RESUMEN
High-dose radiation exposure induces gastrointestinal (GI) stem cell death, resulting in denudation of the intestinal mucosa and lethality from GI syndrome, for which there is currently no effective therapy. Studying an intestinal organoid-based functional model, we found that Sirtuin1(SIRT1) inhibition through genetic knockout or pharmacologic inhibition significantly improved mouse and human intestinal organoid survival after irradiation. Remarkably, mice administered with two doseages of SIRT1 inhibitors at 24 and 96 h after lethal irradiation promoted Lgr5+ intestinal stem cell and crypt recovery, with improved mouse survival (88.89% of mice in the treated group vs. 0% of mice in the control group). Moreover, our data revealed that SIRT1 inhibition increased p53 acetylation, resulting in the stabilization of p53 and likely contributing to the survival of intestinal epithelial cells post-radiation. These results demonstrate that SIRT1 inhibitors are effective clinical countermeasures to mitigate GI toxicity from potentially lethal radiation exposure.
Asunto(s)
Enfermedades Gastrointestinales/tratamiento farmacológico , Inhibidores de Histona Desacetilasas/farmacología , Intestinos/efectos de los fármacos , Niacinamida/farmacología , Traumatismos Experimentales por Radiación/tratamiento farmacológico , Sirtuina 1/antagonistas & inhibidores , Acetilación , Animales , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Enfermedades Gastrointestinales/etiología , Enfermedades Gastrointestinales/metabolismo , Enfermedades Gastrointestinales/patología , Humanos , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Mucosa Intestinal/efectos de la radiación , Intestinos/patología , Intestinos/efectos de la radiación , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Organoides , Traumatismos Experimentales por Radiación/metabolismo , Traumatismos Experimentales por Radiación/patología , Sirtuina 1/metabolismo , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Radiation-induced bowel injury is a common complication of radiation therapy for pelvic malignancy. Given the huge number of patients diagnosed with pelvic malignancy, the number of patients diagnosed with radiation-induced bowel injury increased year by year, which put a great burden on the clinical diagnosis and treatment of radiation-induced bowel injury. In particular, chronic radiation-induced bowel injury, which is manifested in the process of prolonged, repeated and progressive aggravation, seriously affects the physical and mental health of patients and makes clinical diagnosis and treatment difficult. However, due to insufficient attention and understanding from doctors and patients, standardized diagnosis and treatment of radiation-induced bowel injury still have a long way to go. Radiation-induced bowel injury is self-limited but irreversible. During diagnosis, we should pay attention to overall evaluation of the stage of disease based on clinical symptoms, endoscopic examination, imaging examination, pathology and nutritional risk. The treatment methods include health education, drug therapy, enema therapy, formalin local treatment, endoscopic treatment and surgical treatment, etc. The treatment decision-making should be based on clinical symptoms, endoscopic or imaging findings to alleviate the clinical symptoms of patients as the primary goal and to improve the long-term quality of life of patients as the ultimate goal.
Asunto(s)
Enfermedades Intestinales/terapia , Neoplasias Pélvicas/radioterapia , Traumatismos por Radiación/terapia , Radioterapia/efectos adversos , Enfermedad Crónica , Humanos , Enfermedades Intestinales/diagnóstico , Enfermedades Intestinales/etiología , Intestinos/efectos de la radiación , Calidad de Vida , Traumatismos por Radiación/diagnóstico , Traumatismos por Radiación/etiologíaRESUMEN
This study investigated the effects of dietary probiotic Saccharomyces cerevisiae in the striped catfish, Pangasianodon hypophthalmus, which is an important aquaculture species. Freeze-dried microencapsulated probiotic S. cerevisiae with guar gum was performed and used for fish feed supplementation. Striped catfish were fed for 120 days with one of three experimental diets: basal diet (control), basal diet supplemented with 106-CFU S. cerevisiae g-1 diet (S. cerevisiae 106), and basal diet supplemented with 108-CFU S. cerevisiae g-1 diet (S. cerevisiae 108). The S. cerevisiae-supplemented diets significantly improved growth performance including growth rate and feed conversion ratio over 120 days of culture period (P < 0.05). The rate of survival was similar in all experimental groups. Supplementation with S. cerevisiae did not significantly affect whole body proximate composition (P > 0.05). In addition, probiotic S. cerevisiae had no effects on hematological indices and blood chemistry values (glucose, cholesterol, triglycerides, protein, albumin, blood urea nitrogen, chloride, calcium, magnesium, iron, and phosphorus) (P > 0.05). However, dietary S. cerevisiae led to increases in humoral immune parameters including total immunoglobulin, lysozyme, and alternative complement activities (P < 0.05). Dietary S. cerevisiae led to increase intestinal villus height in the anterior part of intestine (P < 0.05). Taken together, while the dietary S. cerevisiae had no detectable effects on hematological indices and several metabolic indicators, significant beneficial probiotic effects were observed on rates of growth, feed conversion ratio, and immune parameters.
