Osteosarcoma, with its high metastatic potential, is the most prevalent malignant bone tumor in children and adolescents. Melatonin possesses multiple tumor‐suppressing properties for a myriad of ...tumors, but little is known about the effects of melatonin on osteosarcoma metastasis. In this study, we demonstrated that melatonin elicited very low cytotoxicity and significantly inhibited cellular motility, migration, and invasion in human osteosarcoma U2OS and HOS cells. Moreover, using RNA sequencing technology, we revealed that melatonin repressed C‐C motif chemokine ligand 24 (CCL24) gene expression in U2OS cells. Manipulation of CCL24 levels influenced the motility of osteosarcoma cells as cell migration and invasion were enhanced by the addition of recombinant human CCL24 and attenuated by the silencing of CCL24. Moreover, melatonin increased and decreased the activation of extracellular signal‐regulated kinase (ERK) 1/2 and c‐Jun N‐terminal kinase (JNK) 1/2, respectively, in a dose‐dependent manner in U2OS and HOS cells while exerting no evident influence on the level and activation of p38, Akt, FAK, steroid receptor coactivator, or Raf. In further functional experiments, the use of JNK inhibitors (SP600125 and DN‐JNK) confirmed that the pharmaceutic inhibition of JNK augmented the melatonin‐mediated CCL24 suppression and migration of U2OS cells. Overall, our results revealed that melatonin attenuated chemokine CCL24 levels through inhibition of the JNK pathway to hinder human osteosarcoma cell invasion, thereby highlighting the therapeutic potential of melatonin for osteosarcoma metastasis.
Background and Purpose
The interleukin (IL)‐36 pathway is a critical player in the pathogenesis of pustular psoriasis. However, therapies targeting this pathway are limited or unaffordable (e.g. the ...anti‐IL‐36 receptor antibody). AMP‐activated protein kinase (AMPK), a regulator of cellular energy and metabolism, is known to participate in inflammatory diseases. However, its role in IL‐36‐induced skin inflammation remains unclear. Therefore, we sought to investigate the role of AMPK signals in regulating IL‐36‐induced responses in the skin.
Experimental Approach
IL‐36‐stimulated primary normal human epidermal keratinocytes (NHEKs) and IL‐36‐injected (intradermally) BALB/c mice served as the cell and animal models, respectively. Additionally, 5‐aminoimidazole‐4‐carboxamide riboside (AICAR) and A769662 served as AMPK activators.
Key Results
AICAR and A769662 significantly suppressed the IL‐36‐induced IL‐8 (CXCL8) and CCL20 production from NHEKs. IL‐36‐induced IκBζ protein expression was prominently reduced and IKK/IκBα phosphorylation was attenuated by AICAR and A769662. Conversely, AMPKα knockdown increased IκBζ protein expression and IKK/IκBα phosphorylation in IL‐36‐treated NHEKs. Furthermore, AICAR and A769662 enhanced IL‐36‐induced‐IκBζ protein degradation via the proteasome‐dependent but not the lysosome‐dependent pathway. Pretreatment of NHEKs with IL‐36 slightly suppressed the AICAR‐ and A769662‐triggered phosphorylation of AMPK and acetyl‐CoA carboxylase. In the mouse model, topical application of AICAR significantly reduced ear swelling, redness, epidermal thickening, neutrophil infiltration and inflammatory and antimicrobial peptide gene expression.
Conclusion and Implications
AMPK activation suppresses IL‐36‐induced IL‐8 and CCL20 release by regulating IκBζ expression in keratinocytes and reduces IL‐36‐induced skin inflammation in mice, suggesting that AMPK activation is a potential strategy for treating patients with IL‐36‐mediated inflammatory skin disorders.
Fucoidan, a heparin-like sulfated polysaccharide, is rich in brown algae. It has a wide assortment of protective activities against cancer, for example, induction of hepatocellular carcinoma ...senescence, induction of human breast and colon carcinoma apoptosis, and impediment of lung cancer cells migration and invasion. However, the anti-metastatic mechanism that fucoidan exploits remains elusive. In this report, we explored the effects of fucoidan on cachectic symptoms, tumor development, lung carcinoma cell spreading and proliferation, as well as expression of metastasis-associated proteins in the Lewis lung carcinoma (LLC) cells-inoculated mice model. We discovered that administration of fucoidan has prophylactic effects on mitigation of cachectic body weight loss and improvement of lung masses in tumor-inoculated mice. These desired effects are attributed to inhibition of LLC spreading and proliferation in lung tissues. Fucoidan also down-regulates expression of matrix metalloproteinases (MMPs), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and vascular endothelial growth factor (VEGF). Moreover, the tumor-bearing mice supplemented with fucoidan indeed benefit from an ensemble of the chemo-phylacticity. The fact is that fucoidan significantly decreases viability, migration, invasion, and MMPs activities of LLC cells. In summary, fucoidan is suitable to act as a chemo-preventative agent for minimizing cachectic symptoms as well as inhibiting lung carcinoma metastasis through down-regulating metastatic factors VEGF and MMPs.
