RESUMEN
BACKGROUND: Although recent studies provide mechanistic understanding to the pathogenesis of radiation induced lung injury (RILI), rare therapeutics show definitive promise for treating this disease. Type II alveolar epithelial cells (AECII) injury in various manner results in an inflammation response to initiate RILI. RESULTS: Here, we reported that radiation (IR) up-regulated the TNKS1BP1, causing progressive accumulation of the cellular senescence by up-regulating EEF2 in AECII and lung tissue of RILI mice. Senescent AECII induced Senescence-Associated Secretory Phenotype (SASP), consequently activating fibroblasts and macrophages to promote RILI development. In response to IR, elevated TNKS1BP1 interacted with and decreased CNOT4 to suppress EEF2 degradation. Ectopic expression of EEF2 accelerated AECII senescence. Using a model system of TNKS1BP1 knockout (KO) mice, we demonstrated that TNKS1BP1 KO prevents IR-induced lung tissue senescence and RILI. CONCLUSIONS: Notably, this study suggested that a regulatory mechanism of the TNKS1BP1/CNOT4/EEF2 axis in AECII senescence may be a potential strategy for RILI.
Asunto(s)
Células Epiteliales Alveolares , Senescencia Celular , Ratones Endogámicos C57BL , Ratones Noqueados , Animales , Humanos , Masculino , Ratones , Células Epiteliales Alveolares/metabolismo , Células Epiteliales Alveolares/efectos de la radiación , Células Epiteliales Alveolares/patología , Células Cultivadas , Senescencia Celular/efectos de la radiación , Senescencia Celular/fisiología , Quinasa del Factor 2 de Elongación/metabolismo , Quinasa del Factor 2 de Elongación/genética , Lesión Pulmonar/metabolismo , Lesión Pulmonar/genética , Lesión Pulmonar/patología , Traumatismos Experimentales por Radiación/metabolismo , Traumatismos Experimentales por Radiación/patología , Traumatismos Experimentales por Radiación/genética , Proteína 1 de Unión a Repeticiones Teloméricas/genética , Proteína 1 de Unión a Repeticiones Teloméricas/metabolismoRESUMEN
BACKGROUND: Radiotherapy is a major therapeutic approach in patients with brain tumors. However, it leads to cognitive impairments. To improve the management of radiation-induced brain sequalae, deformation-based morphometry (DBM) could be relevant. Here, we analyzed the significance of DBM using Jacobian determinants (JD) obtained by non-linear registration of MRI images to detect local vulnerability of healthy cerebral tissue in an animal model of brain irradiation. METHODS: Rats were exposed to fractionated whole-brain irradiation (WBI, 30 Gy). A multiparametric MRI (anatomical, diffusion and vascular) study was conducted longitudinally from 1 month up to 6 months after WBI. From the registration of MRI images, macroscopic changes were analyzed by DBM and microscopic changes at the cellular and vascular levels were evaluated by quantification of cerebral blood volume (CBV) and diffusion metrics including mean diffusivity (MD). Voxel-wise comparisons were performed on the entire brain and in specific brain areas identified by DBM. Immunohistology analyses were undertaken to visualize the vessels and astrocytes. RESULTS: DBM analysis evidenced time-course of local macrostructural changes; some of which were transient and some were long lasting after WBI. DBM revealed two vulnerable brain areas, namely the corpus callosum and the cortex. DBM changes were spatially associated to microstructural alterations as revealed by both diffusion metrics and CBV changes, and confirmed by immunohistology analyses. Finally, matrix correlations demonstrated correlations between JD/MD in the early phase after WBI and JD/CBV in the late phase both in the corpus callosum and the cortex. CONCLUSIONS: Brain irradiation induces local macrostructural changes detected by DBM which could be relevant to identify brain structures prone to radiation-induced tissue changes. The translation of these data in patients could represent an added value in imaging studies on brain radiotoxicity.
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Lesiones Encefálicas , Animales , Ratas , Masculino , Lesiones Encefálicas/etiología , Lesiones Encefálicas/diagnóstico por imagen , Lesiones Encefálicas/patología , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/patología , Traumatismos por Radiación/diagnóstico por imagen , Traumatismos por Radiación/patología , Traumatismos por Radiación/etiología , Encéfalo/efectos de la radiación , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Imagen por Resonancia Magnética/métodos , Traumatismos Experimentales por Radiación/diagnóstico por imagen , Traumatismos Experimentales por Radiación/patología , Traumatismos Experimentales por Radiación/etiología , Imágenes de Resonancia Magnética Multiparamétrica/métodosRESUMEN
In the event of a nuclear or radiation accident, rapid identification is required for those who exposed to potentially lethal dose irradiation. However, existing techniques are not adequate for the classification of lethal injury. Several studies have explored the potential of miRNAs as biomarkers for ionizing radiation injury, however, there are few miRNAs with specific expression for lethal radiation injury. Therefore, the aim of this study was to screen and validate the possibility of serum miRNAs as biomarkers of lethal radiation injury. We found the specific expression of mmu-miR-374c-5p / mmu-miR-194-5p on first day and mmu-miR-192-5p / mmu-miR-223-3p on third day in the mouse serum only under 10â¯Gy irradiation by miRNA sequencing and all significantly correlated with lymphocyte counts by Pearson's correlation analysis. In addition, it was found that among the 4 candidate serum miRNAs, only highly-expressed mmu-miR-192-5p in mouse serum irradiated at lethal doses was returned to sham-like expression levels at 3 days post-irradiation with amifostine pretreatment and closely correlated with survival rate. We demonstrated for the first time that mmu-miR-192-5p screened from lethally irradiated mice sera can be used as a potential biomarker for lethal irradiation injury, which will be helpful to improve efficiency of medical treatment to minimize casualties after a large-scale nuclear accident.