Asunto(s)
Bagres/crecimiento & desarrollo , Probióticos/farmacología , Saccharomyces cerevisiae , Animales , Composición Corporal/efectos de los fármacos , Bagres/sangre , Bagres/inmunología , Suplementos Dietéticos , Composición de Medicamentos , Intestinos/citología , Intestinos/efectos de la radiaciónRESUMEN
Intestinal injury and immune dysfunction are commonly encountered after irradiation therapy. While the curative abilities of ginseng root have been reported in prior studies, there is little known regarding its role in immunoregulation of intestinal repairability in cancer patients treated with irradiation. Our current study aims to closely examine the protective effects of ginseng-derived small molecule oligopeptides (Panax ginseng C. A. Mey.) (GOP) against irradiation-induced immune dysfunction and subsequent intestinal injury, using in vitro and in vivo models. Expectedly, irradiation treatment resulted in increased intestinal permeability along with mucosal injury in both Caco-2 cells and mice, probably due to disruption of the intestinal epithelial barrier, leading to high plasma lipopolysaccharide (LPS) and pro-inflammatory cytokines levels. However, when the cells were treated with GOP, this led to diminished concentration of plasma LPS and cytokines (IL-1 and TNF-α), suggesting its dampening effect on inflammatory and oxidative stress, and potential role in restoring normal baseline intestinal permeability. Moreover, the Caco-2 cells treated with GOP showed high trans-epithelial electrical resistance (TEER) and low FITC-dextran paracellular permeability when compared to the control group. This could be explained by the higher levels of tight junction proteins (ZO-1 and Occludin) expression along with reduced expression of the apoptosis-related proteins (Bax and Caspase-3) noticed in the GOP-treated cells, highlighting its role in preserving intestinal permeability, through prevention of their degradation while maintaining normal levels of expression. Further confirmatory in vivo data showed that GOP-treated mice exhibited high concentrations of lymphocytes (CD3+, CD4+, CD8+) in the intestine, to rescue the irradiation-induced damage and restore baseline intestinal integrity. Therefore, we propose that GOP can be used as an adjuvant therapy to attenuate irradiation-induced immune dysfunction and intestinal injury in cancer patients.
Asunto(s)
Intestinos/efectos de los fármacos , Intestinos/efectos de la radiación , Oligopéptidos/farmacología , Panax/química , Proteínas de Plantas/química , Traumatismos por Radiación/prevención & control , Animales , Peso Corporal/efectos de los fármacos , Células CACO-2 , Permeabilidad de la Membrana Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Citocinas/sangre , Humanos , Inmunoglobulinas/sangre , Intestinos/patología , Ratones , Neoplasias/complicaciones , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/efectos de la radiación , Traumatismos por Radiación/complicaciones , Proteínas de Uniones Estrechas/metabolismo , Irradiación Corporal TotalRESUMEN
BACKGROUND: Intestinal fibrosis is a late complication of pelvic radiotherapy. Epithelial-to-mesenchymal transition (EMT) plays an important role in tissue fibrosis. The aim of this study was to examine the effect of soluble dietary fiber on radiation-induced intestinal EMT and fibrosis in a mouse model. MATERIALS AND METHODS: Apple pectin (4% wt/wt in drinking water) was administered to wild-type and pVillin-Cre-EGFP transgenic mice with intestinal fibrosis induced by a single dose of abdominal irradiation of 10 Gy. The effects of pectin on intestinal EMT and fibrosis, gut microbiota, and short-chain fatty acid (SCFA) concentration were evaluated. RESULTS: Intestinal fibrosis in late radiation enteropathy showed increased submucosal thickness and subepithelial collagen deposition. Enhanced green fluorescent protein (EGFP)+/vimentin+ and EGFP+/α-smooth muscle actin (SMA)+ coexpressing cells were most clearly observed at 2 weeks after irradiation and gradually decreased at 4 and 12 weeks. Pectin significantly attenuated the thickness of submucosa and collagen deposition at 12 weeks (24.3 vs 27.6 µm in the pectin + radiation-treated group compared with radiation-alone group, respectively, P < .05; 69.0% vs 57.1%, P < .001) and ameliorated EMT at 2 and 4 weeks. Pectin also modulated the intestinal microbiota composition and increased the luminal SCFA concentration. CONCLUSION: The soluble dietary fiber pectin protected the terminal ileum against radiation-induced fibrosis. This effect might be mediated by altered SCFA concentration in the intestinal lumen and reduced EMT in the ileal epithelium.
