A5067034646- Advanced NMR Techniques and Applications
- Cancer, Hypoxia, and Metabolism
- Electron Spin Resonance Studies
- Advanced MRI Techniques and Applications
- Solid-state spectroscopy and crystallography
- NMR spectroscopy and applications
- RNA modifications and cancer
- Lanthanide and Transition Metal Complexes
- Protein Structure and Dynamics
- Pancreatic and Hepatic Oncology Research
- Cancer Research and Treatments
- Enzyme Structure and Function
- Lipid Membrane Structure and Behavior
- Magnetism in coordination complexes
- Sirtuins and Resveratrol in Medicine
- Medical Imaging Techniques and Applications
- Cancer Immunotherapy and Biomarkers
- MRI in cancer diagnosis
- Neuroendocrine Tumor Research Advances
- Photoreceptor and optogenetics research
- Supramolecular Self-Assembly in Materials
- Cancer-related molecular mechanisms research
- Amino Acid Enzymes and Metabolism
- Atomic and Subatomic Physics Research
- Nanoplatforms for cancer theranostics
Center for Cancer Research
2017-2025
Cancer Institute (WIA)
2023-2025
National Institutes of Health
2017-2024
National Cancer Institute
2017-2024
Hokkaido University
2019
University of Michigan–Ann Arbor
2006-2017
Tottori University
2016
University of Kochi
2013
University of Alberta
2010
St Mary's Hospital
2010
We investigated the processing enzymes involved in formation of circulating angiotensin-(1-7) after intravenous administration angiotensin I to conscious spontaneously hypertensive and Wistar-Kyoto rats. Immunoreactive products, including I, II, angiotensin-(1-7), were measured arterial blood by three specific radioimmunoassays. Angiotensin infusion (2 nmol) induced a rapid increase immunoreactive II angiotensin-(1-7). Pretreatment with converting enzyme inhibitor enalaprilat mg/kg)...
Microsomal cytochrome b5 (cytb5) is a membrane-bound protein that modulates the catalytic activity of its redox partner, P4502B4 (cytP450). Here, we report first structure full-length rabbit ferric microsomal cytb5 (16 kDa), incorporated in two different membrane mimetics (detergent micelles and lipid bicelles). Differential line broadening NMR resonances site-directed mutagenesis data were used to characterize interaction epitope recognized by cytP450 (56 kDa). Subsequently, data-driven...
Abstract Alzheimer’s disease is characterized by the misfolding and self-assembly of amyloidogenic protein amyloid-β (Aβ). The aggregation Aβ leads to diverse oligomeric states, each which may be potential targets for intervention. Obtaining insight into oligomers at atomic level has been a major challenge most techniques. Here, we use magic angle spinning recoupling 1 H- H NMR experiments overcome many these limitations. Using dipolar couplings as spectral filter remove both high low...
Cytochrome b5 (cyt b5) is a membrane-anchored electron-carrier protein containing heme in its soluble domain. It enhances the enzymatic turnover of selected members cytochrome P450 superfamily catabolic enzymes, localized endoplasmic reticulum liver cells. Remarkably, α-helical membrane-anchoring domain indispensable for cyt b5/cyt interaction. Here, we present first solid-state NMR studies on holo-cyt membrane environment, namely, macroscopically oriented DMPC:DHPC bicelles. We have...
Abstract Metabolic reprogramming is one of the defining features cancer and abnormal metabolism associated with many other pathologies. Molecular imaging techniques capable detecting such changes have become essential for diagnosis, treatment planning, surveillance. In particular, 18 F-FDG (fluorodeoxyglucose) PET has emerged as an modality because its unique ability to detect a disturbed molecular pathway through measurements glucose uptake. However, FDG-PET limitations that restrict...
Recent studies have demonstrated the abilities of solid-state NMR techniques to solve atomic-level-resolution structures and dynamics membrane-associated proteins peptides. However, high-throughput applications spectroscopy are hampered by long acquisition times due low sensitivity technique. In this study, we demonstrate use a paramagnetic copper-chelated lipid enhance spin−lattice relaxation thereby speed up measurements. Fluid lamellar-phase bicelles composed lipid, detergent, containing...
Though the importance of high-resolution structure and dynamics membrane proteins has been well recognized, optimizing sample conditions to retain native-like folding function for Nuclear Magnetic Resonance (NMR) or X-ray measurements a major challenge. While bicelles have shown stabilize are increasingly utilized as model membranes, loss their magnetic-alignment at low temperatures makes them unsuitable study heat-sensitive like cytochrome-P450 protein-protein complexes. In this study, we...
Microsomal monoxygenase enzymes of the cytochrome-P450 family are found in all biological kingdoms and play a central role breakdown metabolic as well xenobiotic, toxic 70% drugs clinical use. Full-length cytochrome-b5 has been shown to be important for catalytic activity cytochrome-P450. Despite significance understanding interactions between these two membrane-associated proteins, only limited high-resolution structural information on full-length cytochromes-b5-P450 complex is available....
Renal oxygenation is essential for maintaining kidney function. Disruptions in oxygen delivery can lead to renal hypoxia, which exacerbate injury through multiple pathways, including inflammation, oxidative stress, and ischemia-reperfusion injury. Despite the recognized importance of pathology, non-invasive reliable methods assessing levels are limited. Current techniques either lack sensitivity or involve invasive procedures, restricting their use routine monitoring. Therefore, there a...
