A5017219674- Extracellular vesicles in disease
- Sphingolipid Metabolism and Signaling
- Neuroinflammation and Neurodegeneration Mechanisms
- Cellular transport and secretion
- Alzheimer's disease research and treatments
- Cancer, Hypoxia, and Metabolism
- Chemical Synthesis and Analysis
- Monoclonal and Polyclonal Antibodies Research
- Peptidase Inhibition and Analysis
- Amyloidosis: Diagnosis, Treatment, Outcomes
- Enzyme function and inhibition
- Epigenetics and DNA Methylation
- Drug Solubulity and Delivery Systems
- Click Chemistry and Applications
- Biochemical and Molecular Research
- Escherichia coli research studies
- Protein purification and stability
- Phytochemical compounds biological activities
- RNA Interference and Gene Delivery
- Moringa oleifera research and applications
- Immune cells in cancer
- Neuroblastoma Research and Treatments
- Phytochemistry and Biological Activities
- Inflammasome and immune disorders
- Prostate Cancer Treatment and Research
Center for Drug Evaluation and Research
2025
United States Food and Drug Administration
2025
Johns Hopkins University
2021-2024
Johns Hopkins Medicine
2021-2024
University of the Pacific
2015-2022
East West University
2013
6-Diazo-5-oxo-l-norleucine (DON) is a glutamine antagonist that suppresses cancer cell metabolism but concurrently enhances the metabolic fitness of tumor CD8
Transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) is a fatal disease with no available disease-modifying therapies. While pathogenic TTR mutations (TTRm) destabilize tetramers, the T119M variant stabilizes TTRm and prevents disease. A comparison of potency for leading stabilizers in clinic structural features important effective stabilization lacking. Here, we found that molecular interactions reflected better binding enthalpy may be critical development improved selectivity. Our studies...
This study leverages physiologically based biopharmaceutics modeling (PBBM) to predict the clinical performance of two itraconazole (ITRA) amorphous solid dispersions (ASDs), Sempera® and Tolsura®, under fasted fed state conditions, exploring potential PBBM in predicting formulation-specific food interactions. The ITRA formulations were subjected extensive vitro biopharmaceutical testing, including solubility studies dissolution tests revealing significant differences behaviors between...
Abstract Background Cognitive decline in Alzheimer’s disease (AD) is associated with hyperphosphorylated tau (pTau) propagation between neurons along synaptically connected networks, part via extracellular vesicles (EVs). EV biogenesis triggered by ceramide enrichment at the plasma membrane from neutral sphingomyelinase2 (nSMase2)-mediated cleavage of sphingomyelin. We report, for first time, that human expression elevates brain ceramides and nSMase2 activity. Methods To determine...
Alzheimer’s disease (AD) is characterized by the progressive accumulation of amyloid-β and hyperphosphorylated tau (pTau), which can spread throughout brain via extracellular vesicles (EVs). Membrane ceramide enrichment regulated enzyme neutral sphingomyelinase 2 (nSMase2) a critical component at least one EV biogenesis pathway. Our group recently identified 2,6-Dimethoxy-4-(5-Phenyl-4-Thiophen-2-yl-1H-Imidazol-2-yl)-Phenol (DPTIP), most potent (30 nM) selective inhibitor nSMase2 reported to...
Extracellular vesicles (EVs) can carry pathological cargo and play an active role in disease progression. Neutral sphingomyelinase-2 (nSMase2) is a critical regulator of EV biogenesis, its inhibition has shown protective effects multiple states. 2,6-Dimethoxy-4-(5-phenyl-4-thiophen-2-yl-1H-imidazol-2-yl)phenol (DPTIP) one the most potent (IC50 = 30 nM) inhibitors nSMase2 discovered to date. However, DPTIP exhibits poor oral pharmacokinetics (PK), limiting clinical development. To overcome...
