Globotriaosylceramide is correlated with oxidative stress and inflammation in Fabry patients treated with enzyme replacement therapy

AbstractFabry disease is an X-linked inborn error of glycosphingolipid catabolism due to deficient activity of α-galactosidase A that leads to accumulation of the enzyme substrates, mainly globotriaosylceramide (Gb3), in body fluids and lysosomes of many cell types. Some pathophysiology hypotheses are intimately linked to reactive species production and inflammation, but until this moment there is no in vivo study about it. Hence, the aim of this study was to investigate oxidative stress parameters, pro-inflammatory cytokines and Gb3 levels in Fabry patients under treatment with enzyme replacement therapy (ERT) and finally to establish a possible relation between them. We analyzed urine and blood samples of patients under ERT (n=14) and healthy age-matched controls (n=14). Patients presented decreased levels of antioxidant defenses, assessed by reduced glutathione (GSH), glutathione peroxidase (GPx) activity and increased superoxide dismutase/catalase (SOD/CAT) ratio in erythrocytes. Concerning to the damage to biomolecules (lipids and proteins), we found that plasma levels of malondialdehyde (MDA) and protein carbonyl groups and di-tyrosine (di-Tyr) in urine were increased in patients. The pro-inflammatory cytokines IL-6 and TNF-α were also increased in patients. Urinary Gb3 levels were positively correlated with the plasma levels of IL-6, carbonyl groups and MDA. IL-6 levels were directly correlated with di-Tyr and inversely correlated with GPx activity. This data suggest that pro-inflammatory and pro-oxidant states occur, are correlated and seem to be induced by Gb3 in Fabry patients

Multiple-Choice Question Generation Using Large Language Models: Methodology and Educator Insights

Integrating Artificial Intelligence (AI) in educational settings has brought new learning approaches, transforming the practices of both students and educators. Among the various technologies driving this transformation, Large Language Models (LLMs) have emerged as powerful tools for creating educational materials and question answering, but there are still space for new applications. Educators commonly use Multiple-Choice Questions (MCQs) to assess student knowledge, but manually generating these questions is resource-intensive and requires significant time and cognitive effort. In our opinion, LLMs offer a promising solution to these challenges. This paper presents a novel comparative analysis of three widely known LLMs - Llama 2, Mistral, and GPT-3.5 - to explore their potential for creating informative and challenging MCQs. In our approach, we do not rely on the knowledge of the LLM, but we inject the knowledge into the prompt to contrast the hallucinations, giving the educators control over the test's source text, too. Our experiment involving 21 educators shows that GPT-3.5 generates the most effective MCQs across several known metrics. Additionally, it shows that there is still some reluctance to adopt AI in the educational field. This study sheds light on the potential of LLMs to generate MCQs and improve the educational experience, providing valuable insights for the future

Evaluation of Municipal Landfill Leachate Treatment by Microalgae

In recent years, municipal waste collection and treatment plants have introduced substantial innovations to minimize the related environmental impacts while producing energy and new materials as by-products. Municipal solid waste (MSW), indeed, is usually valorized in incinerators, landfills or anaerobic digestion plants for for final combined heat and power (CHP) production. In this perspective, the proposed research assesses the feasibility of microalgae bioremediation of leachate from a landfill in Italy. The composition of the leachate was recreated in laboratory and diluted in water and the microalgae culture growth was monitored inside a 5-litre bioreactor. The biochemical characterization of the lipids has been done according to literature. A numerical model is then developed in Aspen based on experimental data to assess the use of microalgae oil for biodiesel production. Eventually, a comparison with to the use of sunflower vegetable oil (SFO) is performed obtaining an increasing in OPEX due to the additional required hydrolysis step. The novelty of this study is the investigation in terms of process requirement for a plausible biodiesel production plant from leachate-harvested microalgae oil

Experimental evidence for protein oxidative damage and altered antioxidant defense in patients with medium-chain acyl-CoA dehydrogenase deficiency

The objective of this study was to test whether macromolecule oxidative damage and altered enzymatic antioxidative defenses occur in patients with medium-chain acyl coenzyme A dehydrogenase (MCAD) deficiency. We performed a cross-sectional observational study of in vivo parameters of lipid and protein oxidative damage and antioxidant defenses in asymptomatic, nonstressed, MCAD-deficient patients and healthy controls. Patients were subdivided into three groups based on therapy: patients without prescribed supplementation, patients with carnitine supplementation, and patients with carnitine plus riboflavin supplementation. Compared with healthy controls, nonsupplemented MCAD-deficient patients and patients receiving carnitine supplementation displayed decreased plasma sulfhydryl content (indicating protein oxidative damage). Increased erythrocyte superoxide dismutase (SOD) activity in patients receiving carnitine supplementation probably reflects a compensatory mechanism for scavenging reactive species formation. The combination of carnitine plus riboflavin was not associated with oxidative damage. These are the first indications that MCAD-deficient patients experience protein oxidative damage and that combined supplementation of carnitine and riboflavin may prevent these biochemical alterations. Results suggest involvement of free radicals in the pathophysiology of MCAD deficiency. The underlying mechanisms behind the increased SOD activity upon carnitine supplementation need to be determined. Further studies are necessary to determine the clinical relevance of oxidative stress, including the possibility of antioxidant therapy

Oxidative stress and inflammation in mucopolysaccharidosis type IVA patients treated with enzyme replacement therapy

AbstractMucopolysaccharidosis type IVA (MPS IVA) is an inborn error of glycosaminoglycan (GAG) catabolism due to the deficient activity of N-acetylgalactosamine-6-sulfate sulfatase that leads to accumulation of the keratan sulfate and chondroitin 6-sulfate in body fluids and in lysosomes. The pathophysiology of this lysosomal storage disorder is not completely understood. The aim of this study was to investigate oxidative stress parameters, pro-inflammatory cytokine and GAG levels in MPS IVA patients. We analyzed urine and blood samples from patients under ERT (n=17) and healthy age-matched controls (n=10–15). Patients presented a reduction of antioxidant defense levels, assessed by a decrease in glutathione content and by an increase in superoxide dismutase activity in erythrocytes. Concerning lipid and protein damage, it was verified increased urine isoprostanes and di-tyrosine levels and decreased plasma sulfhydryl groups in MPS IVA patients compared to controls. MPS IVA patients showed higher DNA damage than control group and this damage had an oxidative origin in both pyrimidine and purine bases. Interleukin 6 was increased in patients and presented an inverse correlation with GSH levels, showing a possible link between inflammation and oxidative stress in MPS IVA disease. The data presented suggest that pro-inflammatory and pro-oxidant states occur in MPS IVA patients even under ERT. Taking these results into account, supplementation of antioxidants in combination with ERT can be a tentative therapeutic approach with the purpose of improving the patient's quality of life. To the best of our knowledge, this is the first study relating MPS IVA patients with oxidative stress