Appropriateness of Ketoanalogues of Amino Acids, Calcium Citrate, and Inulin Supplementation for CKD Management: A RAND/UCLA Consensus.

BACKGROUND: Current treatment for chronic kidney disease (CKD) focuses on improving manifestations and delaying progression. Nutritional approaches play a crucial role in CKD management, and various supplements have become available. Ketoanalogues of amino acids (KAs), calcium citrate, and inulin have been proposed as suitable supplements, yet their widespread use has been limited due to insufficient evidence. This study aimed to generate general guidance statements on the appropriateness of these supplements through a RAND/UCLA consensus process. METHODS: A RAND/UCLA consensus panel was convened to evaluate the appropriateness of these supplements in different clinical scenarios. In this study, we present a subgroup analysis focusing on a panel of eleven clinical nephrologists from among the experts. RESULTS: Supplementation of low-protein diets (LPDs) and very low-protein diets (VLPDs) with KA was considered appropriate to reduce manifestations and delay CKD outcomes, supplementation with calcium citrate is considered appropriate to reduce CKD manifestations, and supplementation with inulin is considered appropriate to delay CKD outcomes and manage comorbidities. CONCLUSIONS: Based on a combination of clinical experience and scientific evidence, the panel reached a consensus that KA supplementation of LPD and VLPD, calcium citrate, and inulin are appropriate in patients with CKD across various scenarios.

Evaluation of HIV-1 derived lentiviral vectors as transductors of Mucopolysaccharidosis type IV a fibroblasts.

Mucopolysaccharidosis type IVA (MPS IVA) is a lysosomal storage disease produced by the deficiency of the N-acetylgalactosamine-6-sulfate sulfatase (GALNS) enzyme, leading to glycosaminoglycans (GAGs) accumulation. Since currently available treatments remain limited and unspecific, novel therapeutic approaches are essential for the disease treatment. In an attempt to reduce treatment limitations, gene therapy rises as a more effective and specific alternative. We present in this study the delivery assessment of GALNS and sulfatase-modifying factor 1 (SUMF1) genes via HIV-1 derived lentiviral vectors into fibroblasts from MPS IVA patients. After transduction, we determined GALNS enzymatic activity, lysosomal mass change, and autophagy pathway impairment. Additionally, we computationally assessed the effect of mutations over the enzyme-substrate interaction and phenotypic effects. The results showed that the co-transduction of MPS IVA fibroblasts with GALNS and SUMF1 cDNAs led to a significant increase in GALNS enzyme activity and a reduction of lysosomal mass. We show that patient-specific differences in cellular response are directly associated with the set of mutations on each patient. Lastly, we present new evidence supporting autophagy impairment in MPS IVA due to the presence and changes in autophagy proteins in treated MPS IVA fibroblasts. Our results offer new evidence that demonstrate the potential of lentiviral vectors as a strategy to correct GALNS deficiency.

Brain lipidomics as a rising field in neurodegenerative contexts: Perspectives with Machine Learning approaches.

Lipids are essential for cellular functioning considering their role in membrane composition, signaling, and energy metabolism. The brain is the second most abundant organ in terms of lipid concentration and diversity only after adipose tissue. However, in the central system (CNS) lipid dysregulation has been linked to the etiology, progression, and severity of neurodegenerative diseases such as Alzheimers, Parkinson, and Multiple Sclerosis. Advances in the human genome and subsequent sequencing technologies allowed us the study of lipidomics as a promising approach to diagnosis and treatment of neurodegeneration. Lipidomics advances rapidly increased the amount and quality of data allowing the integration with other omic types as well as implementing novel bioinformatic and quantitative tools such as machine learning (ML). Integration of lipidomics data with ML, as a powerful quantitative predictive approach, led to improvements in diagnostic biomarker prediction, clinical data integration, network, and systems approaches for neural behavior, novel etiology markers for inflammation, and neurodegeneration progression and even Mass Spectrometry image analysis. In this sense, by exploiting lipidomics data with ML is possible to improve the identification of new biomarkers or unveil new molecular mechanisms associated with lipid impairment across neurodegeneration. In this review, we present the lipidomic neurobiology state-of-the-art highlighting its potential applications to study neurodegenerative conditions. Also, we present theoretical background, applications, and advances in the integration of lipidomics with ML. This review opens the door to new approaches in this rising field.

Structural and functional computational analysis of nicotine analogs as potential neuroprotective compounds in Parkinson disease.

As the mechanism of interaction between nicotinic receptors with nicotine analogs is not yet fully understood, information at molecular level obtained from computational calculations is needed. In this sense, this work is a computational study of eight nicotine analogs, all with pyrrolidine ring modifications over a nicotine-based backbone optimized with B3LYP-D3/aug-cc-pVDZ. A molecular characterization was performed focusing on geometrical parameters such as pseudo-rotation angles, atomic charges, HOMO and LUMO orbitals, reactivity indexes and intermolecular interactions. Three analogs, A2 (3-(1,3-dimethyl-4,5-dihydro-1h-pirazole-5-yl) pyridine), A3 (3-(3-methyl-4,5-dihydro-1H-pyrazol-5-yl)-pyridine) and A8 (5-methyl-3-(pyridine-3-yl)-4,5-dihydroisoxazole), were filtered suggesting putative neuroprotective activity taking into account different reactivity values, such as their lowest hardness: 2.37 eV (A8), 2.43 eV (A2) and 2.56 eV (A3), compared to the highest hardness value found: 2.71 eV for A5 (3-((2S,4R)-4-(fluoromethyl)-1-methylpyrrolidine-2-il) pyridine), similar to the value of nicotine (2.70 eV). Additionally, molecular docking of all 8 nicotine analogs with the α 7 nicotinic acetylcholine receptor (α 7 nAChR) was performed. High values of interaction between the receptor and the three nicotine analogs were obtained: A3 (-7.1 kcal/mol), A2 (-6.9 kcal/mol) and A8 (-6.8 kcal/mol); whereas the affinity energy of nicotine was -6.4 kcal/mol. Leu116 and Trp145 are key residues in the binding site of α 7 nAChR interacting with nicotine analogs. Therefore, based upon these results, possible application of these nicotine analogs as neuroprotective compounds and potential implication at the design of novel Parkinson's treatments is evidenced.