Epigallocatechin-3-gallate (EGCG), the major polyphenolic constituent of green tea, is a potent antioxidant and free radical scavenger that may have therapeutic applications for the treatment of many disorders. Radiation therapy is widely used for the treatment of various types of cancers; however, radiation-induced skin injury remains a serious concern. EGCG has not yet been reported as protecting skin cells against ionizing radiation. In the present study, we investigated whether EGCG confers cytoprotection against ionizing radiation. We found that, compared with the control, pretreatment with EGCG significantly enhanced the viability of human skin cells that were irradiated with X-rays, and decreased apoptosis induced by X-ray irradiation. Mito-Tracker assay showed that EGCG suppressed the damage to mitochondria induced by ionizing radiation via upregulation of SOD2. Reactive oxygen species (ROS) in HaCaT cells were significantly reduced when pretreated with EGCG before irradiation. Radiation-induced γH2AX foci, which are representative of DNA double-strand breaks, were decreased by pretreatment with EGCG. Furthermore, EGCG induced the expression of the cytoprotective molecule heme oxygenase-1 (HO-1) in a dose-dependent manner via transcriptional activation. HO-1 knockdown or treatment with the HO-1 inhibitor tin protoporphyrin (SnPPIX) reversed the protective role of EGCG, indicating an important role for HO-1. These results suggest that EGCG offers a new strategy for protecting skin against ionizing radiation.

The repulsive guidance cue SLIT2 and its receptor ROBO2 are required for kidney development and podocyte foot process structure, but the SLIT2/ROBO2 signaling mechanism regulating podocyte function is not known. Here we report that a potentially novel signaling pathway consisting of SLIT/ROBO Rho GTPase activating protein 1 (SRGAP1) and nonmuscle myosin IIA (NMIIA) regulates podocyte adhesion downstream of ROBO2. We found that the myosin II regulatory light chain (MRLC), a subunit of NMIIA, interacts directly with SRGAP1 and forms a complex with ROBO2/SRGAP1/NMIIA in the presence of SLIT2. Immunostaining demonstrated that SRGAP1 is a podocyte protein and is colocalized with ROBO2 on the basal surface of podocytes. In addition, SLIT2 stimulation inhibits NMIIA activity, decreases focal adhesion formation, and reduces podocyte attachment to collagen. In vivo studies further showed that podocyte-specific knockout of protects mice from hypertension-induced podocyte detachment and albuminuria and also partially rescues the podocyte-loss phenotype in knockout mice. Thus, we have identified SLIT2/ROBO2/SRGAP1/NMIIA as a potentially novel signaling pathway in kidney podocytes, which may play a role in regulating podocyte adhesion and attachment. Our findings also suggest that SLIT2/ROBO2 signaling might be a therapeutic target for kidney diseases associated with podocyte detachment and loss.

Highlights d ALS patient-derived motor neurons are hyperexcitable d A high-throughput GCaMP screen is used to identify ALS excitability modulators d Kv7 ion channels, AMPA receptors, and the type 2 dopamine receptor are major targets d The D2 dopamine receptor modulates both neuronal excitability and survival

Background and Objective To investigate the serum anti‐hepatitis E virus (HEV) antibody positive rate in patients with different types of chronic hepatitis (CH) or cirrhosis. Methods A total of 1751 hospitalized patients were chart reviewed, who were diagnosed with mono‐CH or cirrhosis between 2011 and 2016. Results The total anti‐HEV‐IgG positive rate was 1.33% (13/981) in CH patients, which was significantly lower than that (6.49%; 50/770) in cirrhosis patients (odds ratio [OR], 4.78 [2.51‐9.10]; P = 0.00). The comparison of positive rate of anti‐HEV‐IgG between the same etiology CH and cirrhosis groups was as follows: chronic hepatitis B 1.27% (10/790) versus hepatitis B virus (HBV)‐related cirrhosis 4.21% (22/522) (OR, 3.04 [1.36‐6.77]; P = 0.00); chronic alcoholic hepatitis 1.41% (1/71) versus alcoholic cirrhosis 9.40% (11/117) (OR, 8.00 [1.00‐64.25]; P = 0.03); chronic autoimmune hepatitis 1.69% (1/59) versus autoimmune cirrhosis 13.33% (12/90) (OR, 13.11 [1.49‐115.27]; P = 0.01); the differences above were statistically significant. And chronic hepatitis C 3.23% (1/31) versus hepatitis C virus‐related cirrhosis 10.81% (4/37) (OR, 4.40 [0.45‐43.53]; P > 0.05); chronic NASH 0.00% (0/30) versus NASH‐related cirrhosis 25.00% (1/4) (P > 0.05), the differences were not statistically significant. Anti‐HEV‐IgG positive rates were also compared among different types of CH groups and no significant difference was found. Likewise, anti‐HEV‐IgG positive rate was compared among different types of cirrhosis groups, showing that the positive rates of both alcoholic cirrhosis (9.40%) and autoimmune cirrhosis (13.33%) were significantly higher than that of HBV‐related cirrhosis (4.21%) (P < 0.05). Conclusion We observed that the cirrhosis patients had a significantly higher anti‐HEV‐IgG positive rate comparing with the CH patients, especially in those with HBV‐related, alcohol‐related, and autoimmune‐related cirrhosis (after adjusted for age). Additionally, it seems that the conditions of alcoholic cirrhosis and autoimmune cirrhosis are more susceptible to HEV infection due to the significantly higher positive anti‐HEV‐IgG rate in these patients.

Roundabout guidance receptor 2 (ROBO2) plays an important role during early kidney development. ROBO2 is expressed in podocytes, inhibits nephrin-induced actin polymerization, down-regulates nonmuscle myosin IIA activity, and destabilizes kidney podocyte adhesion. However, the role of ROBO2 during kidney injury, particularly in mature podocytes, is not known. Herein, we report that loss of ROBO2 in podocytes [Robo2 conditional knockout (cKO) mouse] is protective from glomerular injuries. Ultrastructural analysis reveals that Robo2 cKO mice display less foot process effacement and better-preserved slit-diaphragm density compared with wild-type littermates injured by either protamine sulfate or nephrotoxic serum (NTS). The Robo2 cKO mice also develop less proteinuria after NTS injury. Further studies reveal that ROBO2 expression in podocytes is up-regulated after glomerular injury because its expression levels are higher in the glomeruli of NTS injured mice and passive Heymann membranous nephropathy rats. Moreover, the amount of ROBO2 in the glomeruli is also elevated in patients with membranous nephropathy. Finally, overexpression of ROBO2 in cultured mouse podocytes compromises cell adhesion. Taken together, these findings suggest that kidney injury increases glomerular ROBO2 expression that might compromise podocyte adhesion and, thus, loss of Robo2 in podocytes could protect from glomerular injury by enhancing podocyte adhesion that helps maintain foot process structure. Our findings also suggest that ROBO2 is a therapeutic target for podocyte injury and podocytopathy.

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