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#33091667   2020/10/08 To Up

Identification of a potent and selective phosphatidylinositol 3-kinase δ inhibitor for the treatment of non-Hodgkin's lymphoma.

PI3Kδ has proved to be an effective target for anti-lymphoma drugs. However, the application of current approved PI3Kδ inhibitors has been greatly limited due to their specific immune-mediated toxicity and increased risk of infection, it is necessary to develop more PI3Kδ inhibitors with new scaffold. In this study, SAR study with respect to piperazinone-containing purine derivatives led to the discovery of a potent and selective PI3Kδ inhibitor, 4-(cyclobutanecarbonyl)-1-((2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperazin-2-one (WNY1613). WNY1613 exhibits good antiproliferative activity against a panel of non-Hodgkin's lymphoma (NHL) cell lines by inducing cancer cell apoptosis and inhibiting the phosphorylation of PI3K and MAPK downstream components. In addition, it can also prevent the tumor growth in both SU-DHL-6 and JEKO-1 xenograft models without observable toxicity. WNY1613 thus could be developed as a promising candidate for the treatment of NHL after subsequent extensive pharmacodynamics and pharmacokinetics investigation.
Wei-Qiong Zuo, Rong Hu, Wan-Li Wang, Yong-Xia Zhu, Ying Xu, Luo-Ting Yu, Zhi-Hao Liu, Ning-Yu Wang

1903 related Products with: Identification of a potent and selective phosphatidylinositol 3-kinase δ inhibitor for the treatment of non-Hodgkin's lymphoma.

400Tests25 mg96T5 mg5 mg0.2 mg1 mg5mg7 inhibitors 100ul50 ug

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#33091661   2020/10/07 To Up

The blockade of kappa opioid receptors exacerbates alveolar bone resorption in rats.

Bone resorption associated to chronic diseases, such as arthritis and periodontitis, results from exacerbated immuno-inflammatory host response that leads to tissue breakdown. The significance of opioid pathways as endogenous modulators of inflammatory events has already been described. Thus, the aim of this work is to determine whether some of the main three opioid receptors are endogenously activated to prevent bone loss during experimentally-induced alveolar bone resorption.
Marcelo Queiroz D'Ângelo, Celso Martins Queiroz-Junior, Kátia Lucy de Melo Maltos, Anderson José Ferreira, Cinthia Mara da Fonseca Pacheco, Rodrigo Villamarim Soares

2085 related Products with: The blockade of kappa opioid receptors exacerbates alveolar bone resorption in rats.

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#33091380   2020/10/19 To Up

Affinity, potency, efficacy, selectivity, and molecular modeling of substituted fentanyls at opioid receptors.

Substituted fentanyls are abused and cause rapid fatal overdose. As their pharmacology is not well characterized, we examined in vitro pharmacology and structure-activity relationships of 22 substituted fentanyls with modifications of the fentanyl propyl group, and conducted in silico receptor/ligand modeling. Affinities for mu, kappa, and delta opioid receptors (MOR, KOR, and DOR, respectively) heterologously expressed in mammalian cells were assessed in agonist radioligand binding assays. At MOR, furanyl fentanyl had higher affinity than fentanyl, while acryl, isobutyryl and cyclopropyl fentanyls had similar affinities. Comparing affinities, thiophene and methoxyacetyl fentanyls had highest selectivity for MOR (2520- and 2730-fold compared to KOR and DOR, respectively). Functional activities were assessed using [S]GTPγS binding assays. At MOR, furanyl fentanyl had higher potency and 11 substituted fentanyls had similar high potencies compared to fentanyl. Eight compounds were full agonists of MOR and twelve compounds were partial agonists, with efficacies from 8.8% (phenyl fentanyl) to 60.2% (butyryl fentanyl). All efficacious compounds had selective functional potency for MOR. The predicted binding poses of flexible fentanyl and rigid morphine against MOR show partially overlapping binding pockets, with fentanyl maintaining additional interaction with the transmembrane (TM) 2 helix. Subsequent molecular dynamics simulations revealed a predominant fentanyl binding pose involving various TM interactions. The piperidine nitrogen of substituted fentanyls establishes a salt-bridge with the conserved D-147 residue and the propanamide carbonyl group establishes a hydrogen bond with the indole side-chain (-NH) of W-318. The simulation suggests theN-linked phenethyl group may regulate the rotameric switch of W-293. The predicted binding pose, in conjunction with in vitro binding affinity, clarified the molecular basis of the binding/selectivity profile of furanyl fentanyl and other derivatives at the sequence level. In summary, substituted fentanyls with high MOR potencies, selectivities, and efficacies are likely to have abuse and overdose potential. The work presented here is a prototype to investigate fentanyl derivatives and their abuse potential.
Amy J Eshleman, Shanthi Nagarajan, Katherine M Wolfrum, John F Reed, Aaron Nilsen, Randy Torralva, Aaron Janowsky

2562 related Products with: Affinity, potency, efficacy, selectivity, and molecular modeling of substituted fentanyls at opioid receptors.

500g10 mg200ul100μl10reactions 5 mg1 Set100ul5x96 well plate0.1mg5 mg5 mg

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#33090576   2020/10/08 To Up

Molecular pathogenesis of cutaneous lymphoma -future directions.

