A5054943327- Metabolomics and Mass Spectrometry Studies
- Drug Transport and Resistance Mechanisms
- Analytical Chemistry and Chromatography
- Mass Spectrometry Techniques and Applications
- Chronic Lymphocytic Leukemia Research
- PI3K/AKT/mTOR signaling in cancer
- Immunodeficiency and Autoimmune Disorders
- Viral Infectious Diseases and Gene Expression in Insects
- Pharmacogenetics and Drug Metabolism
- DNA and Nucleic Acid Chemistry
- Carcinogens and Genotoxicity Assessment
- Systemic Sclerosis and Related Diseases
- Bioactive Compounds and Antitumor Agents
- Drug-Induced Hepatotoxicity and Protection
- Monoclonal and Polyclonal Antibodies Research
- Virus-based gene therapy research
- Autoimmune and Inflammatory Disorders
- Chronic Myeloid Leukemia Treatments
- Antibiotics Pharmacokinetics and Efficacy
- RNA Interference and Gene Delivery
- TGF-β signaling in diseases
- Protein purification and stability
- RNA and protein synthesis mechanisms
- X-ray Diffraction in Crystallography
- Cancer-related molecular mechanisms research
Bristol-Myers Squibb (United States)
2010-2024
Sun Yat-sen University Cancer Center
2022
Sun Yat-sen University
2022
First Affiliated Hospital of Chengdu Medical College
2022
PAX Scientific (United States)
2015-2016
PaxVax (United States)
2015-2016
Bristol-Myers Squibb (Germany)
2007-2014
Weatherford College
2013
Wuhan Technical College of Communications
2013
University of Chicago
2007-2008
Bruton's tyrosine kinase (BTK), a non-receptor kinase, is member of the Tec family kinases and essential for B cell receptor (BCR) mediated signaling. BTK also plays critical role in downstream signaling pathways Fcγ monocytes, Fcε granulocytes, RANK osteoclasts. As result, pharmacological inhibition anticipated to provide an effective strategy clinical treatment autoimmune diseases such as rheumatoid arthritis lupus. This article will outline evolution our identify covalent, irreversible...
A new strategy using a hybrid linear ion trap/Orbitrap mass spectrometer and multiple post-acquisition data mining techniques was evaluated applied to the detection characterization of in vitro metabolites indinavir. Accurate-mass, full-scan MS MS/MS sets were acquired with generic data-dependent method processed extracted-ion chromatography (EIC), mass-defect filter (MDF), product-ion (PIF), neutral-loss (NLF) techniques. The high-resolution EIC process shown be highly effective common...
Reactive metabolite formation has been associated with drug-induced liver, skin, and hematopoietic toxicity of many drugs that resulted in serious clinical toxicity, leading to development failure, black box warnings, or, some cases, withdrawal from the market. In vitro vivo screening for reactive proposed widely adopted pharmaceutical industry aim minimizing property thus risk (DIT). One most common methods is thiol trapping metabolites. Although it well-documented hepatotoxins form...
Currently, mass spectrometry-based protein bioanalysis is primarily achieved through monitoring the representative peptide(s) resulting from analyte digestion. However, this approach often incapable of differentiating measurement its post-translational modifications (PTMs) and/or potential biotransformation (BTX) products. This disadvantage can be overcome by direct intact analytes. Selected reaction (SRM) on triple quadrupole spectrometers has been used for protein. fragmentation efficiency...
The oxycyclohexyl acid BMS-986278 (33) is a potent lysophosphatidic receptor 1 (LPA1) antagonist, with human LPA1Kb of 6.9 nM. structure-activity relationship (SAR) studies starting from the LPA1 antagonist clinical compound BMS-986020 (1), which culminated in discovery 33, are discussed. detailed vitro and vivo preclinical pharmacology profiles as well its pharmacokinetics/metabolism profile, described. On basis efficacy rodent chronic lung fibrosis models excellent overall ADME...
The present study describes a novel integrated approach for rapid analysis of reactive metabolites with linear ion trap mass spectrometer (LTQ). In this approach, an isotope pattern-dependent scanning method was applied to the data acquisition glutathione (GSH)-trapped metabolites. Recorded full-scan MS and MS/MS sets were further processed neutral loss filtering, product extracted chromatographic search protonated molecules spectra GSH adducts. To evaluate effectiveness reliability adducts...
The bioactivation of ticlopidine, a widely used antiplatelet drug, into reactive metabolites and their subsequent covalent binding to cellular macromolecules are thought be involved in the occurrence idiosyncratic hepatotoxicity patients. In present study, GSH/stable isotope-labeled GSH was as trapping agent investigate pathways ticlopidine rat liver microsomes. samples were analyzed by high-resolution linear ion trap/Orbitrap followed multiple mass defect filtering (MDF). total, 17 adducts...
Advancement of endogenous biomarkers for drug transporters as a tool assessing drug-drug interactions (DDIs) depends on initial identification biomarker candidates and relies heavily validation its response to reference inhibitors in vivo. To identify breast cancer resistance protein (BCRP), we applied metabolomic approaches profile plasma from Bcrp<sup>−/−</sup>, multidrug (Mdr)1a/1b<sup>−/−</sup>, Bcrp/Mdr1a/1b<sup>−/−</sup> mice. Approximately 130 metabolites were significantly altered...
