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Recent studies implicate a strong association between elevated plasma branched-chain amino acids (BCAAs) and insulin resistance (IR). However, a causal relationship and whether interrupted BCAA homeostasis can serve as a therapeutic target for diabetes remain to be established experimentally. In this study, unbiased integrative pathway analyses identified a unique genetic link between obesity-associated IR and BCAA catabolic gene expression at the pathway level in human and mouse populations. In genetically obese (ob/ob) mice, rate-limiting branched-chain α-keto acid (BCKA) dehydrogenase deficiency (i.e., BCAA and BCKA accumulation), a metabolic feature, accompanied the systemic suppression of BCAA catabolic genes. Restoring BCAA catabolic flux with a pharmacological inhibitor of BCKA dehydrogenase kinase (BCKDK) ( a suppressor of BCKA dehydrogenase) reduced the abundance of BCAA and BCKA and markedly attenuated IR in ob/ob mice. Similar outcomes were achieved by reducing protein (and thus BCAA) intake, whereas increasing BCAA intake did the opposite; this corroborates the pathogenic roles of BCAAs and BCKAs in IR in ob/ob mice. Like BCAAs, BCKAs also suppressed insulin signaling via activation of mammalian target of rapamycin complex 1. Finally, the small-molecule BCKDK inhibitor significantly attenuated IR in high-fat diet-induced obese mice. Collectively, these data demonstrate a pivotal causal role of a BCAA catabolic defect and elevated abundance of BCAAs and BCKAs in obesity-associated IR and provide proof-of-concept evidence for the therapeutic validity of manipulating BCAA metabolism for treating diabetes.

Radiolabeled metal‐based nanoparticles (MNPs) have drawn considerable attention in the fields of nuclear medicine and molecular imaging, drug delivery, and radiation therapy, given the fact that they can be potentially used as diagnostic imaging and/or therapeutic agents, or even as theranostic combinations. Here, we present a systematic review on recent advances in the design and synthesis of MNPs with major focuses on their radiolabeling strategies and the determinants of their in vivo pharmacokinetics, and together how their intended applications would be impacted. For clarification, we categorize all reported radiolabeling strategies for MNPs into indirect and direct approaches. While indirect labeling simply refers to the use of bifunctional chelators or prosthetic groups conjugated to MNPs for post‐synthesis labeling with radionuclides, we found that many practical direct labeling methodologies have been developed to incorporate radionuclides into the MNP core without using extra reagents, including chemisorption, radiochemical doping, hadronic bombardment, encapsulation, and isotope or cation exchange. From the perspective of practical use, a few relevant examples are presented and discussed in terms of their pros and cons. We further reviewed the determinants of in vivo pharmacokinetic parameters of MNPs, including factors influencing their in vivo absorption, distribution, metabolism, and elimination, and discussed the challenges and opportunities in the development of radiolabeled MNPs for in vivo biomedical applications. Taken together, we believe the cumulative advancement summarized in this review would provide a general guidance in the field for design and synthesis of radiolabeled MNPs towards practical realization of their much desired theranostic capabilities. This article is categorized under:Nanotechnology Approaches to Biology > Nanoscale Systems in BiologyDiagnostic Tools > Diagnostic NanodevicesTherapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease [ABSTRACT FROM AUTHOR]

The pyruvate dehydrogenase complex (PDH) critically regulates carbohydrate metabolism. Phosphorylation of PDH by one of the pyruvate dehydrogenase kinases 1–4 (PDK1–4) decreases the flux of carbohydrates into the TCA cycle. Inhibition of PDKs increases oxidative metabolism of carbohydrates, so targeting PDKs has emerged as an important therapeutic approach to manage various metabolic diseases. Therefore, it is highly desirable to begin to establish imaging tools for noninvasive measurements of PDH flux in rodent models. In this study, we used hyperpolarized (HP) 13C-magnetic resonance spectroscopy to study the impact of a PDK2/PDK4 double knockout (DKO) on pyruvate metabolism in perfused livers from lean and diet-induced obese (DIO) mice and validated the HP observations with high-resolution 13C-nuclear magnetic resonance (NMR) spectroscopy of tissue extracts and steady-state isotopomer analyses. We observed that PDK-deficient livers produce more HP-bicarbonate from HP-[1-13C]pyruvate than age-matched control livers. A steady-state 13C-NMR isotopomer analysis of tissue extracts confirmed that flux rates through PDH, as well as pyruvate carboxylase and pyruvate cycling activities, are significantly higher in PDK-deficient livers. Immunoblotting experiments confirmed that HP-bicarbonate production from HP-[1-13C]pyruvate parallels decreased phosphorylation of the PDH E1α subunit (pE1α) in liver tissue. Our findings indicate that combining real-time hyperpolarized 13C NMR spectroscopy and 13C isotopomer analysis provides quantitative insights into intermediary metabolism in PDK-knockout mice. We propose that this method will be useful in assessing metabolic disease states and developing therapies to improve PDH flux. [ABSTRACT FROM AUTHOR]