Asunto(s)
Fibras de la Dieta/farmacología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de la radiación , Intestinos/efectos de los fármacos , Radioterapia/efectos adversos , Animales , Modelos Animales de Enfermedad , Ácidos Grasos Volátiles/metabolismo , Fibrosis , Microbioma Gastrointestinal/efectos de los fármacos , Íleon/efectos de los fármacos , Íleon/patología , Íleon/efectos de la radiación , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/patología , Mucosa Intestinal/efectos de la radiación , Intestinos/patología , Intestinos/efectos de la radiación , Malus/química , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Pectinas/farmacologíaRESUMEN
Irradiation therapy is markedly associated with intestinal injure and oxidant stress. This study aimed to investigate the effects of ginseng (Panax ginseng C.A. Mey.) oligopeptides (GOP) on irradiation-induced intestinal injury and antioxidant defense in mice. BALB/c mice (8 weeks old) were randomly divided into six groups: vehicle control, irradiation control (IR), IR+whey protein [0.30 g/kg body weight (BW)], IR+GOP 0.15 g/kg BW, IR+GOP 0.30 g/kg BW and IR+GOP 0.60 g/kg BW. Postirradiation 30-day survival trial, white blood cells count and bone marrow hematopoietic system damage were performed to identify the injury degree induced by irradiation. Then, histopathology analysis was observed and intestinal permeability in vivo was quantified with fluorescein isothiocyanate-dextran. The enzyme-linked immunosorbent assay was used to determine antioxidant ability, plasma inflammatory cytokines, diamine oxidase (DAO) and endotoxin (LPS) levels. The immunohistochemistry assay was used to analyze the expression levels of tight junction proteins. We found that GOP-treated mice exhibited lower concentrations of plasma LPS and DAO and decreased instructors of inflammatory and oxidative stress which were linked to the lower intestinal permeability and higher tight junction proteins expression. The blockage of GOP was linked with the reduction of TNF-α and free radicals. The 15-day pretreatment of GOP could exhibit radioprotective effects, and another 15-day posttreatment benefited the quick repair of irradiation-induced injury. We confirm that GOP would exhibit effective therapeutic value on attenuating irradiation-induced hematopoietic, gastrointestinal and oxidative injury in cancer patients.
Asunto(s)
Inflamación/tratamiento farmacológico , Oligopéptidos/farmacología , Panax/química , Protectores contra Radiación/farmacología , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Antioxidantes/metabolismo , Peso Corporal/efectos de los fármacos , Peso Corporal/efectos de la radiación , Citocinas/sangre , Intestinos/efectos de los fármacos , Intestinos/efectos de la radiación , Recuento de Leucocitos , Masculino , Ratones Endogámicos BALB C , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/efectos de la radiación , Traumatismos Experimentales por Radiación/tratamiento farmacológico , Irradiación Corporal TotalRESUMEN
Radiation-induced gastrointestinal syndrome, including nausea, diarrhea and dehydration, contributes to morbidity and mortality after medical or industrial radiation exposure. No safe and effective radiation countermeasure has been approved for clinical therapy. In this study, we aimed to investigate the potential protective effects of seabuckthorn pulp and seed oils against radiation-induced acute intestinal injury. C57/BL6 mice were orally administered seabuckthorn pulp oil, seed oil and control olive oil once per day for 7 days before exposure to total-body X-ray irradiation of 7.5 Gy. Terminal deoxynucleotidyl transferase dUTP nick end labeling, quantitative real-time polymerase chain reaction and western blotting were used for the measurement of apoptotic cells and proteins, inflammation factors and mitogen-activated protein (MAP) kinases. Seabuckthorn oil pretreatment increased the post-radiation survival rate and reduced the damage area of the small intestine villi. Both the pulp and seed oil treatment significantly decreased the apoptotic cell numbers and cleaved caspase 3 expression. Seabuckthorn oil downregulated the mRNA level of inflammatory factors, including tumor necrosis factor-α, interleukin (IL)-1ß, IL-6 and IL-8. Both the pulp and seed oils elevated the level of phosphorylated extracellular-signal-regulated kinase and reduced the levels of phosphorylated c-Jun N-terminal kinase and p38. Palmitoleic acid (PLA) and alpha linolenic acid (ALA) are the predominant components of pulp oil and seed oil, respectively. Pretreatment with PLA and ALA increased the post-radiation survival time. In conclusion, seabuckthorn pulp and seed oils protect against mouse intestinal injury from high-dose radiation by reducing cell apoptosis and inflammation. ALA and PLA are promising natural radiation countermeasure candidates.
Asunto(s)
Hippophae/química , Intestinos/lesiones , Aceites de Plantas/uso terapéutico , Sustancias Protectoras/uso terapéutico , Traumatismos por Radiación/tratamiento farmacológico , Semillas/química , Enfermedad Aguda , Animales , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Peso Corporal/efectos de los fármacos , Citocinas/metabolismo , Relación Dosis-Respuesta en la Radiación , Ácidos Grasos Insaturados/metabolismo , Mediadores de Inflamación/metabolismo , Intestinos/enzimología , Intestinos/patología , Intestinos/efectos de la radiación , Masculino , Ratones Endogámicos C57BL , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Aceite de Oliva/farmacología , Aceite de Oliva/uso terapéutico , Fosforilación/efectos de los fármacos , Aceites de Plantas/farmacología , Sustancias Protectoras/farmacología , Traumatismos por Radiación/patología , Factores de TiempoRESUMEN
Dihydroxyselenolane (DHS), a simple water-soluble organoselenium compound, was evaluated for radioprotection in BALB/c mice after whole-body irradiation (WBI) (8Gy (60)Co, 1Gy/min), by monitoring 30-d post-irradiation survival and biochemical/histological changes in radiosensitive organs. Intraperitoneal administration of DHS at 2mg/kg for five consecutive days before irradiation and three times per week during the post-irradiation period showed maximum benefit (40% improvement in 30 d post-irradiation survival). DHS treatment, despite inducing expression of glutathione peroxidases (GPx1, GPx2, and GPx4) in spleen and intestine, did not protect against radiation-induced acute (10-day) haematopoietic and gastrointestinal toxicities. DHS treatment significantly reduced radiation-induced DNA damage in peripheral leukocytes and inflammatory responses in intestine, lung, and circulation. The anti-inflammatory effect of DHS was associated with reductions in lipid peroxidation, expression of pro-inflammatory genes such as Icam-1, Ccl-2, and iNos-2, and subsequent infiltration of inflammatory cells. Irradiated mice treated with DHS survived until day 30 post-irradiation and showed restoration of spleen cellularity and intestinal villi, but had moderately increased systemic and tissue-specific inflammatory responses. Another organoselenium compound, selenomethionine, evaluated in parallel with DHS at the same dose and treatment schedule, showed comparable radioprotective effects. The mechanism of radioprotection by DHS is mainly via suppression of inflammatory responses.
