A5100332874- Cancer Mechanisms and Therapy
- Pancreatic function and diabetes
- Mechanisms of cancer metastasis
- Metabolism, Diabetes, and Cancer
- Diabetes Treatment and Management
- Cancer-related molecular mechanisms research
- Radiopharmaceutical Chemistry and Applications
- Pharmacogenetics and Drug Metabolism
- Cancer-related gene regulation
- Peptidase Inhibition and Analysis
- Drug-Induced Adverse Reactions
- Medical Imaging Techniques and Applications
- Food Allergy and Anaphylaxis Research
- Pancreatic and Hepatic Oncology Research
- Metastasis and carcinoma case studies
- Drug Transport and Resistance Mechanisms
- Kruppel-like factors research
- Nanoplatforms for cancer theranostics
- Diabetes and associated disorders
- Cancer, Hypoxia, and Metabolism
- Neuroendocrine Tumor Research Advances
- Calcium signaling and nucleotide metabolism
- Eosinophilic Esophagitis
- Circular RNAs in diseases
- Monoclonal and Polyclonal Antibodies Research
Westlake University
2023-2025
Pfizer (United States)
2024
Institute of Basic Medical Sciences of the Chinese Academy of Medical Sciences
2023
Fudan University
2023
Zhejiang Chinese Medical University
2022
Children's Hospital of Zhejiang University
2021
Center for Life Sciences
2019
Peking University
2019
Janssen (Belgium)
2014-2018
University of Pennsylvania
2018
The mechanism of insulin dysregulation in children with hyperinsulinism associated inactivating mutations short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD) was examined mice a knock-out the hadh gene (hadh(-/-)). hadh(-/-) had reduced levels plasma glucose and elevated levels, similar to SCHAD deficiency. were hypersensitive oral amino acid decrease level elevation insulin. Hypersensitivity can be explained by abnormal responses physiological mixture acids increased sensitivity leucine...
Fructose-1,6-bisphosphate (FBP) aldolase links sensing of declining glucose availability to AMPK activation via the lysosomal pathway. However, how transmits lack occupancy by FBP remains unclear. Here, we show that FBP-unoccupied interacts with and inhibits endoplasmic reticulum (ER)-localized transient receptor potential channel subfamily V, inhibiting calcium release in low glucose. The decrease at contact sites between ER lysosome renders inhibited TRPV accessible bind v-ATPase then...
Abstract: Gold nanoclusters (Au NCs) have exhibited great advantages in medical diagnostics and therapies due to their efficient renal clearance high tumor uptake. The vivo effects of the surface chemistry Au NCs are important for development both nanobiological interfaces potential clinical contrast reagents, but these properties yet be fully investigated. In this study, we prepared glutathione-protected a similar hydrodynamic size with three different charges: positive, negative, neutral....
The reverse transcriptase inhibitor, nevirapine (NVP), causes skin rashes and hepatotoxicity. We used a rat model to determine if the rash is caused by parent drug or reactive metabolite. By manipulation of metabolic pathways testing analogues, we eliminated all but one pathway, 12-hydroxylation, which involves oxidation an exocyclic methyl group, as being responsible for rash. Treatment with 12-OH-NVP rash, analogue in hydrogens were replaced deuterium inhibit 12-OH pathway did not cause...
Canagliflozin is an oral antihyperglycemic agent used for the treatment of type 2 diabetes mellitus. It blocks reabsorption glucose in proximal renal tubule by inhibiting sodium-glucose cotransporter 2. This article describes vivo biotransformation and disposition canagliflozin after a single dose [<sup>14</sup>C]canagliflozin to intact bile duct-cannulated (BDC) mice rats dogs humans. Fecal excretion was primary route elimination drug-derived radioactivity both animals In BDC rats, most...
Incretin impairment, characterized by insufficient secretion of L-cell-derived glucagon-like peptide-1 (GLP-1), is a defining step type 2 diabetes mellitus (T2DM). Ginsenoside compound K (CK) can stimulate GLP-1 secretion; however, the potential mechanism underlying this effect has not been established.CK (40 mg/kg) was administered orally to male db/db mice for 4 weeks. The body weight, oral glucose tolerance, secretion, gut microbiota sequencing, bile acid (BA) profiles, and BA synthesis...
We have recently reported a novel approach to increase cytosolic glucokinase (GK) levels through the binding of small molecule its endogenous inhibitor, regulatory protein (GKRP). These initial investigations culminated in identification 2-(4-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (1, AMG-3969), compound that effectively enhanced GK translocation and reduced blood glucose diabetic animals. Herein we report results our...
Pharmacokinetics and bio-distribution are crucial factors affecting the performance of an intravenous drug. In this study, we explore combined use glucose polyethylene glycol (PEG) ligands to further improve gold nanoparticle (GNP) pharmacokinetics bio-distribution, with aim using drug for in-vivo radiotherapy. The inclusion PEG was found significantly prolong half-life period, where PEG-Glu-GNPs achieved 6.17 +/- 3.71 h, compared 1.23 0.14 h Glu-GNPs 1.07 0.22 uncoated GNPs. Our data...
