Dysfunctional circadian clock accelerates cancer metastasis by intestinal microbiota triggering accumulation of myeloid-derived suppressor cells.

Circadian homeostasis in mammals is a key intrinsic mechanism for responding to the external environment. However, the interplay between circadian rhythms and the tumor microenvironment (TME) and its influence on metastasis are still unclear. Here, in patients with colorectal cancer (CRC), disturbances of circadian rhythm and the accumulation of monocytes and granulocytes were closely related to metastasis. Moreover, dysregulation of circadian rhythm promoted lung metastasis of CRC by inducing the accumulation of myeloid-derived suppressor cells (MDSCs) and dysfunctional CD8+ T cells in the lungs of mice. Also, gut microbiota and its derived metabolite taurocholic acid (TCA) contributed to lung metastasis of CRC by triggering the accumulation of MDSCs in mice. Mechanistically, TCA promoted glycolysis of MDSCs epigenetically by enhancing mono-methylation of H3K4 of target genes and inhibited CHIP-mediated ubiquitination of PDL1. Our study links the biological clock with MDSCs in the TME through gut microbiota/metabolites in controlling the metastatic spread of CRC, uncovering a systemic mechanism for cancer metastasis.

Isorhamnetin prevents H2O2­induced oxidative stress in human retinal pigment epithelial cells.

Isorhamnetin, a 3­O­methylated metabolite of quercetin, exhibits antioxidant effects. However, to the best of our knowledge, no study to date has focused on the effects of isorhamnetin on retinal pigment epithelium (RPE) cells, and its underlying molecular mechanisms. Therefore, the present study aimed to examine the potential protective effect of isorhamnetin against oxidative stress in human RPE cells. The results demonstrated that pretreatment of RPE cells with isorhamnetin significantly protected cell viability against oxidative stress. In addition, isorhamnetin pretreatment inhibited hydrogen peroxide (H2O2)­induced reactive oxygen species (ROS) production and caspase­3 activation in RPE cells. Furthermore, isorhamnetin pretreatment significantly increased the phosphorylation of phosphoinositide 3­kinase (PI3K) and AKT serine/threonine kinase 1 (Akt) in RPE cells exposed to H2O2, compared with cells treated with H2O2 alone. Taken together, the present results demonstrated that isorhamnetin protected human RPE cells from oxidative stress­induced cell death, and this effect was associated with activation of the PI3K/Akt signaling pathway. Thus, isorhamnetin may be considered as a potential antioxidant useful for the prevention of age­related macular degeneration.

[Hydrogen peroxide induces expression and transcription of erythropoietin in the human retinal pigment epithelium cells].

OBJECTIVE: To investigate the expression of erythropoietin (EPO) in human fetal retinal pigment epithelium (hfRPE) cells exposed to oxidative stress induced by hydrogen peroxide (H(2)O(2)) and to study the mechanisms. METHODS: The hfRPE cells were isolated, cultured and identified. The content of malondialdehyde (MDA) and the activity of superoxide dismutase (SOD) of the hfRPE cells were examined. The changes of level of mRNA and protein of EPO in hfRPE cells exposed to oxidative stress were measured by semi-quantitative RT-PCR and immunocytochemical staining techniques. RESULTS: H(2)O(2) could increase the content of MDA and inhibit the activity of SOD in hfRPE cells. RT-PCR detected a significant increase of EPO mRNA level in cultured hfRPE cells exposed to oxidative stress. The level of EPO mRNA in the hfRPE cells reached a peak when exposed to 600 micromol/L H(2)O(2), then decreased after exposing to 800 micromol/L H(2)O(2). The immunocytochemical study detected that the changes of the level of EPO protein were similar to that of EPO mRNA. CONCLUSION: Oxidation stress by exposed to H(2)O(2) induces significant increase of EPO expression of hfRPE cells. Expression of EPO may be related to the survival and tolerance of hfRPE cells.

Identification of rare paired box 3 variant in strabismus by whole exome sequencing.

AIM: To identify the potentially pathogenic gene variants that contributes to the etiology of strabismus. METHODS: A Chinese pedigree with strabismus was collected and the exomes of two affected individuals were sequenced using the next-generation sequencing technology. The resulting variants from exome sequencing were filtered by subsequent bioinformatics methods and the candidate mutation was verified as heterozygous in the affected proposita and her mother by sanger sequencing. RESULTS: Whole exome sequencing and filtering identified a nonsynonymous mutation c.434G-T transition in paired box 3 (PAX3) in the two affected individuals, which were predicted to be deleterious by more than 4 bioinformatics programs. This altered amino acid residue was located in the conserved PAX domain of PAX3. This gene encodes a member of the PAX family of transcription factors, which play critical roles during fetal development. Mutations in PAX3 were associated with Waardenburg syndrome with strabismus. CONCLUSION: Our results report that the c.434G-T mutation (p.R145L) in PAX3 may contribute to strabismus, expanding our understanding of the causally relevant genes for this disorder.