Asunto(s)
Síndrome de Radiación Aguda/tratamiento farmacológico , Antiinflamatorios/uso terapéutico , Compuestos de Organoselenio/uso terapéutico , Protectores contra Radiación/uso terapéutico , Irradiación Corporal Total/efectos adversos , Síndrome de Radiación Aguda/prevención & control , Animales , Antiinflamatorios/administración & dosificación , Antiinflamatorios/farmacología , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Glutatión Peroxidasa/genética , Glutatión Peroxidasa/metabolismo , Inyecciones Intraperitoneales , Molécula 1 de Adhesión Intercelular/genética , Molécula 1 de Adhesión Intercelular/metabolismo , Mucosa Intestinal/metabolismo , Intestinos/efectos de los fármacos , Intestinos/efectos de la radiación , Peroxidación de Lípido , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/efectos de la radiación , Masculino , Ratones , Ratones Endogámicos BALB C , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Especificidad de Órganos , Compuestos de Organoselenio/administración & dosificación , Compuestos de Organoselenio/farmacología , Protectores contra Radiación/administración & dosificación , Protectores contra Radiación/farmacologíaRESUMEN
BACKGROUND: Exogenous replacement of depleted enterocyte intestinal alkaline phosphatase (IAP) decreases intestinal injury in models of colitis. We determined whether radiation-induced intestinal injury could be mitigated by oral IAP supplementation and the impact on tissue-nonspecific AP. METHODS: WAG/RjjCmcr rats (n = 5 per group) received lower hemibody irradiation (13 Gy) followed by daily gavage with phosphate-buffered saline or IAP (40 U/kg/d) for 4 days. Real-time polymerase chain reaction, AP activity, and microbiota analysis were performed on intestine. Lipopolysaccharide and cytokine analysis was performed on serum. Data were expressed as a mean ± SEM with P greater than .05 considered significant. RESULTS: Intestine of irradiated animals demonstrates lower hemibody irradiation and is associated with upregulation of tissue-nonspecific AP, downregulation of IAP, decreased AP activity, and altered composition of the intestinal microbiome. CONCLUSIONS: Supplemental IAP after radiation may be beneficial in mitigating intestinal radiation syndrome as evidenced by improved histologic injury, decreased acute intestinal inflammation, and normalization of intestinal microbiome.
Asunto(s)
Fosfatasa Alcalina/administración & dosificación , Fosfatasa Alcalina/metabolismo , Microbioma Gastrointestinal , Intestinos/enzimología , Radioterapia/efectos adversos , Animales , Citocinas/metabolismo , Regulación hacia Abajo , Evaluación Preclínica de Medicamentos , Íleon/enzimología , Intestinos/efectos de la radiación , Lipopolisacáridos/metabolismo , Masculino , Óxido Nítrico Sintasa/genética , Óxido Nítrico Sintasa/metabolismo , ARN Mensajero/metabolismo , Dosificación Radioterapéutica , Ratas , Reacción en Cadena en Tiempo Real de la Polimerasa , Regulación hacia ArribaRESUMEN
PURPOSE: To determine the maximally tolerated dose of sorafenib delivered before, during, and after stereotactic body radiation therapy (SBRT) in hepatocellular carinoma (HCC). METHODS AND MATERIALS: Eligible patients had locally advanced Child-Pugh class A HCC, showed Eastern Cooperative Oncology Group performance status 0-1, and were ineligible for standard local-regional therapies. Sorafenib was dose escalated in 2 strata: (1) low effective irradiated liver volume (veff) < 30% and (2) high veff 30%to 60%. Sorafenib (400 mg daily = dose level 1) was administered for 12 weeks, with 6 fractions SBRT delivered weeks 2 and 3, and escalation to full dose (400 mg twice daily) after 12 weeks as tolerated. Standard 3 + 3 cohorts with dose escalation of sorafenib were planned. RESULTS: Sixteen patients (4 low veff, median dose 51 Gy; 12 high veff, median dose 33 Gy) were treated at 2 sorafenib dose levels. Of those patients 75% were had Barcelona Clinic Liver Cancer stage C, and 63% had main branch portal vein invasion. In the low veff stratum, no dose-limiting toxicities (DLTs) were observed in 4 patients treated with SBRT and sorafenib 400 mg. Inb the high veff stratum: 2 of 3 evaluable patients treated with sorafenib 400 mg experienced DLT (grade 3 large bowel bleed and grade 4 bowel obstruction 51 and 27 days, respectively, after SBRT). One of 6 evaluable patients at dose level -1 (200 mg once daily) experienced a grade 3 tumor rupture at week 5. Median overall survival and in-field local progression have not been reached. Worsening of Child-Pugh liver function class was seen in 6 of 12 patients in the high veff stratum. CONCLUSIONS: Significant toxicity was observed in the high veff stratum, and concurrent SBRT with sorafenib is not recommended outside a clinical trial.