Androgen receptor signaling plays a critical role in prostate cancer pathogenesis. Yet, the regulation of androgen receptor signaling remains elusive. Even with stringent androgen deprivation ...therapy, androgen receptor signaling persists. Here, our data suggest that there is a complex interaction between the expression of the tumor suppressor miRNA, miR-31, and androgen receptor signaling. We examined primary and metastatic prostate cancer and found that miR-31 expression was reduced as a result of promoter hypermethylation, and importantly, the levels of miR-31 expression were inversely correlated with the aggressiveness of the disease. As the expression of androgen receptor and miR-31 was inversely correlated in the cell lines, our study further suggested that miR-31 and androgen receptor could mutually repress each other. Upregulation of miR-31 effectively suppressed androgen receptor expression through multiple mechanisms and inhibited prostate cancer growth in vivo. Notably, we found that miR-31 targeted androgen receptor directly at a site located in the coding region, which was commonly mutated in prostate cancer. In addition, miR-31 suppressed cell-cycle regulators including E2F1, E2F2, EXO1, FOXM1, and MCM2. Together, our findings suggest a novel androgen receptor regulatory mechanism mediated through miR-31 expression. The downregulation of miR-31 may disrupt cellular homeostasis and contribute to the evolution and progression of prostate cancer. We provide implications for epigenetic treatment and support clinical development of detecting miR-31 promoter methylation as a novel biomarker.
Chemo- and radiotherapy cause multiple forms of DNA damage and lead to the death of cancer cells. Inhibitors of the DNA damage response are candidate drugs for use in combination therapies to ...increase the efficacy of such treatments. In this study, we show that curcumin, a plant polyphenol, sensitizes budding yeast to DNA damage by counteracting the DNA damage response. Following DNA damage, the Mec1-dependent DNA damage checkpoint is inactivated and Rad52 recombinase is degraded by curcumin, which results in deficiencies in double-stand break repair. Additive effects on damage-induced apoptosis and the inhibition of damage-induced autophagy by curcumin were observed. Moreover, rpd3 mutants were found to mimic the curcumin-induced suppression of the DNA damage response. In contrast, hat1 mutants were resistant to DNA damage, and Rad52 degradation was impaired following curcumin treatment. These results indicate that the histone deacetylase inhibitor activity of curcumin is critical to DSB repair and DNA damage sensitivity.
Stroke is a cerebral artery disease that negatively affects activities of daily living (ADLs) and quality of life (QoL). Smartphones have demonstrated strong potential in assessing balance ...performance. However, such smartphone-based tools have thus far not been applied to stroke survivors. The purpose of this study was to develop a smartphone-based balance assessment system for subjects who have experienced strokes and evaluate the system feasibility. The smartphone-based balance assessment application was developed with Android Studio, and reliability and validity tests were conducted. The smartphone was used to record data using a built-in accelerometer and gyroscope, and increased changes represented greater instability. Six postures were tested for 30 s each. Ten healthy adults were recruited in the reliability test, and the intraclass correlation coefficient (ICC) was used to analyze the within-day and between-day reliabilities. Eight subjects with chronic stroke and eight healthy adults were recruited for the validity test, in which balance performance was compared to represent the application validity. The ICC values of the reliability tests were at least 0.76 (
= 0.00). The acceleration data exhibited no difference between individuals who have experienced stroke and healthy subjects; however, all six postures were found to differ significantly between the two groups in the gyroscope data. The study demonstrates that the smartphone application provides a convenient, reliable, and valid tool for the balance assessments of subjects who have experienced chronic stroke.
A novel atomic stacking transporting layer (ASTL) based on 2D atomic sheets of titania (Ti1−δO2) is demonstrated in organic–inorganic lead halide perovskite solar cells. The atomically thin ASTL of ...2D titania, which is fabricated using a solution‐processed self‐assembly atomic layer‐by‐layer deposition technique, exhibits the unique features of high UV transparency and negligible (or very low) oxygen vacancies, making it a promising electron transporting material in the development of stable and high‐performance perovskite solar cells. In particular, the solution‐processable atomically thin ASTL of 2D titania atomic sheets shows superior inhibition of UV degradation of perovskite solar cell devices, compared to the conventional high‐temperature sintered TiO2 counterpart, which usually causes the notorious instability of devices under UV irradiation. The discovery opens up a new dimension to utilize the 2D layered materials with a great variety of homostructrual or heterostructural atomic stacking architectures to be integrated with the fabrication of large‐area photovoltaic or optoelectronic devices based on the solution processes.
