Biology subjects

Minnion, M.

Publications and source records attributed to Minnion, M..

3 recordsLinked to original sources

bioRxiv2025

Liposomal encapsulation of L-arginine and L-citrulline enhances therapeutic effects in a rat model of Preeclampsia and Fetal Growth Restriction

BackgroundL-arginine and L-citrulline improve vascular health in Preeclampsia (PE) and Fetal growth restriction (FGR). However, the short half-life of these amino acids limits their efficacy. This study investigates pharmacokinetics, delivery, and therapeutic outcomes of liposomal encapsulation of L-arginine and L-citrulline in a rat model of PE and FGR. MethodFirstly, the pharmacokinetics of liposome-encapsulated L-arginine (Encapsulated L-arg) was compared to that of free L-arginine (Free L-arg) in normal pregnant (NP) dams, following single intravenous administration. Secondly, the therapeutic effect on maternal blood pressure and fetal weight were studied in NP rats and the reduced uterine perfusion pressure (RUPP) model for PE and FGR. Treatment groups consisted of Encapsulated L-arginine and L-citrulline (Encapsulated AAs); ratio 1:1, Free L-arginine and L-citrulline (AAs), or PBS, administered intravenously for five consecutive days. Blood and organs were analyzed for amino acid concentrations and fluorescence to assess the biodistribution profile of the liposomes. Nitrite and nitrate were quantified to measure changes in endogenous nitric oxide production in the pharmacokinetic study. ResultsLiposomal encapsulation increased the area under the curve of blood arginine concentration-time curves >120-fold. Encapsulated AAs led to a marked increase in plasma and placental tissue concentrations compared to their free forms. Encapsulated AAs reduced maternal blood pressure in RUPP without affecting fetal weight. Enlarged spleens were observed in both Encapsulated AAs groups. ConclusionsThe enhanced pharmacokinetics enabled by liposomal encapsulation effectively increased placental delivery of L-arginine and L-citrulline and reduced hypertension. Optimizing composition could enhance efficacy on FGR, making Encapsulated AAs a promising strategy for managing PE and FGR. The etiology of the observed maternal splenomegaly observed warrants further research before this novel approach can be clinically implemented.

pharmacology and toxicology↗

bioRxiv2024

Chronic inorganic nitrate supplementation does not improve metabolic health and worsens disease progression in mice with diet-induced obesity.

Inorganic nitrate (NO3-) has been proposed to be of therapeutic use as a dietary supplement in obesity and related conditions including the Metabolic Syndrome (MetS), type-II diabetes and metabolic dysfunction associated steatotic liver disease (MASLD). Administration of NO3- to endothelial nitric oxide synthase-deficient mice reversed aspects of MetS, however the impact of NO3- supplementation in diet-induced obesity is not well understood. Here we investigated the whole-body metabolic phenotype and cardiac and hepatic metabolism in mice fed a high-fat high-sucrose (HFHS) diet for up to 12-months of age, supplemented with 1 mM NaNO3 (or NaCl) in their drinking water. HFHS-feeding was associated with a progressive obesogenic and diabetogenic phenotype, which was not ameliorated by NO3-. Furthermore, HFHS-fed mice supplemented with NO3- showed elevated levels of cardiac fibrosis, and accelerated progression of MASLD including development of hepatocellular carcinoma in comparison with NaCl-supplemented mice. NO3- did not enhance mitochondrial {beta}-oxidation capacity in any tissue assayed and did not suppress hepatic lipid accumulation, suggesting it does not prevent lipotoxicity. We conclude that NO3- is ineffective in preventing the metabolic consequences of an obesogenic diet and may instead be detrimental to metabolic health against the background of HFHS-feeding. This is the first report of an unfavorable effect of long-term nitrate supplementation in the context of the metabolic challenges of overfeeding, warranting urgent further investigation into the mechanism of this interaction. New & NoteworthyInorganic nitrate has been suggested to be of therapeutic benefit in obesity-related conditions as it increases nitric oxide bioavailability, enhances mitochondrial {beta}-oxidation and reverses Metabolic Syndrome in eNOS-/- mice. However, we here show that over 12 months, nitrate was ineffective in preventing metabolic consequences in high-fat high-sucrose fed mice, and worsened aspects of metabolic health, impairing cholesterol handling, increasing cardiac fibrosis, and exacerbating steatotic liver disease progression, with acceleration to hepatocellular carcinoma.

physiology↗

bioRxiv2022

mRNA therapy restores ureagenesis and corrects glutathione metabolism in argininosuccinic aciduria

Argininosuccinate lyase (ASL) is a key enzyme integral to the hepatic urea cycle which is required for ammonia detoxification, and the citrulline-nitric oxide (NO) cycle for NO production. ASL deficient patients present with argininosuccinic aciduria (ASA), an inherited metabolic disease with hyperammonaemia and a chronic systemic phenotype with neurocognitive impairment and chronic liver disease. ASL deficiency as an inherited model of systemic NO deficiency, shows enhanced nitrosative and oxidative stress. Here, we describe the dysregulation of glutathione biosynthesis and upstream cysteine utilization in ASL-deficient patients and mice using targeted metabolomics and in vivo positron emission tomography (PET) imaging using (S)-4-(3-18F-fluoropropyl)-L-glutamate ([18F]FSPG). Upregulation of cysteine metabolism contrasted with glutathione depletion and down-regulated antioxidant pathways. hASL mRNA encapsulated in lipid nanoparticles corrected and rescued the neonatal and adult Asl-deficient mouse phenotypes, respectively, enhancing ureagenesis and glutathione metabolism and ameliorating chronic liver disease. We further present [18F]FSPG PET as a novel non-invasive diagnostic tool to assess liver disease and therapeutic efficacy in ASA. These findings support clinical translation of mRNA therapy for ASA.

genetics↗