There is substantial evidence to suggest that polycyclic aromatic hydrocarbons (PAHs) such as benzo[a]pyrene (B[a]P) induce lung cancer through metabolic activation. As part of a program delineate the routes PAH activation, we have examined DNA adducts are formed in human cells. A stable isotope dilution liquid chromatography/multiple reaction monitoring mass spectrometry method was used quantify eight anti-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydro-B[a]P (B[a]PDE)-derived four H358...
The influence of DNA base sequence context on the removal a bulky benzo[a]pyrene diol epoxide-guanine adduct, (+)-trans-B[a]P-N2-dG (G*), by UvrABC nuclease from thermophilic organism Bacillus caldotenax was investigated. lesion flanked either T or C in otherwise identical complementary 43-mer duplexes (TG*T CG*C, respectively). It reported earlier that CG*C context, dominant minor groove adduct structure observed NMR methods with all Watson−Crick pairs intact, and duplex exhibited rigid...
Ticlopidine, an antiplatelet drug, undergoes extensive oxidative metabolism to form S ‐oxide, N hydroxylated and dealkylated metabolites. However, of ticlopidine via conjugation has not been thoroughly investigated. In this study, multiple data acquisition processing tools were applied the detection characterization conjugates in rat bile. Accurate full‐scan mass spectrometry (MS) collision‐induced dissociation (CID) MS/MS sets recorded using isotope pattern‐dependent on LTQ/Orbitrap system....
The fjord polycyclic aromatic hydrocarbon compound dibenzo[a,l]pyrene (DB[a,l]P) is significantly more tumorigenic than the bay region benzo[a]pyrene in animal model systems. molecular origins of unusually strong genotoxic properties DB[a,l]P and its diol epoxide metabolites are great interest believed to be related structural characteristics DNA adducts formed. Site-specifically modified oligonucleotides were prepared by reacting single adenine residue 5'-d(CTCTCACTTCC) (I) with racemic...
Abstract Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental pollutants found in car exhausts, charbroiled food, and tobacco smoke. Three pathways for the metabolic activation of B[ a ]P to ultimate carcinogens have been proposed. The most widely accepted pathway involves cytochrome‐P450 (CYP) 1A1‐ and/or 1B1‐mediated formation ]P‐7,8‐oxide, which undergoes epoxide hydrolase‐mediated metabolism proximate carcinogen ]P‐7,8‐dihydro‐7,8‐diol. Further CYP1A1‐ CYP1B1‐mediated...
PI3Kδ plays an important role controlling immune cell function and has therefore been identified as a potential target for the treatment of immunological disorders. This article highlights our work toward identification potent, selective, efficacious inhibitor. Through careful SAR, successful replacement polar pyrazole group by simple chloro or trifluoromethyl led to improved Caco-2 permeability, reduced efflux, hERG PC activity, increased selectivity profile while maintaining potency in...
IRAK4 is an attractive therapeutic target for the treatment of inflammatory conditions. Structure guided optimization a nicotinamide series inhibitors has been expanded to explore front pocket. This resulted in identification compounds such as 12 with improved potency and selectivity. Additionally demonstrated activity pharmacokinetics/pharmacodynamics (PK/PD) model. Further efforts led highly kinome selective 21, which robust PD effect efficacy TLR7 driven model murine psoriasis.
Polycyclic aromatic hydrocarbons (PAHs) are major environmental carcinogens produced in the combustion of fossil fuels, tobacco, and other organic matter. Current evidence indicates that PAHs transformed enzymatically to active metabolites react with DNA form adducts result mutations. Three activation pathways have been proposed: diol epoxide path, radical-cation quinone path. The latter involves aldo-keto reductase mediated oxidation PAH dihydrodiol catechols enter into redox cycles...
ABSTRACT Replication-competent adenovirus (rcAd)-based vaccine vectors may theoretically provide immunological advantages over replication-incompetent Ad vectors, but they also raise additional potential clinical and regulatory issues. We produced replication-competent serotype 26 (rcAd26) by adding the E1 region back into a Ad26 vector backbone with E3 or E3/E4 regions deleted. assessed effect of vectorization on replicative capacity rcAd26 vaccines. Attenuation occurred in stepwise...
Drug metabolite profiling utilizes liquid chromatography with tandem mass spectrometry (LC/MS/MS) to acquire ample information for identification and structural elucidation. However, there are still challenges in detecting characterizing all potential metabolites that can be masked by a high biological background, especially the unknown uncommon ones. In this work, novel workflow was established on platform using state-of-the-art tribrid high-resolution (HRMS) system. Primarily, an...
Lung carcinoma is the most prevalent malignancy in adults. Lidocaine (Lido) has been confirmed to exert an anti-tumor role many human cancers. However, and underlying mechanism of Lido lung remain poorly understood. Cell proliferation ability, migration, invasion, apoptosis were measured by Colony formation, 5-ethynyl-2'-deoxyuridine (EdU), Counting Kit-8 (CCK-8), transwell, flow cytometry assays. Circ_PDZD8, microRNA-516b-5p (miR-516b-5p), Golgi transport 1A (GOLT1A) levels detected...