RESUMO
It is known that p53 is an important transcription factor and plays a central role in ionizing radiation (IR)-induced DNA damage responses such as cell cycle arrest, DNA repair and apoptosis. We previously reported that regulating p53 protein is an effective strategy for modulating cell fate by reducing the acute side effects of radiation therapy. Herein, we report on the discovery of STK160830 as a new radioprotector from a chemical library at The University of Tokyo and the design, synthesis and biological evaluation of its derivatives. The radioprotective activity of STK160830 itself and its derivatives that were synthesized in this work was evaluated using a leukemia cell line, MOLT-4 cells as a model of normal cells that express the p53 protein in a structure-activity relationships (SAR) study. The experimental results suggest that a direct relationship exists between the inhibitory effect of these STK160830 derivatives on the expression level of p53 and their radioprotective activity and that the suppression of p53 by STK160830 derivatives contribute to protecting MOLT-4 cells from apoptosis that is induced by exposure to radiation.
Assuntos
Apoptose , Proteína Supressora de Tumor p53 , Dano ao DNA , Reparo do DNA , Proteína Supressora de Tumor p53/metabolismoRESUMO
PURPOSE: To investigate how cheese wiring affects lacrimal drainage function by quantitative assessment of tear function and punctal dimensions. METHODS: Patients who underwent lacrimal passage intubation between January 2017 and September 2018 were enrolled prospectively. Among these patients, those with postoperative cheese wiring who received lacrimal passage intubation in one eye met the criteria for further investigation. The subjective symptoms of epiphora, dimensions of puncta, lower tear meniscus, and tear clearance were assessed postoperatively in both the involved eye and untreated contralateral eye. Punctum dimensions were analysed using the digital slit-lamp image. Tear meniscus and tear clearance were assessed by anterior segment optical coherence tomography. RESULTS: Postoperative cheese wiring was observed in 68 of 314 eyes. Among these cases, 36 patients (age 70.5 ± 11.7 years) had cheese wiring only in one eye: with the involvement of both puncta in 15 patients (group A) and only the lower punctum in 21 patients (group B). There was no patient with the involvement of only the upper punctum. While tear function of the involved eyes in group B did not differ from that of the untreated eye, it was significantly decreased in group A compared with that in untreated control eyes (p < 0.05). The tear clearance rate correlated significantly with the upper punctum dimensions (p < 0.05), but not with the lower punctum. CONCLUSION: Analysis of cheese wiring after lacrimal passage intubation with tear function demonstrated that the integrity of the puncta and the canaliculus is important for lacrimal drainage.
Assuntos
Intubação , Aparelho Lacrimal/fisiologia , Obstrução dos Ductos Lacrimais/terapia , Ducto Nasolacrimal/fisiologia , Lágrimas/fisiologia , Idoso , Idoso de 80 Anos ou mais , Pálpebras/fisiologia , Feminino , Humanos , Obstrução dos Ductos Lacrimais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Microscopia com Lâmpada de Fenda , Tomografia de Coerência ÓpticaRESUMO
PURPOSE: To evaluate perioperative dry eye (DE) syndrome and meibomian gland (MG) dysfunction parameters associated with cataract surgery-induced DE symptoms. PATIENTS AND METHODS: This retrospective, single-centered, observational study included 82 eyes of 43 patients without previous subjective DE symptoms, treatment, ocular comorbidities, and previous use of ophthalmic treatment, except for anti-allergic eye drops, who underwent uncomplicated cataract surgery. MG dropout, lid margin abnormality, meibum quality, meibum expressibility, MG orifice obstruction, ocular surface disease index, non-invasive tear break-up time, tear meniscus height, and Schirmer test score were measured at baseline and 1 month postoperatively. Multivariable logistic regression with generalized estimating equation models was used to determine the risk factors for cataract surgery-induced DE symptoms. RESULTS: Twenty-one patients had subjective DE symptoms 1 month following the cataract surgery. Preoperative and postoperative parameters, preoperative upper eyelid MG loss, and female sex (odds ratio [OR] 6.72, P = 0.012; OR 4.20, P = 0.037, respectively) were identified as risk factors for cataract surgery-induced DE symptoms. CONCLUSION: Ocular parameters, including upper eyelid MG findings at baseline, were considered important in predicting persistent DE symptoms following cataract surgery.
