miR-29b-3p’s Effects on Prostate Cancer

Objection: Our research wanted to discuss miR-29b-3p in PCa occurrence and development and relative mechanisms. Methods: Collecting adjacent and cancer tissues from prostate cancer patients and measuring miR-29b-3p expressions by RT-qPCR and ISH assay. Using DU145 and PC3 cell lines which the miR-29b-3p were high expression in our study. Using miR inhibitor to knockdown miR-29b-3p in DU145 and PC3. Using CCK-8 and flow cytometry to measure cell proliferation and cell apoptosis, invasion cell number by transwell and wound healing rate by wound healing assay. The relative proteins expressions were measured using WB assay. p-AKT nuclear levels were evaluated using Cell immunofluorescence test. Using dual-luciferase reporter gene assay to analysis correlation miR-29b-3p and PTEN. Results: miR-29b-3p gene significantly increased. miR-29b-3p knockdown had effects to depress cell proliferation, increase cell apoptosis, depress invasion cells number and wound healing rates. PTEN proteins were significantly up-regulation and p-AKT and MMP-9 proteins expressions were significantly down-regulation (P < 0.001, respectively). And p-AKT nuclear volume were significantly depressed. And miR-29b-3p could target PTEN. Conclusion: miR-29b-3p played an oncology gene in prostate cancer via regulation PTEN/AKT pathway in vitro study.

Dracunculin Inhibits Adipogenesis in Human Bone Marrow-Derived Mesenchymal Stromal Cells by Activating AMPK and Wnt/β-Catenin Signaling

Increased bone marrow adiposity is widely observed in patients with obesity and osteoporosis and reported to have deleterious effects on bone formation. Dracunculin (DCC) is a coumarin isolated from Artemisia spp. but, until now, has not been studied for its bioactive potential except antitrypanosomal activity. In this context, current study has reported the anti-adipogenic effect of DCC in human bone marrow-derived mesenchymal stromal cells (hBM-MSCs). DCC dose-dependently inhibited the lipid accumulation and expression of adipogenic transcription factors peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer binding protein α (C/EBPα) in hBM-MSCs induced to undergo adipogenesis. To elucidate its action mechanism, the effect of DCC on Wnt/β-catenin and AMPK pathways was examined. Results showed that DCC treatment activated Wnt/β-catenin signaling pathway via AMPK evidenced by increased levels of AMPK phosphorylation and Wnt10b expression after DCC treatment. In addition, DCC treated adipo-induced hBM-MSCs exhibited significantly increased nuclear levels of β-catenin compared with diminished nuclear PPARγ levels. In conclusion, DCC was shown to be able to hinder adipogenesis by activating the β-catenin via AMPK, providing potential utilization of DCC as a nutraceutical against bone marrow adiposity.

Измерения зеемановско-сверхтонкого псевдовырожденного квадруплета в CaF-=SUB=-2-=/SUB=-:Ho-=SUP=-3+-=/SUP=-

We report Zeeman infra-red spectroscopy of electronic-nuclear levels of 5I8 →5I7 transitions of Ho3+ in the C4v(F−) centre in CaF2 with the magnetic field along the ⟨111⟩ direction of the crystal. Transitions to the lowest 5I7 state, an isolated electronic doublet, and the next group of states, a pseudo-quadruplet consisting of a doublet and two nearby singlets, exhibit strongly non-linear Zeeman splittings and intensity variations. Simulated spectra based upon a crystal-field analysis give an excellent approximation to the data, illustrating the strong predictive ability of the parametrised crystal-field approach. Anti-crossings in the hyperfine splittings, the basis of quantum information storage in rare-earth doped insulating dielectrics, are also predicted.

LASP1 Induces Epithelial-Mesenchymal Transition in Lung Cancer through the TGF-β1/Smad/Snail Pathway

