Regulation of CLC-1 chloride channel biosynthesis by FKBP8 and Hsp90β.

Mutations in human CLC-1 chloride channel are associated with the skeletal muscle disorder myotonia congenita. The disease-causing mutant A531V manifests enhanced proteasomal degradation of CLC-1. We recently found that CLC-1 degradation is mediated by cullin 4 ubiquitin ligase complex. It is currently unclear how quality control and protein degradation systems coordinate with each other to process the biosynthesis of CLC-1. Herein we aim to ascertain the molecular nature of the protein quality control system for CLC-1. We identified three CLC-1-interacting proteins that are well-known heat shock protein 90 (Hsp90)-associated co-chaperones: FK506-binding protein 8 (FKBP8), activator of Hsp90 ATPase homolog 1 (Aha1), and Hsp70/Hsp90 organizing protein (HOP). These co-chaperones promote both the protein level and the functional expression of CLC-1 wild-type and A531V mutant. CLC-1 biosynthesis is also facilitated by the molecular chaperones Hsc70 and Hsp90β. The protein stability of CLC-1 is notably increased by FKBP8 and the Hsp90β inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) that substantially suppresses cullin 4 expression. We further confirmed that cullin 4 may interact with Hsp90β and FKBP8. Our data are consistent with the idea that FKBP8 and Hsp90β play an essential role in the late phase of CLC-1 quality control by dynamically coordinating protein folding and degradation

Acute Viral Hepatitis C-Induced Jaundice in Pregnancy

SummaryObjectiveAcute viral hepatitis C-induced jaundice in pregnancy is very rare and may be fatal. Here, we report a complicated case with acute hepatitis C-induced jaundice in pregnancy with successful managementCase ReportA 27-year-old pregnant woman, gravida 2, para 1, with gestational age of 36 weeks and 5 days, was referred to our hospital due to jaundice and elevated liver enzymes of undetermined cause. She had been suffering from general weakness, diarrhea and vomiting for 1 week, and jaundice with tea-colored urine for 3 days. At our medical center, acute viral hepatitis C-induced jaundice was suspected. Since her general condition deteriorated at 36 weeks and 6 days of gestation, we decided to induce labor. A male baby was born smoothly via the vaginal route, with birth weight 2,857 g, birth length 48.6 cm, and 1- and 5-minute Apgar scores of 7 and 9, respectively. Maternal condition improved dramatically after delivery and her serum liver enzymes and bilirubin levels gradually approached normal ranges.ConclusionMothers and fetuses with acute viral hepatitis C-induced jaundice during pregnancy are at great risk of mortality and morbidity. Timely termination may be one of the choices of treatment when fetal maturity has been reached and the maternal condition has deteriorated

A retrospective study on the course and outcome of fetal ventriculomegaly

AbstractObjectiveTo evaluate the outcomes associated with fetal ventriculomegaly.Materials and methodsReports of women who underwent ultrasound scanning between 18 and 36 weeks of gestation during the period from January 1, 2000, to December 31, 2010, were reviewed. According to the defined severity of ventriculomegaly of affected fetuses, the women were divided into the following groups: (1) mild ventriculomegaly (Group A); (2) moderate ventriculomegaly (Group B); and (3) severe ventriculomegaly (Group C). The women were classified into the “gray zone” group if the fetal lateral ventricle measured between 7 mm and <10 mm. All cases were followed up with additional ultrasound scans. Postnatal information was obtained from the computer database or the medical charts.ResultsA total of 41 cases were recruited for this analysis. Four (9.8%) cases had an abnormal karyotype. Twelve women (29.3%) opted for termination of pregnancy. Of the 29 women who delivered, 56.1% (N = 23) were from Group A, 14.6% (N = 6) were from Group B, and none was from Group C. All children in Group A had normal neurological development. Three children in Group B had normal neurological development, whereas the other three had neurologic deficits. A total of 432 cases were classified into the “gray zone” group. Of these cases, 2.8% (N = 12) progressed to ventriculomegaly.ConclusionCases of isolated and mild ventriculomegaly without additional structural anomalies or chromosomal aberrations had good prognoses. However, the parents of fetuses with moderate or severe ventriculomegaly should be counseled regarding related risks. If the ventricular size of the fetus falls within the “gray zone”, at least one additional exam in the third trimester should be performed, for early detection of ventriculomegaly and other related abnormalities. It is important to make the parents of these fetuses aware of these risks, from a medico-legal point of view

