PP2A Inhibitors Arrest G2/M Transition Through JNK/Sp1-Dependent Down-Regulation of CDK1 and Autophagy-Dependent Up-Regulation of p21

Protein phosphatase 2A (PP2A) plays an important role in the control of the cell cycle. We previously reported that the PP2A inhibitors, cantharidin and okadaic acid (OA), efficiently repressed the growth of cancer cells. In the present study, we found that PP2A inhibitors arrested the cell cycle at the G2 phase through a mechanism that was dependent on the JNK pathway. Microarrays further showed that PP2A inhibitors induced expression changes in multiple genes that participate in cell cycle transition. To verify whether these expression changes were executed in a PP2A-dependent manner, we targeted the PP2A catalytic subunit (PP2Ac) using siRNA and evaluated gene expression with a microarray. After the cross comparison of these microarray data, we identified that CDK1 was potentially the same target when treated with either PP2A inhibitors or PP2Ac siRNA. In addition, we found that the down-regulation of CDK1 occurred in a JNK-dependent manner. Luciferase reporter gene assays demonstrated that repression of the transcription of CDK1 was executed through the JNK-dependent activation of the Sp1 transcription factor. By constructing deletion mutants of the CDK1 promoter and by using ChIP assays, we identified an element in the CDK1 promoter that responded to the JNK/Sp1 pathway after stimulation with PP2A inhibitors. Cantharidin and OA also up-regulated the expression of p21, an inhibitor of CDK1, via autophagy rather than PP2A/JNK pathway. Thus, this present study found that the PP2A/JNK/Sp1/CDK1 pathway and the autophagy/p21 pathway participated in G2/M cell cycle arrest triggered by PP2A inhibitors

Studies on Anti-Depressant Activity of Four Flavonoids Isolated from Apocynum venetum Linn (Apocynaceae) Leaf in Mice

Purpose: To investigate the anti-depressant activity of kaempferol, quercetin, kaempferol-3-O-β-Dglucose and quercetin-3-O-β-D-glucose isolated from Apocynum venetum Linn. (Apocynaceae) leaf and their mechanisms of action.Methods: The four flavonoids were isolated from Apocynum venetum leaf by chromatography. Mice were divided into vehicle, fluoxetine, kaempferol, quercetin, kaempferol-3-O-β-D-glucose and quercetin- 3-O-β-D-glucose groups (n = 10). Forced swimming (FST), tail suspension (TST) and locomotor activity (LAT) tests were used to evaluate the effects of the four flavonoids (0.35 mM/kg) on immobility time, monoamine neurotransmitters, viz, norepinephrine (NE), dopamine (DA) and 5-hydroxytryptamine (5- HT), as well as on the metabolite (5-HIAA) in mice brain and central nervous system (CNS) with the aid of video camera, HPLC-ECD and activity-monitoring system.Results: The four flavonoids significantly (p < 0.05) reduced mice immobility time (72.58 - 90.24; 52.58 - 70.24 s), 5-HIAA levels (940.8 - 1244.7; 880.8 - 1164.1 ng/g) and 5-HIAA/5-HT ratio (1.77 - 4.76; 1.83 - 4.16), but increased NE, DA and 5-HT levels (238.7 - 405.7, 308.4 - 528.1, 261.4 - 531.9; 243.9 - 423.6, 296.7 - 534.9, 279.8 - 481.4 ng/g) in FST and TST, compared with control group (146.18, 126.18 s; 1363.4, 1240.9 ng/g; 7.43, 6.16; 138.4, 235.4, 183.4 and 143.7, 218.6, 201.4 ng/g). The effects of the four flavonoids on the above indices were significant (p < 0.05) and positively related to their polarity. They had no CNS-stimulating effects in LAT.Conclusion: The anti-depressant activities of the four flavonoids are positively related to their polarity, and the mechanisms may be due to increased NE, DA and 5-HT and reduced 5-HT metabolism.Keywords: Kaempferol, Quercetin, Forced swimming test, Tail suspension test, Locomotor activity test, Neurotransmitter

