación , Permeabilidad de la Membrana Celular/efectos de los fármacos , Permeabilidad de la Membrana Celular/efectos de la radiación , Dasatinib/farmacología , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/efectos de la radiación , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/patología , Endotelio Vascular/efectos de la radiación , Efrina-A1/metabolismo , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/efectos de la radiación , Humanos , Intestinos/efectos de los fármacos , Intestinos/patología , Leucocitos/efectos de los fármacos , Leucocitos/efectos de la radiación , Ligandos , Masculino , Ratones Endogámicos C57BL , Fosforilación/efectos de los fármacos , Fosforilación/efectos de la radiación , Radiación Ionizante , Receptor EphA2/metabolismoRESUMEN
Although radiotherapy plays a crucial in the management of pelvic tumors, its toxicity on surrounding healthy tissues such as the small intestine, colon, and rectum is one of the major limitations associated with its use. In particular, proctitis is a major clinical complication of pelvic radiotherapy. Recent evidence suggests that endothelial injury significantly affects the initiation of radiation-induced inflammation. The damaged endothelial cells accelerate immune cell recruitment by activating the expression of endothelial adhesive molecules, which participate in the development of tissue damage. Pravastatin, a cholesterol lowering drug, exerts persistent anti-inflammatory and anti-thrombotic effects on irradiated endothelial cells and inhibits the interaction of leukocytes and damaged endothelial cells. Here, we aimed to investigate the effects of pravastatin on radiation-induced endothelial damage in human umbilical vein endothelial cell and a murine proctitis model. Pravastatin attenuated epithelial damage and inflammatory response in irradiated colorectal lesions. In particular, pravastatin improved radiation-induced endothelial damage by regulating thrombomodulin (TM) expression. In addition, exogenous TM inhibited leukocyte adhesion to the irradiated endothelial cells. Thus, pravastatin can inhibit endothelial damage by inducing TM, thereby alleviating radiation proctitis. Therefore, we suggest that pharmacological modulation of endothelial TM may limit intestinal inflammation after irradiation.
Asunto(s)
Células Endoteliales/citología , Pravastatina/administración & dosificación , Proctitis/tratamiento farmacológico , Trombomodulina/metabolismo , Animales , Modelos Animales de Enfermedad , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Células Endoteliales/efectos de la radiación , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana , Humanos , Leucocitos/efectos de los fármacos , Leucocitos/metabolismo , Ratones , Pravastatina/farmacología , Proctitis/etiología , Células THP-1RESUMEN
BACKGROUND: It is difficult to distinguish parathyroid lesions (PLs) from thyroid lesions using fine needle aspiration cytology (FNAC) because of their proximity and their similar cytomorphological features. METHODS: FNAC smears of 46 patients with pathologically proven PLs that were histologically diagnosed as parathyroid adenoma (PA, n = 35), parathyroid hyperplasia (PH, n = 3), atypical parathyroid adenoma (APA, n = 1), and parathyroid carcinoma (PC, n = 7) were retrospectively reviewed and analyzed. RESULTS: Our initial cytological diagnoses indicated correct diagnoses in 31 of 46 PL patients (67%). The 15 erroneous diagnoses were 5 patients with non-specific benign disease (11%), 4 with nodular hyperplasia of the thyroid (9%), 5 with atypical cells (11%), and 1 with a metastatic papillary thyroid carcinoma (2%). Follicular pattern, papillary structures, colloid-like material, and macrophages, which often suggest thyroid lesions, were also present in some PLs. We found that branching capillaries along the papillary structures, stippled nuclear chromatin, and frequent occurrence of naked nuclei were useful for determining a parathyroid origin. CONCLUSIONS: It is important to be aware that PLs are frequently mistaken for thyroid lesions based on FNAC. The specific and unique characteristics of PLs identified here may be helpful in diagnosis.
Asunto(s)
Neoplasias de la Tiroides , Biopsia con Aguja Fina , Diagnóstico Diferencial , Humanos , Estudios Retrospectivos , Neoplasias de la Tiroides/diagnósticoRESUMEN
Hyaluronic acid synthase 2 (HAS2) is suggested to play a critical role in malignancy and is abnormally expressed in many carcinomas. However, its role in colorectal cancer (CRC) malignancy and specific signaling mechanisms remain obscure. Here, we report that HAS2 was markedly increased in both CRC tissue and malignant CRC cell lines. Depletion of HAS2 in HCT116 and DLD1 cells, which express high levels of HAS2, critically increased sensitivity of radiation/oxaliplatin-mediated apoptotic cell death. Moreover, downregulation of HAS2 suppressed migration, invasion and metastasis in nude mice. Conversely, ectopic overexpression of HAS2 in SW480 cells, which express low levels of HAS2, showed the opposite effect. Notably, HAS2 loss- and gain-of-function experiments revealed that it regulates CRC malignancy through TGF-ß expression and SMAD2/Snail downstream components. Collectively, our findings suggest that HAS2 contributes to malignant phenotypes of CRC, at least partly, through activation of the TGF-ß signaling pathway, and shed light on the novel mechanisms behind the constitutive activation of HAS2 signaling in CRC, thereby highlighting its potential as a therapeutic target.