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Biomarcadores , MicroARNs , Animales , MicroARNs/sangre , MicroARNs/genética , Ratones , Masculino , Biomarcadores/sangre , Traumatismos Experimentales por Radiación/sangre , Traumatismos Experimentales por Radiación/genética , Traumatismos por Radiación/sangre , Traumatismos por Radiación/genética , Ratones Endogámicos C57BLRESUMEN
Radiation injury to the intestine is one of the most common complications in patients undergoing abdominal or pelvic cavity radiotherapy, limiting the clinical application of this treatment. Evidence shows the potential benefits of dietary restriction in improving metabolic profiles and age-related diseases. The present study investigated the effects and mechanisms of dietary restriction in radiation-induced intestinal injury. The mice were randomly divided into the control group, 10 Gy total abdominal irradiation (TAI) group, and groups pretreated with 30% caloric restriction (CR) for 7 days or 24 h fasting before TAI. After radiation, the mice were returned to ad libitum. The mice were sacrificed 3.5 days after radiation, and tissue samples were collected. CR and fasting reduced radiation-induced intestinal damage and promoted intestinal recovery by restoring the shortened colon length, improving the impaired intestinal structure and permeability, and remodeling gut microbial structure. CR and fasting also significantly reduced mitochondrial damage and DNA damage, which in turn reduced activation of the cyclic GMP-AMP synthase/stimulator of interferon gene (cGAS/STING) pathway and the production of type I interferon and other chemokines in the jejunum. Since the cGAS/STING pathway is linked with innate immunity, we further showed that CR and fasting induced polarization to immunosuppressive M2 macrophage, decreased CD8+ cytotoxic T lymphocytes, and downregulated proinflammatory factors in the jejunum. Our findings indicated that CR and fasting alleviate radiation-induced intestinal damage by reducing cGAS/STING-mediated harmful immune responses.
Asunto(s)
Restricción Calórica , Ayuno , Proteínas de la Membrana , Ratones Endogámicos C57BL , Nucleotidiltransferasas , Animales , Nucleotidiltransferasas/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Ratones , Masculino , Intestinos/efectos de la radiación , Microbioma Gastrointestinal/efectos de la radiación , Transducción de Señal , Traumatismos Experimentales por Radiación/metabolismo , Traumatismos Experimentales por Radiación/prevención & control , Traumatismos por Radiación/metabolismo , Daño del ADN , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efectos de la radiaciónRESUMEN
Animal studies are needed that best simulate a large-scale, inhomogeneous body exposure after a radiological or nuclear incident and that provides a platform for future development of medical countermeasures. A partial-body irradiation (PBI) model using 137Cs gamma rays with hind limb (tibia) shielding was developed and assessed for the sequalae of radiation injuries to gastrointestinal tract, bone marrow (BM) and lung and among different genetic mouse strains (C57BL/6J, C57L/J, CBA/J and FVB/NJ). In this case, a marginal level of BM shielding (â¼2%) provided adequate protection against lethality from infection and hemorrhage and enabled escalation of radiation doses with evaluation of both acute and delayed radiation syndromes. A steep radiation dose-dependent body weight loss was observed over the first 5 days attributed to enteritis with C57BL/6J mice appearing to be the most sensitive strain. Peripheral blood cell analysis revealed significant depression and recovery of leukocytes and platelets over the first month after PBI and were comparable among the four different mouse strains. Latent pulmonary injury was observed on micro-CT imaging at 4 months in C57L/J mice and confirmed histologically as severe pneumonitis that was lethal at 12 Gy. The lethality and radiological densitometry (HUs) dose responses were comparable to previous studies on C57L/J mice after total-body irradiation (TBI) and BM transplant rescue as well as after localized whole-thorax irradiation (WTI). Indeed, the lethal radiation doses and latency appeared similar for pneumonitis appearing in rhesus macaques after WTI or PBI as well as predicted for patients given systemic radiotherapy. In contrast, PBI treatment of C57BL/6 mice at a higher dose of 14 Gy had far longer survival times and developed extreme and debilitating pIeural effusions; an anomaly as similarly reported in previous thorax irradiation studies on this mouse strain. In summary, a radiation exposure model that delivers PBI to unanesthetized mice in a device that provides consistent shielding of the hind limb BM was developed for 137Cs gamma rays with physical characteristics and relevance to relatively high photon energies expected from the detonation of a nuclear device or accidental release of ionizing radiation. Standard strains such as C57BL/6J mice may be used reliably for early GI or hematological radiation syndromes while the C57L/J mouse strain stands out as the most appropriate for evaluating the delayed pulmonary effects of acute radiation exposure and recapitulating this disease in humans.
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Rayos gamma , Animales , Ratones , Rayos gamma/efectos adversos , Traumatismos Experimentales por Radiación/patología , Traumatismos Experimentales por Radiación/etiología , Traumatismos Experimentales por Radiación/diagnóstico por imagen , Relación Dosis-Respuesta en la Radiación , Masculino , Ratones Endogámicos C57BL , Femenino , Especificidad de la Especie , Radioisótopos de Cesio , Médula Ósea/efectos de la radiación , Médula Ósea/patologíaRESUMEN
BACKGROUND: Radionecrosis is a common complication in radiation oncology, while mechanisms and risk factors have yet to be fully explored. We therefore conducted a systematic review to understand the pathogenesis and identify factors that significantly affect the development. METHODS: We performed a systematic literature search based on the PRISMA guidelines using PubMed, Ovid, and Web of Science databases. The complete search strategy can be found as a preregistered protocol on PROSPERO (CRD42023361662). RESULTS: We included 83 studies, most involving healthy animals (n = 72, 86.75 %). High doses of hemispherical irradiation of 30 Gy in rats and 50 Gy in mice led repeatedly to radionecrosis among different studies and set-ups. Higher dose and larger irradiated volume were associated with earlier onset. Fractionated schedules showed limited effectiveness in the prevention of radionecrosis. Distinct anatomical brain structures respond to irradiation in various ways. White matter appears to be more vulnerable than gray matter. Younger age, more evolved animal species, and genetic background were also significant factors, whereas sex was irrelevant. Only 13.25 % of the studies were performed on primary brain tumor bearing animals, no studies on brain metastases are currently available. CONCLUSION: This systematic review identified various factors that significantly affect the induction of radionecrosis. The current state of research neglects the utilization of animal models of brain tumors, even though patients with brain malignancies constitute the largest group receiving brain irradiation. This latter aspect should be primarily addressed when developing an experimental radionecrosis model for translational implementation.
