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Metabolic-dysfunction-associated steatotic liver disease (MASLD) is the most common liver disease in children in the US and, if untreated, may progress to end-stage liver disease. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have shown improvement in MASLD markers in adults with type 2 diabetes mellitus (T2DM). Currently, there is a lack of medications available for the treatment of pediatric MASLD. We aimed to provide preliminary data on the effects of GLP-1 RAs on markers of MASLD in a retrospective study, in an effort to bridge this gap in the pharmacotherapies available. Nine patients from a T2DM clinic who met the following inclusion criteria were included in this study: patients diagnosed with pre-diabetes or T2DM, prescribed a GLP-1 RA in the prior 12 months, and having alanine aminotransferase (ALT) elevated to twice the upper limit of the normal range, indicating evidence of MASLD. The average change between baseline and the first measurement after starting a GLP-1 RA was calculated for ALT, hemoglobin A1c, and BMI. ALT decreased by an average of 98 points. A1c decreased by an average of 2.2 points. BMI decreased by an average of 2.4 points. There was greater reduction in ALT and A1c compared to BMI, suggesting that improvement in MASLD may be independent of weight loss. This is a preliminary study that shows potential, and prospective studies are needed to evaluate the effects of GLP-1 RAs in the management of pediatric MASLD.

RESUMEN

Deposition of amyloid ß (Aß) fibrils in the brain is a key pathologic hallmark of Alzheimer's disease. A class of polyphenolic biflavonoids is known to have anti-amyloidogenic effects by inhibiting aggregation of Aß and promoting disaggregation of Aß fibrils. In the present study, we further sought to investigate the structural basis of the Aß disaggregating activity of biflavonoids and their interactions at the atomic level. A thioflavin T (ThT) fluorescence assay revealed that amentoflavone-type biflavonoids promote disaggregation of Aß fibrils with varying potency due to specific structural differences. The computational analysis herein provides the first atomistic details for the mechanism of Aß disaggregation by biflavonoids. Molecular docking analysis showed that biflavonoids preferentially bind to the aromatic-rich, partially ordered N-termini of Aß fibril via the π-π interactions. Moreover, docking scores correlate well with the ThT EC50 values. Molecular dynamic simulations revealed that biflavonoids decrease the content of ß-sheet in Aß fibril in a structure-dependent manner. Hydrogen bond analysis further supported that the substitution of hydroxyl groups capable of hydrogen bond formation at two positions on the biflavonoid scaffold leads to significantly disaggregation of Aß fibrils. Taken together, our data indicate that biflavonoids promote disaggregation of Aß fibrils due to their ability to disrupt the fibril structure, suggesting biflavonoids as a lead class of compounds to develop a therapeutic agent for Alzheimer's disease.

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Alzheimer's disease (AD) is a devastating neurodegenerative disease and a major cause of dementia in elderly individuals worldwide. Increased deposition of insoluble amyloid ß (Aß) fibrils in the brain is thought be a key neuropathological hallmark of AD. Many recent studies show that natural products such as polyphenolic flavonoids inhibit the formation of insoluble Aß fibrils and/or destabilize ß-sheet-rich Aß fibrils to form non-cytotoxic aggregates. In the present study, we explored the structure-activity relationship of naturally-occurring biflavonoids on Aß amyloidogenesis utilizing an in vitro thioflavin T assay with Aß1-42 peptide which is prone to aggregate more rapidly to fibrils than Aß1-40 peptide. Among the biflavonoids we tested, we found amentoflavone revealed the most potent effects on inhibiting Aß1-42 fibrillization (IC50: 0.26 µM), as well as on disassembling preformed Aß1-42 fibrils (EC50: 0.59 µM). Our structure-activity relationship study suggests that the hydroxyl groups of biflavonoid compounds play an essential role in their molecular interaction with the dynamic process of Aß1-42 fibrillization. Our atomic force microscopic imaging analysis demonstrates that amentoflavone directly disrupts the fibrillar structure of preformed Aß1-42 fibrils, resulting in conversion of those fibrils to amorphous Aß1-42 aggregates. These results indicate that amentoflavone affords the most potent anti-amyloidogenic effects on both inhibition of Aß1-42 fibrillization and disaggregation of preformed mature Aß1-42 fibrils.

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There is growing evidence that extracellular haemoglobin and haem mediate inflammatory and oxidative damage in sickle cell disease. Haptoglobin (Hp), the scavenger for free haemoglobin, is depleted in most patients with sickle cell disease due to chronic haemolysis. Although single infusions of Hp can ameliorate vaso-occlusion in mouse models of sickle cell disease, prior studies have not examined the therapeutic benefits of more chronic Hp dosing on sickle cell disease manifestations. In the present study, we explored the effect of Hp treatment over a 3-month period in sickle mice at two dosing regimens: the first at a moderate dose of 200 mg/kg thrice weekly and the second at a higher dose of 400 mg/kg thrice weekly. We found that only the higher dosing regimen resulted in increased haem-oxygenase-1 and heavy chain ferritin (H-ferritin) expression and decreased iron deposition in the kidney. Despite the decreased kidney iron deposition following Hp treatment, there was no significant improvement in kidney function. However, there was a nearly significant trend towards decreased liver infarction.

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Gene therapy for sickle cell disease is currently in active trials. Collecting hematopoietic progenitor cells safely and effectively is challenging, however, because granulocyte colony stimulating factor, the drug used most commonly for mobilization, can cause life-threatening vaso-occlusion in patients with sickle cell disease, and bone marrow harvest requires general anesthesia and multiple hip bone punctures. Plerixafor is an inhibitor of the CXCR4 chemokine receptor on hematopoietic progenitor cells, blocking its binding to SDF-1 (CXCL12) on bone marrow stroma. In support of a clinical trial in patients with sickle cell disease of plerixafor mobilization (NCT02193191), we administered plerixafor to sickle cell mice and found that it mobilizes hematopoietic progenitor cells without evidence of concomitant cell activation or brain vaso-occlusion.

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