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Neoplasias Colorrectales/patología , Resistencia a Antineoplásicos , Hialuronano Sintasas/metabolismo , Tolerancia a Radiación , Transducción de Señal , Animales , Línea Celular Tumoral , Movimiento Celular , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Transición Epitelial-Mesenquimal , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Células HCT116 , Humanos , Hialuronano Sintasas/genética , Ratones , Ratones Desnudos , Invasividad Neoplásica , Trasplante de Neoplasias , Análisis de Matrices Tisulares , Factor de Crecimiento Transformador beta/metabolismo , Regulación hacia ArribaRESUMEN
Recurrence and chemoresistance in colorectal cancer remain important issues for patients treated with conventional therapeutics. Metformin and phenformin, previously used in the treatment of diabetes, have been shown to have anticancer effects in various cancers, including breast, lung and prostate cancers. However, their molecular mechanisms are still unclear. In this study, we examined the effects of these drugs in chemoresistant rectal cancer cell lines. We found that SW837 and SW1463 rectal cancer cells were more resistant to ionizing radiation and 5-fluorouracil than HCT116 and LS513 colon cancer cells. In addition, metformin and phenformin increased the sensitivity of these cell lines by inhibiting cell proliferation, suppressing clonogenic ability and increasing apoptotic cell death in rectal cancer cells. Signal transducer and activator of transcription 3 and transforming growth factor-ß/Smad signaling pathways were more activated in rectal cancer cells, and inhibition of signal transducer and activator of transcription 3 expression using an inhibitor or siRNA sensitized rectal cancer cells to chemoresistant by inhibition of the expression of antiapoptotic proteins, such as X-linked inhibitor of apoptosis, survivin and cellular inhibitor of apoptosis protein 1. Moreover, metformin and phenformin inhibited cell migration and invasion by suppression of transforming growth factor ß receptor 2-mediated Snail and Twist expression in rectal cancer cells. Therefore, metformin and phenformin may represent a novel strategy for the treatment of chemoresistant rectal cancer by targeting signal transducer and activator of transcription 3 and transforming growth factor-ß/Smad signaling.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Metformina/farmacología , Fenformina/farmacología , Neoplasias del Recto/terapia , Transducción de Señal/efectos de los fármacos , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Movimiento Celular/efectos de la radiación , Proliferación Celular/efectos de los fármacos , Proliferación Celular/efectos de la radiación , Quimioradioterapia/métodos , Colon/patología , Neoplasias del Colon/patología , Neoplasias del Colon/terapia , Transición Epitelial-Mesenquimal/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de la radiación , Fluorouracilo/farmacología , Fluorouracilo/uso terapéutico , Humanos , Masculino , Metformina/uso terapéutico , Ratones , Ratones Desnudos , Recurrencia Local de Neoplasia , Fenformina/uso terapéutico , Neoplasias del Recto/patología , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de la radiación , Proteínas Smad/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: The skin is impacted by every form of external radiation therapy. However, effective therapeutic options for severe, acute radiation-induced skin reactions are limited. Although platelet-rich plasma (PRP) is known to improve cutaneous wound healing, its effects in the context of high-dose irradiation are still poorly understood. METHODS: We investigated the regenerative functions of PRP by subjecting the dorsal skin of mice to local irradiation (40 Gy) and exposing HaCaT cells to gamma rays (5 Gy). The cutaneous benefits of PRP were gauged by wound size, histologic features, immunostains, western blot, and transepithelial water loss (TEWL). To assess the molecular effects of PRP on keratinocytes of healing radiation-induced wounds, we evaluated AKT signaling. RESULTS: Heightened expression of keratin 14 (K14) was documented in irradiated HaCaT cells and skin tissue, although the healing capacity of injured HaCaT cells declined. By applying PRP, this capacity was restored via augmented AKT signaling. In our mouse model, PRP use achieved the following: (1) healing of desquamated skin, acutely injured by radiation; (2) activated AKT signaling, improving migration and proliferation of K14 cells; (3) greater expression of involucrin in keratin 10 cells and sebaceous glands; and (4) reduced TEWL, strengthening the cutaneous barrier function. CONCLUSIONS: Our findings indicate that PRP enhances the functions of K14 cells via AKT signaling, accelerating the regeneration of irradiated skin. These wound-healing benefits may have merit in a clinical setting.
