Chitinase 3-like 1 induces cancer cell migration in solitary fibrous tumors.

Solitary fibrous tumor (SFT) is a rare mesenchymal tumor that is diagnosed through the detection of the NAB2-STAT6 fusion gene. SFT rarely progresses to malignant tumors; however, metastasis is exhibited in approximately 20% of patients with SFT. In this study, we found that chitinase 3-like 1 (CHI3L1), which induces cancer cell migration, was upregulated in NIH-3T3 cells that were transfected with the NAB2-STAT6 fusion gene. Moreover, the expression levels of the migration markers MMP2 and MMP9 were increased and the p-Akt level was also upregulated. In addition, it was observed that when CHI3L1 siRNA was transfected into NAB2-STAT6-transfected cells, cell migration and proliferation were reduced. Therefore, this study demonstrated that CHI3L1 activates Akt signaling to induce cell migration.

NAB2-STAT6 fusion protein mediates cell proliferation and oncogenic progression via EGR-1 regulation.

Solitary fibrous tumors are rare mesenchymal tumors derived from soft tissues and vascular walls. NAB2-STAT6 fusion gene serves as a marker gene for this disease and consists of the truncated repressor domain of NGFI-A-Binding protein 2 (NAB2) and the intact activation domain of STAT6. In this study, we found that EGR-1 and the proliferation-related EGR-1 target gene IGF2 were upregulated in NIH-3T3 cells transfected with NAB2-STAT6. Additionally, p-Rb (Ser795) and cyclin D1 levels were upregulated, and cell proliferation was also enhanced. We identified that treatment with the IGF2 inhibitor reduced cell proliferation in NIH-3T3 cells transfected with NAB2-STAT6. The oncogenic progression was enhanced in NIH-3T3 cells transfected with NAB2-STAT6 compared with those transfected with the empty vector. Taken together, our study suggests that the NAB2-STAT6 fusion gene is associated with cell proliferation through EGR-1 transcriptional expression and IGF2 can be a drug target for the treatment of solitary fibrous tumors.

Auxin mediates the touch-induced mechanical stimulation of adventitious root formation under windy conditions in Brachypodium distachyon.

BACKGROUND: It is widely perceived that mechanical or thigmomorphogenic stimuli, such as rubbing and bending by passing animals, wind, raindrop, and flooding, broadly influence plant growth and developmental patterning. In particular, wind-driven mechanical stimulation is known to induce the incidence of radial expansion and shorter and stockier statue. Wind stimulation also affects the adaptive propagation of the root system in various plant species. However, it is unknown how plants sense and transmit the wind-derived mechanical signals to launch appropriate responses, leading to the wind-adaptive root growth. RESULTS: Here, we found that Brachypodium distachyon, a model grass widely used for studies on bioenergy crops and cereals, efficiently adapts to wind-mediated lodging stress by forming adventitious roots (ARs) from nonroot tissues. Experimental dissection of wind stimuli revealed that not bending of the mesocotyls but physical contact of the leaf nodes with soil particles triggers the transcriptional induction of a group of potential auxin-responsive genes encoding WUSCHEL RELATED HOMEOBOX and LATERAL ORGAN BOUNDARIES DOMAIN transcription factors, which are likely to be involved in the induction of AR formation. CONCLUSIONS: Our findings would contribute to further understanding molecular mechanisms governing the initiation and development of ARs, which will be applicable to crop agriculture in extreme wind climates.

Shoot phytochrome B modulates reactive oxygen species homeostasis in roots via abscisic acid signaling in Arabidopsis.