Asunto(s)
Necrosis , Traumatismos por Radiación , Animales , Traumatismos por Radiación/patología , Traumatismos por Radiación/etiología , Modelos Animales de Enfermedad , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/patología , Traumatismos Experimentales por Radiación/patología , Traumatismos Experimentales por Radiación/etiología , Ratas , Ratones , Encéfalo/efectos de la radiación , Encéfalo/patologíaRESUMEN
Victims of a radiation terrorist event will include pregnant women and unborn fetuses. Mitochondrial dysfunction and oxidative stress are key pathogenic factors of fetal radiation injury. The goal of this preclinical study is to investigate the efficacy of mitigating fetal radiation injury by maternal administration of the mitochondrial-targeted gramicidin S (GS)-nitroxide radiation mitigator JP4-039. Pregnant female C57BL/6NTac mice received 3 Gy total-body irradiation (TBI) at mid-gestation embryonic day 13.5 (E13.5). Using novel time-and-motion-resolved 4D in utero magnetic resonance imaging (4D-uMRI), we found TBI caused extensive injury to the fetal brain that included cerebral hemorrhage, loss of cerebral tissue, and hydrocephalus with excessive accumulation of cerebrospinal fluid (CSF). Histopathology of the fetal mouse brain showed broken cerebral vessels and elevated apoptosis. Further use of novel 4D Oxy-wavelet MRI capable of probing in vivo mitochondrial function in intact brain revealed a significant reduction of mitochondrial function in the fetal brain after 3 Gy TBI. This was validated by ex vivo Oroboros mitochondrial respirometry. One day after TBI (E14.5) maternal administration of JP4-039, which passes through the placenta, significantly reduced fetal brain radiation injury and improved fetal brain mitochondrial respiration. Treatment also preserved cerebral brain tissue integrity and reduced cerebral hemorrhage and cell death. JP4-039 administration following irradiation resulted in increased survival of pups. These findings indicate that JP4-039 can be deployed as a safe and effective mitigator of fetal radiation injury from mid-gestational in utero ionizing radiation exposure.
Asunto(s)
Feto , Mitocondrias , Irradiación Corporal Total , Animales , Femenino , Embarazo , Mitocondrias/efectos de los fármacos , Mitocondrias/efectos de la radiación , Mitocondrias/metabolismo , Ratones , Irradiación Corporal Total/efectos adversos , Feto/efectos de la radiación , Feto/efectos de los fármacos , Traumatismos por Radiación/tratamiento farmacológico , Traumatismos por Radiación/diagnóstico por imagen , Ratones Endogámicos C57BL , Encéfalo/efectos de la radiación , Encéfalo/efectos de los fármacos , Encéfalo/diagnóstico por imagen , Encéfalo/embriología , Protectores contra Radiación/farmacología , Óxidos de Nitrógeno , Traumatismos Experimentales por Radiación/tratamiento farmacológico , Traumatismos Experimentales por Radiación/diagnóstico por imagen , Traumatismos Experimentales por Radiación/patología , Imagen por Resonancia MagnéticaRESUMEN
BACKGROUND: Radiotherapy is a primary local treatment for tumors, yet it may lead to complications such as radiation-induced heart disease (RIHD). Currently, there is no standardized approach for preventing RIHD. Dexmedetomidine (Dex) is reported to have cardio-protection effects, while its role in radiation-induced myocardial injury is unknown. In the current study, we aimed to evaluate the radioprotective effect of dexmedetomidine in X-ray radiation-treated mice. METHODS: 18 male mice were randomized into 3 groups: control, 16 Gy, and 16 Gy + Dex. The 16 Gy group received a single dose of 16 Gy X-ray radiation. The 16 Gy + Dex group was pretreated with dexmedetomidine (30 µg/kg, intraperitoneal injection) 30 min before X-ray radiation. The control group was treated with saline and did not receive X-ray radiation. Myocardial tissues were collected 16 weeks after X-ray radiation. Hematoxylin-eosin staining was performed for histopathological examination. Terminal deoxynucleotidyl transferase dUTP nick-end labeling staining was performed to assess the state of apoptotic cells. Immunohistochemistry staining was performed to examine the expression of CD34 molecule and von Willebrand factor. Besides, western blot assay was employed for the detection of apoptosis-related proteins (BCL2 apoptosis regulator and BCL2-associated X) as well as autophagy-related proteins (microtubule-associated protein 1 light chain 3, beclin 1, and sequestosome 1). RESULTS: The findings demonstrated that 16 Gy X-ray radiation resulted in significant changes in myocardial tissues, increased myocardial apoptosis, and activated autophagy. Pretreatment with dexmedetomidine significantly protects mice against 16 Gy X-ray radiation-induced myocardial injury by inhibiting apoptosis and autophagy. CONCLUSION: In summary, our study confirmed the radioprotective effect of dexmedetomidine in mitigating cardiomyocyte apoptosis and autophagy induced by 16 Gy X-ray radiation.