RESUMO
Purpose: Soft contact lenses (SCLs) are effective for refractive error correction, but prolonged wear triggers discomfort and discontinuation. This study investigates whether water gradient technology of delefilcon A-based SCLs improve tear film dynamics. Methods: This retrospective observational study included 50 asymptomatic delefilcon A or narafilcon A users. Data on thin aqueous layer break (TALB; %), noninvasive tear break-up time (NIBUT), tear meniscus height (TMH; mm), subjective dryness, and higher-order aberrations (HOAs) were collected. Measurements of the bare eye, the SCL-worn eye after 15 minutes (visit 1 [v1]) and 30 ± 5 days after v1 after SCL was worn for ≥5 hours (visit 2 [v2]) were recorded. Results: TALB was significantly reduced in the delefilcon A group compared to the narafilcon A group (33.3% vs. 85.5% at v1; P < 0.0001 and 31.7% vs. 80.4% at v2; P < 0.0001). The NIBUT was also significantly higher in the former (4.2 ± 2.1 seconds vs. 2.9 ± 1.5 at v1; P < 0.01 and 4.1 ± 2.3 seconds vs. 2.7 ± 1.6 seconds at v2; P < 0.01) across both visits. The TMH was significantly reduced in the former in both v1 and v2. The total ocular HOAs were significantly lower in the former at v1 (P < 0.001) and v2 (P < 0.05) compared to the bare eye. Conclusions: The water gradient technology of delefilcon A reduces TALB and increases NIBUT. Translational Relevance: The use of water gradient technology improves tear film dynamics and alleviate pathological break-up pattern, improving lens performance.
Assuntos
Lentes de Contato Hidrofílicas , Silicones , Hidrogéis , Lágrimas , ÁguaRESUMO
RNA synthesis inhibitors and protein synthesis inhibitors are useful for investigating whether biological events with unknown mechanisms require transcription or translation; however, the dependence of RNA synthesis has been difficult to verify because many RNA synthesis inhibitors cause adverse events that trigger a p53 response. In this study, we screened a library containing 9600 core compounds and obtained STK160830 that shows anti-apoptotic effects in irradiated wild-type-p53-bearing human T-cell leukemia MOLT-4 cells and murine thymocytes. In many of the p53-impaired cells and p53-knockdown cells tested, STK160830 did not show a remarkable anti-apoptotic effect, suggesting that the anti-apoptotic activity is p53-dependent. In the expression analysis of p53, p53-target gene products, and reference proteins by immunoblotting, STK160830 down-regulated the expression of many of the proteins examined, and the downregulation correlated strongly with its inhibitory effect on cell death. mRNA expression analyses by qPCR and nascent RNA capture kit revealed that STK160830 showed a decreased mRNA expression, which was similar to that induced by the RNA synthesis inhibitor actinomycin D but differed to some extent. Furthermore, unlike other RNA synthesis inhibitors such as actinomycin D, p53 accumulation by STK160830 alone was negligible, and a DNA melting-curve analysis showed very weak DNA-intercalating activity, indicating that STK160830 is a useful inhibitor for RNA synthesis without triggering p53-mediated damage responses.
RESUMO
PURPOSE: Our previous study indicated that sodium orthovanadate (vanadate), a strong inhibitor of p53, effectively suppressed the lethality from the hematopoietic (HP) and gastrointestinal (GI) syndromes after 12 Gy total-body irradiation (TBI) in mice. This conclusion, however, was inconsistent with the fact that p53 plays a radioprotective role in the intestinal epithelium. The death after TBI of around 12 Gy was attributed to a combined effect of HP and GI syndromes. To verify the effect from prophylactic administration of p53 inhibitor on protection of HP and GI syndromes, in this study, the radioprotective effects from vanadate were investigated in TBI and lower half-body irradiation (partial-body irradiation: PBI) mouse models. METHODS: Female ICR mice were given a single injection of vanadate or vehicle, followed by a lethal dose of TBI or PBI. Radioprotective effects of vanadate against the irradiations were evaluated by analyzing survival rate, body weight, hematopoietic parameters, and histological changes in the bone marrow and intestinal epithelium. RESULTS: TBI-induced HP syndrome was effectively suppressed by vanadate treatment. After TBI, the vanadate-treated mice retained better bone marrow cellularity and showed markedly higher survival rate compared to the vehicle-treated animals. In contrast, vanadate did not relieve loss of intestinal crypts and failed to rescue mice from GI death after PBI. CONCLUSION: Vanadate is a p53 inhibitor that has been shown to be beneficial as a radiation protective agent against HP but was not effective in protecting against acute GI radiation injury.
