quantitative-micro-ct-analysis-aortopathy-mouse-model

Quantitative Micro-CT Analysis of Aortopathy in a Mouse Model of &#946;-aminopropionitrile-induced Aortic Aneurysm and Dissection

Aortic aneurysm and dissection is associated with significant morbidity and mortality in the population and can be highly lethal. While animal models of ...

nitropeptide-profiling-identification-illustrated-angiotensin

Nitropeptide Profiling and Identification Illustrated by Angiotensin II

Protein nitration is one of the most important post-translational modifications (PTM) on tyrosine residues and it can be induced by chemical actions of ...

University of Maryland School of Medicine

University of Notre Dame

Indiana University Melvin and Bren Simon Cancer Center

Perinatal hypoxia ischemia (HI) is a significant cause of brain injury in surviving infants. Although hypothermia improves outcomes in some infants, additional therapies are needed since about 40% of infants still have a poor outcome. Acetyl-L-carnitine (ALCAR), an acetylated derivative of L-carnitine, protected against early changes in brain metabolites and mitochondrial function after HI on postnatal day (PND) 7 in a rat pup model of near-term HI injury. However, its efficacy in long-term structural and functional outcomes remains unexplored. We determined the efficacy of ALCAR therapy administered to rat pups after HI at PND 7, using both longitudinal in vivo magnetic resonance imaging and behavioral tests, in male and female rats. HI led to sex-specific behavioral impairment, with males exhibiting more global functional deficits than females. Interestingly, HI reduced the volume of the contralateral hemisphere in males only, suggesting that the brain injury is more diffuse in males than in females. Treatment with ALCAR improved both morphological and functional outcomes in both male and female rats. These results suggest that ALCAR may be a potential therapy for clinical use since the treatment attenuated the moderate injury produced under the experimental conditions used and improved the functional outcome in preclinical studies.

Neuroprotective Effects of Acetyl-L-Carnitine on Neonatal Hypoxia Ischemia-Induced Brain Injury in Rats.

Traumatic brain injury (TBI) is known to cause perturbations in the energy metabolism of the brain, but current tests of metabolic activity are only indirect markers of energy use or are highly invasive. Here we show that hyperpolarized C magnetic resonance spectroscopic imaging (MRSI) can be used as a direct, non-invasive method for studying the effects of TBI on energy metabolism. Measurements were performed on rats with moderate TBI induced by controlled cortical impact on one cerebral hemisphere. Following injection of hyperpolarized [1-C]pyruvate, the resulting C-bicarbonate signal was found to be 24 ± 6% lower in the injured hemisphere compared with the non-injured hemisphere, while the hyperpolarized bicarbonate-to-lactate ratio was 33 ± 8% lower in the injured hemisphere. In a control group, no significant difference in signal was found between sides of the brain. The results suggest an impairment in mitochondrial pyruvate metabolism, resulting in a decrease in aerobic respiration at the location of injury following TBI.

Metabolic imaging of energy metabolism in traumatic brain injury using hyperpolarized [1-C]pyruvate.

Chronic inflammation may contribute to insulin resistance via molecular cross-talk between pathways for pro-inflammatory and insulin signaling. Interleukin 1 receptor-associated kinase 1 (IRAK-1) mediates pro-inflammatory signaling via IL-1 receptor/Toll-like receptors, which may contribute to insulin resistance, but this hypothesis is untested. Here, we used male  null (k/o) mice to investigate the metabolic role of IRAK-1. C57BL/6 wild-type (WT) and k/o mice had comparable body weights on low-fat and high-fat diets (LFD and HFD, respectively). After 12 weeks on LFD (but not HFD), k/o mice ( WT) had substantially improved glucose tolerance (assessed by the intraperitoneal glucose tolerance test (IPGTT)). As assessed with the hyperinsulinemic euglycemic glucose clamp technique, insulin sensitivity was 30% higher in the  k/o mice on chow diet, but the  deletion did not affect IPGTT outcomes in mice on HFD, suggesting that the deletion did not overcome the impact of obesity on glucose tolerance. Moreover, insulin-stimulated glucose-disposal rates were higher in the k/o mice, but we detected no significant difference in hepatic glucose production rates (± insulin infusion). Positron emission/computed tomography scans indicated higher insulin-stimulated glucose uptake in muscle, but not liver, in  k/o mice  Moreover, insulin-stimulated phosphorylation of Akt was higher in muscle, but not in liver, from  k/o mice  In conclusion,  deletion improved muscle insulin sensitivity, with the effect being most apparent in LFD mice.

