RESUMO
Herein, we describe the synthesis of a water-soluble photodynamically active fullerene bearing a polyethylene glycol chain and a hydrophilic cationic group, revealing that the solubility of the above derivative in aqueous medium depends on ultrasonication time, with the particle size of aggregates being correlated with concentration.
Assuntos
Fulerenos/química , Fármacos Fotossensibilizantes/química , Polietilenoglicóis/química , Pirrolidinas/química , Células A549 , Sobrevivência Celular/efeitos dos fármacos , Fulerenos/farmacologia , Humanos , Interações Hidrofóbicas e Hidrofílicas , Cinética , Nanopartículas , Tamanho da Partícula , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/farmacologia , Pirrolidinas/síntese química , Pirrolidinas/farmacologia , Solubilidade , Água/químicaRESUMO
Cerebrospinal fluid is thought to be mainly absorbed into arachnoid granules in the subarachnoid space and drained into the sagittal sinus. However, some observations such as late outbreak of arachnoid granules in fetus brain and recent cerebrospinal fluid movements study by magnetic resonance images, conflict with this hypothesis. In this study, we investigated the movement of cerebrospinal fluid in fetuses. Several kinds of fluorescent probes with different molecular weights were injected into the lateral ventricle or subarachnoid space in mouse fetuses at a gestational age of 13 days. The movements of the probes were monitored by live imaging under fluorescent microscope. Following intraventricular injection, the probes dispersed into the 3rd ventricle and aqueduct immediately, but did not move into the 4th ventricle and spinal canal. After injection of low and high molecular weight conjugated probes, both probes dispersed into the brain but only the low molecular weight probe dispersed into the whole body. Following intra-subarachnoid injection, both probes diffused into the spinal canal gradually. Neither probe dispersed into the brain and body. The probe injected into the lateral ventricle moved into the spinal central canal by the fetus head compression, and returned into the aqueduct by its release. We conclude this study as follows: (i) The movement of metabolites in cerebrospinal fluid in the ventricles will be restricted by molecular weight; (ii) Cerebrospinal fluid in the ventricle and in the subarachnoid space move differently; and (iii) Cerebrospinal fluid may not appear to circulate. In the event of high intracranial pressure, the fluid may move into the spinal canal.
Assuntos
Aqueduto do Mesencéfalo/metabolismo , Ventrículos Cerebrais/metabolismo , Corantes Fluorescentes/metabolismo , Medula Espinal/metabolismo , Espaço Subaracnóideo/metabolismo , Seio Sagital Superior/metabolismo , Animais , Transporte Biológico , Aqueduto do Mesencéfalo/anatomia & histologia , Ventrículos Cerebrais/anatomia & histologia , Feminino , Feto , Corantes Fluorescentes/administração & dosagem , Idade Gestacional , Injeções Intraventriculares , Pressão Intracraniana/fisiologia , Camundongos , Camundongos Endogâmicos ICR , Microscopia de Fluorescência , Peso Molecular , Gravidez , Medula Espinal/anatomia & histologia , Espaço Subaracnóideo/anatomia & histologia , Seio Sagital Superior/anatomia & histologiaRESUMO
Paraquat (PQ), a herbicide used worldwide, causes fatal injury to organs upon high dose ingestion. Treatments for PQ poisoning are unreliable, and numerous deaths have been attributed inappropriate usage of the agent. It is generally speculated that a microsomal drug-metabolizing enzyme system is responsible for PQ toxicity. However, recent studies have demonstrated cytotoxicity via mitochondria, and therefore, the cytotoxic mechanism remains controversial. Here, we demonstrated that mitochondrial NADH-dependent PQ reductase containing a voltage-dependent anion channel 1 (VDAC1) is responsible for PQ cytotoxicity. When mitochondria were incubated with NADH and PQ, superoxide anion (O(2)(*)) was produced, and the mitochondria ruptured. Outer membrane extract oxidized NADH in a PQ dose-dependent manner, and oxidation was suppressed by VDAC inhibitors. Zymographic analysis revealed the presence of VDAC1 protein in the oxidoreductase, and the direct binding of PQ to VDAC1 was demonstrated using biotinylated PQ. VDAC1-overexpressing cells showed increased O(2)(*) production and cytotoxicity, both of which were suppressed in VDAC1 knockdown cells. These results indicated that a VDAC1-containing mitochondrial system is involved in PQ poisoning. These insights into the mechanism of PQ poisoning not only demonstrated novel physiological functions of VDAC protein, but they may facilitate the development of new therapeutic approaches.