Underground roots normally reside in darkness. However, they are often exposed to ambient light that penetrates through cracks in the soil layers which can occur due to wind, heavy rain or temperature extremes. In response to light exposure, roots produce reactive oxygen species (ROS) which promote root growth. It is known that ROS-induced growth promotion facilitates rapid escape of the roots from non-natural light. Meanwhile, long-term exposure of the roots to light elicits a ROS burst, which causes oxidative damage to cellular components, necessitating that cellular levels of ROS should be tightly regulated in the roots. Here we demonstrate that the red/far-red light photoreceptor phytochrome B (phyB) stimulates the biosynthesis of abscisic acid (ABA) in the shoots, and notably the shoot-derived ABA signals induce a peroxidase-mediated ROS detoxification reaction in the roots. Accordingly, while ROS accumulate in the roots of the phyb mutant that exhibits reduced primary root growth in the light, such an accumulation of ROS did not occur in the dark-grown phyb roots that exhibited normal growth. These observations indicate that mobile shoot-to-root ABA signaling links shoot phyB-mediated light perception with root ROS homeostasis to help roots adapt to unfavorable light exposure. We propose that ABA-mediated shoot-to-root phyB signaling contributes to the synchronization of shoot and root growth for optimal propagation and performance in plants.

Systemic Immunity Requires SnRK2.8-Mediated Nuclear Import of NPR1 in Arabidopsis.

In plants, necrotic lesions occur at the site of pathogen infection through the hypersensitive response, which is followed by induction of systemic acquired resistance (SAR) in distal tissues. Salicylic acid (SA) induces SAR by activating NONEXPRESSER OF PATHOGENESIS-RELATED GENES1 (NPR1) through an oligomer-to-monomer reaction. However, SA biosynthesis is elevated only slightly in distal tissues during SAR, implying that SA-mediated induction of SAR requires additional factors. Here, we demonstrated that SA-independent systemic signals induce a gene encoding SNF1-RELATED PROTEIN KINASE 2.8 (SnRK2.8), which phosphorylates NPR1 during SAR. The SnRK2.8-mediated phosphorylation of NPR1 is necessary for its nuclear import. Notably, although SnRK2.8 transcription and SnRK2.8 activation are independent of SA signaling, the SnRK2.8-mediated induction of SAR requires SA. Together with the SA-mediated monomerization of NPR1, these observations indicate that SA signals and SnRK2.8-mediated phosphorylation coordinately function to activate NPR1 via a dual-step process in developing systemic immunity in Arabidopsis thaliana.

Development of Houttuynia cordata Extract-Loaded Solid Lipid Nanoparticles for Oral Delivery: High Drug Loading Efficiency and Controlled Release.

Houttuynia cordata (H. cordata) has been used for diuresis and detoxification in folk medicine as well as a herbal medicine with antiviral and antibacterial activities. H. cordata extract-loaded solid lipid nanoparticles (H-SLNs) were prepared with various concentration of poloxamer 188 or poloxamer 407 by a hot homogenization and ultrasonication method. H-SLNs dispersion was freeze-dried with or without trehalose as a cryoprotectant. The physicochemical characteristics of H-SLNs were evaluated by dynamic laser scattering (DLS), differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FT-IR), and scanning electron microscopy (SEM). Additionally, the in vitro release and in vitro cytotoxicity of H-SLNs were measured. Encapsulation efficiencies of H-SLNs (as quercitrin) were 92.9-95.9%. The SEM images of H-SLNs showed that H-SLNs have a spherical morphology. DSC and FT-IR showed that there were no interactions between ingredients. The increased extent of particle size of freeze-dried H-SLNs with trehalose was significantly lower than that of H-SLNs without trehalose. H-SLNs provided sustained release of quercitrin from H. cordata extracts. Cell viability of Caco-2 cells was over 70% according to the concentration of various formulation. Therefore, it was suggested that SLNs could be good carrier for administering H. cordata extracts.

Preformulation Studies of Bee Venom for the Preparation of Bee Venom-Loaded PLGA Particles.

It is known that allergic people was potentially vulnerable to bee venom (BV), which can induce an anaphylactic shock, eventually leading to death. Up until recently, this kind of allergy was treated only by venom immunotherapy (VIT) and its efficacy has been recognized worldwide. This treatment is practiced by subcutaneous injections that gradually increase the doses of the allergen. This is inconvenient for patients due to frequent injections. Poly (D,L-lactide-co-glycolide) (PLGA) has been broadly studied as a carrier for drug delivery systems (DDS) of proteins and peptides. PLGA particles usually induce a sustained release. In this study, the physicochemical properties of BV were examined prior to the preparation of BV-loaded PLGA nanoparticles NPs). The content of melittin, the main component of BV, was 53.3%. When protected from the light BV was stable at 4 °C in distilled water, during 8 weeks. BV-loaded PLGA particles were prepared using dichloromethane as the most suitable organic solvent and two min of ultrasonic emulsification time. This study has characterized the physicochemical properties of BV for the preparation BV-loaded PLGA NPs in order to design and optimize a suitable sustained release system in the future.