Asunto(s)
Apoptosis , Autofagia , Dexmedetomidina , Miocitos Cardíacos , Traumatismos Experimentales por Radiación , Animales , Autofagia/efectos de los fármacos , Autofagia/efectos de la radiación , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , Miocitos Cardíacos/efectos de la radiación , Miocitos Cardíacos/metabolismo , Apoptosis/efectos de los fármacos , Masculino , Dexmedetomidina/farmacología , Traumatismos Experimentales por Radiación/prevención & control , Traumatismos Experimentales por Radiación/patología , Traumatismos Experimentales por Radiación/metabolismo , Traumatismos Experimentales por Radiación/tratamiento farmacológico , Protectores contra Radiación/farmacología , Modelos Animales de Enfermedad , Transducción de Señal/efectos de los fármacos , Ratones , Proteínas Relacionadas con la Autofagia/metabolismo , Ratones Endogámicos C57BL , Proteínas Reguladoras de la Apoptosis/metabolismoRESUMEN
Radiation-induced cognitive impairment has recently fueled scientific interest with an increasing prevalence of cancer patients requiring whole brain irradiation (WBI) in their treatment algorithm. Saxagliptin (SAXA), a dipeptidyl peptidase-IV (DPP-IV) inhibitor, has exhibited competent neuroprotective effects against varied neurodegenerative disorders. Hence, this study aimed at examining the efficacy of SAXA in alleviating WBI-induced cognitive deficits. Male Sprague Dawley rats were distributed into control group, WBI group exposed to 20 Gy Ï-radiation, SAXA group treated for three weeks with SAXA (10 mg/kg. orally, once daily), and WBI/SAXA group exposed to 20 Gy Ï-radiation then treated with SAXA (10 mg/kg. orally, once daily). SAXA effectively reversed memory deterioration and motor dysfunction induced by 20 Gy WBI during behavioural tests and preserved normal histological architecture of the hippocampal tissues of irradiated rats. Mechanistically, SAXA inhibited WBI-induced hippocampal oxidative stress via decreasing lipid peroxidation while restoring catalase antioxidant activity. Moreover, SAXA abrogated radiation-induced hippocampal neuronal apoptosis through downregulating proapoptotic Bcl-2 Associated X-protein (Bax) and upregulating antiapoptotic B-cell lymphoma 2 (Bcl-2) expressions and eventually diminishing expression of cleaved caspase 3. Furthermore, SAXA boosted hippocampal neurogenesis by upregulating brain-derived neurotrophic factor (BDNF) expression. These valuable neuroprotective capabilities of SAXA were linked to activating protein kinase B (Akt), and cAMP-response element-binding protein (CREB) along with elevating the expression of sirtuin 1 (SIRT-1). SAXA successfully mitigated cognitive dysfunction triggered by WBI, attenuated oxidative injury, and neuronal apoptosis, and enhanced neurogenesis through switching on Akt/CREB/BDNF/SIRT-1 signaling axes. Such fruitful neurorestorative effects of SAXA provide an innovative therapeutic strategy for improving the cognitive capacity of cancer patients exposed to radiotherapy.
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Adamantano , Factor Neurotrófico Derivado del Encéfalo , Disfunción Cognitiva , Proteína de Unión a Elemento de Respuesta al AMP Cíclico , Dipéptidos , Fármacos Neuroprotectores , Proteínas Proto-Oncogénicas c-akt , Ratas Sprague-Dawley , Transducción de Señal , Sirtuina 1 , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Masculino , Sirtuina 1/metabolismo , Fármacos Neuroprotectores/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Dipéptidos/farmacología , Ratas , Disfunción Cognitiva/prevención & control , Disfunción Cognitiva/etiología , Disfunción Cognitiva/tratamiento farmacológico , Adamantano/análogos & derivados , Adamantano/farmacología , Hipocampo/efectos de los fármacos , Hipocampo/efectos de la radiación , Hipocampo/metabolismo , Hipocampo/patología , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/efectos de la radiación , Irradiación Craneana/efectos adversos , Traumatismos Experimentales por Radiación/prevención & control , Traumatismos Experimentales por Radiación/patología , Traumatismos Experimentales por Radiación/tratamiento farmacológico , Conducta Animal/efectos de los fármacos , Conducta Animal/efectos de la radiaciónRESUMEN
Radiation-induced intestinal injury is the most common side effect during radiotherapy of abdominal or pelvic solid tumors, significantly impacting patients' quality of life and even resulting in poor prognosis. Until now, oral application of conventional formulations for intestinal radioprotection remains challenging with no preferred method available to mitigate radiation toxicity in small intestine. Our previous study revealed that nanomaterials derived from spore coat of probiotics exhibit superior anti-inflammatory effect and even prevent the progression of cancer. The aim of this work is to determine the radioprotective effect of spore coat (denoted as spore ghosts, SGs) from three clinically approved probiotics (B.coagulans, B.subtilis and B.licheniformis). All the three SGs exhibit outstanding reactive oxygen species (ROS) scavenging ability and excellent anti-inflammatory effect. Moreover, these SGs can reverse the balance of intestinal flora by inhibiting harmful bacteria and increasing the abundance of Lactobacillus. Consequently, administration of SGs significantly reduce radiation-induced intestinal injury by alleviating diarrhea, preventing X-ray induced apoptosis of small intestinal epithelial cells and promoting restoration of barrier integrity in a prophylactic study. Notably, SGs markedly improve weight gain and survival of mice received total abdominal X-ray radiation. This work may provide promising radioprotectants for efficiently attenuating radiation-induced gastrointestinal syndrome and promote the development of new intestinal predilection.
