Type One Protein Phosphatase 1 and Its Regulatory Protein Inhibitor 2 Negatively Regulate ABA Signaling

The phytohormone abscisic acid (ABA) regulates plant growth, development and responses to biotic and abiotic stresses. The core ABA signaling pathway consists of three major components: ABA receptor (PYR1/PYLs), type 2C Protein Phosphatase (PP2C) and SNF1-related protein kinase 2 (SnRK2). Nevertheless, the complexity of ABA signaling remains to be explored. To uncover new components of ABA signal transduction pathways, we performed a yeast two-hybrid screen for SnRK2-interacting proteins. We found that Type One Protein Phosphatase 1 (TOPP1) and its regulatory protein, At Inhibitor-2 (AtI-2), physically interact with SnRK2s and also with PYLs. TOPP1 inhibited the kinase activity of SnRK2.6, and this inhibition could be enhanced by AtI-2. Transactivation assays showed that TOPP1 and AtI-2 negatively regulated the SnRK2.2/3/6-mediated activation of the ABA responsive reporter gene RD29B, supporting a negative role of TOPP1 and AtI-2 in ABA signaling. Consistent with these findings, topp1 and ati-2 mutant plants displayed hypersensitivities to ABA and salt treatments, and transcriptome analysis of TOPP1 and AtI-2 knockout plants revealed an increased expression of multiple ABA-responsive genes in the mutants. Taken together, our results uncover TOPP1 and AtI-2 as negative regulators of ABA signaling. © 2016 Hou et al

Effect of Phacoemulsification on Anterior Chamber Angle in Eyes with Medically Uncontrolled Filtered Primary Angle-Closure Glaucoma

Purpose. To evaluate the effect of phacoemulsification and intraocular lens (IOLs) implantation in eyes with medically uncontrolled primary angle-closure glaucoma (PACG) previously treated with trabeculectomy and to quantify the anatomical changes in the anterior chamber angle by ultrasound biomicroscopy (UBM). Methods. Forty-four eyes of 37 consecutive patients with medically uncontrolled PACG coexisting cataracts with a surgical history of trabeculectomy were included in this study. Each patient underwent phacoemulsification and IOL implantation. Indentation gonioscopy and UBM were performed preoperatively and then again 3 months after surgery. The main outcome measures were best-corrected visual acuity (BCVA), intraocular pressure (IOP), number of antiglaucoma medications and anatomical changes in the anterior chamber angle. Results. The mean logarithm of the minimum angle of resolution BCVA significantly improved from 0.52 ± 0.30 preoperatively to 0.26 ± 0.23 postoperatively (p0.05). Some parameters, including anterior central chamber depth, angle opening distance at 500 μm, trabecular-iris angle, and scleral ciliary process angle, were significantly higher after than before surgery (p<0.001). However, the crystalline lens rise was significantly smaller following the surgery (p<0.001). Conclusions. Phacoemulsification and IOL implantation reduced the IOP and improved vision in eyes with medically uncontrolled filtered PACG. The mechanism underlying the outcomes observed following surgery might be related to the anterior chamber deepening, widened drainage angle, and improved aqueous fluid flow to the trabecular meshwork

Overexpression of Mcl-1 Confers Multidrug Resistance, Whereas Topoisomerase IIb Downregulation Introduces Mitoxantrone- Specific Drug Resistance in Acute Myeloid Leukemia

ABSTRACT Drug resistance is a serious challenge in cancer treatment and can be acquired through multiple mechanisms. These molecular changes may introduce varied extents of resistance to different therapies and need to be characterized for optimal therapy choice. A recently discovered small molecule, ethyl-2-amino-6-(3,5-dimethoxyphenyl)-4-(2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate) (CXL017), reveals selective cytotoxicity toward drug-resistant leukemia. A drug-resistant acute myeloid leukemia cell line, HL60/MX2, also failed to acquire resistance to CXL017 upon chronic exposure and regained sensitivity toward standard therapies. In this study, we investigated the mechanisms responsible for HL60/MX2 cells&apos; drug resistance and the molecular basis for its resensitization. Results show that the HL60/MX2 cell line has an elevated level of Mcl-1 protein relative to the parental cell line, HL60, and its resensitized cell line, HL60/ MX2/CXL017, whereas it has a reduced level of topoisomerase IIb. Mcl-1 overexpression in HL60/MX2 cells is mainly regulated through phospho-extracellular signal-regulated protein kinases 1 and 2-mediated Mcl-1 stabilization, whereas the reduction of topoisomerase IIb in HL60/MX2 cells is controlled through genetic downregulation. Upregulating Mcl-1 introduces multidrug resistance to standard therapies, whereas its downregulation results in significant cell death. Downregulating topoisomerase IIb confers resistance specifically to mitoxantrone, not to other topoisomerase II inhibitors. Overall, these data suggest that Mcl-1 overexpression is a critical determinant for cross-resistance to standard therapies, whereas topoisomerase IIb downregulation is specific to mitoxantrone resistance