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Plasma Rico en Plaquetas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Traumatismos por Radiación/complicaciones , Transducción de Señal , Piel/lesiones , Cicatrización de Heridas , Animales , Línea Celular , Proliferación Celular/efectos de la radiación , Modelos Animales de Enfermedad , Humanos , Queratinocitos/patología , Queratinocitos/efectos de la radiación , Queratinas/metabolismo , Ratones , Transducción de Señal/efectos de la radiación , Piel/patología , Piel/efectos de la radiación , Cicatrización de Heridas/efectos de la radiación , Rayos XRESUMEN
Radiation-induced enteropathy remains a major complication after accidental or therapeutic exposure to ionizing radiation. Recent evidence suggests that intestinal microvascular damage significantly affects the development of radiation enteropathy. Mesenchymal stem cell (MSC) therapy is a promising tool to regenerate various tissues, including skin and intestine. Further, photobiomodulation (PBM), or low-level light therapy, can accelerate wound healing, especially by stimulating angiogenesis, and stem cells are particularly susceptible to PBM. Here, we explored the effect of PBM on the therapeutic potential of MSCs for the management of radiation enteropathy. In vitro, using human umbilical cord blood-derived MSCs, PBM increased proliferation and self-renewal. Intriguingly, the conditioned medium from MSCs treated with PBM attenuated irradiation-induced apoptosis and impaired tube formation in vascular endothelial cells, and these protective effects were associated with the upregulation of several angiogenic factors. In a mouse model of radiation-induced enteropathy, treatment with PBM-preconditioned MSCs alleviated mucosal destruction, improved crypt cell proliferation and epithelial barrier functions, and significantly attenuated the loss of microvascular endothelial cells in the irradiated intestinal mucosa. This treatment also significantly increased angiogenesis in the lamina propria. Together, we suggest that PBM enhances the angiogenic potential of MSCs, leading to improved therapeutic efficacy for the treatment of radiation-induced enteropathy.
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Síndrome de Radiación Aguda/terapia , Mucosa Intestinal/patología , Terapia por Luz de Baja Intensidad/métodos , Trasplante de Células Madre Mesenquimatosas/métodos , Neovascularización Fisiológica , Proteínas Angiogénicas/genética , Proteínas Angiogénicas/metabolismo , Animales , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Células Endoteliales de la Vena Umbilical Humana/efectos de la radiación , Humanos , Mucosa Intestinal/irrigación sanguínea , Mucosa Intestinal/efectos de la radiación , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
BACKGROUND AND AIM: Radiation-induced colitis is a common clinical problem associated with radiotherapy and accidental exposure to ionizing radiation. Goblet cells play a pivotal role in the intestinal barrier against pathogenic bacteria. Rebamipide, an anti-gastric ulcer drug, has the effects to promote goblet cell proliferation. The aim of this study was to investigate whether radiation-induced colonic injury could be alleviated by rebamipide. METHODS: This study orally administered rebamipide for 6 days to mice, which were subjected to 13 Gy abdominal irradiation, to evaluate the therapeutic effects of rebamipide against radiation-induced colitis. To confirm the effects of rebamipide on irradiated colonic epithelial cells, this study used the HT29 cell line. RESULTS: Rebamipide clearly alleviated the acute radiation-induced colitis, as reflected by the histopathological data, and significantly increased the number of goblet cells. The drug also inhibited intestinal inflammation and protected from bacterial translocation during acute radiation-induced colitis. Furthermore, rebamipide significantly increased mucin 2 expression in both the irradiated mouse colon and human colonic epithelial cells. Additionally, rebamipide accelerated not only the recovery of defective tight junctions but also the differentiation of impaired goblet cells in an irradiated colonic epithelium, which indicates that rebamipide has beneficial effects on the colon. CONCLUSIONS: Rebamipide is a therapeutic candidate for radiation-induced colitis, owing to its ability to inhibit inflammation and protect the colonic epithelial barrier.
