Search results for: Inhibitor
#32745992 2020/07/31 To Up
Microglia facilitate loss of perineuronal nets in the Alzheimer's disease brain.Microglia, the brain's principal immune cell, are increasingly implicated in Alzheimer's disease (AD), but the molecular interfaces through which these cells contribute to amyloid beta (Aβ)-related neurodegeneration are unclear. We recently identified microglial contributions to the homeostatic and disease-associated modulation of perineuronal nets (PNNs), extracellular matrix structures that enwrap and stabilize neuronal synapses, but whether PNNs are altered in AD remains controversial.
Joshua D Crapser, Elizabeth E Spangenberg, Rocio A Barahona, Miguel A Arreola, Lindsay A Hohsfield, Kim N Green
1516 related Products with: Microglia facilitate loss of perineuronal nets in the Alzheimer's disease brain.96 tests96 tests96 tests96 tests 50 UG1-99 mg/ml/ea price x 2
#32745972 2020/07/22 To Up
PARP inhibitors in castration-resistant prostate cancer.Somatic or germline mutations in genes regulating DNA damage repair have been noted in around 20% of patients with advanced prostate cancer. Poly-ADP-ribose polymerase (PARP) inhibitors have shown encouraging efficacy in prostate cancer patients with DNA repair mutations. Two PARP inhibitors, olaparib, and rucaparib have recently received FDA approval for treatment of patients with advanced castration-resistant prostate cancer (CRPC), while several trials with other PARP inhibitors are ongoing. Here, we briefly summarize the current data supporting the efficacy of PARP inhibitors in advanced CRPC.
Abhishek Tripathi, Pragathi Balakrishna, Neeraj Agarwal
#32745950 2020/07/27 To Up
Inhibition of firefly luciferase activity by a HIF prolyl hydroxylase inhibitor.The three hypoxia-inducible factor (HIF) prolyl-4-hydroxylase domain (PHD) 1-3 enzymes confer oxygen sensitivity to the HIF pathway and are novel therapeutic targets for treatment of renal anemia. Inhibition of the PHDs may further be beneficial in other hypoxia-associated diseases, including ischemia and chronic inflammation. Several pharmacologic PHD inhibitors (PHIs) are available, but our understanding of their selectivity and its chemical basis is limited. We here report that the PHI JNJ-42041935 (JNJ-1935) is structurally similar to the firefly luciferase substrate D-luciferin. Our results demonstrate that JNJ-1935 is a novel inhibitor of firefly luciferase enzymatic activity. In contrast, the PHIs FG-4592 (roxadustat) and FG-2216 (ICA, BIQ, IOX3, YM 311) did not affect firefly luciferase. The JNJ-1935 mode of inhibition is competitive with a K of 1.36 μM. D-luciferin did not inhibit the PHDs, despite its structural similarity to JNJ-1935. This study provides insights into a previously unknown JNJ-1935 off-target effect as well as into the chemical requirements for firefly luciferase and PHD inhibitors and may inform the development of novel compounds targeting these enzymes.
Julia Günter, Roland H Wenger, Carsten C Scholz
2208 related Products with: Inhibition of firefly luciferase activity by a HIF prolyl hydroxylase inhibitor.48 assays 96 assays 48 assays 0.1ml (1mg/ml)96 assays 48 assays 96 assays
#32745931 2020/07/26 To Up
Glucose modulates proliferation in root apical meristems via TOR in maize during germination.The Glucose-Target of Rapamycin (Glc-TOR) pathway has been studied in different biological systems, but scarcely during early seed germination. This work examines its importance for cell proliferation, expression of cell cycle key genes, their protein levels, besides morphology and cellularization of the root apical meristem of maize (Zea mays) embryo axes during germination under the influence of two simple sugars, glucose and sucrose, and a specific inhibitor of TOR activity, AZD 8055. The two sugars promote germination similarly and to an extent, independently of TOR activity. However, the Glc-TOR pathway increases the number of cells committed to proliferation, increasing the expression of a cell cycle gene, ZmCycD4;2, a putative G1/S regulator. Also, Glc-TOR may have influence on the protein stability of another G1/S cyclin, ZmCycD3, but had no influence on ZmCDKA;1 or ZmKRP3 or their proteins. Results suggest that the Glc-TOR pathway participates in the regulation of proliferation through different mechanisms that, in the end, modify the timing of seed germination.
