It is currently believed that aging is closely linked with mitochondrial dysfunction, and that resveratrol exhibits anti-aging and neuroprotective effects by improving mitochondrial function, even though the mechanisms are not well defined. This study explored mitochondrial quality (mitochondrial DNA integrity and copy number), mitochondrial function (fusion/fission, mitophagy/autophagy), antioxidant system and activity of the Akt/mTOR and Ampk/Sirt1/Pgc1α pathways, and inflammation in aging zebrafish retinas to identify the probable mechanisms of resveratrol’s anti-aging and neuroprotective effects. mtDNA integrity, mtDNA copy number, mitochondrial fusion regulators, mitophagy, and antioxidant-related genes were all decreased whereas Akt/mTOR activity and inflammation was increased upon aging in zebrafish retinas. Resveratrol was shown to not only increase mitochondrial quality and function, but also to suppress Akt/mTOR activity in zebrafish retinas. These results support the notion that mitochondrial dysfunction and increased Akt/mTOR activity are major players in age-related retinal neuropathy in zebrafish, and demonstrate a trend towards mitochondrial fragmentation in the aging retina. Importantly, resveratrol promoted mitochondrial function, up-regulating Ampk/Sirt1/Pgc1α, and down-regulated Akt/mTOR pathway activity in zebrafish retinas, suggesting that it may be able to prevent age-related oculopathy.

BACKGROUND Epilepsy is a complex neurological disorder characterized by recurrent, unprovoked seizures resulting from the sudden abnormal discharge of brain neurons. It leads to transient brain dysfunction, manifested by abnormal physical movements and consciousness. It can occur at any age, affecting approximately 65 million worldwide, one third of which are still estimated to suffer from refractory seizures. There is an urgent need for further establishment of seizure models in animals, which provides an approach to model epilepsy and could be used to identify novel anti-epileptic therapeutics in the future. AIM To compare three administration modes for establishing a seizure model caused by N-Methyl-D-aspartic acid (NMDA) in zebrafish. METHODS Three administration routes of NMDA, including immersion, intravitreal injection and intraperitoneal injection, were compared with regard to their effects on inducing seizure-like behaviors in adult zebrafish. We evaluated neurotoxicity by observing behavioral changes in zebrafish and graded those behaviors with a seizure score. In addition, the protective effects of MK-801 (Dizocilpine) and natural active constituent resveratrol against NMDA-induced alterations were studied. RESULTS The three NMDA-administration methods triggered different patterns of the epileptic process in adult zebrafish. Seizure scores were increased after increasing NMDA concentration regardless of the mode of administration. However, the curve of immersion continuously rose to a high plateau (after 50 min), while the curves of intravitreal injection and intraperitoneal injection showed a spike in the early stage (10-20 min) followed by a steady decrease in seizure scores. Furthermore, pretreatment with resveratrol and MK-801 significantly delayed seizure onset time and lowered seizure scores. CONCLUSION By comparing the three methods of administration, intravitreal injection of NMDA was the most suitable for establishing an acute epileptic model in zebrafish. Thus, intraperitoneal injection in zebrafish can be applied to simulate diseases such as epilepsy. In addition, NMDA immersion may be an appropriate method to induce persistent seizures. Moreover, MK-801 and resveratrol showed strong anti-epileptic effects; thus, both of them may be clinically valuable treatments for epilepsy.

Objectives In this study, we aimed to investigate the effect of p62 on angiogenesis and microRNA (miRNA) expression profiles in acute myeloid leukemia (AML) exosomes. Methods An Exiqon v19.0 microRNA MicroArray was used to profile miRNAs in exosomes derived from parental and p62-knockdown U937 cells. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases were used to predict the biological functions and potential mechanisms of differentially expressed miRNAs in AML exosomes. Endothelial cell tube formation assays using human umbilical vein endothelial cells (HUVECs) were performed to investigate the effect of AML exosomes on angiogenesis. Results We demonstrated that 2,080 miRNAs were expressed in exosomes derived from our cultured cell samples, of which 215 and 208 miRNAs were upregulated and downregulated, respectively, in p62-knockdown U937 cells (fold change ≥ 2, P < 0.05). GO analysis indicated that miRNAs were most enriched in the intercellular pathways. Biological process analysis revealed that 1460 biological processes were associated with downregulated transcripts, including 19 pathways related to vesicles, and 1,515 pathways were upregulated, including 8 pathways related to vesicles. Molecular function analysis indicated that protein binding, transcription regulator activity, and DNA-binding transcription factor activity were enriched (P < 0.05). Pathway analysis indicated that 84 pathways corresponded to upregulated transcripts, and 55 pathways corresponded to downregulated transcripts (P < 0.05). We also found that exosomes derived from U937 cells promoted angiogenesis in HUVECs. Conclusions Our data suggest that exosomal miRNAs may play important roles in the pathogenesis of AML, which may be treated by p62 knockdown with exosomal miRNAs to inhibit angiogenesis.