Exploring the boundary of quantum correlations with a time-domain optical processor

Contextuality is a hallmark feature of the quantum theory that captures its incompatibility with any noncontextual hidden-variable model. The Greenberger--Horne--Zeilinger (GHZ)-type paradoxes are proofs of contextuality that reveal this incompatibility with deterministic logical arguments. However, the simplest GHZ-type paradox with the fewest number of complete contexts and the largest amount of nonclassicality remains elusive. Here, we derive a GHZ-type paradox utilizing only three complete contexts and show this number saturates the lower bound posed by quantum theory. We demonstrate the paradox with a time-domain fiber optical platform and recover all essential ingredients in a 37-dimensional contextuality test based on high-speed modulation, convolution, and homodyne detection of time-multiplexed pulsed coherent light. By proposing and observing a strong form of contextuality in high Hilbert-space dimensions, our results pave the way for the exploration of exotic quantum correlations with time-multiplexed optical systems.Comment: 19 pages, 8 figures, improved presentation with additional discussion

A Chinese Herbal Formula to Improve General Psychological Status in Posttraumatic Stress Disorder: A Randomized Placebo-Controlled Trial on Sichuan Earthquake Survivors

Introduction. Posttraumatic stress disorder (PTSD) is accompanied by poor general psychological status (GPS). In the present study, we investigated the effects of a Chinese herbal formula on GPS in earthquake survivors with PTSD. Methods. A randomized, double-blind, placebo-controlled trial compared a Chinese herbal formula, Xiao-Tan-Jie-Yu-Fang (XTJYF), to placebo in 2008 Sichuan earthquake survivors with PTSD. Patients were randomized into XTJYF (n = 123) and placebo (n = 122) groups. Baseline-to-end-point score changes in the three global indices of the Symptom Checklist-90-Revised (SCL-90-R) and rates of response in the SCL global severity index (GSI) were the primary endpoints. A subanalysis of the nine SCL factors and the sleep quality score were secondary endpoints. Results and Discussion. Compared to placebo, the XTJYF group was significantly improved in all three SCL global indices (P = 0.001~0.028). More patients in the XTJYF group reported “much improved” than the placebo group (P = 0.001). The XTJYF group performed significantly better than control in five out of nine SCL factors (somatization, obsessive-compulsive behavior, depression, anxiety, and hostility (P = 0.001~0.036)), and in sleep quality score (P < 0.001). XTJYF produced no serious adverse events. These findings suggest that XTJYF may be an effective and safe treatment option for improving GPS in patients with PTSD

A genome-wide association study identifies a genomic region for the polycerate phenotype in sheep (Ovis aries)

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Wen-Luo-Tong Decoction Attenuates Paclitaxel-Induced Peripheral Neuropathy by Regulating Linoleic Acid and Glycerophospholipid Metabolism Pathways

Chemotherapy-induced peripheral neuropathy (CIPN) is a serious dose-limiting toxicity of many anti-neoplastic agents, especially paclitaxel, and oxaliplatin. Up to 62% of patients receiving paclitaxel regimens turn out to develop CIPN. Unfortunately, there are so few agents proved effective for prevention or management of CIPN. The reason for the current situation is that the mechanisms of CIPN are still not explicit. Traditional Chinese Medicine (TCM) has unique advantages for dealing with complex diseases. Wen-Luo-Tong (WLT) is a TCM ointment for topical application. It has been applied for prevention and management of CIPN clinically for more than 10 years. Previous animal experiments and clinical studies had manifested the availability of WLT. However, due to the unclear mechanisms of WLT, further transformation has been restricted. To investigate the therapeutic mechanisms of WLT, a metabolomic method on the basis of UPLC- MS was developed in this study. Multivariate analysis techniques, such as principal component analysis (PCA) and partial least squares discriminate analysis (PLS-DA), were applied to observe the disturbance in the metabolic state of the paclitaxel-induced peripheral neuropathy (PIPN) rat model, as well as the recovering tendency of WLT treatment. A total of 19 significant variations associated with PIPN were identified as biomarkers. Results of pathway analysis indicated that the metabolic disturbance of pathways of linoleic acid (LA) metabolism and glycerophospholipid metabolism. WLT attenuated mechanical allodynia and rebalanced the metabolic disturbances of PIPN by primarily regulating LA and glycerophospholipid metabolism pathway. Further molecular docking analysis showed some ingredients of WLT, such as hydroxysafflor yellow A (HSYA), icariin, epimedin B and 4-dihydroxybenzoic acid (DHBA), had high affinity to plenty of proteins within these two pathways