The pathogenesis of cutaneous T-cell lymphomas is not clear. In recent years the genetic changes in CTCL were explored. The detected mutations showed a great deal of heterogeneity between individual patients. The studies documented various copy number variations (CNV) and single nucleotide variations (SNV) in multiple genes involved in multiple signaling pathways. Recurrently mutated signaling pathways include JAK-STAT, MAPK, T cell receptor, TNF receptor and NFκB signaling. In the period between 2018 and today additional studies towards the genetic changes in CTCL were carried out. Genetic changes in gamma delta T cell lymphoma are also shown in genes of the JAK-STAT, MAPK, MYC and chromatin signaling pathways. These studies might indicate a shift away from targeted sequencing approaches towards whole genome sequencing. This approach demands additional resources in terms of funding but has the advantage of finding mutations in non-coding regions. These mutations were neglected for a long time, but as shown in contemporary research these regions harbor highly recurrent mutations affecting gene expression and regulation. Nevertheless, the detection of specific molecular changes in known pathways enables considerations for targeted therapies.
Rudolf Stadler, Carsten Hain, Cassandra Cieslak, René Stranzenbach

2713 related Products with: Molecular pathogenesis of cutaneous lymphoma -future directions.

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#33090507   2020/10/22 To Up

Fatty acid-binding protein 3 controls contact hypersensitivity through regulating skin dermal Vγ4 γ/δ T cell in a murine model.

Fatty acid-binding protein 3 (FABP3) is a cytosolic carrier protein of polyunsaturated fatty acids (PUFAs) and regulates cellular metabolism. However, the physiological functions of FABP3 in immune cells and how FABP3 regulates inflammatory responses remain unclear.
Shuhei Kobayashi, Hai The Phung, Yoshiteru Kagawa, Hirofumi Miyazaki, Yu Takahashi, Atsuko Asao, Takashi Maruyama, Akihiko Yoshimura, Naoto Ishii, Yuji Owada

2721 related Products with: Fatty acid-binding protein 3 controls contact hypersensitivity through regulating skin dermal Vγ4 γ/δ T cell in a murine model.

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#33090112   2020/10/22 To Up

A Telemonitoring and Hybrid Virtual Coaching Solution "CAir" for Patients with Chronic Obstructive Pulmonary Disease: Protocol for a Randomized Controlled Trial.

Chronic obstructive pulmonary disease (COPD) is one of the most common disorders in the world. COPD is characterized by airflow obstruction, which is not fully reversible. Patients usually experience breathing-related symptoms with periods of acute worsening and a substantial decrease in the health-related quality-of-life. Active and comprehensive disease management can slow down the progressive course of the disease and improve patients' disabilities. Technological progress and digitalization of medicine have the potential to make elaborate interventions easily accessible and applicable to a broad spectrum of patients with COPD without increasing the costs of the intervention.
Christoph Gross, Dario Kohlbrenner, Christian F Clarenbach, Adam Ivankay, Thomas Brunschwiler, Yves Nordmann, Florian V Wangenheim

1827 related Products with: A Telemonitoring and Hybrid Virtual Coaching Solution "CAir" for Patients with Chronic Obstructive Pulmonary Disease: Protocol for a Randomized Controlled Trial.

100ug1 LITRE5 g100 assays10 mg0.2 mg 100ul100ug100Tests0.1ml (1mg/ml)

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#33090103   // To Up

Molecular epidemiology of Hepatitis B virus, Hepatitis C virus, and Hepatitis D virus in general population of Afghanistan.

This study gives a clue about genotypes, subgenotypes and subtypes of HBV, HCV and HDV viruses in general population of Afghanistan.
Abbas Ali Husseini, Khwaja Mir Islam Saeed, Esra Yurdcu, A Mithat Bozdayı

1297 related Products with: Molecular epidemiology of Hepatitis B virus, Hepatitis C virus, and Hepatitis D virus in general population of Afghanistan.

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#33090017   2020/10/22 To Up

Urinary proteins detected using modern proteomics intervene in early type 2 diabetic kidney disease - a pilot study.

An advanced proteomics platform for protein biomarker discovery in diabetic chronic kidney disease (DKD) was developed, validated and implemented. Three Type 2 diabetes mellitus patients and three control subjects were enrolled. Urinary peptides were extracted, samples were analyzed on a hybrid LTQ-Orbitrap Velos Pro instrument. Raw data were searched using the SEQUEST algorithm and integrated into Proteome Discoverer platform. Unique peptide sequences, resulted sequence coverage, scoring of peptide spectrum matches were reported to albuminuria and databases. Five proteins that can be associated with early DKD were found: apolipoprotein AI, neutrophil gelatinase-associated lipocalin, cytidine deaminase, S100-A8 and hemoglobin subunit delta. Urinary proteome analysis could be used to evaluate mechanisms of pathogenesis of DKD.
Alina Golea-Secara, Cristian Munteanu, Mirela Sarbu, Octavian M Cretu, Silvia Velciov, Adrian Vlad, Flaviu Bob, Florica Gadalean, Cristina Gluhovschi, Oana Milas, Anca Simulescu, Maria Mogos-Stefan, Mihaela Patruica, Ligia Petrica, Alina D Zamfir

2446 related Products with: Urinary proteins detected using modern proteomics intervene in early type 2 diabetic kidney disease - a pilot study.

25mg500 tests200ul3

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