Mechanical Behaviors of the Origami-Inspired Horseshoe-Shaped Solar Arrays

The importance of flexibility has been widely noticed and concerned in the design and application of space solar arrays. Inspired by origami structures, we introduce an approach to realizing stretchable and bendable solar arrays via horseshoe-shaped substrate design. The structure has the ability to combine rigid solar cells and soft substrates skillfully, which can prevent damage during deformations. The finite deformation theory is adapted to find the analytic model of the horseshoe-shaped structure via simplified beam theory. In order to solve the mechanical model, the shooting method, a numerical method to solve ordinary differential equation (ODE) is employed. Finite element analyses (FEA) are also performed to verify the developed theoretical model. The influences of the geometric parameters on deformations and forces are analyzed to achieve the optimal design of the structures. The stretching tests of horseshoe-shaped samples manufactured by three-dimensional (3D) printing are implemented, whose results shows a good agreement with those from theoretical predictions. The developed models can serve as the guidelines for the design of flexible solar arrays in spacecraft

Measuring the Chemical and Cytotoxic Variability of Commercially Available Kava (<i>Piper methysticum</i> G. Forster)

<div><p>Formerly used world-wide as a popular botanical medicine to reduce anxiety, reports of hepatotoxicity linked to consuming kava extracts in the late 1990s have resulted in global restrictions on kava use and have hindered kava-related research. Despite its presence on the United States Food and Drug Administration consumer advisory list for the past decade, export data from kava producing countries implies that US kava imports, which are not publicly reported, are both increasing and of a fairly high volume. We have measured the variability in extract chemical composition and cytotoxicity towards human lung adenocarcinoma A549 cancer cells of 25 commercially available kava products. Results reveal a high level of variation in chemical content and cytotoxicity of currently available kava products. As public interest and use of kava products continues to increase in the United States, efforts to characterize products and expedite research of this potentially useful botanical medicine are necessary.</p></div

CXL146, a Novel 4H-Chromene Derivative, Targets GRP78 to Selectively Eliminate Multidrug-Resistant Cancer Cells

The 78-kDa glucose-regulated protein (GRP78), an endoplasmic reticulum (ER) chaperone, is a master regulator of the ER stress. A number of studies revealed that high levels of GRP78 protein in cancer cells confer multidrug resistance (MDR) to therapeutic treatment. Therefore, drug candidate that reduces GRP78 may represent a novel approach to eliminate MDR cancer cells. Our earlier studies showed that a set of 4H-chromene derivatives induced selective cytotoxicity in MDR cancer cells. In the present study, we elucidated its selective mechanism in four MDR cancer cell lines with one lead candidate (CXL146). Cytotoxicity results confirmed the selective cytotoxicity of CXL146 toward the MDR cancer cell lines. We noted significant overexpression of GRP78 in all four MDR cell lines compared with the parental cell lines. Unexpectedly, CXL146 treatment rapidly and dose-dependently reduced GRP78 protein in MDR cancer cell lines. Using human leukemia (HL) 60/mitoxantrone (MX) 2 cell line as the model, we demonstrated that CXL146 treatment activated the unfolded protein response (UPR); as evidenced by the activation of inositol-requiring enzyme 1 alpha, protein kinase R-like ER kinase, and activating transcription factor 6. CXL146-induced UPR activation led to a series of downstream events, including extracellular signal-regulated kinase 1/2 and c-Jun N-terminal kinase activation, which contributed to CXL146-induced apoptosis. Targeted reduction in GRP78 resulted in reduced sensitivity of HL60/MX2 toward CXL146. Long-term sublethal CXL146 exposure also led to reduction in GRP78 in HL60/MX2. These data collectively support GRP78 as the target of CXL146 in MDR treatment. Interestingly, HL60/MX2 upon long-term sublethal CXL146 exposure regained sensitivity to mitoxantrone treatment. Therefore, further exploration of CXL146 as a novel therapy in treating MDR cancer cells is warranted. SIGNIFICANCE STATEMENT Multidrug resistance is one major challenge to cancer treatment. This study provides evidence that cancer cells overexpress 78-kDa glucose-regulated protein (GRP78) as a mechanism to acquire resistance to standard cancer therapies. A chromenebased small molecule, CXL146, selectively eliminates cancer cells with GRP78 overexpression via activating unfolded protein response-mediated apoptosis. Further characterization indicates that CXL146 and standard therapies complementarily target different populations of cancer cells, supporting the potential of CXL146 to overcome multidrug resistance in cancer treatment

Smoking-Cessation Methods and Outcomes Among Cancer Survivors

Salloum RG, Lee J, Lee J-H, Böckmann M, Xing C, Warren GW. Smoking-Cessation Methods and Outcomes Among Cancer Survivors. American Journal of Preventive Medicine. 2020