Asunto(s)
Probióticos , Protectores contra Radiación , Esporas Bacterianas , Animales , Probióticos/farmacología , Ratones , Administración Oral , Protectores contra Radiación/farmacología , Protectores contra Radiación/uso terapéutico , Protectores contra Radiación/química , Esporas Bacterianas/efectos de la radiación , Traumatismos por Radiación/tratamiento farmacológico , Especies Reactivas de Oxígeno/metabolismo , Intestino Delgado/microbiología , Intestino Delgado/efectos de la radiación , Intestino Delgado/patología , Humanos , Apoptosis/efectos de los fármacos , Masculino , Microbioma Gastrointestinal/efectos de los fármacos , Intestinos/efectos de la radiación , Intestinos/microbiología , Intestinos/patología , Traumatismos Experimentales por Radiación/patologíaRESUMEN
Radiation injury to the intestine is one of the most common complications in patients undergoing abdominal or pelvic cavity radiotherapy. In this study, we investigated the potential protective effect of Lactobacillus rhamnosus GG (LGG) on radiation-induced intestinal injury and its underlying mechanisms. Mice were assigned to a control group, a 10â¯Gy total abdominal irradiation (TAI) group, or a group pretreated with 108 CFU LGG for three days before TAI. Small intestine and gut microbiota were analyzed 3.5 days post-exposure. LGG intervention improved intestinal structure, reduced jejunal DNA damage, and inhibited the inflammatory cGAS/STING pathway. Furthermore, LGG reduced M1 proinflammatory macrophage and CD8+ T cell infiltration, restoring the balance between Th17 and Treg cells in the inflamed jejunum. LGG also partially restored the gut microbiota. These findings suggest the possible therapeutic radioprotective effect of probiotics LGG in alleviating radiation-induced intestinal injury by maintaining immune homeostasis and reshaping gut microbiota.
Asunto(s)
Microbioma Gastrointestinal , Lacticaseibacillus rhamnosus , Ratones Endogámicos C57BL , Probióticos , Animales , Microbioma Gastrointestinal/efectos de la radiación , Ratones , Probióticos/administración & dosificación , Traumatismos por Radiación/inmunología , Macrófagos/inmunología , Intestinos/microbiología , Intestinos/efectos de la radiación , Intestinos/inmunología , Daño del ADN , Linfocitos T CD8-positivos/inmunología , Proteínas de la Membrana/metabolismo , Linfocitos T Reguladores/inmunología , Masculino , Células Th17/inmunología , Yeyuno/efectos de la radiación , Yeyuno/inmunología , Yeyuno/microbiología , Protectores contra Radiación/farmacología , Protectores contra Radiación/uso terapéutico , Traumatismos Experimentales por Radiación/inmunología , Traumatismos Experimentales por Radiación/prevención & control , NucleotidiltransferasasRESUMEN
BACKGROUND: The incidental use of statins during radiation therapy has been associated with a reduced long-term risk of developing atherosclerotic cardiovascular disease. We examined whether irradiation causes chronic vascular injury and whether short-term administration of statins during and after irradiation is sufficient to prevent chronic injury compared with long-term administration. METHODS AND RESULTS: C57Bl/6 mice were pretreated with pravastatin for 72 hours and then exposed to 12 Gy X-ray head-and-neck irradiation. Pravastatin was then administered either for an additional 24 hours or for 1 year. Carotid arteries were tested for vascular reactivity, altered gene expression, and collagen deposition 1 year after irradiation. Treatment with pravastatin for 24 hours after irradiation reduced the loss of endothelium-dependent vasorelaxation and protected against enhanced vasoconstriction. Expression of markers associated with inflammation (NFκB p65 [phospho-nuclear factor kappa B p65] and TNF-α [tumor necrosis factor alpha]) and with oxidative stress (NADPH oxidases 2 and 4) were lowered and subunits of the voltage and Ca2+ activated K+ BK channel (potassium calcium-activated channel subfamily M alpha 1 and potassium calcium-activated channel subfamily M regulatory beta subunit 1) in the carotid artery were modulated. Treatment with pravastatin for 1 year after irradiation completely reversed irradiation-induced changes. CONCLUSIONS: Short-term administration of pravastatin is sufficient to reduce chronic vascular injury at 1 year after irradiation. Long-term administration eliminates the effects of irradiation. These findings suggest that a prospective treatment strategy involving statins could be effective in patients undergoing radiation therapy. The optimal duration of treatment in humans has yet to be determined.
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Inhibidores de Hidroximetilglutaril-CoA Reductasas , Ratones Endogámicos C57BL , Estrés Oxidativo , Pravastatina , Animales , Pravastatina/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/efectos de la radiación , Factores de Tiempo , Vasoconstricción/efectos de los fármacos , Vasoconstricción/efectos de la radiación , Vasodilatación/efectos de los fármacos , Vasodilatación/efectos de la radiación , Masculino , NADPH Oxidasa 2/metabolismo , NADPH Oxidasa 2/genética , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Transcripción ReIA/metabolismo , NADPH Oxidasas/metabolismo , Ratones , Traumatismos Experimentales por Radiación/prevención & control , Traumatismos Experimentales por Radiación/metabolismo , Traumatismos Experimentales por Radiación/tratamiento farmacológico , Esquema de Medicación , Arterias Carótidas/efectos de la radiación , Arterias Carótidas/efectos de los fármacos , Enfermedad Crónica , Modelos Animales de Enfermedad , NADPH Oxidasa 4RESUMEN
Radiation-induced brain injury (RIBI) is a significant challenge in radiotherapy for head and neck tumors, impacting patients' quality of life. In exploring potential treatments, this study focuses on memantine hydrochloride and hydrogen-rich water, hypothesized to mitigate RIBI through inhibiting the NLRP3/NLRC4/Caspase-1 pathway. In a controlled study involving 40 Sprague-Dawley rats, divided into five groups including a control and various treatment groups, we assessed the effects of these treatments on RIBI. Post-irradiation, all irradiated groups displayed symptoms like weight loss and salivation, with notable variations among different treatment approaches. Particularly, hydrogen-rich water showed a promising reduction in these symptoms. Histopathological analysis indicated substantial hippocampal damage in the radiation-only group, while the groups receiving memantine and/or hydrogen-rich water exhibited significant mitigation of such damage. Molecular studies, revealed a decrease in oxidative stress markers and an attenuated inflammatory response in the treatment groups. Immunohistochemistry further confirmed these molecular changes, suggesting the effectiveness of these agents. Echoing recent scientific inquiries into the protective roles of specific compounds against radiation-induced damages, our study adds to the growing body of evidence on the potential of memantine and hydrogen-rich water as novel therapeutic strategies for RIBI.
