RESUMO
Normal-tension glaucoma (NTG) is a heterogeneous disease characterized by retinal ganglion cell (RGC) death leading to cupping of the optic nerve head and visual field loss at normal intraocular pressure (IOP). The pathogenesis of NTG remains unclear. Here, we describe a single nucleotide mutation in exon 2 of the methyltransferase-like 23 (METTL23) gene identified in 3 generations of a Japanese family with NTG. This mutation caused METTL23 mRNA aberrant splicing, which abolished normal protein production and altered subcellular localization. Mettl23-knock-in (Mettl23+/G and Mettl23G/G) and -knockout (Mettl23+/- and Mettl23-/-) mice developed a glaucoma phenotype without elevated IOP. METTL23 is a histone arginine methyltransferase expressed in murine and macaque RGCs. However, the novel mutation reduced METTL23 expression in RGCs of Mettl23G/G mice, which recapitulated both clinical and biological phenotypes. Moreover, our findings demonstrated that METTL23 catalyzed the dimethylation of H3R17 in the retina and was required for the transcription of pS2, an estrogen receptor α target gene that was critical for RGC homeostasis through the negative regulation of NF-κB-mediated TNF-α and IL-1ß feedback. These findings suggest an etiologic role of METTL23 in NTG with tissue-specific pathology.
Assuntos
Glaucoma , Histonas , Animais , Camundongos , Modelos Animais de Doenças , Glaucoma/metabolismo , Histonas/genética , Histonas/metabolismo , Pressão Intraocular/genética , Metilação , Mutação , Células Ganglionares da Retina/metabolismoRESUMO
BACKGROUND/AIMS: We analyzed the effects of the Kampo medicine "Dai-kenchu-to" (DKT) on clinical aspects in colorectal surgery. METHODOLOGY: Total 122 patients who underwent colorectal cancer surgery were divided into a DKT group (n = 53) and a non-DKT group (n = 69). The differences of postoperative course and anti-inflammatory responses between those two groups were analyzed. RESULTS: The 53 out of 59 patients could completely take DKT. In the postoperative course, significant difference was observed in the first flatus day. In the anti-inflammatory effects, differences were observed in the heart rate (HR) of the 3rd POD. In the change between 1st POD and 3rd POD, HR in the DKT group was well controlled compared to the non-DKT group. In the patients who had over 37.5°C of body temperature in 1st POD (n = 53), inflammatory response of the DKT group was reduced compared to the non-DKT group. CONCLUSIONS: The DKT might have the favorable influences on postoperative bowel movement and systemic inflammatory reaction, and induce the better postoperative course.
Assuntos
Anti-Inflamatórios/uso terapêutico , Neoplasias Colorretais/cirurgia , Febre/epidemiologia , Íleus/epidemiologia , Extratos Vegetais/uso terapêutico , Complicações Pós-Operatórias/epidemiologia , Idoso , Estudos de Casos e Controles , Defecação , Procedimentos Cirúrgicos do Sistema Digestório , Feminino , Flatulência , Frequência Cardíaca , Humanos , Inflamação/epidemiologia , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Panax , Zanthoxylum , ZingiberaceaeRESUMO
BACKGROUND: We examined the association of the physical, nutritional, and immune status with adverse events in patients treated with mFOLFOX6 adjuvant chemotherapy after colorectal cancer surgery. METHOD: This study included 17 patients, 7 male and 10 female. The median age was 62( range, 32-75) years. The median number of treatment cycles was 12 (range, 4-12). Age, performance status( PS), body mass index( BMI),serum albumin level( Alb),Onodera's prognostic nutritional index( PNI), controlling nutritional status( CONUT),Glasgow prognostic score( GPS),the granulocyte/lymphocyte ratio( G/L),neutrophil count, and the total lymphocyte count( TLC) were evaluated with regard to the nutrition and immunity status of the host before chemotherapy. The incidents of toxicity of greater than Grade 2 severity, excluding gastrointestinal events or gastrointestinal toxicities, were analyzed to determine the correlation with host status. RESULT: Any toxicities and toxicities without digestive symptoms were observed in 11 patients( 64.7%),and the number of incidents was significantly increased in patients with a PNI of <45. Gastrointestinal toxicities were observed in 4 patients (23.5%), but there were no significant correlations with any of the factors investigated. CONCLUSION: Toxicities are observed to a greater extent in patients with a PNI of <45 during adjuvant chemotherapy. These findings suggest that nutritional support may be required to safely administer mFOLFOX6 adjuvant chemotherapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Índice de Massa Corporal , Quimioterapia Adjuvante , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/cirurgia , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/efeitos adversos , PrognósticoRESUMO
PURPOSE: To investigate the neuroprotective effect of alpha2-adrenergic agonist brimonidine in the presence of glutamate-induced neurotoxicity, oxidative stress, and hypoxia on in vitro cultures of purified rat retinal ganglion cells (RGCs). METHODS: Purified RGC cultures were obtained from retinas of 6-8-day old Wistar rats, following a two-step immunopanning procedure. After 72 h of cultivation, the neuroprotective effect of brimonidine (0.01 microM, 0.1 microM, and 1 microM) was investigated by culturing the RGCs under glutamate, oxidative, and hypoxic stress for a further 72 h, 24 h, and 12 h, respectively. Glutamate neurotoxicity was induced by adding glutamate (25 microM), while oxidative stress was induced by substituting the culture medium with B27 supplement without antioxidants, and hypoxia was induced by cultivation in a controlled-atmosphere incubator with oxygen levels 5% of the normal partial pressure. The RGC viability under each stress condition normalized to that under normal condition was evaluated as live cell percentage based on a total of 7-8 full repeated experiments. RESULTS: The cell survival percentages of cultures exposed to glutamate, oxidative, and hypoxic stress were 58.2%, 59.3%, and 53.2%, respectively. Brimonidine dose dependently increased RGC survival in the presence of glutamate (80.6% at 1 microM), oxidative (79.8% at 1 microM), and hypoxic (72.3 and 77.4% at 0.1 and 1 microM, respectively) stress. In the presence of alpha2-adrenergic antagonist yohimbine (10 microM), brimonidine (1 microM) showed no protective effects on RGC viability. CONCLUSIONS: At a concentration of 0.1 microM or higher, brimonidine increased survival of purified rat RGCs in the presence of glutamate neurotoxicity, oxidative stress, and hypoxia. The neuroprotective effect of brimonidine is mediated via alpha2-adrenergic receptors at the RGC level.