Toxic effect on the membrane system and cell proliferation of Prorocentrum donghaiense caused by the novel algicidal fungus Talaromyces purpurogenus YL13

2016 ◽  
Vol 29 (1) ◽  
pp. 275-284 ◽  
Author(s):  
Wanjiao Shu ◽  
Ling Zhao ◽  
Shaoling Hou ◽  
Qiming Jimmy Yu ◽  
Shuo Tan ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Toxic Effect ◽  
Membrane System ◽  
The Novel ◽  
Prorocentrum Donghaiense

scholarly journals Novel Pyrazolo[3,4-c]pyridine Antagonists with Nanomolar affinity for A1 / A3 Adenosine Receptors: Binding Kinetics and Exploration of their Binding Profile Using Mutagenesis Experiments, MD simulations and TI/MD calculations

2021 ◽  
Author(s):  
Margarita Stampelou ◽  
Anna Suchankova ◽  
Eva Tzortzini ◽  
Lakshiv Dhingra ◽  
Kerry Barkan ◽  
...  
Keyword(s):  
Drug Design ◽  
Transmembrane Helix ◽  
Rank Correlation ◽  
Membrane System ◽  
Md Simulations ◽  
Dissociation Rate ◽  
The Novel ◽  
Free Energies ◽  
Electronegative Group ◽  
Good Agreement

Drugs targeting the four adenosine receptor (AR) subtypes can provide “soft" treatment of various significant diseases. Even for the two experimentally resolved AR subtypes the description of the orthosteric binding area and structure-activity relationships of ligands remains a demanding task due to the high similar amino acids sequence but also the broadness and flexibility of the ARs binding area. The identification of new pharmacophoric moieties and nanomolar leads and the exploration of their binding area with mutagenesis and state-of-the-art computational methods useful also for drug design purposes remains a challenging aim for all ARs. Here, we identified several low nanomolar ligands and potent competitive antagonists against A1R / A3R, containing the novel pyrazolo[3,4-c]pyridine pharmacophore for ARs, from a screen of an in-house library of only 52 compounds, originally designed for anti-proliferative activity. We identified L2-L10, A15, A17 with 3-aryl, 7-anilino and a electronegative group at 5-position as low micromolar to low nanomolar A1R / A3R antagonists. A17 has for A1R Kd = 5.62 nM and a residence time (RT) 41.33 min and for A3R Kd = 13.5 nM, RT = 47.23 min. The kinetic data showed that compared to the not potent or mediocre congeners the active compounds have similar association, for example at A1R Kon = 13.97 x106 M-1 (A17) vs Kon = 3.36 x106 M-1 (A26) but much lower dissociation rate Koff = 0.024 min-1 (A17) vs 0.134 min-1 (A26). Using molecular dynamics (MD) simulations and mutagenesis experiments we investigated the binding site of A17 showing that it can interact with an array of residues in transmembrane helix 5 (TM5), TM6, TM7 of A1R or A3R including residues E5.30, E5.28, T7.35 in A1R instead of Q5.28, V5.30 , L7.35 in A3R. A striking observation for drug design purposes is that for L2506.51A the binding affinity of A17 significantly increased at A1R. A17 provides a lead representative of a promising series and by means of the Thermodynamics Integration coupled with MD simulations (TI/MD) method, first applied here on whole GPCR- membrane system and showing a very good agreement between calculated and experimental relative binding free energies for A1R and A3R (spearman rank correlation p = 0.82 and 0.84, respectively), and kinetic experiments can lead to ligands with improved profile against ARs.

scholarly journals The Novel Impact Of Treadmill Exercise And Sex Difference On Cell Proliferation and Cell Survival In The Dentate Gyrus Of G93A Mice

2008 ◽  
Vol 22 (S1) ◽  
Author(s):  
Xiaoxing Ma ◽  
Mazen J Hamadeh ◽  
Bingjun Zhang ◽  
Brian Christie ◽  
Mark A Tarnopolsky
Keyword(s):  
Cell Proliferation ◽  
Dentate Gyrus ◽  
Cell Survival ◽  
Sex Difference ◽  
Treadmill Exercise ◽  
The Novel

