Acute inhibition of OGA sex-dependently alters the networks associated with bioenergetics, autophagy, and neurodegeneration.

The accumulation of neurotoxic proteins characteristic of age-related neurodegenerative pathologies such as Alzheimer's and Parkinson's diseases is associated with the perturbation of metabolism, bioenergetics, and mitochondrial quality control. One approach to exploit these interactions therapeutically is to target the pathways that regulate metabolism. In this respect, the nutrient-sensing hexosamine biosynthesis pathway is of particular interest since it introduces a protein post-translational modification known as O-GlcNAcylation, which modifies different proteins in control versus neurodegenerative disease postmortem brains. A potent inhibitor of the O-GlcNAcase enzyme that removes the modification from proteins, Thiamet G (TG), has been proposed to have potential benefits in Alzheimer's disease. We tested whether key factors in the O-GlcNAcylation are correlated with mitochondrial electron transport and proteins related to the autophagy/lysosomal pathways in the cortex of male and female mice with and without exposure to TG (10 mg/kg i.p.). Mitochondrial complex activities were measured in the protein homogenates, and a panel of metabolic, autophagy/lysosomal proteins and O-GlcNAcylation enzymes were assessed by either enzyme activity assay or by western blot analysis. We found that the networks associated with O-GlcNAcylation enzymes and activities with mitochondrial parameters, autophagy-related proteins as well as neurodegenerative disease-related proteins exhibited sex and TG dependent differences. Taken together, these studies provide a framework of interconnectivity for multiple O-GlcNAc-dependent pathways in mouse brain of relevance to aging and sex/age-dependent neurodegenerative pathogenesis and response to potential therapies.

Levocarnitine for pegaspargase-induced hepatotoxicity in older children and young adults with acute lymphoblastic leukemia.

BACKGROUND: Pegaspargase (PEG-ASP) is an integral component of therapy for acute lymphoblastic leukemia (ALL) but is associated with hepatotoxicity that may delay or limit future therapy. Obese and adolescent and young adult (AYA) patients are at high risk. Levocarnitine has been described as potentially beneficial for the treatment or prevention of PEG-ASP-associated hepatotoxicity. METHODS: We collected data for patients age ≥10 years who received levocarnitine during induction therapy for ALL, compared to a similar patient cohort who did not receive levocarnitine. The primary endpoint was conjugated bilirubin (c.bili) >3 mg/dl. Secondary endpoints were transaminases >10× the upper limit of normal and any Grade ≥3 hepatotoxicity. RESULTS: Fifty-two patients received levocarnitine for prophylaxis (n = 29) or rescue (n = 32) of hepatotoxicity. Compared to 109 patients without levocarnitine, more patients receiving levocarnitine were obese and/or older and had significantly higher values for some hepatotoxicity markers at diagnosis and after PEG-ASP. Levocarnitine regimens varied widely; no adverse effects of levocarnitine were identified. Obesity and AYA status were associated with an increased risk of conjugated hyperbilirubinemia and severe transaminitis. Multivariable analysis identified a protective effect of levocarnitine on the development of c.bili >3 mg/dl (OR 0.12, p = 0.029). There was no difference between groups in CTCAE Grade ≥3 hepatotoxicity. C.bili >3 mg/dl during induction was associated with lower event-free survival. CONCLUSIONS: This real-world data on levocarnitine supplementation during ALL induction highlights the risk of PEG-ASP-associated hepatotoxicity in obese and AYA patients, and hepatotoxicity's potential impact on survival. Levocarnitine supplementation may be protective, but prospective studies are needed to confirm these findings.

Rice husk and melaleuca biochar additions reduce soil CH 4 and N 2O emissions and increase soil physicochemical properties.