Asunto(s)
Caspasa 1 , Hidrógeno , Memantina , Proteína con Dominio Pirina 3 de la Familia NLR , Piroptosis , Ratas Sprague-Dawley , Agua , Animales , Memantina/farmacología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Hidrógeno/farmacología , Piroptosis/efectos de los fármacos , Ratas , Caspasa 1/metabolismo , Masculino , Transducción de Señal/efectos de los fármacos , Lesiones Encefálicas/etiología , Lesiones Encefálicas/metabolismo , Lesiones Encefálicas/tratamiento farmacológico , Lesiones Encefálicas/prevención & control , Lesiones Encefálicas/patología , Traumatismos por Radiación/tratamiento farmacológico , Traumatismos por Radiación/metabolismo , Traumatismos por Radiación/patología , Estrés Oxidativo/efectos de los fármacos , Traumatismos Experimentales por Radiación/tratamiento farmacológico , Traumatismos Experimentales por Radiación/metabolismo , Traumatismos Experimentales por Radiación/patología , Traumatismos Experimentales por Radiación/prevención & controlRESUMEN
Radiation retinopathy (RR) is a major side effect of ocular tumor treatment by plaque brachytherapy or proton beam therapy. RR manifests as delayed and progressive microvasculopathy, ischemia and macular edema, ultimately leading to vision loss, neovascular glaucoma, and, in extreme cases, secondary enucleation. Intravitreal anti-VEGF agents, steroids and laser photocoagulation have limited effects on RR. The role of retinal inflammation and its contribution to the microvascular damage occurring in RR remain incompletely understood. To explore cellular and vascular events after irradiation, we analyzed their time course at 1 week, 1 month and 6 months after rat eyes received 45 Gy X-beam photons. Müller glial cells, astrocytes and microglia were rapidly activated, and these markers of retinal inflammation persisted for 6 months after irradiation. This was accompanied by early cell death in the outer retina, which persisted at later time points, leading to retinal thinning. A delayed loss of small retinal capillaries and retinal hypoxia were observed after 6 months, indicating inner bloodâretinal barrier (BRB) alteration but without cell death in the inner retina. Moreover, activated microglial cells invaded the entire retina and surrounded retinal vessels, suggesting the role of inflammation in vascular alteration and in retinal cell death. Radiation also triggered early and persistent invasion of the retinal pigment epithelium by microglia and macrophages, contributing to outer BRB disruption. This study highlights the role of progressive and long-lasting inflammatory mechanisms in RR development and demonstrates the relevance of this rat model to investigate human pathology.
Asunto(s)
Modelos Animales de Enfermedad , Retina , Animales , Ratas , Retina/patología , Retina/efectos de la radiación , Enfermedades de la Retina/etiología , Enfermedades de la Retina/patología , Inflamación/patología , Inflamación/etiología , Traumatismos Experimentales por Radiación/patología , Traumatismos por Radiación/patología , Traumatismos por Radiación/etiología , Masculino , Microglía/efectos de la radiación , Microglía/patologíaRESUMEN
Exposure to high, marginally lethal doses or higher of ionizing radiation, either intentional or accidental, results in injury to various organs. Currently, there is only a limited number of safe and effective radiation countermeasures approved by US Food and Drug Administration for such injuries. These approved agents are effective for only the hematopoietic component of the acute radiation syndrome and must be administered only after the exposure event: currently, there is no FDA-approved agent that can be used prophylactically. The nutraceutical, gamma-tocotrienol (GT3) has been found to be a promising radioprotector of such exposure-related injuries, especially those of a hematopoietic nature, when tested in either rodents or nonhuman primates. We investigated the nature of injuries and the possible protective effects of GT3 within select organ systems/tissues caused by both non-lethal level (4.0 Gy), as well as potentially lethal level (5.8 Gy) of ionizing radiation, delivered as total-body or partial-body exposure. Results indicated that the most severe, dose-dependent injuries occurred within those organ systems with strong self-renewing capacities (e.g., the lymphohematopoietic and gastrointestinal systems), while in other tissues (e.g., liver, kidney, lung) endowed with less self-renewal, the pathologies noted tended to be less pronounced and less dependent on the level of exposure dose or on the applied exposure regimen. The prophylactic use of the test nutraceutical, GT3, appeared to limit the extent of irradiation-associated pathology within blood forming tissues and, to some extent, within the small intestine of the gastrointestinal tract. No distinct, global pattern of bodily protection was noted with the agent's use, although a hint of a possible radioprotective benefit was suggested not only by a lessening of apparent injury within select organ systems, but also by way of noting the lack of early onset of moribundity within select GT3-treated animals.