Asunto(s)
Antineoplásicos/efectos adversos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/cirugía , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/cirugía , Niacinamida/análogos & derivados , Compuestos de Fenilurea/efectos adversos , Radiocirugia/métodos , Anciano , Antineoplásicos/administración & dosificación , Fraccionamiento de la Dosis de Radiación , Femenino , Humanos , Intestinos/efectos de los fármacos , Intestinos/efectos de la radiación , Hígado/efectos de los fármacos , Hígado/efectos de la radiación , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Niacinamida/administración & dosificación , Niacinamida/efectos adversos , Compuestos de Fenilurea/administración & dosificación , Radiocirugia/efectos adversos , Dosificación Radioterapéutica , SorafenibRESUMEN
PURPOSE: STW 5 (marketed as Iberogast(®), Steigerwald Arzneimittelwerk GmbH, Darmstadt, Germany) is a herbal preparation reported to possess anti-inflammatory properties and antioxidant activity. We investigated the effect of STW 5 against intestinal injury induced after whole body exposure to ionizing radiation (IR). MATERIALS AND METHODS: Intestinal mucositis was induced in rats by irradiation at a level of 6 Gy. STW 5 (5 ml/kg) was delivered orally for 5 days before irradiation and 2 days after. Rats were sacrificed, jejunum homogenates were tested to assess biochemical parameters indicating intestinal injury and jejunum segments were exposed to semi-quantitative histological examination. RESULTS: IR led to an increase in overall damage severity (ODS) score associated with a significant rise in tumor necrosis factor (TNF-α) and thiobarbituric acid reactive substances (TBARS) by 46% and 50% (p ≤ 0.05), respectively, whereas the reduced glutathione (GSH), sucrase and alkaline phosphatase enzyme activities were significantly decreased by 68%, 76% and 25% (p ≤ 0.05), respectively, in intestinal homogenates. IR led to a reduction of plasma citrulline. Pre-treatment with STW 5 guarded against the changes in ODS score and in all parameters measured. CONCLUSION: Pre-treatment with STW 5 has the potential to decrease the severity of radiation-induced mucositis.
Asunto(s)
Rayos gamma/efectos adversos , Intestinos/efectos de los fármacos , Intestinos/efectos de la radiación , Preparaciones de Plantas/farmacología , Protectores contra Radiación/farmacología , Animales , Mucosa Intestinal/metabolismo , Intestinos/patología , Masculino , Ratas , Ratas WistarRESUMEN
Dendritic cells (DCs) comprise distinct populations with specialized immune-regulatory functions. However, the environmental factors that determine the differentiation of these subsets remain poorly defined. Here, we report that retinoic acid (RA), a vitamin A derivative, controls the homeostasis of pre-DC (precursor of DC)-derived splenic CD11b(+)CD8α(-)Esam(high) DCs and the developmentally related CD11b(+)CD103(+) subset within the gut. Whereas mice deprived of RA signaling significantly lost both of these populations, neither pre-DC-derived CD11b(-)CD8α(+) and CD11b(-)CD103(+) nor monocyte-derived CD11b(+)CD8α(-)Esam(low) or CD11b(+)CD103(-) DC populations were deficient. In fate-tracking experiments, transfer of pre-DCs into RA-supplemented hosts resulted in near complete conversion of these cells into the CD11b(+)CD8α(-) subset, whereas transfer into vitamin A-deficient (VAD) hosts caused diversion to the CD11b(-)CD8α(+) lineage. As vitamin A is an essential nutrient, we evaluated retinoid levels in mice and humans after radiation-induced mucosal injury and found this conditioning led to an acute VAD state. Consequently, radiation led to a selective loss of both RA-dependent DC subsets and impaired class II-restricted auto and antitumor immunity that could be rescued by supplemental RA. These findings establish a critical role for RA in regulating the homeostasis of pre-DC-derived DC subsets and have implications for the management of patients with immune deficiencies resulting from malnutrition and irradiation.