Background. LIM and SH3 domain protein 1 (LASP1), highly expressed in a variety of tumors, is considered as a novel tumor metastasis biomarker. However, it is unknown which signaling pathway works and how the signal transduces into cell nucleus to drive tumor progression by LASP1. The aim of this study is to explore the essential role of LASP1 in TGF-β1-induced epithelial-mesenchymal transition (EMT) in lung cancer cells. Methods. The gene and protein levels of LASP-1 were successfully silenced or overexpressed by LASP-1 shRNA lentivirus or pcDNA in TGF-β1-treated lung cancer cell lines, respectively. Then, the cells were developed EMT by TGF-β1. The cell abilities of invasion, migration, and proliferation were measured using Transwell invasion assay, wound healing assay, and MTT assay, respectively. Western blotting was used to observe the protein levels of EMT-associated molecules, including N-cadherin, vimentin, and E-cadherin, and the key molecules in the TGF-β1/Smad/Snail signaling pathway, including pSmad2 and Smad2, pSmad3 and Smad3, and Smad7 in cell lysates, as well as Snail1, pSmad2, and pSmad3 in the nucleus. Results. TGF-β1 induced higher LASP1 expression. LASP1 silence and overexpression blunted or promoted cell invasion, migration, and proliferation upon TGF-β1 stimulation. LASP1 also regulated the expression of vimentin, N-cadherin, and E-cadherin in TGF-β1-treated cells. Activity of key Smad proteins (pSmad2 and pSmad3) and protein level of Smad7 were markedly regulated through LASP1. Furthermore, LASP1 affected the nuclear localizations of pSmad2, pSmad3, and Snail1. Conclusion. This study reveals that LASP1 regulates the TGF-β1/Smad/Snail signaling pathway and EMT markers and features, involving in key signal molecules and their nuclear levels. Therefore, LASP1 might be a drug target in lung cancer.

Differential Expression Patterns of TDP-43 in Single Moderate versus Repetitive Mild Traumatic Brain Injury in Mice

Traumatic brain injury (TBI) is a disabling disorder and a major cause of death and disability in the world. Both single and repetitive traumas affect the brain acutely but can also lead to chronic neurodegenerative changes. Clinical studies have shown some dissimilarities in transactive response DNA binding protein 43 (TDP-43) expression patterns following single versus repetitive TBI. We explored the acute cortical post-traumatic changes of TDP-43 using the lateral fluid percussion injury (LFPI) model of single moderate TBI in adult male mice and investigated the association of TDP-43 with post-traumatic neuroinflammation and synaptic plasticity. In the ipsilateral cortices of animals following LFPI, we found changes in the cytoplasmic and nuclear levels of TDP-43 and the decreased expression of postsynaptic protein 95 within the first 3 d post-injury. Subacute pathological changes of TDP-43 in the hippocampi of animals following LFPI and in mice exposed to repetitive mild TBI (rmTBI) were studied. Changes in the hippocampal TDP-43 expression patterns at 14 d following different brain trauma procedures showed pathological alterations only after single moderate, but not following rmTBI. Hippocampal LFPI-induced TDP-43 pathology was not accompanied by the microglial reaction, contrary to the findings after rmTBI, suggesting that different types of brain trauma may cause diverse pathophysiological changes in the brain, specifically related to the TDP-43 protein as well as to the microglial reaction. Taken together, our findings may contribute to a better understanding of the pathophysiological events following brain trauma.

CLAVATA3 mediated simultaneous control of transcriptional and post-translational processes provides robustness to the WUSCHEL gradient

Regulation of the homeodomain transcription factor WUSCHEL concentration is critical for stem cell homeostasis in Arabidopsis shoot apical meristems. WUSCHEL regulates the transcription of CLAVATA3 through a concentration-dependent activation-repression switch. CLAVATA3, a secreted peptide, activates receptor kinase signaling to repress WUSCHEL transcription. Considering the revised regulation, CLAVATA3 mediated repression of WUSCHEL transcription alone will lead to an unstable system. Here we show that CLAVATA3 signaling regulates nuclear-cytoplasmic partitioning of WUSCHEL to control nuclear levels and its diffusion into adjacent cells. Our work also reveals that WUSCHEL directly interacts with EXPORTINS via EAR-like domain which is also required for destabilizing WUSCHEL in the cytoplasm. We develop a combined experimental and computational modeling approach that integrates CLAVATA3-mediated transcriptional repression of WUSCHEL and post-translational control of nuclear levels with the WUSCHEL concentration-dependent regulation of CLAVATA3. We show that the dual control by the same signal forms a seamless connection between de novo WUSCHEL synthesis and sub-cellular partitioning in providing robustness to the WUSCHEL gradient.