Deletion of interleukin 1 receptor-associated kinase 1 () improves glucose tolerance primarily by increasing insulin sensitivity in skeletal muscle.

Potent immunosuppressive mechanisms within the tumor microenvironment contribute to the resistance of aggressive human cancers to immune checkpoint blockade (ICB) therapy. One of the main mechanisms for myeloid-derived suppressor cells (MDSCs) to induce T cell tolerance is through secretion of reactive nitrogen species (RNS), which nitrates tyrosine residues in proteins involved in T cell function. However, so far very few nitrated proteins have been identified. Here, using a transgenic mouse model of prostate cancer and a syngeneic cell line model of lung cancer, we applied a nitroproteomic approach based on chemical derivation of 3-nitrotyrosine and identified that lymphocyte-specific protein tyrosine kinase (LCK), an initiating tyrosine kinase in the T cell receptor signaling cascade, is nitrated at Tyr394 by MDSCs. LCK nitration inhibits T cell activation, leading to reduced interleukin 2 (IL2) production and proliferation. In human T cells with defective endogenous LCK, wild type, but not nitrated LCK, rescues IL2 production. In the mouse model of castration-resistant prostate cancer (CRPC) by prostate-specific deletion of , , and , CRPC is resistant to an ICB therapy composed of antiprogrammed cell death 1 (PD1) and anticytotoxic-T lymphocyte-associated protein 4 (CTLA4) antibodies. However, we showed that ICB elicits strong anti-CRPC efficacy when combined with an RNS neutralizing agent. Together, these data identify a previously unknown mechanism of T cell inactivation by MDSC-induced protein nitration and illuminate a clinical path hypothesis for combining ICB with RNS-reducing agents in the treatment of CRPC.

Myeloid-derived suppressor cells inhibit T cell activation through nitrating LCK in mouse cancers.

This Article was mistakenly not made Open Access when originally published; this has now been amended, and information about the Creative Commons Attribution 4.0 International License has been added into the 'Additional information' section.

Publisher Correction: Past and future spread of the arbovirus vectors Aedes aegypti and Aedes albopictus.

Targeted antibody blocking enables characterization of binding sites on immunoglobulin G (IgG), and can efficiently eliminate harmful antibodies from organisms. In this report, we present a novel peptide-denoted as a dual-functional conjugate of antigenic peptide and Fc-III mimetics (DCAF)-for targeted blocking of antibodies. Synthesis of DCAF was achieved by native chemical ligation, and the molecule consists of three functional parts: a specific antigenic peptide, a linker and the Fc-III mimetic peptide, which has a high affinity toward the Fc region of IgG molecules. We demonstrate that DCAF binds the cognate antibody with high selectivity by simultaneously binding to the Fab and Fc regions of IgG. Animal experiments revealed that DCAF molecules diminish the antibody-dependent enhancement effect in a dengue virus infection model, and rescue the acetylcholine receptor by inhibiting the complement cascade in a  model. These results suggest that DCAFs could have utility in the development of new therapeutics against harmful antibodies.

ArticleTotal : 2	Year
Publication title Cited by 6	2018
Publication title Cited by 1	2019

Article	Year
Neuroprotective Effects of Acetyl-L-Carnitine on Neonatal Hypoxia Ischemia-Induced Brain Injury in Rats. Developmental neuroscience\| PubMed ID: 28226317	2016
Metabolic imaging of energy metabolism in traumatic brain injury using hyperpolarized [1-C]pyruvate. Scientific reports\| PubMed ID: 28507314	2017
Deletion of interleukin 1 receptor-associated kinase 1 () improves glucose tolerance primarily by increasing insulin sensitivity in skeletal muscle. The Journal of biological chemistry\| PubMed ID: 28572512	2017
Myeloid-derived suppressor cells inhibit T cell activation through nitrating LCK in mouse cancers. Proceedings of the National Academy of Sciences of the United States of America\| PubMed ID: 30232256	2018
Publisher Correction: Past and future spread of the arbovirus vectors Aedes aegypti and Aedes albopictus. Nature microbiology\| PubMed ID: 30962571	2019
Development of a dual-functional conjugate of antigenic peptide and Fc-III mimetics (DCAF) for targeted antibody blocking. Chemical science\| PubMed ID: 30996912	2019

Xin Lu

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