Radiolabeled metal-based nanoparticles (MNPs) have drawn considerable attention in the fields of nuclear medicine and molecular imaging, drug delivery, and radiation therapy, given the fact that they can be potentially used as diagnostic imaging and/or therapeutic agents, or even as theranostic combinations. Here, we present a systematic review on recent advances in the design and synthesis of MNPs with major focuses on their radiolabeling strategies and the determinants of their in vivo pharmacokinetics, and together how their intended applications would be impacted. For clarification, we categorize all reported radiolabeling strategies for MNPs into indirect and direct approaches. While indirect labeling simply refers to the use of bifunctional chelators or prosthetic groups conjugated to MNPs for post-synthesis labeling with radionuclides, we found that many practical direct labeling methodologies have been developed to incorporate radionuclides into the MNP core without using extra reagents, including chemisorption, radiochemical doping, hadronic bombardment, encapsulation, and isotope or cation exchange. From the perspective of practical use, a few relevant examples are presented and discussed in terms of their pros and cons. We further reviewed the determinants of in vivo pharmacokinetic parameters of MNPs, including factors influencing their in vivo absorption, distribution, metabolism, and elimination, and discussed the challenges and opportunities in the development of radiolabeled MNPs for in vivo biomedical applications. Taken together, we believe the cumulative advancement summarized in this review would provide a general guidance in the field for design and synthesis of radiolabeled MNPs towards practical realization of their much desired theranostic capabilities. This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Diagnostic Tools > Diagnostic Nanodevices Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease., (© 2020 Wiley Periodicals LLC.)

Since most d-amino acids (DAAs) are utilized by bacterial cells but not by mammalian eukaryotic hosts, recently DAA-based molecular imaging strategies have been extensively explored for noninvasively differentiating bacterial infections from the host's inflammatory responses. Given glutamine's pivotal role in bacterial survival, cell growth, biofilm formation, and even virulence, here we report a new positron emission tomography (PET) imaging approach using d-5-[ 11 C]glutamine (d-[5- 11 C]-Gln) for potential clinical assessment of bacterial infection through a comparative study with its l-isomer counterpart, l-[5- 11 C]-Gln. In both control and infected mice, l-[5- 11 C]-Gln had substantially higher uptake levels than d-[5- 11 C]-Gln in most organs except the kidneys, showing the expected higher use of l-[5- 11 C]-Gln by mammalian tissues and more efficient renal excretion of d-[5- 11 C]-Gln. Importantly, our work demonstrates that PET imaging with d-[5- 11 C]-Gln is capable of detecting infections induced by both Escherichia coli ( E. coli ) and methicillin-resistant Staphylococcus aureus (MRSA) in a dual-infection murine myositis model with significantly higher infection-to-background contrast than with l-[5- 11 C]-Gln (in E. coli , 1.64; in MRSA, 2.62, p = 0.0004). This can be attributed to the fact that d-[5- 11 C]-Gln is utilized by bacteria while being more efficiently cleared from the host tissues. We confirmed the bacterial infection imaging specificity of d-[5- 11 C]-Gln by comparing its uptake in active bacterial infections versus sterile inflammation and with 2-deoxy-2-[ 18 F]fluoroglucose ([ 18 F]FDG). These results together demonstrate the translational potential of PET imaging with d-[5- 11 C]-Gln for the noninvasive detection of bacterial infectious diseases in humans.