Víctor Hugo Díaz-Granados, Jorge Manuel López-López, Jesús Flores-Sánchez, Roxana Olguin-Alor, Andrea Bedoya-López, Tzvetanka D Dinkova, Kenia Salazar-Díaz, Sonia Vázquez-Santana, Jorge Manuel Vázquez-Ramos, Aurora Lara-Núñez
2314 related Products with: Glucose modulates proliferation in root apical meristems via TOR in maize during germination.96 assays100 ml.2 Pieces/Box25 ml.5 mg100 μg100 assays2 Pieces/Box100 μg100 MG100 μg
#32745818 2020/07/18 To Up
Identifying representative kinases for inhibitor evaluation via systematic analysis of compound-based target relationships.We have investigated the question if kinases could be identified whose compound binding characteristics represent those of many other kinases. Therefore, compound-based relationships between kinases were systematically explored on the basis of a large curated collection of inhibitors with multi-kinase activity. With the aid of network analysis, individual kinases were identified that shared at least 50 inhibitors with more than 100 other kinases. Combinations of three to four kinases with many compound-based relationships were found to represent ∼150 kinases distributed across the human kinome. These findings have implications for the practice of medicinal chemistry because small numbers of kinases can be prioritized for compound testing that are expected to account for binding characteristics of many others. Hence, choosing three or four representative kinases may be sufficient for a first-path control evaluation of new candidate compounds to assess their potential for promiscuity in kinase inhibition.
Oliver Laufkötter, Stefan Laufer, Jürgen Bajorath
2361 related Products with: Identifying representative kinases for inhibitor evaluation via systematic analysis of compound-based target relationships.0.1 mg250 ml0.1 mg50ul (1mg/ml)1 LITRE25 µg0.2 mg100 ml0.25 mg0.2 mg0.1ml (1mg/ml)
#32745767 2020/07/31 To Up
Itaconate regulates the glycolysis/pentose phosphate pathway transition to maintain boar sperm linear motility by regulating redox homeostasis.Mammalian cells improve redox homeostasis under reactive oxygen species (ROS) stress conditions via the enhancement of the pentose phosphate pathway (PPP). However, it is not clear how the cell reprograms glucose metabolism from glycolysis to the PPP. Hence, in the present study, we used boar sperm as a model to elucidate the mechanism by which the glycolysis/PPP transition occurs under ROS stress. The boar sperm treated with moderate glucose levels for 3 h exhibited increased sperm linear motility patterns, ATP levels and GSH/GSSG ratios and decreased ROS levels compared to the boar sperm treated without glucose. In addition, the hexokinase activity, glucose-6-phosphate dehydrogenase (G6PD) activity, NADPH level, NADPH/NADP ratio and mitochondrial activity were higher in the sperm treated with moderate glucose than in those not treated with glucose. Interestingly, the enzyme activity of fructose-1,6-bisphosphate aldolase (ALDOA) was not significantly changed during the incubation. The sperm linear motility patterns were decreased by treatment with the G6PD inhibitor 6-aminonicotinamide. Moreover, moderate glucose treatment significantly increased the itaconate levels in sperm. Both endogenous and exogenous itaconate increased the total itaconate modifications and the itaconate-modified ALDOA levels in sperm, suggesting that under moderate-glucose conditions, glycolysis in the sperm was suppressed by an increase in the itaconate levels. Furthermore, the addition of itaconate improved the sperm linear motility patterns by suppressing glycolysis and enhancing oxidative phosphorylation (OXPHOS). Therefore, the itaconate generated from OXPHOS regulates the glycolysis/PPP transition to maintain redox homeostasis. In sperm, this itaconate-dependent mechanism plays an important role in maintaining their high linear motility.