Strain-assisted, low-temperature synthesis of high-performance thermoelectric materials.

Utilizing internal energy artificially implemented by cold-pressing in the specimens, we demonstrate a way to synthesize high-quality bulk thermoelectric materials at otherwise too low a temperature to approach to an equilibrium state. This low-temperature synthesis technique will provide a new opportunity to integrate high-performance thermoelectric materials into various electronic devices for a built-in energy source, as well as to develop low-cost fabrication methods.

Radiolucent Pure Matrix Stones on Computed Tomography Scan, Arising in Patient with Type I Diabetes and Chronic Kidney Disease: A Case Report.

Kidney matrix stones are a rare form of calculi, which are challenging to diagnose. Matrix stones consist of a proteinaceous material which has a radiolucent appearance that might be overlooked on imaging. Recently, endourological intervention has been the standard treatment method for matrix stones. We report a case of urinary matrix stones in a patient with type 1 diabetes mellitus and chronic kidney disease, in whom the stones formed into a pure matrix and were not visualized in the computed tomography scan. The stones were found after additional work-up, and they were managed using a transureteral stone basket, not through endourological intervention.

Influence of temperature shifts on the onset and development of red sea bream iridoviral disease in rock bream Oplegnathus fasciatus.

The effects of various water temperature treatments on the development of red sea bream iridovirus disease (RSIVD) in rock bream Oplegnathus fasciatus challenged with iridovirus Sachun (IVS-1) were determined by measuring the mortality and the viral concentration in the spleen of infected fish. Experimental infections of rock bream with IVS-1 at water temperatures of 18, 21, and 25 degrees C resulted in a cumulative mortality of 100%, but infections at 13 degrees C resulted in 0% mortality, even after 45 d. The disease progressed more rapidly at higher water temperatures; at 25, 21, and 18 degrees C, the mean numbers of days until death were 17, 20, and 30 d, respectively. When the water temperature for fish infected with iridovirus by intramuscular injection was shifted from 13 to 25 degrees C, the cumulative mortality reached 100%, with rapid onset of the disease, independent of the time at which the temperature was shifted, i.e. 7, 14, or 30 d after injection at 13 degrees C. Real-time PCR data revealed that the viral genome copy number in the spleen of rock bream maintained at 13 degrees C increased with time, suggesting the occurrence of viral replication even at 13 degrees C. In the reverse experiment, when the water temperature for fish that were infected at a higher temperature was shifted to 13 degrees C, 3 or 7 d after injection at 25 degrees C, the fish showed 100% cumulative mortality, although the mean number of days until death was higher than that observed for fish maintained at a constant temperature of 25 degrees C. The viral DNA concentration in the spleen of rock bream that had been shifted down to 13 degrees C, 3 or 7 d after injection at 25 degrees C, was not suppressed, but increased and eventually reached levels sufficient to induce mortality at 13 degrees C. However, the level of viral genome copy numbers in the spleen of dead fish at 25 degrees C, regardless of whether those fish were held at a constant temperature of 25 degrees C or shifted up from 13 degrees C, appeared to be greater than the level found in the dead fish shifted down to 13 degrees C after inoculation at 25 degrees C.

Roles of G protein and beta-arrestin in dopamine D2 receptor-mediated ERK activation.