The novel microRNA hsa-miR-CHA1 regulates cell proliferation and apoptosis in human lung cancer by targeting XIAP

Lung Cancer ◽  
2019 ◽  
Vol 132 ◽  
pp. 99-106 ◽  
Author(s):  
Jung Ki Yoo ◽  
Ji Min Lee ◽  
Seung Hee Kang ◽  
Seong Ho Jeon ◽  
Chang Min Kim ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Proliferation ◽  
Human Lung ◽  
Human Lung Cancer ◽  
The Novel ◽  
Proliferation And Apoptosis

scholarly journals The Novel Long Noncoding RNA TUSC7 Inhibits Proliferation by Sponging MiR-211 in Colorectal Cancer

2017 ◽  
Vol 41 (2) ◽  
pp. 635-644 ◽  
Author(s):  
Jian Xu ◽  
Rui Zhang ◽  
Jian Zhao
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Tumor Suppressor ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Proliferation Rate ◽  
Expression Level ◽  
The Novel ◽  
Cell Proliferation Rate ◽  
Potential Tumor Suppressor

Background/Aims: The novel long noncoding RNA (lncRNA) tumor suppressor candidate 7 (TUSC7) has been reported as a potential tumor suppressor, while the functional role of TUSC7 is still unknown in colorectal cancer (CRC). Here, we characterized TUSC7 expression profile in CRC patients and investigated its biological function and potential molecular mechanism. Methods: RNA isolation, qRT-PCR, cell counter kit-8 assay, cell cycle assay, EdU assay, and western blot were performed. Statistical analyses were performed using SPSS 18.0 software and p value < 0.05 was considered as statistically significant. Results: In a cohort of CRC patients, we found TUSC7 was significantly downregulated in CRC tissues compared with adjacent non-tumor tissues (P < 0.01). Patients with high expression of TUSC7 had better survival than those with low expression of TUSC7 (HR = 0.342, 95% CI: 0.120-0.972, P = 0.044). Cell count kit 8 and EdU assays showed that ectopic expression of TUSC7 in HCT116 and SW480 cells significantly inhibited cell proliferation rate. After silence of TUSC7 with small interfering RNA, cell proliferation rate increased. Flow cytometry analyses revealed cycles were arrested at G1 phase after TUSC7 overexpression. We found there were 2 binding sites of miR-211-3p within the sequence of TUSC7 and TUSC7 expression level was negatively correlated with miR-211-3p. TUSC7 overexpression increased the expression level of CDK6, which is a downstream target of miR-211-3p, in both RNA and protein level. Furthermore, luciferase reporter assay indicated that TUSC7 could sponge miR-211-3p. Conclusion: To summary, we demonstrated that TUSC7 is a potential tumor suppressor in CRC, and TUSC7 could inhibit CRC cell proliferation by completely sponging miR-211-3p.

TGF-β Receptor Kinase Inhibitor LY2109761 Reverses the Anti-Apoptotic Effects of TGF-β1 in Leukemic Cells Co-Cultured with Stromal Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2846-2846
Author(s):  
Yoko Tabe ◽  
Yuanyuan Xu ◽  
Teresa McQueen ◽  
Michael Andreeff ◽  
Marina Konopleva
Keyword(s):  
Cell Proliferation ◽  
Stromal Cells ◽  
Leukemic Cells ◽  
Leukemia Cells ◽  
U937 Cells ◽  
The Novel ◽  
Β Receptor ◽  
Tgf Β1 ◽  
Cells Cultured