The synthetic triterpenoids CDDO-TFEA and CDDO-Me, but not CDDO, are potent BACH1 inhibitors

The transcription factor BACH1 is a potential target against a variety of chronic conditions linked to oxidative stress and inflammation, and formation of cancer metastasis. However, only a few BACH1 degraders/inhibitors have been described. BACH1 is a transcriptional repressor of heme oxygenase 1 (HMOX1), which is positively regulated by transcription factor NRF2 and is highly inducible by derivatives of the synthetic oleanane triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO). Most of the therapeutic activities of these compounds are due to their anti-inflammatory and antioxidant properties, which are widely attributed to their ability to activate NRF2. However, with such a broad range of action, these drugs may have other molecular targets that have not been fully identified and could also be of importance for their therapeutic profile. Herein we identified BACH1 as a target of CDDO-derivatives, but not CDDO. While both CDDO and CDDO-derivatives activate NRF2 similarly, only CDDO-derivatives inhibit BACH1, which explains the much higher potency of CDDO-derivatives as HMOX1 inducers compared with unmodified CDDO. Notably, we demonstrate that CDDO-derivatives inhibit BACH1 via a novel mechanism that reduces BACH1 nuclear levels while accumulating its cytoplasmic form. Altogether, our study identifies CDDO-derivatives as dual KEAP1/BACH1 inhibitors, providing a rationale for further therapeutic uses of these drugs

Abstract P335: Nanoparticle-mediated Delivery Of TT-10 Promotes Myocardial Repair

The pharmaceutical product TT-10 increases cardiomyocyte proliferation and survival by upregulating nuclear levels of Yes-associated protein (Yap) and the expression of Yap-targeted genes. When evaluated in a mouse model of myocardial infarction (MI), intraperitoneal TT-10 administration was associated with improvements in infarct size and cardiac function one week after treatment, but functional parameters progressively declined at later time points [1]. Here, we tested our hypothesis that the potency of TT-10 for myocardial repair could be increased by loading it into poly-lactic-co-glycolic acid nanoparticles (NPs) before intramyocardial administration. Mice were treated with injections of DPBS (n=9), empty nanoparticles (Empty-NPs, n=8), TT-10 solution (TT-10-sol, n=8), or TT-10-loaded NPs (TT-10-NPs, n=9) immediately after MI was induced via permanent ligation of the coronary artery. Cardiac function was assessed via transthoracic echocardiography, infarct size via histological Fast-Green staining, cardiac hypertrophy via measures of the heart-weight:bodyweight (HW:BW) ratio, cardiomyocyte proliferation via staining for Ki67 and phosphorylated histone 3 (PH3), and apoptosis via TUNEL. In vitro assessments confirmed that TT-10 was released from the TT-10-NPs for up to four weeks, and that the NPs were taken up by cultured cardiomyocytes. One and four weeks after MI induction and treatment, measures of left-ventricular (LV) ejection fraction (EF) and fractional shortening (FS) were significantly greater in TT-10-NP animals than in the TT-10-sol, Empty-NP, or DPBS groups; LV EF and FS also remained stable in the TT-10-NP group, while measurements in all other groups worsened (but not significantly) (LV EF at Week 4: TT-10-sol vs TT-10-NPs; 22.25 ± 1.474 vs 43.95 ± 1.884, p<0.05), between the two time points. TT-10-NP treatment was also associated with significantly smaller (by ~20%, p<0.05) infarcts and significantly lower HW:BW ratios at Week 4; with significantly greater proportions of Ki67 + , PH3 + , and nuclear-Yap + cardiomyocytes at Week 1; and with significant declines in TUNEL + cardiomyocytes 72 hours after MI and treatment. Thus, NP-mediated delivery of TT-10 results in the efficacy of both the magnitude and durability of the benefits associated with promotion of myocyte proliferation in a mouse MI model. [1] H. Hara, N. Takeda, M. Kondo, M. Kubota, T. Saito, J. Maruyama, et al., Discovery of a Small Molecule to Increase Cardiomyocytes and Protect the Heart After Ischemic Injury, JACC Basic Transl Sci, 3 (2018) 639-653.

Some Issues Related to the Direct Detection of Dark Matter

In this paper we review the theoretical issues involved in the direct detectionof supersymmetric (SUSY) dark matter. After a brief discussion of the allowedSYSY parameter space we focus on the determination of the traditional neutralinodetection rates, in experiments which measure the energy of the recoiling nucleus,such as the coherent and spin induced rates and the dependence of the rate onthe motion of the Earth (modulation effect). Then we examine the novel featuresappearing in directional experiments, which detect the recoiling nucleus in a givendirection. Next we estimate the branching ratios for transitions to accessibleexcited nuclear levels. Finally we estimate the event rates leading to the atomionization and subsequent detection of the outgoing electrons.