Aminopeptidases (APs) in the renin-angiotensin system (RAS) and their activity balance play a crucial role regulating vascular functions. Multiplexed analysis of RAS-related AP activities is useful for diagnosing diseases, including cancer. Dynamic nuclear polarization coupled magnetic resonance imaging (DNP-MRI) enables simultaneous detection multiple enzymatic vivo. However, developing practical DNP-MRI probes, especially multiplexed detection, remains challenging. Here, we report design...
This paper presents a theoretical, numerical, and experimental study of new class separated local field (SLF) techniques. These techniques are based on the heteronuclear isotropic mixing leading to spin exchange via (HIMSELF). It is shown that highly efficient robust SLF experiments can be designed double channel windowless homonuclear decoupling sequences. Compared rotating frame Hartmann-Hahn cross polarization, approach less susceptible frequency offset chemical shift interaction applied...
Magnetically aligned bicelles are increasingly being used as model membranes in solution- and solid-state NMR studies of the structure, dynamics, topology, interaction membrane-associated peptides proteins. These commonly utilize PISEMA pulse sequence to measure dipolar coupling chemical shift, two key parameters subsequent structural analysis. In present study, we demonstrate that other rotating-frame sequences not suitable for measurement long-range heteronuclear couplings, they provide...
The intermolecular interaction between mefenamic acid (MFA), a poorly water-soluble nonsteroidal anti-inflammatory drug, and Eudragit EPO (EPO), polymer, is investigated in their supersaturated solution using high-resolution magic-angle spinning (HRMAS) nuclear magnetic resonance (NMR) spectroscopy. stable with high MFA concentration of 3.0 mg/mL prepared by dispersing the amorphous solid dispersion into d-acetate buffer at pH 5.5 37 °C. By virtue MAS 2.7 kHz, extremely broad unresolved (1)H...
Purpose: To evaluate the potential of hyperpolarized [1-13C]-pyruvate magnetic resonance spectroscopic imaging (MRSI) prostate cancer as a predictive biomarker for targeting Warburg effect.Experimental Design: Two human cell lines (DU145 and PC3) were grown xenografts. The conversion pyruvate to lactate in xenografts was measured with MRSI after systemic delivery [1-13C] pyruvic acid. Steady-state metabolomic analysis xenograft tumors performed mass spectrometry steady-state concentrations...
Aims: In hypoxic tumor microenvironments, the strongly reducing redox environment reduces evofosfamide (TH-302) to release a cytotoxic bromo-isophosphoramide (Br-IPM) moiety. This drug therefore preferentially attacks regions in tumors where other standard anticancer treatments such as chemotherapy and radiation therapy are often ineffective. Various combination therapies with have been proposed tested preclinical clinical settings. However, treatment effect of monotherapy on hypoxia has not...
Metabolic differences among and within tumors can be an important determinant in cancer treatment outcome. However, methods for determining these non-invasively vivo is lacking. Using pancreatic ductal adenocarcinoma as a model, we demonstrate that tumor xenografts with similar genetic background distinguished by their differing rates of the metabolism 13C labeled glucose tracers, which imaged without hyperpolarization using newly developed techniques noise suppression. this method, subtypes...
α-Ketoglutarate is a key biomolecule involved in number of metabolic pathways─most notably the TCA cycle. Abnormal α-ketoglutarate metabolism has also been linked with cancer. Here, isotopic labeling was employed to synthesize [1-13C,5-12C,D4]α-ketoglutarate future goal utilizing its [1-13C]-hyperpolarized state for real-time imaging analytes and downstream metabolites vivo. The signal amplification by reversible exchange shield enables alignment transfer heteronuclei (SABRE-SHEATH)...
Bicelles are increasingly being used as membrane mimicking systems in NMR experiments to investigate the structure of proteins. In this study, we demonstrate effectiveness a 2D solid-state approach that can be measure structural constraints, such heteronuclear dipolar couplings between 1H, 13C, and 31P nuclei, bicelles without need for isotopic enrichment. This method does not require high radio frequency power unlike presently rotating-frame separated-local-field (SLF) techniques, PISEMA....
Bicelles of various lipid/detergent ratios are commonly used in nuclear magnetic resonance (NMR) studies membrane-associated molecules without the need to freeze sample. While a decrease size (defined at low temperature or by q value) bicelle decreases its overall order parameter, variation lipid dynamics with change ratio is unknown. In this study, we report thorough atomistic level analysis on and hydration bicelles composed phospholipid, 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC),...
The dynamic protein-protein and protein-ligand interactions of integral bitopic membrane proteins with a single membrane-spanning helix play plethora vital roles in the cellular processes associated human health diseases, including signaling enzymatic catalysis. While an increasing number high-resolution structural studies have successfully manifested in-depth understanding their biological functions, intact membrane-bound complexes pose tremendous challenges for by crystallography or...
Molecular imaging approaches for metabolic and physiologic of tumors have become important treatment planning response monitoring. However, the relationship between aspects is not fully understood. Here, we developed new hyperpolarized MRI electron paramagnetic resonance procedures that allow more direct assessment tumor glycolysis oxygenation status quantitatively. We investigated spatial hypoxia, glucose uptake, in three human pancreatic ductal adenocarcinoma xenografts with differing...
PEGylated human hyaluronidase (PEGPH20) enzymatically depletes hyaluronan, an important component of the extracellular matrix, increasing delivery therapeutic molecules. Combinations chemotherapy and PEGPH20, however, have been unsuccessful in Phase III clinical trials. We hypothesize that by tumor oxygenation improving vascular patency perfusion, PEGPH20 will also act as a radiosensitization agent.The effect on radiation treatment was analyzed with respect to growth, survival time, p02,...