Effects of mycophenolate mofetil on cutaneous lupus erythematosus in (NZB × NZW) F1 mice

AbstractBackgroundFew studies have evaluated the effects and precise molecular mechanism of mycophenolate mofetil (MMF) in the treatment of human cutaneous lupus erythematosus (CLE). Our findings shed light on the therapeutic effects of MMF in a UVB-induced NZB × NZW (NZBW) F1 CLE mouse model.MethodsContinuous MMF treatment (60 mg/kg/day) was administered up to Day 50 from the beginning of UVB induction (Day 0; 20 weeks old), as the pathologic features of CLE are present after 50 days. The therapeutic effects of MMF treatment in NZBW lupus mice were examined by comparing histopathological changes, lupus band test (deposition of immune complexes at the dermal–epidermal junction) and colocalization of autoantibodies with a dermal autoantigen Dsg3, and by evaluating the associations of local matrix metalloprotease activities.ResultsMMF improved survival in the NZBW lupus mice from 35.7% to 81.8%. The proteinuria, blood urea nitrogen, and interleukin 6 levels were significantly reduced after MMF treatment. The dermal lymphocytic infiltration, deposition of immune complexes at the dermal–epidermal junction, colocalized autoantibodies with Dsg3, and epidermal matrix metalloprotease activity were also attenuated in MMF-treated NZBW F1 mice.ConclusionThe results confirmed that MMF could substantially attenuate skin damage due to CLE in the NZBW F1 mouse model

Clinical Implications of High MET Gene Dosage in Non-Small Cell Lung Cancer Patients without Previous Tyrosine Kinase Inhibitor Treatment

Introduction:Recently, two studies revealed that MET amplification was associated with secondary epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance in non-small cell lung cancer (NSCLC) patients. But it remains uncertain whether MET amplification could be related to primary TKI resistance in NSCLC because of limited data.Materials and Methods:MET gene dosage of the tumor tissues from 208 NSCLC patients was investigated by real time quantitative polymerase chain reaction and compared with molecular and clinical features, including EGFR mutations, KRAS mutations, EGFR gene copy numbers, and patient survivals. Three copies were used as the cutoff. Among them, 25 patients were also evaluable for EGFR TKI responsiveness.Results:The proportion of high MET gene dosage was 10.58% (22/208) with higher incidence in squamous cell carcinoma (11.86%) and smokers (16.18%), although the differences with adenocarcinoma and nonsmokers were nonsignificant. Coexisting EGFR mutations were identified, and the incidence (8.54%) was similar to wild type (12.0%). High MET gene dosage was significantly associated with higher tumor stage (stage I + II versus stage III + IV; p = 0.0254) and prior chemotherapy for stage III + IV adenocarcinoma patients (35.71% versus 7.41%; p = 0.0145) but not correlated with primary TKI resistance. Among the 155 surgically resectable patients (stage I to IIIA), high MET gene dosage was significantly associated with shorter median survival (21.0 months versus 47.1 months; p = 0.042) by univariate analysis.Conclusions:High MET gene dosage was not related to primary TKI resistance and the incidence was increased after chemotherapy, suggesting high MET gene dosage may also be related to chemotherapy resistance

Melatonin acts synergistically with pazopanib against renal cell carcinoma cells through p38 mitogen-activated protein kinase-mediated mitochondrial and autophagic apoptosis