The hydrophobicity of many chemotherapeutic agents usually results in their nonselective passive distribution into healthy cells and organs causing collateral toxicity. Ligand-targeted drugs (LTDs) are a promising class targeted anticancer agents. hydrophilicity the targeting ligands LTDs limits its tissue toxicity to cells. In addition, small size allows for better tumor penetration, especially case solid tumors. However, short circulation half-life LTDs, due size, remains significant...
This work describes the enhancement of a novel antitumor therapeutic platform that combines advantages from small-molecule drug conjugates (SMDCs) and antibody (ADCs). Valine-citrulline (VCit) dipeptide linkers are commonly used cathepsin B cleavable for ADCs. However, instability these in mouse serum makes translating efficacy data to human more challenging. Replacing VCit linker with glutamic acid-valine-citrulline (EVCit) has been reported enhance stability ADCs serum. effect EVCit on...
Purpose: To investigate the crude n-hexane, ethyl acetate and methanol extracts of Aphanamixis polystachya fruit for their cytotoxic, antimicrobial, antioxidant thrombolytic activities.Methods: The were screened major phytochemical compounds using in vitro established procedures. Antimicrobial cytotoxic studies conducted disc diffusion brine shrimp lethality bioassay methods, respectively, while an model was used to assess clot lysis effect with streptokinase as positive control. Antioxidant...
The rising rate of antimicrobial resistance continues to threaten global public health. Further hastening is the lack new antibiotics against targets. bacterial enzyme, 1-deoxy-d-xylulose 5-phosphate synthase (DXPS), thought play important roles in central metabolism, including processes required for pathogen adaptation fluctuating host environments. Thus, impairing DXPS function represents a possible antibacterial strategy. We previously investigated DXPS-dependent metabolic as potential...
Abstract Background Cognitive decline in Alzheimer’s disease (AD) is associated with prion-like tau propagation between neurons along synaptically connected networks, part via extracellular vesicles (EV). EV biogenesis triggered by ceramide enrichment at the plasma membrane from neutral sphingomyelinase2(nSMase2)-mediated cleavage of sphingomyelin. We report, for first time, that expression triggers an elevation brain ceramides and nSMase2 activity. Methods To determine therapeutic benefit...
Metabolomic analyses from our group and others have shown that tumors treated with glutamine antagonists (GA) exhibit robust accumulation of formylglycinamide ribonucleotide (FGAR), an intermediate in the de novo purine synthesis pathway. The increase FGAR is attributed to inhibition enzyme amidotransferase (FGAR-AT) catalyzes ATP-dependent amidation formylglycinamidine (FGAM). While perturbation this pathway resulting GA therapy has long been recognized, no study reported systematic...
Glutamate carboxypeptidase-II (GCPII) is a zinc-dependent metalloenzyme implicated in numerous neurological disorders. The pharmacophoric requirements of active-site GCPII inhibitors makes them highly charged, manifesting poor pharmacokinetic (PK) properties. Herein, we describe the discovery and characterization catechol-based including L-DOPA, D-DOPA, caffeic acid, with sub-micromolar potencies. Of these, D-DOPA emerged as most promising compound, good metabolic stability, excellent PK...
Background: Extracellular vesicles (EVs) can carry pathological cargo, contributing to disease progression. The enzyme neutral sphingomyelinase 2 (nSMase2) plays a critical role in EV biogenesis, making it promising therapeutic target. Our lab previously identified potent and selective inhibitor of nSMase2, named DPTIP (IC50 = 30 nM). Although promising, exhibits poor pharmacokinetics (PKs) with low oral bioavailability (%F < 5), short half-life (t1/2 ≤ 0.5 h). To address these limitations,...
Abstract Background Alzheimer’s Disease (AD) is the most common form of dementia worldwide and characterized by progressive neurodegeneration cognitive decline, putatively driven accumulation Amyloid‐b hyperphosphorylated Tau. Clinical trial successes focusing on reducing plaque levels in patient brains have been modest, spurring a renewed focus tau. Tau spreads throughout brain along anatomical pathways, correlating strongly with disease progression severity. Recent evidence has highlighted...