The Hidden Nematic Fluctuations in the Triclinic (Ca0.85La0.15)10(Pt3As8)(Fe2As2)5 Superconductor Revealed by Ultrafast Optical Spectroscopy

We reported the quasiparticle relaxation dynamics of an optimally doped triclinic iron-based superconductor (Ca$_{0.85}$La$_{0.15}$)$_{10}$(Pt$_3$As$_8$)(Fe$_2$As$_2$)$_5$ with bulk $T_c$ = 30 K using polarized ultrafast optical pump-probe spectroscopy. Our results reveal anisotropic transient reflectivity induced by nematic fluctuations develops below $T_{nem}$ $\approx$ 120 K and persists in the superconducting states. Measurements under high pump fluence reveal three distinct, coherent phonon modes at frequencies of 1.6, 3.5, and 4.7 THz, corresponding to $A_{1g}(1)$, $E_g$, and $A_{1g}(2)$ modes, respectively. The high-frequency $A_{1g}(2)$ mode corresponds to the $c$-axis polarized vibrations of FeAs planes with a nominal electron-phonon coupling constant $\lambda _{A_{1g}(2)}$ $\approx$ 0.139 $\pm$ 0.02. Our findings suggest that the superconductivity and nematic state are compatible but competitive at low temperatures, and the $A_{1g}$ phonons play an important role in the formation of Cooper pairs in (Ca$_{0.85}$La$_{0.15}$)$_{10}$(Pt$_3$As$_8$)(Fe$_2$As$_2$)$_5$.Comment: 6 pages, 3 figures and Supplemental Material

β-Carboline Alkaloids From the Deep-Sea Fungus Trichoderma sp. MCCC 3A01244 as a New Type of Anti-pulmonary Fibrosis Agent That Inhibits TGF-β/Smad Signaling Pathway

Pulmonary fibrosis is a scarring disease of lung tissue, which seriously threatens human health. Treatment options are currently limited, and effective strategies are still lacking. In the present study, 25 compounds were isolated from the deep-sea fungus Trichoderma sp. MCCC 3A01244. Among them, two β-carboline alkaloids, trichocarbolines A (1) and C (4) are new compounds. The chemical structures of these compounds were elucidated based on their HRESIMS, 1D and 2D NMR spectra, optical rotation calculation, and comparisons with data reported in the literature. Trichocarboline B [(+)- and (–)-enantiomers] had previously been synthesized, and this is its first report as a natural product. Their anti-pulmonary fibrosis (PF) activity and cytotoxicity were investigated. Compounds 1, 11, and 13 strongly inhibited TGF-β1-induced total collagen accumulation and showed low cytotoxicity against the HFL1 cell line. Further studies revealed compound 1 inhibited extracellular matrix (ECM) deposition by downregulating the expression of protein fibronectin (FN), proliferating cell nuclear antigen (PCNA), and α-smooth muscle actin (α-SMA). Mechanistic study revealed that compound 1 decreased pulmonary fibrosis by inhibiting the TGF-β/Smad signaling pathway. As a newly identified β-carboline alkaloid, compound 1 may be used as a lead compound for developing more efficient anti-pulmonary fibrosis agents