The self‐assembly atomic stacking transporting layer based on 2D titania atomic sheets exhibits unique advantages when used as an electron transporting layer for the development of stable and high‐performance perovskite solar cells. The advantages are shown to include high UV transparency, negligible (or very low) oxygen vacancies, and solution processability.
Modulation of band bending at a complex oxide heterointerface by a ferroelectric layer is demonstrated. The as‐grown polarization (Pup) leads to charge depletion and consequently low conduction. ...Switching the polarization direction (Pdown) results in charge accumulation and enhances the conduction at the interface. The metal–insulator transition at a conducting polar/nonpolar oxide heterointerface can be controlled by ferroelectric doping.
Abstract
High-temperature superconductive (SC) cuprates exhibit not only a SC phase, but also competing orders, suppressing superconductivity. Charge order (CO) has been recognized as an important ...competing order, but its microscopic spatial interplay with SC phase as well as the interlayer coupling in CO and SC phases remain elusive, despite being essential for understanding the physical mechanisms of competing orders and hence superconductivity. Here we report the achievement of direct real-space imaging with atomic-scale resolution of cryogenically cleaved YBa
2
Cu
3
O
6.81
using cross-sectional scanning tunneling microscopy/spectroscopy. CO nanodomains are found embedded in the SC phase with a proximity-like boundary region characterized by mutual suppression of CO and superconductivity. Furthermore, SC coherence as well as CO occur on both CuO chain and plane layers, revealing carrier transport and density of states mixing between layers. The CO antiphase correlation along the
c
direction suggests a dominance of Coulomb repulsion over Josephson tunneling between adjacent layers.
Increased intracranial pressure (ICP) in patients with traumatic brain injury (TBI) is associated with a higher mortality rate and poor outcome. Mannitol and hypertonic saline (HTS) have both been ...used to treat high ICP, but it is unclear which one is more effective. Here, the authors compare the effect of mannitol versus HTS on lowering the cumulative and daily ICP burdens after severe TBI.
The Brain Trauma Foundation TBI-trac New York State database was used for this retrospective study. Patients with severe TBI and intracranial hypertension who received only 1 type of hyperosmotic agent, mannitol or HTS, were included. Patients in the 2 groups were individually matched for Glasgow Coma Scale score (GCS), pupillary reactivity, craniotomy, occurrence of hypotension on Day 1, and the day of ICP monitor insertion. Patients with missing or erroneous data were excluded. Cumulative and daily ICP burdens were used as primary outcome measures. The cumulative ICP burden was defined as the total number of days with an ICP of > 25 mm Hg, expressed as a percentage of the total number of days of ICP monitoring. The daily ICP burden was calculated as the mean daily duration of an ICP of > 25 mm Hg, expressed as the number of hours per day. The numbers of intensive care unit (ICU) days, numbers of days with ICP monitoring, and 2-week mortality rates were also compared between the groups. A 2-sample t-test or chi-square test was used to compare independent samples. The Wilcoxon signed-rank or Cochran-Mantel-Haenszel test was used for comparing matched samples.
A total of 35 patients who received only HTS and 477 who received only mannitol after severe TBI were identified. Eight patients in the HTS group were excluded because of erroneous or missing data, and 2 other patients did not have matches in the mannitol group. The remaining 25 patients were matched 1:1. Twenty-four patients received 3% HTS, and 1 received 23.4% HTS as bolus therapy. All 25 patients in the mannitol group received 20% mannitol. The mean cumulative ICP burden (15.52% HTS vs 36.5% mannitol; p = 0.003) and the mean (± SD) daily ICP burden (0.3 ± 0.6 hours/day HTS vs 1.3 ± 1.3 hours/day mannitol; p = 0.001) were significantly lower in the HTS group. The mean (± SD) number of ICU days was significantly lower in the HTS group than in the mannitol group (8.5 ± 2.1 vs 9.8 ± 0.6, respectively; p = 0.004), whereas there was no difference in the numbers of days of ICP monitoring (p = 0.09). There were no significant differences between the cumulative median doses of HTS and mannitol (p = 0.19). The 2-week mortality rate was lower in the HTS group, but the difference was not statistically significant (p = 0.56).
HTS given as bolus therapy was more effective than mannitol in lowering the cumulative and daily ICP burdens after severe TBI. Patients in the HTS group had significantly lower number of ICU days. The 2-week mortality rates were not statistically different between the 2 groups.
PDF