Background Mounting evidence indicates that melatonin has possible activity against different tumors. Pazopanib is an anticancer drug used to treat renal cell carcinoma (RCC). This study tested the anticancer activity of melatonin combined with pazopanib on RCC cells and explored the underlying mechanistic pathways of its action. Methods The 786-O and A-498 human RCC cell lines were used as cell models. Cell viability and tumorigenesis were detected with the MTT and colony formation assays, respectively. Apoptosis and autophagy were assessed using TUNEL, annexin V/propidium iodide, and acridine orange staining with flow cytometry. The expression of cellular signaling proteins was investigated with western blotting. The in vivo growth of tumors derived from RCC cells was evaluated using a xenograft mouse model. Results Together, melatonin and pazopanib reduced cell viability and colony formation and promoted the apoptosis of RCC cells. Furthermore, the combination of melatonin and pazopanib triggered more mitochondrial, caspase-mediated, and LC3-II-mediated autophagic apoptosis than melatonin or pazopanib alone. The combination also induced higher activation of the p38 mitogen-activated protein kinase (p38MAPK) in the promotion of autophagy and apoptosis by RCC cells than melatonin or pazopanib alone. Finally, tumor xenograft experiments confirmed that melatonin and pazopanib cooperatively inhibited RCC growth in vivo and predicted a possible interaction between melatonin/pazopanib and LC3-II. Conclusion The combination of melatonin and pazopanib inhibits the growth of RCC cells by inducing p38MAPK-mediated mitochondrial and autophagic apoptosis. Therefore, melatonin might be a potential adjuvant that could act synergistically with pazopanib for RCC treatment

Influences of Stacking Architectures of TiO 2

We investigated the influences of stacking architectures of the TiO2 nanoparticle layers on characteristics and performances of DSSCs. TiO2 nanoparticles of different sizes and compositions were characterized for their morphological and optical/scattering properties in thin films. They were used to construct different stacking architectures of the TiO2 nanoparticle layers for use as working electrodes of DSSCs. Characteristics and performances of DSSCs were examined to establish correlation of the stacking architectures of TiO2 nanoparticle layers with characteristics of DSSCs. The results suggest that the three-layer DSSC architecture, with sandwiching a 20 nm TiO2 nanoparticle layer between a 37 nm TiO2 nanoparticle layer and a hundred nm sized TiO2 back scattering/reflection layer, is effective in enhancing DSSC efficiencies. The high-total-transmittance 37 nm TiO2 nanoparticle layer with a larger haze can serve as an effective front scattering layer to scatter a portion of the incident light into larger oblique angles and therefore increase optical paths and absorption

Anti-Cancer Effects of Radix Angelica Sinensis (Danggui) and N-Butylidenephthalide on Gastric Cancer: Implications for REDD1 Activation and mTOR Inhibition

Background/Aims: Radix Angelica Sinensis (danggui in Chinese) is widely used in traditional chinese medicine (TCM). N-butylidenephthalide (BP), a bioactive compound in danggui, is a potential antitumor agent for various cancer types. However, its clinical effect and mechanism in the treatment of gastric cancer remain undetermined. Methods: The in vivo protective effect of danggui in patients with gastric cancer were validated using data from Taiwan’s National Health Insurance Research Database (NHIRD). The genes induced by BP-treatment were analyzed by whole transcriptome RNA sequencing (RNA-seq) and validated by real-time PCR, western blot and siRNA transfection. The effect of BP on AGS cell migration and invasion was evaluated in transwell assays. The antitumor effects of BP were evaluated in vivo in an AGS xenograft animal model. Results: Danggui users were found to have an increased survival rate when compared with danggui nonusers (log-rank test p = 0.002) . The use of danggui highly associated with decreased mortality (the adjusted hazard ratio (HR) of danggui user was 0.72 [95 % CI, 0.57-0.92] (p = 0.009). The in vitro results showed that BP inhibited gastric cancer cell proliferation, and triggered cellular apoptosis depending on the activation of mitochondrial apoptotic pathway. Using RNA-seq analysis we found that REDD1 was the highest transcript induced by BP in gastric cancer cells. BP induce an increase of REDD1 expression that inhibits mTOR signaling, thus inhibiting gastric cancer growth. We used RNA interference to demonstrate that the knock-down of REDD1 attenuated the BP-induced mTORC1 activation and growth inhibition. BP suppressed the growth of AGS xenografts tumor in vivo. Conclusion: Danggui can prolong the survival rate of gastric cancer patients in Taiwan. BP caused gastric cancer cell death through the activation of mitochondria-intrinsic pathway and induced the REDD1 expression leading to mTOR signal pathway inhibition in gastric cancer cells. BP inhibited the in vivo growth of AGS xenograft tumors. These results may provide the basis for a new therapeutic approach toward the treatment of gastric cancer progression