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Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Homeostasis/inmunología , Tretinoina/metabolismo , Animales , Diferenciación Celular/inmunología , Proliferación Celular , Supervivencia Celular , Células Dendríticas/citología , Células Dendríticas/efectos de la radiación , Femenino , Antígenos de Histocompatibilidad Clase II/inmunología , Humanos , Inmunofenotipificación , Mucosa Intestinal/metabolismo , Intestinos/inmunología , Intestinos/efectos de la radiación , Ratones , Neoplasias/inmunología , Neoplasias/metabolismo , Especificidad de Órganos/inmunología , Fenotipo , Receptores de Ácido Retinoico/metabolismo , Transducción de Señal , Bazo/inmunología , Bazo/metabolismo , Bazo/efectos de la radiación , Vitamina A/metabolismo , Irradiación Corporal Total/efectos adversosRESUMEN
PURPOSE: Intestinal mucosa, a rapidly proliferating tissue, is highly sensitive to radiation and undergoes apoptosis as a consequence of over generation of oxidative free radicals and the lack of the antioxidants. Thus the present study was designed to investigate the intestinal damage induced by radiation and to study if supplementation of the diet with antioxidant vitamins could ameliorate the intestinal damage and its digestive activity, as determined by the expression of various border enzymes. MATERIALS AND METHODS: Swiss Albino rats (150-200 g body weight) were divided into six groups. Group I: Control untreated; Group II: Irradiated; Group III: Irradiated + vitamin A; Group IV: Irradiated + vitamin C; Group V: Irradiated + vitamin E; and Group VI: Irradiated + lycopene. Animals were exposed to whole body γ-radiation from (60)Co at the rate of 8 Gy for 15 min/rat. Intestinal morphology and changes in various digestive enzymes together with, DNA damage was studied in six groups and each group consisted of 18 animals. RESULTS: The gastrointestinal toxicity resulted in malabsorption, diarrhoea, weight loss, loss of appetite, abdominal haemorrhage and hair loss. The activities of sucrase and alkaline phosphatase were elevated and those of lactase, leucine aminopeptidase (LAP) and gamma-glutamyl transpeptidase or tranferase (γ-GTP) were markedly reduced. Antioxidant vitamin A, C or E supplementations prevented changes in brush border enzyme activities as compared to lycopene administration in rat intestine by radiation exposure. Intestinal histology showed that the vitamin supplementation to irradiated rats minimized the intestinal damage in rats. CONCLUSION: These findings suggest that the epithelial lining of the intestine is highly sensitive to radiation exposure and supplementation of antioxidant vitamins is helpful in minimizing the intestinal damage and supplementation by vitamin E was most potent in ameliorating the intestinal aberrations.
Asunto(s)
Antioxidantes/farmacología , Mucosa Intestinal/fisiopatología , Mucosa Intestinal/efectos de la radiación , Intestinos/enzimología , Animales , Ácido Ascórbico/farmacología , Carotenoides/farmacología , Radioisótopos de Cobalto/química , Daño del ADN , Suplementos Dietéticos , Enzimas/biosíntesis , Radicales Libres/química , Mucosa Intestinal/efectos de los fármacos , Intestinos/efectos de los fármacos , Intestinos/efectos de la radiación , Licopeno , Microvellosidades/efectos de los fármacos , Microvellosidades/efectos de la radiación , Oxígeno/química , Traumatismos por Radiación/prevención & control , Radioterapia/efectos adversos , Ratas , Vitamina A/farmacología , Vitamina E/farmacologíaRESUMEN
It remains unknown if the oxidative stress can be regulated by low-level laser therapy (LLLT) in lung inflammation induced by intestinal reperfusion (i-I/R). A study was developed in which rats were irradiated (660 nm, 30 mW, 5.4 J) on the skin over the bronchus and euthanized 2 h after the initial of intestinal reperfusion. Lung edema and bronchoalveolar lavage fluid neutrophils were measured by the Evans blue extravasation and myeloperoxidase (MPO) activity respectively. Lung histology was used for analyzing the injury score. Reactive oxygen species (ROS) was measured by fluorescence. Both expression intercellular adhesion molecule 1 (ICAM-1) and peroxisome proliferator-activated receptor-y (PPARy) were measured by RT-PCR. The lung immunohistochemical localization of ICAM-1 was visualized as a brown stain. Both lung HSP70 and glutathione protein were evaluated by ELISA. LLLT reduced neatly the edema, neutrophils influx, MPO activity and ICAM-1 mRNA expression. LLLT also reduced the ROS formation and oppositely increased GSH concentration in lung from i-I/R groups. Both HSP70 and PPARy expression also were elevated after laser irradiation. Results indicate that laser effect in attenuating the acute lung inflammation is driven to restore the balance between the pro- and antioxidants mediators rising of PPARy expression and consequently the HSP70 production.
