Interaction of Necl‐4/CADM4 with ErbB3 and integrin α6β4 and inhibition of ErbB2/ErbB3 signaling and hemidesmosome disassembly

Nectin‐like molecule 4 (Necl‐4)/CADM4, a transmembrane cell–cell adhesion molecule with three Ig‐like domains, was shown to serve as a tumor suppressor, but its mode of action has not been elucidated. In this study, we showed that Necl‐4 interacted in cis with ErbB3 through their extracellular regions, recruited PTPN13 and inhibited the heregulin‐induced activation of the ErbB2/ErbB3 signaling. In addition, we extended our previous finding that Necl‐4 interacts in cis with integrin α₆β₄ through their extracellular regions and found that Necl‐4 inhibited the phorbol ester‐induced disassembly of hemidesmosomes. These results indicate that Necl‐4 serves as a tumor suppressor by inhibiting the ErbB2/ErbB3 signaling and hemidesmosome disassembly.     

Expression and regulation of periostin/OSF-2 gene in rat uterus and human endometrium

Periostin/OSF2 is a ligand for alphavbeta3 and alphavbeta5 integrins and activates the Akt/PKB pathway. Recent reports of periostin/OSF2 gene disrupted mice indicate that periostin/OSF-2 plays an important role in implantation. Quantitative RT-PCR revealed that the expression of periostin/OSF-2 mRNA in rat uteri was reduced to approximately 10% at 12 h after 17beta-estradiol (E2) injection, but was not changed after progesterone (P) injection. RT-PCR revealed the expression of periostin/OSF-2 in human endometrium, cultured human endometrial stromal cells (ESCs), and cultured human endometrial epithelial cells. In ESCs, the expression of periostin/OSF-2 mRNA was reduced to approximately 50% at 6 h after E2 treatment. The amount of periostin/OSF2 mRNA in human endometrium significantly increased during mid-proliferative and early secretory phases of menstrual cycle, and decreased during late-proliferative, mid-secretory and late secretory phases. The expression of periostin/OSF2 mRNA significantly decreased in ESCs decidualized by treatment with E2 and P for 7 and 11 days. By immunohistochemistry, the expression of periostin/OSF-2 was strongly detected in endometrial stromal cells during early proliferative, mid-proliferative and early secretory phases, and was strongly detected in endometrial epithelial cells during late secretory phase. This study demonstrated that the expression of periostin/OSF-2 is regulated by ovarian steroid hormones in rat uterus and human endometrium.     

Age-related changes in barrier function in mouse brain II. Accumulation of serum albumin in the olfactory bulb of SAM mice increased with aging

Brain transfer rate (BTR) and brain to plasma concentration ratio (BPCR) of radiolabelled human serum albumin injected intravenously were calculated to evaluate the brain transfer of serum albumin in the cerebral cortex, the right hemi-brain and the olfactory bulb of senescence accelerated prone mice (SAMP8) and senescence accelerated resistant mice (SAMR1). BTR and BPCR in SAMP8 and SAMR1 were significantly higher in the olfactory bulb than in the cerebral cortex or the right hemi-brain. Age-related significant changes in BTR and BPCR were observed in the olfactory bulb of SAMP8 and SAMR1. These findings suggest that the barrier function to serum albumin in the olfactory bulb of SAMP8 and SAMR1 is not so tight as it is in the cerebral cortex and becomes weaker with age and that the age-related changes are manifested at a younger age in SAMP8 than in SAMR1.     

Humic acid induces the endothelial nitric oxide synthase phosphorylation at Ser1177 and Thr495 Via Hsp90α and Hsp90β upregulation in human umbilical vein endothelial cells

Humic acid (HA) has been implicated as a contributory factor for blackfoot disease, which is an endemic peripheral vascular disease. We investigated the effect of HA on the regulation of endothelial nitric oxide (NO) synthase (eNOS) in human umbilical vein endothelial cells (HUVECs) to evaluate the involvement of eNOS and related factors in peripheral vascular impairment with HA exposure. Treatment of HUVECs with HA induced upregulation of eNOS. This result coincides with those of previous studies. Furthermore this is the first study to report that HA induces upregulation of heat shock protein (Hsp)90α, Hsp90β, eNOS phosphorylation at Ser1177, and eNOS phosphorylation at Thr495, as compared to that in the control. In contrast, treatment with BAPTA, an intracellular Ca²⁺ chelator, inhibited upregulation of these proteins induced by HA. This study demonstrates that HA treatment leads to increases in both Hsp90α and Hsp90β proteins and indicates that Hsp90α leads to eNOS phosphorylation at Ser1177 and that Hsp90β leads to eNOS phosphorylation at Thr495, respectively. Upregulation of eNOS, Hsp90α, and Hsp90β in HUVECs is regulated by intracellular Ca²⁺ accumulation induced by HA. These results suggest that upregulation of eNOS phosphorylation at Ser1177 and eNOS phosphorylation at Thr495 produce NO and superoxide anions, respectively, resulting in generation of peroxynitrite, which causes impairment of vascular endothelial cells. © 2013 Wiley Periodicals, Inc. Environ Toxicol 30: 223–231, 2015.     

Whole-pelvic volumetric-modulated arc therapy for high-risk prostate cancer: treatment planning and acute toxicity

The objectives of this study were to evaluate dosimetric quality and acute toxicity of volumetric-modulated arc therapy (VMAT) and daily image guidance in high-risk prostate cancer patients. A total of 100 consecutive high-risk prostate cancer patients treated with definitive VMAT with prophylactic whole-pelvic radiotherapy (WPRT) were enrolled. All patients were treated with a double-arc VMAT plan delivering 52 Gy to the prostate planning target volume (PTV), while simultaneously delivering 46.8 Gy to the pelvic nodal PTV in 26 fractions, followed by a single-arc VMAT plan delivering 26 Gy to the prostate PTV in 13 fractions. Image-guided RT was performed with daily cone-beam computed tomography. Dose–volume parameters for the PTV and the organs at risk (OARs), total number of monitor units (MUs) and treatment time were evaluated. Acute toxicity was assessed using the Common Terminology Criteria for Adverse Events, version 4.0. All dosimetric parameters met the present plan acceptance criteria. Mean MU and treatment time were 471 and 146 s for double-arc VMAT, respectively, and were 520 and 76 s for single-arc VMAT, respectively. No Grade 3 or higher acute toxicity was reported. Acute Grade 2 proctitis, diarrhea, and genitourinary toxicity occurred in 12 patients (12%), 6 patients (6%) and 13 patients (13%), respectively. The present study demonstrated that VMAT for WPRT in prostate cancer results in favorable PTV coverage and OAR sparing with short treatment time and an acceptable rate of acute toxicity. These findings support the use of VMAT for delivering WPRT to high-risk prostate cancer patients.