Asunto(s)
Suplementos Dietéticos , Protectores contra Radiación , Animales , Protectores contra Radiación/farmacología , Vitamina E/farmacología , Vitamina E/análogos & derivados , Síndrome de Radiación Aguda/prevención & control , Síndrome de Radiación Aguda/tratamiento farmacológico , Síndrome de Radiación Aguda/patología , Cromanos/farmacología , Masculino , Traumatismos Experimentales por Radiación/prevención & control , Traumatismos Experimentales por Radiación/patología , Macaca mulatta , Hígado/efectos de los fármacos , Hígado/efectos de la radiación , Hígado/patologíaRESUMEN
In patients with high-level radiation exposure, gastrointestinal injury is the main cause of death. Despite the severity of damage to the gastrointestinal tract, no specific therapeutic option is available. Tauroursodeoxycholic acid (TUDCA) is a conjugated form of ursodeoxycholic acid that suppresses endoplasmic reticulum (ER) stress and regulates various cell-signaling pathways. We investigated the effect of TUDCA premedication in alleviating intestinal damage and enhancing the survival of C57BL/6 mice administered a lethal dose (15Gy) of focal abdominal irradiation. TUDCA was administered to mice 1 h before radiation exposure, and reduced apoptosis of the jejunal crypts 12 h after irradiation. At later timepoint (3.5 days), irradiated mice manifested intestinal morphological changes that were detected via histological examination. TUDCA decreased the inflammatory cytokine levels and attenuated the decrease in serum citrulline levels after radiation exposure. Although radiation induced ER stress, TUDCA pretreatment decreased ER stress in the irradiated intestinal cells. The effect of TUDCA indicates the possibility of radiation therapy for cancer in tumor cells. TUDCA did not affect cell proliferation and apoptosis in the intestinal epithelium. TUDCA decreased the invasive ability of the CT26 metastatic colon cancer cell line. Reduced invasion after TUDCA treatment was associated with decreased matrix metalloproteinase (MMP)-7 and MMP-13 expression, which play important roles in invasion and metastasis. This study shows a potential role of TUDCA in protecting against radiation-induced intestinal damage and inhibiting tumor cell migration without any radiation and radiation therapy effect.
Asunto(s)
Apoptosis , Estrés del Retículo Endoplásmico , Ratones Endogámicos C57BL , Protectores contra Radiación , Ácido Tauroquenodesoxicólico , Animales , Ácido Tauroquenodesoxicólico/farmacología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Estrés del Retículo Endoplásmico/efectos de la radiación , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Protectores contra Radiación/farmacología , Ratones , Masculino , Intestinos/efectos de la radiación , Intestinos/efectos de los fármacos , Intestinos/patología , Modelos Animales de Enfermedad , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/efectos de la radiación , Mucosa Intestinal/patología , Mucosa Intestinal/metabolismo , Traumatismos Experimentales por Radiación/prevención & control , Traumatismos Experimentales por Radiación/patología , Traumatismos Experimentales por Radiación/tratamiento farmacológico , Traumatismos Experimentales por Radiación/metabolismo , Metaloproteinasa 13 de la Matriz/metabolismo , Proliferación Celular/efectos de los fármacos , Proliferación Celular/efectos de la radiaciónRESUMEN
PURPOSE: Preclinical studies have shown a preferential normal tissue sparing effect of FLASH radiation therapy with ultra-high dose rates. The aim of the present study was to use a murine model of acute skin toxicity to investigate the biologic effect of varying dose rates, time structure, and introducing pauses in the dose delivery. METHODS AND MATERIALS: The right hind limbs of nonanaesthetized mice were irradiated in the entrance plateau of a pencil beam scanning proton beam with 39.3 Gy. Experiment 1 was with varying field dose rates (0.7-80 Gy/s) without repainting, experiment 2 was with varying field dose rates (0.37-80 Gy/s) with repainting, and in experiment 3, the dose was split into 2, 3, 4, or 6 identical deliveries with 2-minute pauses. In total, 320 mice were included, with 6 to 25 mice per group. The endpoints were skin toxicity of different levels up to 25 days after irradiation. RESULTS: The dose rate50, which is the dose rate to induce a response in 50% of the animals, depended on the level of skin toxicity, with the higher toxicity levels displaying a FLASH effect at 0.7-2 Gy/s. Repainting resulted in higher toxicity for the same field dose rate. Splitting the dose into 2 deliveries reduced the FLASH effect, and for 3 or more deliveries, the FLASH effect was almost abolished for lower grades of toxicity. CONCLUSIONS: The dose rate that induced a FLASH effect varied for different skin toxicity levels, which are characterized by a differing degree of sensitivity to radiation dosage. Conclusions on a threshold for the dose rate needed to obtain a FLASH effect can therefore be influenced by the dose sensitivity of the used endpoint. Splitting the total dose into more deliveries compromised the FLASH effect. This can have an impact for fractionation as well as for regions where 2 or more FLASH fields overlap within the same treatment session.
Asunto(s)
Terapia de Protones , Piel , Animales , Ratones , Piel/efectos de la radiación , Terapia de Protones/efectos adversos , Terapia de Protones/métodos , Relación Dosis-Respuesta en la Radiación , Femenino , Factores de Tiempo , Miembro Posterior/efectos de la radiación , Traumatismos Experimentales por Radiación , Dosificación RadioterapéuticaRESUMEN
Photobiomodulation (PBM) therapy uses light of different wavelengths to treat various retinal degeneration diseases, but the potential damage to the retina caused by long-term light irradiation is still unclear. This study were designed to detect the difference between long- and short-wavelength light (650-nm red light and 450-nm blue light, 2.55 mW/cm2, reference intensity in PBM)-induced injury. In addition, a comparative study was conducted to investigate the differences in retinal light damage induced by different irradiation protocols (short periods of repeated irradiation and a long period of constant irradiation). Furthermore, the protective role of PARP-1 inhibition on the molecular mechanism of blue light-induced injury was confirmed by a gene knockdown technique or a specific inhibitor through in vitro and in vivo experiments. The results showed that the susceptibility to retinal damage caused by irradiation with long- and short-wavelength light is different. Shorter wavelength lights, such as blue light, induce more severe retinal damage, while the retina exhibits better resistance to longer wavelength lights, such as red light. In addition, repeated irradiation for short periods induces less retinal damage than constant exposure over a long period. PARP-1 plays a critical role in the molecular mechanism of blue light-induced damage in photoreceptors and retina, and inhibiting PARP-1 can significantly protect the retina against blue light damage. This study lays an experimental foundation for assessing the safety of phototherapy products and for developing target drugs to protect the retina from light damage.