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Lesión Pulmonar Aguda/radioterapia , Intestinos/efectos de la radiación , Terapia por Luz de Baja Intensidad , Pulmón/efectos de la radiación , Edema Pulmonar/radioterapia , Daño por Reperfusión/radioterapia , Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/patología , Animales , Líquido del Lavado Bronquioalveolar/citología , Recuento de Células , Regulación de la Expresión Génica , Glutatión/biosíntesis , Proteínas HSP70 de Choque Térmico/genética , Proteínas HSP70 de Choque Térmico/metabolismo , Molécula 1 de Adhesión Intercelular/genética , Molécula 1 de Adhesión Intercelular/metabolismo , Mucosa Intestinal/metabolismo , Intestinos/patología , Pulmón/metabolismo , Pulmón/patología , Masculino , Neutrófilos/patología , Estrés Oxidativo , PPAR gamma/genética , PPAR gamma/metabolismo , Peroxidasa/metabolismo , Edema Pulmonar/metabolismo , Edema Pulmonar/patología , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patologíaRESUMEN
PURPOSE: The objective of this study was to elucidate the action of α-tocopherol succinate (TS)- and AMD3100-mobilized progenitors in mitigating radiation-induced injuries. MATERIAL AND METHODS: CD2F1 mice were exposed to a high dose of radiation and then transfused intravenously with 5 million peripheral blood mononuclear cells (PBMC) from TS- and AMD3100-injected mice after irradiation. Intestinal and splenic tissues were harvested after irradiation and cells of those tissues were analyzed for markers of apoptosis and mitosis. Bacterial translocation from gut to heart, spleen, and liver in TS-treated and irradiated mice was evaluated by bacterial culture. RESULTS: We observed that the infusion of PBMC from TS- and AMD3100-injected mice significantly inhibited apoptosis, increased cell proliferation in the analyzed tissues of recipient mice, and inhibited bacterial translocation to various organs compared to mice receiving cells from vehicle-mobilized cells. This study further supports our contention that the infusion of TS-mobilized progenitor-containing PBMC acts as a bridging therapy by inhibiting radiation-induced apoptosis, enhancing cell proliferation, and inhibiting bacterial translocation in irradiated mice. CONCLUSIONS: We suggest that this novel bridging therapeutic approach that involves the infusion of TS-mobilized hematopoietic progenitors following acute radiation injury might be applicable to humans as well.
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Movimiento Celular/efectos de los fármacos , Intestinos/efectos de los fármacos , Intestinos/efectos de la radiación , Protectores contra Radiación/farmacología , Células Madre/citología , Irradiación Corporal Total/efectos adversos , alfa-Tocoferol/farmacología , Animales , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Bacterias/efectos de los fármacos , Bacterias/efectos de la radiación , Movimiento Celular/efectos de la radiación , Proliferación Celular/efectos de los fármacos , Proliferación Celular/efectos de la radiación , Roturas del ADN/efectos de los fármacos , Roturas del ADN/efectos de la radiación , Endotoxinas/sangre , Rayos gamma/efectos adversos , Intestinos/citología , Intestinos/microbiología , Yeyuno/citología , Yeyuno/efectos de los fármacos , Yeyuno/efectos de la radiación , Masculino , Ratones , Traumatismos por Radiación/prevención & control , Bazo/citología , Bazo/efectos de los fármacos , Bazo/efectos de la radiación , Células Madre/efectos de los fármacos , Células Madre/efectos de la radiaciónRESUMEN
The purpose of the present study was to assess changes in health-related quality of life (HRQL) among patients with radiation injury one year after hyperbaric oxygen (HBO2 therapy). HBO2 therapy was given once daily, five times a week in monoplace hyperbaric chambers for at least 19 days. HRQL was measured by SF-36 (Short Form with 36 questions). The study population was 101 patients, and among these 53.5% had radiation injury to the head and neck region, 35.6% to the intestine and 10.9% to the bladder. Testing for differences before and one year after HBO2 therapy showed significant improvement for the following SF-36 scales: Physical Function an increase of 4.54 (p = 0.01). Role Performance an increase of 8.79 (p = 0.04). Vitality an increase of 6.88 (p = 0.001). Social Function an increase of 8.04 (p = 0.002). Time since radiation at HBO2 therapy was 1-39 years. A total of 82% received radiation more than one year ago, and 33% more than seven years ago. Changes in physical and mental sum scores were not associated with time since radiation. Patients below the age of 70 seemed to have the best effect of HBO2 therapy measured by HRQL.
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Estado de Salud , Oxigenoterapia Hiperbárica/métodos , Calidad de Vida , Traumatismos por Radiación/terapia , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Femenino , Cabeza/efectos de la radiación , Humanos , Intestinos/efectos de la radiación , Masculino , Salud Mental , Persona de Mediana Edad , Actividad Motora , Noruega , Terapia por Inhalación de Oxígeno/métodos , Aptitud Física , Traumatismos por Radiación/psicología , Participación Social , Encuestas y Cuestionarios , Factores de Tiempo , Resultado del Tratamiento , Vejiga Urinaria/efectos de la radiación , Adulto JovenRESUMEN
The current study was to test an experimental model of actinic lesions in the distal intestine of rats and to determine the possible protective effect of hyperbaric oxygen therapy (HBO2) in radio-induced lesions when concomitantly applied with ionizing radiation. Twenty-four Wistar rats were divided into four groups: G1 (control group); G2 (animals irradiated); G3 (animals irradiated plus HBO2); G4 (only HBO2). The animals were evaluated for 28 days after the end of treatment and then euthanized. The distal intestine was resected for macroscopic and microscopic evaluation and immunohistochemistry. The animals in the G3 group lost weight during the treatment; all of the animals in the G2 group presented macroscopic mucosal lesions up until 28 days; the animals in the other three groups did not present macroscopic lesions. Microscopic mucosal lesions were observed in the specimens of the animals treated with ionizing radiation; in the animals from the G3 and G4 groups the lesions were less intense. For the immunohistochemical analysis, we observed the specimens taken from G3 group animals had more CD34+ cells. The experimental model proved to be useful in causing radio-induced lesions, and concomitantly applied HBO2 is capable of reducing late actinic lesions.