Zhendong Zhu, Takashi Umehara, Natsumi Tsujita, Tomoko Kawai, Masaaki Goto, Bo Cheng, Wenxian Zeng, Masayuki Shimada
2550 related Products with: Itaconate regulates the glycolysis/pentose phosphate pathway transition to maintain boar sperm linear motility by regulating redox homeostasis.100ul100 mg5 x 1 ml 1 G 25 MG200 1000 ml 1KG
#32745765 2020/07/31 To Up
Hypoxic preconditioning combined with curcumin promotes cell survival and mitochondrial quality of bone marrow mesenchymal stem cells, and accelerates cutaneous wound healing via PGC-1α/SIRT3/ HIF-1α signaling.Restrained survival and function of relocated bone marrow mesenchymal stem cells (BMSCs) is a major impediment to BMSCs-mediated tissue repair. Accumulating evidences have indicated that hypoxic preconditioning of BMSCs could enhance BMSCs' adaptability after transplantation and thus improve their therapeutic properties. Curcumin, a natural dietary product, is known to exert profound protective effects on various cellular processes. Here we showed that mild hypoxic preconditioning combined with curcumin significantly increased cell survival, enriched more cells in G2/M and S phase, and improved mitochondrial function in BMSCs. Meanwhile, hypoxic preconditioning combined with curcumin altered mitochondrial cristae shape and strongly inhibited mitochondrial cytochrome c release, which consequently suppressed an apoptosis signal as revealed by reduced caspase-3 cleavage in BMSCs. Moreover, hypoxic preconditioning remarkably promoted mitochondrial quality via increasing mitochondrial fusion and elevating the activity of oxidative phosphorylation (OXPHOS) and mitochondrial complex Ⅰ enzyme in BMSCs, which were in accordance with the up-regulated expression of OPA1, PINK1 and Parkin. At the mechanistic level, the destabilization of HIF-1α and the up-regulated expression of PGC-1α and SIRT3 synergistically contributed to the protective effects of hypoxic preconditioning combined with curcumin in BMSCs. The proteasome inhibitor MG132 stabilized HIF-1a expression, but not PGC-1α or SIRT3, and dramatically restrained BMSCs survival under hypoxia combined with curcumin condition. MG132 also increased mitochondrial superoxide and intracellular hydrogen peroxide (HO) production and caspase-3 activation in hypoxia combined with curcumin-treated BMSCs. Furthermore, knockdown of SIRT3 and PGC-1α by RNAi both led to caspase-3 activation in BMSCs after hypoxia and curcumin treatment. Notably, SIRT3 RNAi suppressed OXPHOS activity, while PGC-1α RNAi triggered mitochondrial superoxide and intracellular HO production in hypoxia combined with curcumin-treated BMSCs. Finally, we showed that hypoxia combined with curcumin-treated BMSCs accelerated the cutaneous wound healing process in a mice wound model. Overall, this study suggests that hypoxic preconditioning combined with curcumin could serve as an attractive strategy for facilitating BMSCs-mediated tissue repair, and further sheds new light on the rich repertoire of PGC-1α/SIRT3/HIF-1α signaling involved in the regulation of mitochondrial quality and function for cellular adaption to hypoxia.