Background: Biochar is a promising material in mitigating greenhouse gases (GHGs) emissions from paddy fields due to its remarkable structural properties. Rice husk biochar (RhB) and melaleuca biochar (MB) are amendment materials that could be used to potentially reduce emissions in the Vietnamese Mekong Delta (VMD). However, their effects on CH 4 and N 2O emissions and soil under local water management and conventional rice cultivation have not been thoroughly investigated. Methods: We conducted a field experiment using biochar additions to the topsoil layer (0-20 cm). Five treatments comprising 0 t ha -1 (CT0); 5 t ha -1 (RhB5) and 10 t ha -1 (RhB10), and 5 t ha -1 (MB5) and 10 t ha -1 (MB10) were designed plot-by-plot (20 m 2) in triplicates. Results: The results showed that biochar application from 5 to 10 t ha -1 significantly decreased cumulative CH 4 (24.2 - 28.0%, RhB; 22.0 - 14.1%, MB) and N 2O (25.6 - 41.0%, RhB; 38.4 - 56.4%, MB) fluxes without a reduction in grain yield. Increasing the biochar application rate further did not decrease significantly total CH 4 and N 2O fluxes but was seen to significantly reduce the global warming potential (GWP) and yield-scale GWP in the RhB treatments. Biochar application improved soil Eh but had no effects on soil pH. Whereas CH 4 flux correlated negatively with soil Eh ( P < 0.001; r 2 = 0.552, RhB; P < 0.001; r 2 = 0.502, MB). The soil physicochemical properties of bulk density, porosity, organic matter, and anaerobically mineralized N were significantly improved in biochar-amended treatments, while available P also slightly increased. Conclusions: Biochar supplementation significantly reduced CH 4 and N 2O fluxes and improved soil mineralization and physiochemical properties toward beneficial for rice plant. The results suggest that the optimal combination of biochar-application rates and effective water-irrigation techniques for soil types in the MD should be further studied in future works.

Nutrient dynamics in water and soil under conventional rice cultivation in the Vietnamese Mekong Delta.

Background The evaluation of nutrient variability plays a crucial role in accessing soil potentials and practical intervention responses in rice production systems. Synthetic fertilizer applications and cultivation practices are considered key factors affecting nutrient dynamics and availability. Here, we assessed the nutrient dynamics in surface, subsurface water and soil under local water management and conventional rice cultivation practices in the Vietnamese Mekong Delta. Methods We implemented a field experiment (200 m 2) in the 2018 wet season and the 2019 dry season in a triple rice-cropping field. Eight samples of surface water, subsurface water (30-45 cm), and topsoil (0-20 cm) were collected and analysed during the rice-growing seasons. Results The results showed that N-NH 4 +, P-PO 4 3- and total P peaks were achieved after fertilizing. Irrespective of seasons, the nutrient content in surface water was always greater than that of subsurface water ( P < 0.001), with the exception of N-NO 3 -, which was insignificant ( P > 0.05). When comparing the wet and dry seasons, nutrient concentrations exhibited minor differences ( P > 0.05). Under conventional rice cultivation, the effects of synthetic fertilizer topdressing on the total N, soil organic matter (SOM), and total P were negligible in the soil. Higher rates of N fertilizer application did not significantly increase soil N-NH 4 +, total N, yet larger P fertilizer amounts substantially enhanced soil total P ( P < 0.001). Conclusions Under conventional rice cultivation, N-NH 4 +, P-PO 4 3- and total P losses mainly occur through runoff rather than leaching. While N-NO 3 - loss is similar in surface water and subsurface water. Notably, nutrient content in soil was high; whilst SOM was seen to be low-to-medium between seasons. Future work should consider the nutrient balance and dynamic simulation in the lowland soil of the Vietnamese Mekong Delta's paddy fields.

Enhanced resolution triple-quadrupole mass spectrometry for ultra-sensitive and quantitative analysis of the investigational anticancer agent EO9 (apaziquone) and its metabolite EO5a in human and dog plasma to support (pre)-clinical studies of EOquin given intravesically.

A highly sensitive and selective liquid chromatography/tandem mass spectrometric (LC/MS/MS) method was developed to quantify the experimental anticancer agent EO9 and its metabolite EO5a in biological matrices. A 200-microL aliquot of human/dog plasma was spiked with a mixture of deuterated internal standards EO9-d3 and EO5a-d4 and extracted with 1.25 mL of ethyl acetate. Dried extracts were reconstituted in 0.1 M ammonium acetate/methanol (7:3, v/v) and 20-microL volumes were injected onto the LC system. Separation was achieved on a 150 x 2.1 mm C18 column using an alkaline eluent (1 mM ammonium hydroxide/methanol (gradient system)). The detection was performed by a Finnigan TSQ Quantum Ultra equipped with an electrospray ionization source operated in positive mode and enhanced mass resolution capability. It demonstrated improved sensitivity with a factor 10-20 for EO9 and EO5a over a 3-decades dynamic range, with acceptable accuracy and precision, when compared with the previously described assay for EO9 and EO5a, developed by our group, using an API 2000. The assay quantifies a range from 0.5 to 500 ng/mL for EO9 and EO5a using 200-microL human plasma and dog samples. The described mass resolution method was successfully applied for the evaluation of the pharmacokinetic profile of EO9 and its metabolite EO5a in human and dog plasma.