ERK activation by dopamine D(2) receptor (D(2)R) has been extensively characterized in various cell types including brain tissues. However, the involvement of beta-arrestin in the D(2)R-mediated ERK activation is not clear yet. Three different strategies were employed in this study to determine the roles of G protein or beta-arrestin in D(2)R-mediated ERK activation. The cellular level of beta-arrestins was reduced by RNA interference and pertussis toxin-insensitive Gi proteins were used to identify the G protein involved. Finally point mutations of D(2)R in which coupling with G protein was abolished but the interaction with beta-arrestin was increased, were employed to determine whether the affinity between D(2)R and beta-arrestin is a critical factor for beta-arrestin-mediated ERK activation. Our results show that G(i2) protein is involved in D(2)R-mediated ERK activation but beta-arrestins are either not involved or play minor role.

Characterization of functional roles of DRY motif in the 2nd intracellular loop of dopamine D2 and D3 receptors.

Dopamine D(2)R and D(3)R (D(2)R, D(3)R) show very high sequence homology and employ virtually identical signaling pathways even though D(2)R is 2 approximately 5 times more active. Among the structural motifs identified, a triplet sequence, Asp-Arg-Tyr (DRY motif), plays critical roles in the determination of receptor conformations for signaling and intracellular trafficking of G protein-coupled receptors by forming intramolecular interactions. Thus, it is possible that different signaling efficiencies of D(2)R and D(3)R might be caused by the receptor activation levels stabilized by their own DRY motifs. In this study, the Arg and Asp residues of D(2)R and D(3)R were mutated, and resulting changes in their signaling and intracellular trafficking properties were comparatively studied. Mutation of the Arg residues of D(2)R and D(3)R abolished their signaling but differently affected their intracellular localizations. The wildtype and R132H-D(2)R were expressed mainly on the plasma membrane. On the other hand, compared with the wildtype D(3)R, a substantial amount of R128H-D(3)R was localized intracellularly. The expression of receptor proteins on the plasma membrane and their signaling efficiencies were more drastically affected by the mutation of the Asp residue of D(3)R than D(2)R. Therefore, it was concluded that the different levels of conformational strain exerted by the DRY motif might partly determine the quantitative differences in the signaling efficiencies between D(2)R and D(3)R.

Nasal delivery of chitosan/alginate nanoparticle encapsulated bee (Apis mellifera) venom promotes antibody production and viral clearance during porcine reproductive and respiratory syndrome virus infection by modulating T cell related responses.

In this study, we administered specially developed chitosan/alginate nanoparticle encapsulated BV (CH/AL-BV) which has slow-releasing properties and mucosal adhesiveness to pig via nasal route and evaluate whether it can facilitate systemic immune response and improve clearance of porcine reproductive and respiratory syndrome virus (PRRSV). The CH/AL-BV-administered group with PRRSV vaccination showed significantly enhanced Th1-related responses including a high population of CD4+ T lymphocyte and cytokine mRNA levels including interferon-gamma (IFN-γ) and interleukin (IL)-12 and increased PRRSV-specific IgG levels. In the PRRSV challenge experiment, the CH/AL-BV group showed a significant decrease of viral burden in the sera and tissues (lung and bronchial lymph node) and mild interstitial pneumonia signs on both lung gross examination and microscopic evaluation with high levels of PRRSV-specific IgG and viral neutralizing antibody. CH/AL-BV also effectively induced not only Th1-related immune responses including increase in portion of CD4+ T lymphocyte, cytokines (IFN-γ and IL-12), and transcriptional factors (STAT4 and T-bet), but also stimulated IFN-γ-secreting cell families such as CD4+ T lymphocytes and Th/memory cells. Interestingly, the CH/AL-BV group showed decrease in PRRSV-specific immune-suppressive actions, including the T regulatory cell population and its related cytokines (IL-10 and TGF-ß) and transcriptional factors (STAT5 and Foxp3). Therefore, nasal-delivered CH/AL-BV may effectively induce non-specific immune stimulating actions, particularly those related to Th1 responses and viral clearance activities against PRRSV infection. Based on these results, CH/AL-BV could be a promising strategy for overcoming the disadvantages of classical PRRSV vaccination and can be applied as a preventive agent against PRRSV and other viral diseases, particularly those with immune-suppressive characteristics.

TRIB2 regulates the differentiation of MLL-TET1 transduced myeloid progenitor cells.

