Rhamnetin and Cirsiliol Induce Radiosensitization and Inhibition of Epithelial-Mesenchymal Transition (EMT) by miR-34a-mediated Suppression of Notch-1 Expression in Non-small Cell Lung Cancer Cell Lines

Radioresistance is a major cause of decreasing the efficiency of radiotherapy for non-small cell lung cancer (NSCLC). To understand the radioresistance mechanisms in NSCLC, we focused on the radiation-induced Notch-1 signaling pathway involved in critical cell fate decisions by modulating cell proliferation. In this study, we investigated the use of Notch-1-regulating flavonoid compounds as novel therapeutic drugs to regulate radiosensitivity in NSCLC cells, NCI-H1299 and NCI-H460, with different levels of radioresistance. Rhamnetin and cirsiliol were selected as candidate Notch-1-regulating radiosensitizers based on the results of assay screening for activity and pharmacological properties. Treatment with rhamnetin or cirsiliol reduced the proliferation of NSCLC cells through the suppression of radiation-induced Notch-1 expression. Indeed, rhamnetin and cirsiliol increased the expression of tumor-suppressive microRNA, miR-34a, in a p53-dependent manner, leading to inhibition of Notch-1 expression. Consequently, reduced Notch-1 expression promoted apoptosis through significant down-regulation of the nuclear factor-κB pathway, resulting in a radiosensitizing effect on NSCLC cells. Irradiation-induced epithelial-mesenchymal transition was also notably attenuated in the presence of rhamnetin and cirsiliol. Moreover, an in vivo xenograft mouse model confirmed the radiosensitizing and epithelial-mesenchymal transition inhibition effects of rhamnetin and cirsiliol we observed in vitro. In these mice, tumor volume was significantly reduced by combinational treatment with irradiation and rhamnetin or cirsiliol compared with irradiation alone. Taken together, our findings provided evidence that rhamnetin and cirsiliol can act as promising radiosensitizers that enhance the radiotherapeutic efficacy by inhibiting radiation-induced Notch-1 signaling associated with radioresistance possibly via miR-34a-mediated pathways.     

QTLs for resistance to Phomopsis seed decay are associated with days to maturity in soybean (Glycine max)

Phomopsis seed decay (PSD), primarily caused by Phomopsis longicolla, is a major contributor to poor soybean seed quality and significant yield loss, particularly in early maturing soybean genotypes. However, it is not yet known whether PSD resistance is associated with early maturity. This study was conducted to identify quantitative trait loci (QTLs) for resistance to PSD and days to maturity using a recombinant inbred line (RIL) population derived from a cross between the PSD-resistant Taekwangkong and the PSD-susceptible SS2-2. Based on a genetic linkage map incorporating 117 simple sequence repeat markers, QTL analysis revealed two and three QTLs conferring PSD resistance and days to maturity, respectively, in the RIL population. Two QTLs (PSD-6-1 and PSD-10-2) for PSD resistance were identified in the intervals of Satt100–Satt460 and Sat_038–Satt243 on chromosomes 6 and 10, respectively. Two QTLs explained phenotypic variances in PSD resistance of 46.3 and 14.1 %, respectively. At the PSD-6-1 QTL, the PSD-resistant cultivar Taekwangkong contributed the allele with negative effect decreasing the infection rate of PSD and this QTL does not overlap with any previously reported loci for PSD resistance in other soybean genotypes. Among the three QTLs for days to maturity, two (Mat-6-2 and Mat-10-3) were located at positions similar to the PSD-resistance QTLs. The identification of the QTLs linked to both PSD resistance and days to maturity indicates a biological correlation between these two traits. The newly identified QTL for resistance to PSD associated with days to maturity in Taekwangkong will help improve soybean resistance to P. longicolla.     

Quinic acid derivatives from Pimpinella brachycarpa exert anti-neuroinflammatory activity in lipopolysaccharide-induced microglia

Five new quinic acid derivatives (1–5), together with 10 known quinic acid derivatives (6–15), were isolated from the MeOH extract of Pimpinella brachycarpa (Umbelliferae). Their structures were established on the basis of spectroscopic analyses including extensive 2D NMR studies (COSY, HMQC and HMBC). Isolated compounds 1–15 were evaluated for their inhibitory activities on nitric oxide (NO) production in an activated murine microglial cell line. Compounds 2, 3, 8 and 11 significantly inhibited NO production without high cell toxicity in lipopolysaccharide (LPS)-activated BV-2 cells, a microglia cell line (IC₅₀ = 4.66, 12.52, 9.04 and 12.11 μM, respectively).     

Synthesis and biological evaluation of novel 3,4-diaryl lactam derivatives as triple reuptake inhibitors

A series of 3,4-diarylpyrrolidin-2-one was designed, prepared and evaluated as triple reuptake inhibitors for antidepressant. Most compounds exhibited comparable in vitro efficacy as norepinephrine and dopamine transporter reuptake inhibitors. Especially, 2i showed better potency than GBR-12909 (IC₅₀ = 14 nM) which was used as reference compound for dopamine transporter. In addition, 2a and 2b showed inhibition (5.17 μM–85.6 nM) for three transporters.     