Assuntos
Protetores contra Radiação/química , Protetores contra Radiação/farmacologia , Sódio/química , Vanadatos/química , Vanadatos/farmacologia , Irradiação Corporal Total/efeitos adversos , Animais , Medula Óssea/efeitos da radiação , Relação Dose-Resposta à Radiação , Trato Gastrointestinal/efeitos da radiação , Camundongos , Camundongos Endogâmicos ICR , Proteína Supressora de Tumor p53/metabolismoRESUMO
Radiation damage to normal tissues is one of the most serious concerns in radiation therapy, and the tolerance dose of the normal tissues limits the therapeutic dose to the patients. p53 is well known as a transcription factor closely associated with radiation-induced cell death. We recently demonstrated the protective effects of several p53 regulatory agents against low-LET X- or γ-ray-induced damage. Although it was reported that high-LET heavy ion radiation (>85 keV/µm) could cause p53-independent cell death in some cancer cell lines, whether there is any radioprotective effect of the p53 regulatory agents against the high-LET radiation injury in vivo is still unclear. In the present study, we verified the efficacy of these agents on bone marrow and intestinal damages induced by high-LET heavy-ion irradiation in mice. We used a carbon-beam (14 keV/µm) that was shown to induce a p53-dependent effect and an iron-beam (189 keV/µm) that was shown to induce a p53-independent effect in a previous study. Vanadate significantly improved 60-day survival rate in mice treated with total-body carbon-ion (p < 0.0001) or iron-ion (p < 0.05) irradiation, indicating its effective protection of the hematopoietic system from radiation injury after high-LET irradiation over 85 keV/µm. 5CHQ also significantly increased the survival rate after abdominal carbon-ion (p < 0.02), but not iron-ion irradiation, suggesting the moderate relief of the intestinal damage. These results demonstrated the effectiveness of p53 regulators on acute radiation syndrome induced by high-LET radiation.
Assuntos
Íons Pesados/efeitos adversos , Lesões por Radiação/prevenção & controle , Radiação Ionizante , Proteína Supressora de Tumor p53/efeitos dos fármacos , Animais , Humanos , Transferência Linear de Energia , CamundongosRESUMO
Radiation damage to normal tissues is a serious concern in radiation therapy. Advances in radiotherapeutic technology have improved the dose distribution of the target volumes and risk organs, but damage to risk organs that are located within the irradiation field still limits the allowable prescription dose. To overcome this dose-limiting toxicity, and to further improve the efficacy of radiotherapy, the development of drugs that protect normal tissues but not cancer tissues from the effects of radiation are expected to be developed based on molecular target-based drugs. p53 is a well-known transcription factor that is closely associated with radiation-induced cell death. In radiation-injured tissues, p53 induces apoptosis in hematopoietic lineages, whereas it plays a radioprotective role in the gastrointestinal epithelium. These facts suggest that p53 inhibitor would be effective for radioprotection of the hematopoietic system, and that a drug that upregulates the radioprotective functions of p53 would enhance the radioresistance of gastrointestinal tissues. In this review, we summarize recent progress regarding the prevention of radiation injury by regulating p53 and provide new strategic insights into the development of radioprotectors in radiotherapy. J. Med. Invest. 66 : 219-223, August, 2019.
Assuntos
Desenvolvimento de Medicamentos , Tolerância a Radiação/efeitos dos fármacos , Protetores contra Radiação/farmacologia , Proteína Supressora de Tumor p53/antagonistas & inibidores , Apoptose/efeitos da radiação , Quelantes/farmacologia , Cloroquinolinóis/farmacologia , Humanos , Proteína Supressora de Tumor p53/fisiologiaRESUMO
PURPOSE: To investigate visual function and optical quality in eyes with epiphora undergoing lacrimal passage intubation. DESIGN: Prospective case series. METHODS: Thirty-four eyes of 30 patients with lacrimal passage obstruction were enrolled. Before and 1 month after lacrimal passage intubation, functional visual acuity (FVA), higher-order aberrations (HOAs), lower tear meniscus, and tear clearance were assessed. An FVA measurement system was used to examine changes in continuous visual acuity (VA) over time, and visual function parameters such as FVA, visual maintenance ratio, and blink frequency were obtained. Sequential ocular HOAs were measured for 10 seconds after the blink using a wavefront sensor. Aberration data were analyzed in the central 4 mm for coma-like, spherical-like, and total HOAs. Fluctuation and stability indices of the total HOAs over time were calculated. Lower tear meniscus was assessed by anterior segment optical coherence tomography. RESULTS: After lacrimal passage intubation, visual function significantly improved, as indicated by improved FVA (P = .003) and visual maintenance ratio (P < .001). Blink frequency decreased significantly after treatment (P = .01). Optical quality significantly improved, as indicated by a decrease in coma-like aberrations (P = .003), spherical-like aberrations (P = .018), and total HOAs (P = .001). Stability index increased (P < .001) and fluctuation index decreased (P = .019), and tear meniscus dimension decreased (P < .001). CONCLUSIONS: Lacrimal passage intubation for eyes with epiphora significantly improved visual function and optical quality via patency of the lacrimal passage.