Asunto(s)
Luz , Poli(ADP-Ribosa) Polimerasa-1 , Retina , Degeneración Retiniana , Animales , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Ratones , Luz/efectos adversos , Retina/efectos de la radiación , Retina/patología , Degeneración Retiniana/etiología , Degeneración Retiniana/metabolismo , Degeneración Retiniana/patología , Degeneración Retiniana/prevención & control , Ratones Endogámicos C57BL , Traumatismos Experimentales por Radiación/patología , Traumatismos Experimentales por Radiación/metabolismo , Modelos Animales de Enfermedad , Western Blotting , Masculino , Terapia por Luz de Baja Intensidad , Luz AzulRESUMEN
Intestinal stem cells (ISCs) are pivotal for the maintenance and regeneration of the intestinal epithelium. Berberine (BBR) exhibits diverse biological activities, but it remains unclear whether BBR can modulate ISCs' function. Therefore, we investigated the effects of BBR on ISCs in healthy and radiation-injured mice and explored the potential underlying mechanisms involved. The results showed that BBR significantly increased the length of the small intestines, the height of the villi, and the depth and density of the crypts, promoted the proliferation of cryptal epithelial cells and increased the number of OLFM4+ ISCs and goblet cells. Crypts from the BBR-treated mice were more capable of growing into enteroids than those from untreated mice. BBR alleviated WAI-induced intestinal injury. BBR suppressed the apoptosis of crypt epithelial cells, increased the quantity of goblet cells, and increased the quantity of OLFM4+ ISCs and tdTomato+ progenies of ISCs after 8 Gy WAI-induced injury. Mechanistically, BBR treatment caused a significant increase in the quantity of p-S6, p-STAT3 and p-ERK1/2 positive cryptal epithelial cells under physiological conditions and after WAI-induced injury. In conclusion, BBR is capable of enhancing the function of ISCs either physiologically or after radiation-induced injury, indicating that BBR has potential value in the treatment of radiation-induced intestinal injury.
Asunto(s)
Berberina , Mucosa Intestinal , Ratones Endogámicos C57BL , Células Madre , Animales , Berberina/farmacología , Berberina/uso terapéutico , Células Madre/efectos de los fármacos , Ratones , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/efectos de la radiación , Mucosa Intestinal/patología , Masculino , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Proliferación Celular/efectos de los fármacos , Proliferación Celular/efectos de la radiación , Traumatismos Experimentales por Radiación/tratamiento farmacológico , Traumatismos Experimentales por Radiación/patología , Células Caliciformes/efectos de los fármacos , Células Caliciformes/efectos de la radiación , Células Caliciformes/patología , Traumatismos por Radiación/tratamiento farmacológico , Traumatismos por Radiación/patología , Factor de Transcripción STAT3/metabolismo , Intestino Delgado/efectos de los fármacos , Intestino Delgado/efectos de la radiación , Intestino Delgado/patología , Intestino Delgado/lesiones , Intestinos/efectos de los fármacos , Intestinos/efectos de la radiaciónRESUMEN
BACKGROUND: Exposure to high doses of total body irradiation (TBI) may lead to the development of acute radiation syndrome (ARS). This study was conducted to establish an experimental rat model of TBI to assess the impact of different doses of TBI on survival and the kinetics of changes within the hematopoietic system in ARS. MATERIALS AND METHODS: In this study, 132 Lewis rats irradiated with a 5Gy or 7Gy dose served as experimental models to induce ARS and to evaluate the hematopoietic response of the bone marrow (BM) compartment. Animals were divided into 22 experimental groups (n = 6/group): groups 1-11 irradiated with 5Gy dose and groups 12-22 irradiated with 7Gy dose. The effects of TBI on the hematopoietic response were assessed at 2, 4, 6, 8 hours and 5, 10, 20, 30, 40, 60 and 90 days following TBI. Signs of ARS were evaluated by analyzing blood samples through complete blood count in addition to the clinical assessment. RESULTS: Groups irradiated with 5Gy TBI showed 100% survival, whereas after 7Gy dose, 1.6% mortality rate was observed. Assessment of the complete blood count revealed that lymphocytes were the first to be affected, regardless of the dose used, whereas an "abortive rise" of granulocytes was noted for both TBI doses. None of the animals exhibited signs of severe anemia or thrombocytopenia. All animals irradiated with 5Gy dose regained initial values for all blood cell subpopulations by the end of observation period. Body weight loss was reported to be dose-dependent and was more pronounced in the 7Gy groups. However, at the study end point at 90 days, all animals regained or exceeded the initial weight values. CONCLUSIONS: We have successfully established a rat experimental model of TBI. This study revealed a comparable hematopoietic response to the sublethal or potentially lethal doses of ionizing radiation. The experimental rat model of TBI may be used to assess different therapeutic approaches including BM-based cell therapies for long-term reconstitution of the hematopoietic and BM compartments allowing for comprehensive analysis of both the hematological and clinical symptoms associated with ARS.