Oxazolopyridines and thiazolopyridines as monoamine oxidase B inhibitors for the treatment of Parkinson’s disease

In Parkinson’s disease, the motor impairments are mainly caused by the death of dopaminergic neurons. Among the enzymes which are involved in the biosynthesis and catabolism of dopamine, monoamine oxidase B (MAO-B) has been a therapeutic target of Parkinson’s disease. However, due to the undesirable adverse effects, development of alternative MAO-B inhibitors with greater optimal therapeutic potential towards Parkinson’s disease is urgently required. In this study, we designed and synthesized the oxazolopyridine and thiazolopyridine derivatives, and biologically evaluated their inhibitory activities against MAO-B. Structure–activity relationship study revealed that the piperidino group was the best choice for the R¹ amino substituent to the oxazolopyridine core structure and the activities of the oxazolopyridines with various phenyl rings were between 267.1 and 889.5 nM in IC₅₀ values. Interestingly, by replacement of the core structure from oxazolopyrine to thiazolopyridine, the activities were significantly improved and the compound 1n with the thiazolopyridine core structure showed the most potent activity with the IC₅₀ value of 26.5 nM. Molecular docking study showed that van der Waals interaction in the human MAO-B active site could explain the enhanced inhibitory activities of thiazolopyridine derivatives.     

A novel metformin derivative,HL010183, inhibits proliferation and invasion of triple-negative breast cancer cells

Mounting evidence suggests that metformin (N,N-dimethylbiguanide), a widely prescribed drug for the treatment of type II diabetes, exerts an anti-tumor effect on several cancers including breast cancer. Breast cancer has been estimated as one of the most commonly diagnosed types of cancer among women. In particular, triple-negative breast cancers are associated with poor prognosis and metastatic growth. In the present study, we synthesized a novel metformin derivative 5 (HL010183) and metformin salts, 9a, 9b, and 9c (metformin gamma-aminobutyric acid (GABA) salt, metformin pregabalin salt and metformin gabapentin salt), which exerted more potent inhibitory effects on the proliferation and invasiveness of Hs578T triple-negative breast carcinoma cells than metformin. Importantly, 5 showed approximately 100-fold more potent effects compared to metformin. In a triple-negative breast cancer xenograft model, 5 showed a comparable degree of inhibitory effect on in vivo tumor growth at the 100 mg/kg dose to that of metformin at 500 mg/kg. Our results clearly demonstrate that 5 exerts a potent anti-tumor effect both in vitro and in vivo, paving the way for a strategy for treatment of triple-negative breast cancer.     

Role of areoles on prey abundance and diversity in the hooded pitcher plant (<Emphasis Type="Italic">Sarracenia minor</Emphasis>, <Emphasis Type="Italic">Sarraceniaceae</Emphasis>)

The hooded pitcher plant, Sarracenia minor, is a carnivorous facultative wetland species native to the southeastern USA and is listed as threatened by the state of Florida. Pitchers of S. minor possess white, semitranslucent spots (areoles), which have been hypothesized to aid in the capture of prey (= visual lures) by increasing the amount of light entering the back of the hood, which persuades insects to enter and fall into the base of the pitcher. In this study, the role of the areoles in prey capture abundance and diversity were experimentally investigated under variable lighting conditions in situ. Plants in two populations experiencing different light intensities, which varied in the amount of canopy cover and incident light reaching the plants, were experimentally manipulated by coloring varying percentages of areoles, ranging from 0 to 100 % (in increments of 25 %), with indelible ink. After 2 months, pitchers were collected and dissected to determine the number and identity of prey captured (approximately 18,000 prey were sampled). Although total prey abundance was approximately five times higher at McGirt’s Creek (sunny site) compared to UNF (shaded site), the effect of areoles on prey capture rates and biodiversity was site dependent. Reducing the number of visual lures of plants at the sunny site produced a significant decrease in the number of prey captured, but prey biodiversity (community composition) was unaffected. However, total prey capture was unaffected at the shaded site, while prey biodiversity was negatively correlated with the percent of areoles colored. Results from the current study suggest that areoles conditionally act as visual lures, but their overall importance is dependent on local environmental variables—especially canopy cover and the amount of incident sunlight reaching the plants.     

Parallelized Nanopillar Perovskites for Semitransparent Solar Cells Using an Anodized Aluminum Oxide Scaffold

Semitransparent solar cells have attracted significant attention for practical applications, such as windows in buildings and automobiles. Here, semitransparent, highly efficient, 1D nanostructured perovskite solar cells are demonstrated employing anodized aluminum oxide (AAO) as a scaffold layer. The parallel nanopillars in the perovskite layer enable construction of haze‐free semitransparent devices without any hysteresis behavior. By controlling the pore size in the AAO, the volume occupied by the perovskite layer can be precisely varied, and the color neutrality of the resulting devices can be achieved. With the incorporation of a transparent cathodic electrode (indium tin oxide) with a buffer layer (MoO_x), a highly efficient semitransparent nanopillared perovskite solar cell is achievable with a power‐conversion efficiency of 9.6% (7.5%) and a whole device average visible light transmittance of 33.4% (41.7%). To determine the role of the scaffold layer in improving the photoelectrical properties of the cell, impedance spectroscopy analyses are performed, revealing that the AAO‐structured perovskite layer suppresses internal ion diffusion and enables critical improvements in long‐term stability under continuous illumination.