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Oxigenoterapia Hiperbárica/métodos , Intestinos/efectos de la radiación , Traumatismos Experimentales por Radiación/prevención & control , Animales , Peso Corporal/efectos de la radiación , Hemorragia Gastrointestinal/etiología , Mucosa Intestinal/efectos de la radiación , Masculino , Traumatismos Experimentales por Radiación/patología , Ratas , Ratas WistarRESUMEN
BACKGROUND AND STUDY AIMS: Oxidative stress plays an important role in development of intestinal injury after abdomino-pelvic radiation therapy. Teucrium polium (TP) is a medicinal plant which has antioxidant and anti-inflammatory properties. The aim of this study was to investigate the effect of TP on radiation-induced intestinal oxidative damage in rats. MATERIALS AND METHODS: Group 1 (n = 8), the control group; Group 2 (n = 8), the RAD (radiation) group in which each rat received a single whole-body 800 cGy radiation performed with a LINAC ; Group 3 (n = 8), the RAD + TP group in which rats were exposed to radiation as in Group 2, followed by intragastric administration of 0.5 g/kg/daily TP extract for 7 consecutive days; and Group 4 (n = 8), the TP group, rats received only intragastric TP for 7 days. RESULTS: Radiation led to intestinal damage, which was accompanied by an increase in intestinal thiobarbituric-acid-reactive substances (TBARS) and myeloperoxidase (MPO) levels, and a decrease in reduced glutathione (GSH) levels. Although TP significantly decreased intestinal MPO levels and inflammation scores, it neither reverted intestinal TBARS and GSH levels nor ameliorated other histological parameters of the disease. CONCLUSIONS: Our results suggest that TP reduces inflammation but does not ameliorate the increased oxidative stress conditions in radiation-induced intestinal damage in rats.
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Estrés Oxidativo , Fitoterapia , Teucrium , Animales , Intestinos/patología , Intestinos/efectos de la radiación , Masculino , Ratas , Ratas Sprague-Dawley , Sustancias Reactivas al Ácido TiobarbitúricoRESUMEN
On Jeju Island, South Korea, the leaves of Eurya emarginata have been traditionally used to treat ulcers or as a diuretic. Eutigoside C isolated from the leaves has been reported to have in vitro anti-inflammatory effects. We evaluated the radioprotective effects of eutigoside C on jejunal cell apoptosis and crypt survival in mice subjected to gamma irradiation. In addition, the ability of eutigoside C to protect against radiation-induced oxidative stress was examined by evaluating the activities of superoxide dismutase (SOD) and catalase (CAT) in radiation-induced hepatic injury. Eutigoside C was administered intraperitoneally at 48, 12, and 1 h before irradiation. The administration of eutigoside C (10, 50, or 100 mg/kg body weight) before irradiation protected the intestinal crypts from radiation-induced apoptosis (p < 0.05), and attenuated radiation-induced decrease of villous height (p < 0.05). Pretreating mice prior to irradiation with eutigoside C (100 mg/kg) significantly improved the survival of the jejunal crypt (p < 0.01). The dose reduction factor was 1.09 at 3.5 days after irradiation. Treatment of eutigoside C prior to irradiation significantly protected SOD and CAT activities in radiation-induced hepatic injury (p < 0.05). These results suggest that eutigoside C is a useful radioprotector capable of defending intestinal progenitor cells against indirect depletion, such as oxidative stress and inflammatory response caused by gamma irradiation.
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Glucósidos/farmacología , Intestinos/efectos de la radiación , Fenoles/farmacología , Traumatismos Experimentales por Radiación/tratamiento farmacológico , Protectores contra Radiación/farmacología , Animales , Apoptosis/efectos de los fármacos , Catalasa/metabolismo , Rayos gamma , Yeyuno/efectos de la radiación , Magnoliopsida/química , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos ICR , Estrés Oxidativo/efectos de los fármacos , Fitoterapia , Superóxido Dismutasa/metabolismoRESUMEN
The radioprotective effect of Rosemarinus officinalis extract (ROE) was studied in mice exposed to 3 Gy gamma radiation. Crypt survival, villus length, apoptotic cells, mitotic figures and goblet cells in intestine were studied at different autopsy intervals i.e. 12 hrs to 30 days after irradiation. Maximum changes in all the intestinal parameters were observed on day 3 after irradiation. Irradiated animals with ROE pretreatment exhibited a significant increase in the number of crypt cells, mitotic figures and villus length; whereas a significant decrease in the counts of apoptotic and goblet cells showed a significant decrease respective controls at all the autopsy intervals. Irradiation of animals resulted an elevation in lipid peroxidation and a reduction in glutathione concentration in the intestine at 1 hour post-irradiation. In contrast, ROE treatment before irradiation caused a significant depletion in lipid peroxidation and elevation in glutathione levels.