The blood vasculature instructs lymphatic patterning in a SOX7-dependent manner.

Despite a growing catalog of secreted factors critical for lymphatic network assembly, little is known about the mechanisms that modulate the expression level of these molecular cues in blood vascular endothelial cells (BECs). Here, we show that a BEC-specific transcription factor, SOX7, plays a crucial role in a non-cell-autonomous manner by modulating the transcription of angiocrine signals to pattern lymphatic vessels. While SOX7 is not expressed in lymphatic endothelial cells (LECs), the conditional loss of SOX7 function in mouse embryos causes a dysmorphic dermal lymphatic phenotype. We identify novel distant regulatory regions in mice and humans that contribute to directly repressing the transcription of a major lymphangiogenic growth factor (Vegfc) in a SOX7-dependent manner. Further, we show that SOX7 directly binds HEY1, a canonical repressor of the Notch pathway, suggesting that transcriptional repression may also be modulated by the recruitment of this protein partner at Vegfc genomic regulatory regions. Our work unveils a role for SOX7 in modulating downstream signaling events crucial for lymphatic patterning, at least in part via the transcriptional repression of VEGFC levels in the blood vascular endothelium.

[Role of IRE1 in autophagy induced by vitamin E succinate in human gastric cancer cell].

OBJECTIVE: To investigate the role of inositol-requiring enzyme 1(IRE1) in autophagy of human gastric cancer cells induced by vitamin E succinate(VES). METHODS: Human gastric cancer SGC-7901 cells were cultured in vitro and divided into solvent control group(0.1% ethanol absolute), different doses(5, 10, 15 and 20 µg/mL) VES group, 4µ8C group, and VES + 4µ8C group. The endoplasmic reticulum stress-related molecules glucose regulated protein 78(GRP78) and C/EBP homologous protein(CHOP), autophagy marker microtubule associated Protein1 light chain 3(LC3), Beclin-1, unfolded protein response branching pathway Inositol-requiring enzyme 1(IRE1), X box-binding protein 1(XBP1), c-Jun n-terminal kinase(JNK) and p-JNK were detected by Western blot in the solvent control group and different doses of VES group. IRE1 was inhibited by 4µ8C. The expressions of IRE1, XBP1, JNK, p-JNK, GRP78 and CHOP were detected by Western blot, and the expressions of LC3 and Beclin-1 were detected. RESULTS: The expression of GRP78(1.16±0.06) and CHOP(1.36±0.11) in 20 µg/mL VES group were significantly higher than those in solvent control group GRP78(0.36±0.10) and CHOP(0.48±0.05)(P<0.001). The expression of Beclin-1(1.09±0.20) and LC3-Ⅱ/LC3-Ⅰ(1.29±0.03) in 20 µg/mL VES group were significantly higher than those in solvent control group(0.27±0.07) and LC3-Ⅱ/LC3-Ⅰ(0.43±0.06)(P<0.001). The expression levels of IRE1(1.07±0.20), XBP1(1.33±0.07) and p-JNK/JNK(1.19±0.31) in 20 µg/mL VES group were significantly higher than those in the solvent control group(P<0.01). After IRE1 is inhibited: The expression level of IRE1(0.63±0.27), XBP1(0.74±0.09), p-JNK/JNK(0.35±0.04), GRP78(0.66±0.02), CHOP(0.51±0.02), LC3-Ⅱ/LC3-Ⅰ(0.72±0.01), Beclin-1(0.70±0.15) was significantly lower than that of VES group(P<0.05). CONCLUSION: VES may participate in the regulation of autophagy in gastric cancer cells by upregulating IRE1 pathway.

Validation of an in vivo electrochemical immunosensing platform for simultaneous detection of multiple cytokines in Parkinson's disease mice model.

Parkinson's Disease (PD) is a neurodegenerative chronic disorder which destroys brain tissue and result in impaired movement. Early diagnosis of PD before the appearance of clinical symptom is vital for effective treatment. High levels of proinflammatory cytokines found in PD patient's brains, as natural inflammation response product, are potential biomarkers for PD detection in the early stage. Herein, we developed an in vivo electrochemical immunosensing device based on glassy carbon rod to simultaneously detect three proinflammatory cytokines (IL-1ß, IL-6 and TNF-α). The levels of IL-1ß, IL-6 and TNF-α secreted by N2a cells significantly increased within 24 h after lipopolysaccharide (LPS) stimulation. Under in vivo conditions, the concentrations of IL-1ß, IL-6 and TNF-α in PD model group achieved by injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intraperitoneally, were significantly higher than those in the control mouse group. The concentrations of three cytokines in vivo/vitro detected by this immunosensing device was comparable to that obtained by ELISA. Furthermore, this deployable immunosensing device was proved to be highly sensitive with the limits of detection (LODs) of 5 pg mL-1 for each cytokine, specific and reliable, suggesting its potential to be a universal immunosensing platform for early identification and diagnosis of PD in vivo in the future.