Regional Brain Analysis of Modified Amino Acids and Dipeptides during the Sleep/Wake Cycle

Sleep is a state in which important restorative and anabolic processes occur. Understanding changes of these metabolic processes during the circadian rhythm in the brain is crucial to elucidate neurophysiological mechanisms important for sleep function. Investigation of amino acid modifications and dipeptides has recently emerged as a valuable approach in the metabolic profiling of the central nervous system. Nonetheless, very little is known about the effects of sleep on the brain levels of amino acid analogues. In the present study, we examined brain regional sleep-induced alterations selective for modified amino acids and dipeptides using UPLC-MS/MS based metabolomics. Our approach enabled the detection and identification of numerous amino acid-containing metabolites in the cortex, the hippocampus, the midbrain, and the cerebellum. In particular, analogues of the aromatic amino acids phenylalanine, tyrosine and tryptophan were significantly altered during sleep in the investigated brain regions. Cortical levels of medium and long chain N-acyl glycines were higher during sleep. Regional specific changes were also detected, especially related to tyrosine analogues in the hippocampus and the cerebellum. Our findings demonstrate a strong correlation between circadian rhythms and amino acid metabolism specific for different brain regions that provide previously unknown insights in brain metabolism.

Cysteine Restriction in Murine L929 Fibroblasts as an Alternative Strategy to Methionine Restriction in Cancer Therapy

Methionine restriction (MetR) is an efficient method of amino acid restriction (AR) in cells and organisms that induces low energy metabolism (LEM) similar to caloric restriction (CR). The implementation of MetR as a therapy for cancer or other diseases is not simple since the elimination of a single amino acid in the diet is difficult. However, the in vivo turnover rate of cysteine is usually higher than the rate of intake through food. For this reason, every cell can enzymatically synthesize cysteine from methionine, which enables the use of specific enzymatic inhibitors. In this work, we analysed the potential of cysteine restriction (CysR) in the murine cell line L929. This study determined metabolic fingerprints using mass spectrometry (LC/MS). The profiles were compared with profiles created in an earlier work under MetR. The study was supplemented by proliferation studies using D-amino acid analogues and inhibitors of intracellular cysteine synthesis. CysR showed a proliferation inhibition potential comparable to that of MetR. However, the metabolic footprints differed significantly and showed that CysR does not induce classic LEM at the metabolic level. Nevertheless, CysR offers great potential as an alternative for decisive interventions in general and tumour metabolism at the metabolic level.

The Role of PET in Supratentorial and Infratentorial Pediatric Brain Tumors

Objective: This review aims to provide a summary of the clinical indications and limitations of PET imaging with different radiotracers, including 18F-fluorodeoxyglucose (18F-FDG) and other radiopharmaceuticals, in pediatric neuro-oncology, discussing both supratentorial and infratentorial tumors, based on recent literature (from 2010 to present). Methods: A literature search of the PubMed/MEDLINE database was carried out searching for articles on the use of PET in pediatric brain tumors. The search was updated until December 2020 and limited to original studies published in English after 1 January 2010. Results: 18F-FDG PET continues to be successfully employed in different settings in pediatric neuro-oncology, including diagnosis, grading and delineation of the target for stereotactic biopsy, estimation of prognosis, evaluation of recurrence, treatment planning and assessment of treatment response. Nevertheless, non-18F-FDG tracers, especially amino acid analogues seem to show a better performance in each clinical setting. Conclusions: PET imaging adds important information in the diagnostic work-up of pediatric brain tumors. International or national multicentric studies are encouraged in order to collect larger amount of data.

Metabolomic profiling identifies complex lipid species and amino acid analogues associated with response to weight loss interventions

Obesity is an epidemic internationally. While weight loss interventions are efficacious, they are compounded by heterogeneity with regards to clinically relevant metabolic responses. Thus, we sought to identify metabolic biomarkers that are associated with beneficial metabolic changes to weight loss and which distinguish individuals with obesity who would most benefit from a given type of intervention. Liquid chromatography mass spectrometry-based profiling was used to measure 765 metabolites in baseline plasma from three different weight loss studies: WLM (behavioral intervention, N = 443), STRRIDE-PD (exercise intervention, N = 163), and CBD (surgical cohort, N = 125). The primary outcome was percent change in insulin resistance (as measured by the Homeostatic Model Assessment of Insulin Resistance [%ΔHOMA-IR]) over the intervention. Overall, 92 individual metabolites were associated with %ΔHOMA-IR after adjustment for multiple comparisons. Concordantly, the most significant metabolites were triacylglycerols (TAGs; p = 2.3e-5) and diacylglycerols (DAGs; p = 1.6e-4), with higher baseline TAG and DAG levels associated with a greater improvement in insulin resistance with weight loss. In tests of heterogeneity, 50 metabolites changed differently between weight loss interventions; we found amino acids, peptides, and their analogues to be most significant (4.7e-3) in this category. Our results highlight novel metabolic pathways associated with heterogeneity in response to weight loss interventions, and related biomarkers which could be used in future studies of personalized approaches to weight loss interventions.

Synthetic Analogues of Aminoadamantane as Influenza Viral Inhibitors—In Vitro, In Silico and QSAR Studies

A series of nineteen amino acid analogues of amantadine (Amt) and rimantadine (Rim) were synthesized and their antiviral activity was evaluated against influenza virus A (H3N2). Among these analogues, the conjugation of rimantadine with glycine illustrated high antiviral activity combined with low cytotoxicity. Moreover, this compound presented a profoundly high stability after in vitro incubation in human plasma for 24 h. Its thermal stability was established using differential and gravimetric thermal analysis. The crystal structure of glycyl-rimantadine revealed that it crystallizes in the orthorhombic Pbca space group. The structure–activity relationship for this class of compounds was established, with CoMFA (Comparative Molecular Field Analysis) 3D-Quantitative Structure Activity Relationships (3D-QSAR) studies predicting the activities of synthetic molecules. In addition, molecular docking studies were conducted, revealing the structural requirements for the activity of the synthetic molecules.

Synthesis of Phospho-Amino Acid Analogues as Tissue Adhesive Cement Additives

We report the synthesis of a library of phospho-amino acid analogues using a novel allyl-phosphoester deprotection strategy. By reacting phenols and alcohols with a combination of POCl3 and allyl alcohol we generate protected phosphoesters that can be subsequently deprotected via treatment with Pd(OAc)2. We go on to show that the generated phosphoserine and phosphotyrosine analogues can be used to generate adhesive calcium phosphate cements with potential applications in the treatment of bone defects. In particular, we use mechanical testing to demonstrate the importance of multiple calcium binding motifs and steric arrangement in promoting adhgesive strength.

Synthesis of Phospho-Amino Acid Analogues as Tissue Adhesive Cement Additives

We report the synthesis of a library of phospho-amino acid analogues using a novel allyl-phosphoester deprotection strategy. By reacting phenols and alcohols with a combination of POCl3 and allyl alcohol we generate protected phosphoesters that can be subsequently deprotected via treatment with Pd(OAc)2. We go on to show that the generated phosphoserine and phosphotyrosine analogues can be used to generate adhesive calcium phosphate cements with potential applications in the treatment of bone defects. In particular, we use mechanical testing to demonstrate the importance of multiple calcium binding motifs and steric arrangement in promoting adhgesive strength.