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Alanina/análogos & derivados , Antiulcerosos/farmacología , Antiulcerosos/uso terapéutico , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Colitis/tratamiento farmacológico , Colitis/patología , Células Caliciformes/citología , Quinolonas/farmacología , Quinolonas/uso terapéutico , Traumatismos Experimentales por Radiación/complicaciones , Radioterapia/efectos adversos , Alanina/farmacología , Alanina/uso terapéutico , Animales , Colitis/etiología , Colon , Modelos Animales de Enfermedad , Células Epiteliales/metabolismo , Células Epiteliales/efectos de la radiación , Expresión Génica/efectos de los fármacos , Células HT29 , Humanos , Masculino , Ratones Endogámicos C57BL , Mucina 2/genética , Mucina 2/metabolismo , Radiación IonizanteRESUMEN
Inevitable exposure to ionizing radiation from natural and human-made sources has been increasing over time. After nuclear disasters, such as the Fukushima accident, the public concerns on health risk of radiation exposure because of radioactive contamination of the environment have increased. However, it is very difficult to assess the biological effects of exposure caused by environmental radiation. A reliable and rapid bioassay to monitor the physiological effects of radiation exposure is therefore needed. Here, we quantitatively analyzed the changes in cell shape in Drosophila epidermis after irradiation as a model for biomonitoring of radiation. Interestingly, the number of irregularly shaped epithelial cells was increased by irradiation in a dose-dependent manner. A dose-response curve constructed with the obtained data suggests that the measurement of the number of irregular shaped cell in the epidermis is useful for the assessment of radiation dose. In addition, a comparison of the variation in the different samples and the data scored by different observers showed that our evaluation for cellular morphology was highly reliable and accurate and would, therefore, have immense practical application. Overall, our study suggests that detection of morphological changes in the epithelial cells is one of the efficient ways to quantify the levels of exposure to radioactive radiation from the environment.
Asunto(s)
Forma de la Célula/efectos de la radiación , Drosophila/efectos de la radiación , Células Epiteliales/efectos de la radiación , Exposición a la Radiación/análisis , Monitoreo de Radiación/métodos , Animales , Relación Dosis-Respuesta en la Radiación , Drosophila/ultraestructura , Células Epiteliales/ultraestructura , Dosis de Radiación , Radiación IonizanteRESUMEN
Radiation-induced skin injury can take the form of serious cutaneous damage and have specific characteristics. Asymptomatic periods are classified as the latent stage. The skin barrier plays a critical role in the modulation of skin permeability and hydration and protects the body against a harsh external environment. However, an analysis on skin barrier dysfunction against radiation exposure in the latent stage has not been conducted. Thus, we investigated whether the skin barrier is impaired by irradiation in the latent stage and aimed to identify the molecules involved in skin barrier dysfunction. We analyzed skin barrier function and its components in SKH1 mice that received 20 and 40 Gy local irradiation. Increased transepidermal water loss and skin pH were observed in the latent stage of the irradiated skin. Skin barrier components, such as structural proteins and lipid synthesis enzymes in keratinocyte, increased in the irradiated group. Interestingly, we noted sebaceous gland atrophy and increased serine protease and inflammatory cytokines in the irradiated skin during the latent period. This finding indicates that the main factor of skin barrier dysfunction in the latent stage of radiation-induced skin injury is sebaceous gland deficiency, which could be an intervention target for skin barrier impairment.
Asunto(s)
Traumatismos por Radiación/patología , Glándulas Sebáceas/patología , Piel/patología , Animales , Citocinas/metabolismo , Queratinocitos/metabolismo , Metabolismo de los Lípidos , Masculino , Ratones , Traumatismos por Radiación/metabolismo , Serina Proteasas/metabolismo , Piel/metabolismo , Piel/efectos de la radiaciónRESUMEN
Risk projection models estimating the lifetime cancer risk from radiation exposure are generally based on exposure dose, age at exposure, attained age, gender and study-population-specific factors such as baseline cancer risks and survival rates. Because such models have mostly been based on the Life Span Study cohort of Japanese atomic bomb survivors, the baseline risks and survival rates in the target population should be considered when applying the cancer risk. The survival function used in the risk projection models that are commonly used in the radiological protection field to estimate the cancer risk from medical or occupational exposure is based on all-cause mortality. Thus, it may not be accurate for estimating the lifetime risk of high-incidence but not life-threatening cancer with a long-term survival rate. Herein, we present the lifetime attributable risk (LAR) estimates of all solid cancers except thyroid cancer, thyroid cancer, and leukemia except chronic lymphocytic leukemia in South Korea for lifetime exposure to 1 mGy per year using the cancer-free survival function, as recently applied in the Fukushima health risk assessment by the World Health Organization. Compared with the estimates of LARs using an overall survival function solely based on all-cause mortality, the LARs of all solid cancers except thyroid cancer, and thyroid cancer evaluated using the cancer-free survival function, decreased by approximately 13% and 1% for men and 9% and 5% for women, respectively. The LAR of leukemia except chronic lymphocytic leukemia barely changed for either gender owing to the small absolute difference between its incidence and mortality. Given that many cancers have a high curative rate and low mortality rate, using a survival function solely based on all-cause mortality may cause an overestimation of the lifetime risk of cancer incidence. The lifetime fractional risk was robust against the choice of survival function.