Abstract Transforming growth factor β1 (TGF-β1) is an essential regulator of cell proliferation, survival, and apoptosis, depending on the cellular context. TGF-β1 is also known to affect cell-to-cell interactions between tumor and stromal cells through production of the extracellular matrix and stimulation of integrin receptors. We investigated the role of TGF-β1 in the survival of human leukemic cells growing in the context of bone marrow (BM) microenvironment, and the anti-leukemia effects of the novel TGF-β receptor inhibitor LY2109761. BM-derived mesenchymal stem cells (MSC) produced TGF-β in an autocrine fashion. Treatment with rhTGF-β1 (2ng/mL) inhibited the spontaneous and Ara-C-induced apoptosis in U937 cells (% AnnexinV(+), control 34.5±8.4; TGF-β1 18.4±4.5; Ara-C 88.6±3.0; Ara-C/TGF-β1 60.4±8.0, p=0.04). These effects were more prominent in U937 cells co-cultured with MSC (% AnnexinV(+), control 19.4±2.8; TGF-β1 3.5±1.0; Ara-C 69.0±3.6; Ara-C+TGF-β1 24.9±3.3; p=0.01). In U937 cells co-cultured with MSC, rhTGF-β1 conferred higher cell protective effects on leukemia cells attached to MSC than on floating cells. Conversely, the pro-survival effects of TGF-β1 were inhibited by 5mM LY2109761 (%AnnexinV(+); MSC(−), control 31.8±2.3, TGF-β1 19.5±3.0, LY 28.4±4.4, TGF-β1+LY 37.7±2.0; MSC(+), control 22.1±1.7, TGF-β1 7.8±0.9, LY16.1±2.6, TGF-β1+ LY 18.0±1.1, p<0.01). Similar results were obtained using TGF-β1 neutralizing antibody. TGF-β1 induced pro-survival phosphorylation of Akt in U937 cells cultured alone or co-cultured with MSC, which was abrogated by LY2109761. Further, rhTGF-β1 induced a moderate increase in C/EBPβ gene and LAP isoform (cell cycle arrest inducing) of C/EBPβ protein in U937 cells cultured without MSCs, while markedly upregulating C/EBPβ gene and protein, both LIP (cell proliferation inducing) and LAP isoforms, under MSCs co-culture condition, suggesting the novel role of C/EBPβ in TGF-β1-mediated U937 cell survival. In summary, these results indicate that TGF-β1-secreting BM stromal cells promote the survival of U937 leukemia cells via direct cell-to-cell interaction and promote chemoresistance of leukemia cells through the activation of Akt signaling and upregulation of C/EBPβ. The blockade of TGF-β signaling by LY2109761, which effectively inhibited the pro-survival signaling, may enhance the efficacy of chemotherapy against leukemia cells in the BM microenvironment.

scholarly journals An In Silico Study for the Identification of Novel Putative Compounds Against the Wild and Mutant Type Penicillin Binding Protein 2 of Neisseria Gonorrhoeae

2020 ◽  
Vol 11 (2) ◽  
pp. 8996-9006
Keyword(s):  
Cell Proliferation ◽  
Cell Wall ◽  
Hot Spots ◽  
Structural Changes ◽  
Binding Protein ◽  
Cell Wall Biosynthesis ◽  
The Novel ◽  
Penicillin Binding Protein ◽  
Mutant Type ◽  
In Silico Study

Penicillin-binding protein 2 (PBP2) is an enzyme crucial for cell wall biosynthesis during cell proliferation of N. gonorrhoeae. In the present work, the crystal structures of wild and mutant type PBP2 were analyzed to identify structural changes leading to antibiotic resistance. Other than these two targets, three other targets were generated by analyzing possible hot spots for mutations in PBP2. By using a reverse screening approach, fifteen molecules were screened and processed for ligand binding analysis with all five targets. The analysis of the above studies suggested that two compounds Guanosine 5’-diphosphate and Thymidine 3', 5’-diphosphate show the good binding affinity than Ceftriaxone and other compounds. Further, we have generated ten novel compounds using Ceftriaxone, Guanosine 5’-diphosphate, and Thymidine 3', 5’-diphosphate. To identify the novel findings, all novel compounds were docked against aforesaid five targets. The studies resulted in the finding of three best molecules that may be considered as suitable, potent, and generic inhibitors against N. gonorrhoeae other than Ceftriaxone.

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