The function and mechanism of action of MLL-TET1 (MT1) fusion protein in hematological cells are unclear and require further investigation. In the present study, we found that the MT1 fusion protein attenuated the expression of Cebpa, Csf1r, and Cd11b and inhibited the differentiation of myeloid progenitor cells. Increased binding of the MT1 fusion protein to the Trib2 promoter upregulated Trib2 mRNA and protein expression and downregulated Cebpa expression. Trib2 knockdown relieved the inhibition of myeloid cell differentiation induced by the MT1 fusion protein. Thus, TRIB2 is important for the survival of leukemia cells during MT1-related leukemogenesis and is important in maintaining differentiation blockade of leukemic cells. KEY MESSAGES: • MLL-TET1 fusion decreases the 5-hmC levels in the myeloid progenitor cells. • MLL-TET1 fusion inhibits myeloid differentiation through decreased expression of Cebpa. • MLL-TET1 fusion blocks the differentiation of the myeloid progenitor cells by overexpressing Trib2. • Knockdown of Trib2 in MLL-TET1 transduced cells induces myeloid differentiation.

HOS1 acts as a key modulator of hypocotyl photomorphogenesis.

Plants recognize light as an environmental signal to determine the proper timing of growth and development. In Arabidopsis seedlings, hypocotyl growth is promoted in the dark but suppressed in the light. It is known that the red/far-red light-sensing receptor phytochrome B (phyB) suppresses the function of PHYTOCHROME INTERACTING FACTOR (PIF) transcription factors, which act as photomorphogenic repressors. However, molecular mechanisms underlying the phyB-mediated inhibition of PIF functioning remain unclear. We recently demonstrated that HIGH EXPRESSION OF OSMOTICALLY RESPONSIVE GENES 1 (HOS1) facilitates the phyB-mediated suppression of PIF4 during the light period to achieve hypocotyl photomorphogenesis. HOS1 inhibits the transcriptional activation activity of PIF4 by forming protein complexes. Notably, phyB-mediated light signals induce HOS1 activity, thus promoting hypocotyl photomorphogenesis. While HOS1 is known to act as an E3 ubiquitin ligase or a chromatin remodeling factor, our data illustrate a novel role of HOS1: it acts as a component of phyB-mediated light signaling in hypocotyl photomorphogenesis.

HOS1 Facilitates the Phytochrome B-Mediated Inhibition of PIF4 Function during Hypocotyl Growth in Arabidopsis.

Upon exposure to light, developing seedlings undergo photomorphogenesis, as illustrated by inhibition of hypocotyl elongation, cotyledon opening, and leaf greening. During hypocotyl photomorphogenesis, light signals are sensed by multiple photoreceptors, among which the red/far-red light-sensing phytochromes have been extensively studied. However, it is not fully understood how the phytochromes modulate hypocotyl growth. Here, we demonstrated that HIGH EXPRESSION OF OSMOTICALLY RESPONSIVE GENES 1 (HOS1), which is known to either act as E3 ubiquitin ligase or affect chromatin organization, inhibits the transcriptional activation activity of PHYTOCHROME INTERACTING FACTOR 4 (PIF4), a key transcription factor that promotes hypocotyl growth. Consistent with the negative regulatory role of HOS1 in hypocotyl growth, HOS1-defective mutants exhibited elongated hypocotyls in the light. Notably, phyB induces HOS1 activity in inhibiting PIF4 function. Taken together, these observations provide a molecular basis for the phyB-mediated suppression of hypocotyl growth in Arabidopsis.

Modification of paclitaxel-loaded solid lipid nanoparticles with 2-hydroxypropyl-ß-cyclodextrin enhances absorption and reduces nephrotoxicity associated with intravenous injection.