Previously, we reported a new animal model of an idiosyncratic drug reaction in which nevirapine causes skin rash some rats that has characteristics similar to the occurs humans. Strong evidence is immune-mediated was found; specifically, low-dose pretreatment induced tolerance, while with rechallenge, time onset decreased and severity increased. Furthermore, splenocytes from rechallenged transferred susceptibility naïve recipients. We now report results studies explore immune aspects this...
The HTS-based discovery and structure-guided optimization of a novel series GKRP-selective GK-GKRP disrupters are revealed. Diarylmethanesulfonamide hit 6 (hGK-hGKRP IC50 = 1.2 μM) was optimized to lead compound 32 (AMG-0696; hGK-hGKRP 0.0038 μM). A stabilizing interaction between nitrogen atom lone pair an aromatic sulfur system (nN → σ*S-X) in exploited conformationally constrain biaryl linkage allow contact with key residues GKRP. Lead shown induce GK translocation from the nucleus...
The high expression of proviral insertion site Moloney murine leukemia virus kinases (Pim-1, -2, and -3) in cancers, particularly the hematopoietic malignancies, is believed to play a role promoting cell survival proliferation while suppressing apoptosis. three isoforms Pim protein appear largely redundant their oncogenic functions. Thus, pan-Pim kinase inhibitor highly desirable. However, active inhibitors have proven difficult develop because Pim-2 has low Km for ATP therefore requires...
Small molecule activators of glucokinase have shown robust efficacy in both preclinical models and humans. However, overactivation (GK) can cause excessive glucose turnover, leading to hypoglycemia. To circumvent this adverse side effect, we chose modulate GK activity by targeting the endogenous inhibitor GK, regulatory protein (GKRP). Disrupting GK-GKRP complex results an increase amount unbound cytosolic without altering inherent kinetics enzyme. Herein report identification compounds that...
Abstract We report here the two‐dimensional protein database of human pancreas. The proteins were analyzed by electrophoresis followed matrix‐assisted laser desorption/ionization‐time flight‐mass spectrometry (MALDI‐TOF‐MS). Totally, 302 identified, which about 27% enzymes with a broad range catalytic activities. Several these are specifically expressed in pancreas, such as pancreatic amylase, stone protein, pancreatitis‐associated lipase, elastase, etc. Structural and cytoskeletal also...
The identification of Pim-1/2 kinase overexpression in B-cell malignancies suggests that Pim inhibitors will have utility the treatment lymphoma, leukemia, and multiple myeloma. Starting from a moderately potent quinoxaline-dihydropyrrolopiperidinone lead, we recognized potential for macrocyclization developed series 13-membered macrocycles. structure-activity relationships macrocyclic linker were systematically explored, leading to 9c as potent, subnanomolar inhibitor Pim-1 -2. This...
We synthesized a novel, multi-functional, radiosensitizing agent by covalently linking 6-fluoro-6-deoxy-D-glucose (6-FDG) to gold nanoparticles (6-FDG-GNPs) via thiol functional group. then assessed the bio-distribution and pharmacokinetic properties of 6-FDG-GNPs in vivo using murine model. At 2 h, following intravenous injection into model, approximately 30% were distributed three major organs: liver, spleen kidney. PEGylation was found significantly improve avoiding unintentional uptake...
The glucokinase-glucokinase regulatory protein (GK-GKRP) complex plays an important role in controlling glucose homeostasis the liver. We have recently disclosed a series of arylpiperazines as vitro and vivo disruptors GK-GKRP with efficacy rodent models type 2 diabetes mellitus (T2DM). Herein, we describe new class aryl sulfones complex, where central piperazine scaffold has been replaced by aromatic group. Conformational analysis exploration structure-activity relationships this compounds...
In the previous report, we described discovery and optimization of novel small molecule disruptors GK-GKRP interaction culminating in identification 1 (AMG-1694). Although this analogue possessed excellent vitro potency was a useful tool compound initial proof-of-concept experiments, high metabolic turnover limited its advancement. Guided by combination metabolite structure-based design, have successfully discovered potent metabolically stable disruptor (27, AMG-3969). When administered to...
Obesogenic lipids and the sphingolipid ceramide have been implicated as potential cofactors in alcoholic liver disease (ALD) patients. However, mechanisms by which these modulate lipid trafficking ethanol-treated human cells to promote steatosis, an early stage of ALD, are poorly understood. We measured fatty acid (FA) uptake, triglyceride export, FA synthesis oxidation hepatoma (VL-17A) response ethanol exogenous oleate, palmitate C2 ceramide. found that combination with ethanol, both...