Asunto(s)
Betacoronavirus/patogenicidad , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/terapia , Flagelina/inmunología , Flagelina/uso terapéutico , Inmunidad Innata/inmunología , Neutrófilos/inmunología , Neumonía Viral/inmunología , Neumonía Viral/terapia , Receptor Toll-Like 5/inmunología , Animales , Antivirales/farmacología , Antivirales/uso terapéutico , Proteínas Reguladoras de la Apoptosis/metabolismo , Betacoronavirus/inmunología , COVID-19 , Proteínas de Unión al Calcio/metabolismo , Quimioterapia Adyuvante , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/prevención & control , Desoxirribonucleasa I/metabolismo , Desoxirribonucleasa I/farmacología , Desoxirribonucleasa I/uso terapéutico , Flagelina/administración & dosificación , Humanos , Inmunidad Innata/efectos de los fármacos , Inflamación/complicaciones , Inflamación/inmunología , Inflamación/patología , Virus de la Influenza A/inmunología , Interferón beta/biosíntesis , Interferón beta/inmunología , Interleucina-18/inmunología , Ratones , Modelos Inmunológicos , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Pandemias/prevención & control , Péptidos/uso terapéutico , Neumonía Viral/complicaciones , Neumonía Viral/prevención & control , Pseudomonas aeruginosa/inmunología , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/inmunología , SARS-CoV-2 , Receptor Toll-Like 5/agonistasRESUMEN
In the study here, the potential applicability of KMRC011 - an agonist of toll-like receptor-5 - as a countermeasure for radiation toxicities was evaluated. Following a single 5.5 Gy total body irradiation (TBI, surface absorbed dose = 7 Gy) of Co60 γ-rays, mortality rates and degrees of pathological lesions that developed over 80 days were compared in monkeys that received TBI only and a group that was injected once with KMRC011 (10 µg/kg) after TBI. Compared to the TBI-only hosts (80%), the death rate was significantly improved by the use of KMRC011 (40%), all deaths in both groups occurred in the period from Days 19-24 post-TBI. Further analysis of monkeys that survived until the end of the experiment showed that AST and ALT levels were elevated only in the TBI group, and that radiation-induced tissue damage was alleviated by the KMRC011 injection. Additionally, expression of cell death-related proteins was lower in tissues from the KMRC011-treated hosts than in those in the TBI-only group. Other measured parameters, including body weight, food uptake, and hematological values did not significantly differ between the two groups over the entire period. The results of this study, thus demonstrate that KMRC011 could potentially be used as a medical countermeasure for the treatment of acute radiation exposure.
Asunto(s)
Fragmentos de Péptidos/farmacología , Traumatismos Experimentales por Radiación/prevención & control , Protectores contra Radiación/farmacología , Receptor Toll-Like 5/agonistas , Animales , Evaluación Preclínica de Medicamentos , Humanos , Inmunidad Innata/efectos de los fármacos , Inmunidad Innata/efectos de la radiación , Inyecciones Intramusculares , Macaca fascicularis , Masculino , Fragmentos de Péptidos/uso terapéutico , Traumatismos Experimentales por Radiación/inmunología , Protectores contra Radiación/uso terapéutico , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Transducción de Señal/efectos de la radiación , Receptor Toll-Like 5/metabolismo , Irradiación Corporal TotalRESUMEN
CBLB502, a Toll-like receptor (TLR)5 agonist derived from Salmonella flagellin, was shown to protect mammalian hematopoietic and gastrointestinal systems from acute irradiation syndrome and to stimulate regeneration. To explore whether CBLB502 can improve testicular injuries caused by irradiation, mice were intraperitoneally injected with 0.2 mg/kg CBLB502 or vehicle control 30 min prior to applying 5.0 Gy ionizing radiation (IR). We observed these mice for the following 120 days and determined that CBLB502 pretreatment alleviated IR-induced oxidative stress, alleviated the distorted architecture of seminiferous tubules, reversed the decline of sperm quantity and quality, and helped recover male mouse fertility. Additionally, CBLB502 efficiently reduced DNA damage and chromosomal aberrations in IR-treated mice and their offspring. Due to the suppression of p53-dependent apoptosis, in IR-treated mice, CBLB502 was shown to significantly activate the nuclear factor kappa B (NFκB) pathway and reduce the apoptotic rate in association with an increase in anti-apoptotic B-cell lymphoma 2 levels and a decrease in the levels of DNA repair protein and proliferating cell nuclear antigen. Moreover, an IR-induced reduction in serum testosterone and superoxide dismutase levels and an increase in malondialdehyde levels were considerably reversed in CBLB502-pretreated mice. No significant reverse effects were found in Tlr5 knockout mice, suggesting that protection of the testis against IR by CBLB502 is primarily dependent on the TLR5 signaling pathway. Our results may help further investigations into potential CBLB502 applications for the protection of the male reproductive system during radiotherapy.