Xujie Wang, Kuo Shen, Jing Wang, Kaituo Liu, Gaofeng Wu, Yan Li, Liang Luo, Zhao Zheng, Dahai Hu
2775 related Products with: Hypoxic preconditioning combined with curcumin promotes cell survival and mitochondrial quality of bone marrow mesenchymal stem cells, and accelerates cutaneous wound healing via PGC-1α/SIRT3/ HIF-1α signaling.5 x 10A5 cells/vial1 vial1 x 10^6 cells/vial10 ug1.5 x 10^6 cells24 wells24 wells24 wells1.5x10(6) cells100 ug/vial1One Vial: 5 X 10^6 Cells
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#32745606 2020/07/31 To Up
High dose of baicalin or baicalein can reduce tight junction integrity by partly targeting the first PDZ domain of zonula occludens-1 (ZO-1).The tight junction (TJ) is the apical-most intercellular junction complex, serving as a biological barrier of intercellular spaces between epithelial cells. The TJ's integrity is maintained by a key protein-protein interaction between C-terminal motifs of claudins (CLDs) and the postsynaptic density 95 (PSD-95)/discs large/zonula occludens 1 (ZO-1; PDZ) domains of ZO-1. Weak but direct interaction of baicalin and its aglycon, baicalein-which are pharmacologically active components of Chinese skullcap (Radix scutellariae)-with ZO-1(PDZ1) have been observed in NMR experiments. Next, we observed TJ-mitigating activity of these flavonoids against Madin-Darby canine kidney (MDCK) II cells with the downregulation of subcellular localization of CLD-2 at TJs. Meanwhile, baicalein-but not baicalin-induced a slender morphological change of MDCK cells' shape from their normal cobblestone-like shapes. Since baicalin and baicalein did not induce a localization change of occludin (OCLN), a "partial" epithelial-mesenchymal transition (EMT) induced by these flavonoids was considered. SB431542, an ALK-5 inhibitor, reversed the CLD-2 downregulation of both baicalin and baicalein, while SB431542 did not reverse the slender morphology. In contrast, the MEK/ERK inhibitor U0126 reversed the slender shape change. Thus, in addition to inhibition of the ZO-1-CLD interaction, activation of both transforming growth factor-β (TGF-β) and MEK/ERK signaling pathways have been suggested to be involved in TJ reduction by these flavonoids. Finally, we demonstrated that baicalin enhanced the permeability of fluorescence-labeled insulin via the paracellular pathway of the Caco-2 cell layer. We propose that baicalin, baicalein, and Radix scutellariae extract are useful as drug absorption enhancers.
Misaki Hisada, Minami Hiranuma, Mio Nakashima, Natsuko Goda, Takeshi Tenno, Hidekazu Hiroaki
1841 related Products with: High dose of baicalin or baicalein can reduce tight junction integrity by partly targeting the first PDZ domain of zonula occludens-1 (ZO-1).100 G100ug Lyophilized100reactions 100ug Lyophilized100ul100ug100μg
#32745564 2020/07/31 To Up
Dual Formulation and Interaction Strategies to Enhance the Oral Bioavailability of Paclitaxel.A self-microemulsifying drug delivery system (SMEDDS) was developed to enhance Paclitaxel (PTX) solubility and membrane permeability, thus improve its bioavailability. Pre-formulation studies were performed to optimize PTX-SMEDDS formulation. Then, in vitro characteristics of the formulation were determined and PTX oral absorption was investigated in rabbits. The optimized PTX-SMEDDS showed emulsification time of 31 ± 4 sec, droplet size of 19.4 ± 0.5 nm, poly-dispersibility index of 0.35 ± 0.08, percentage transmittance after dilution of 99 ± 0.02%, zeta potential of 36.82 ± 1.8 mv, cloud point of 78 ± 0.5 ºC and infinite dilution capability. The formulation maintained its physical and chemical stability during storage at 4 ºC for three months. Oral administration of 10 mg/kg of 1.5% w/w PTX-loaded SMEDDS to rabbits increased PTX bioavailability by 4.5 fold in comparison to untreated PTX suspension. While when the rabbits received 1.5% w/w PTX-loaded SMEDDS after pretreated with 1 dose and 2 doses of cyclosporine A, PTX bioavailability increased by 4.4 and 7.8 fold, respectively. This indicates that the combined effect of the SMEDDS formulation in addition to pretreatment with P-gp and CYP3A4 inhibitor, can improve the oral bioavailability of poorly soluble and poorly permeable drugs such as PTX in rabbits.
Bashaier Mohammed Al-Kandari, Monerah H Al-Soraj, Mohsen A Hedaya
2937 related Products with: Dual Formulation and Interaction Strategies to Enhance the Oral Bioavailability of Paclitaxel.1 Set1 Set1 Set1 Set 100 G100 U
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