BACKGROUND: Paclitaxel (PTX) solid lipid nanoparticles (SLNs) modified with 2-hydroxypropyl-ß-cyclodextrin (HPCD) were evaluated for their ability to enhance PTX absorption and reduce the nephrotoxicity accompanying intravenous administration. METHODS: PTX-loaded SLNs (PS) and PTX-loaded SLNs modified using HPCD (PSC) were prepared by hot-melted sonication. The anticancer activity of PSC was evaluated in MCF-7 cells, and confocal microscopy was used to quantify the cellular uptake. The pharmacokinetic profiles of PTX released from PSC after intravenous administration were studied in rats. Furthermore, kidney toxicity was determined by measuring the kidney size and plasma creatinine level. RESULTS: PSC were successfully prepared by hot-melted sonication and had smaller diameters than PS. PSC exhibited improved anticancer activity and cellular uptake in MCF-7 cells. Furthermore, PSC showed higher bioavailability in rats after intravenous administration than PTX solution; however, no significant differences in kidney toxicity were observed. CONCLUSION: Based on these results, PSC could be considered as a potential therapeutic PTX delivery system for breast cancer with low renal toxicity.

Effects of having usual source of care on preventive services and chronic disease control: a systematic review.

BACKGROUND: Having usual source of care has been associated with improved receipt of preventive services and control of chronic diseases (such as hypertension, diabetes, and hypercholesterolemia). The objective of this study was to examine whether having usual source of care is associated with improved receipt of preventive services and control of chronic diseases. METHODS: We searched MEDLINE, EMBASE, Cochrane, CINAHL, KMbase, KoreaMed, RiSS4U, National Assembly Library, and KISS for studies released through May 31st 2011. Two authors independently extracted the data. We manually searched the references and twenty recent related articles on PubMed. To assess the risk of bias RoBANS tool was used. RESULTS: We identified 10 studies. Most having usual source of care were associated with improved receipt of preventive services (cervical cancer screening, clinical breast exam, mammogram, prostate cancer screening, and flu shot) compared with no usual source of care. However, gastric cancer and colon cancer screening were difficult to conclude and blood pressure checkup showed mixed results. Overall there was no association between having usual source of care and smoking behaviors and the effect on chronic disease control was difficult to conclude. CONCLUSION: Having usual source of care was associated with improved receipt of preventive services and overall the results were consistent. So, the results suggested that having usual source of care may help to receive preventive services. Hereafter, cohort studies are needed to evaluate casual relationships and more studies are needed in various countries and systems.

A Comparison of Efficacy and Safety of Non-steroidal Anti-inflammatory Drugs versus Acetaminophen in the Treatment of Episodic Tension-type Headache: A Meta-analysis of Randomized Placebo-controlled Trial Studies.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen are widely used in the treatment of tension headache. The objective of this study was to evaluate and compare the efficacy and safety of single doses of acetaminophen and NSAIDs using meta-analysis of randomized placebo-controlled trial studies. METHODS: We searched MEDLINE, EMBASE, CINAHL, Cochrane, KMbase, KoreaMed, RiCH, National Assembly Library, Riss4u, and DBPIA for studies released through 27th July 2010. Two authors independently extracted the data. To assess the risk of bias, the Cochrane Collaborations risk of bias tool was used. Review Manager 5.0 was used for statistics. RESULTS: We identified 6 studies. The relative benefit of the NSAIDs group compared to the acetaminophen group for participants with at least 50% pain relief was 1.18 (95% confidence interval [CI], 0.99 to 1.39; I(2) = 85%). We did subgroup analysis based on allocation concealment versus non-allocation concealment, and low-dose NSAIDs versus high-dose NSAIDs. The relative benefit of the low-dose NSAIDs subgroup to the acetaminophen group was 0.98 (95% CI, 0.91 to 1.06; I(2) = 0%). However, the heterogeneity of other subgroup analysis was not settled. The relative risk for using rescue medication of the NSAIDs group compared to the acetaminophen group was 0.84 (95% CI, 0.64 to 1.12; I(2) = 47%). The relative risk for adverse events was 1.31(95% CI, 0.96 to 1.80; I(2) = 0%). CONCLUSION: In this meta-analysis, there was no difference between low-dose NSAIDs and acetaminophen in the efficacy of the treatment for tension type headache. The results suggested that high-dose NSAIDs have more effect but also have more adverse events. The balance of benefit and harm needs to be considered when using high-dose NSAIDs for tension headache.