ABSTRACT
The dysfunction of TAR DNA-binding protein 43 (TDP-43) is implicated in various neurodegenerative diseases, though the specific contributions of its toxic gain-of-function versus loss-of-function effects remain unclear. This study investigates the impact of TARDBP loss on cellular metabolism and viability using human-induced pluripotent stem cell-derived motor neurons and HeLa cells. TARDBP silencing led to reduced metabolic activity and cell growth, accompanied by neurite degeneration and decreased oxygen consumption rates in both cell types. Notably, TARDBP depletion induced a metabolic shift, impairing ATP production, increasing metabolic inflexibility, and elevating free radical production, indicating a critical role for TDP-43 in maintaining cellular bioenergetics. Furthermore, TARDBP loss triggered non-apoptotic cell death, increased ACSL4 expression, and reprogrammed lipid metabolism towards lipid droplet accumulation, while paradoxically enhancing resilience to ferroptosis inducers. Overall, our findings highlight those essential cellular traits such as ATP production, metabolic activity, oxygen consumption, and cell survival are highly dependent on TARDBP function.
ABSTRACT
As obesity incidence is alarmingly rising among young individuals, we aimed to characterize an experimental model of this situation, considering the similarity between human and porcine physiology. For this reason, we fed prepubertal (63 days old) Duroc breed females (n=21) either with a standard growth diet (3800 kcal/day) or one with a high-calorie content (5200 kcal/day) during 70 days. Computerized tomography, mass-spectrometry-based metabolomics and lipidomics, as well as peripheral blood mononuclear cell transcriptomics, were applied to define traits linked to high-calorie intake. Samples from a human cohort confirmed potential lipidomic markers. Compared to those fed a standard growth diet, pigs fed a high-calorie diet showed an increased weight gain (13%), much higher adiposity (53%), hypertriacylglyceridemia and hypercholesterolemia in parallel to insulin resistance. This diet induced marked changes in the circulating lipidome, particularly in phosphatidylethanolamine-type molecules. Also, circulating specific diacylglycerol and monoacylglycerol contents correlated with visceral fat and intrahepatic triacylglycerol concentrations. Specific lipids associated with obesity in swine (mainly belonging to glycerophospholipid, triacylglyceride and sterol classes) were also linked with obesity traits in the human cohort, reinforcing the usefulness of the chosen approach. Interestingly, no overt inflammation in plasma or adipose tissue was evident in this model. The presented model is useful as a preclinical surrogate of prepubertal obesity in order to ascertain the pathophysiology interactions between energy intake and obesity development.
Subject(s)
Diet, High-Fat/adverse effects , Pediatric Obesity/etiology , Puberty/metabolism , Adiposity , Animals , Disease Models, Animal , Eating , Female , Humans , Leukocytes, Mononuclear/metabolism , Pediatric Obesity/metabolism , Pediatric Obesity/physiopathology , Phenomics , Puberty/genetics , Triglycerides/bloodABSTRACT
Prolonged caloric intake above energy needs disturbs the body's ability to store and manage the excess of energy intake, leading to the onset of chronic degenerative diseases. This study aimed to compare the effect of three foods, which contain demonstrated bioactive compounds in the treatment of obesity and as an adjuvant in obesity energy restriction treatments. In a mice obesity model induced through a high-fat diet; fish oil, soluble fibre, and soy were incorporated to evaluate its capacity to modulate metabolic factors in adipose tissue during a continued fat intake or weight reduction through a normocaloric diet. As a result, fish oil improved mitochondrial related, adipose tissue hormone expression, and oxidation products when high-fat diets are consumed; while soluble fibre improved glucose and inflammation pathways during high-fat diet intake. In weight reduction treatments few differential features, as a treatment adjuvant, were observed for fish oil and soy; while soluble fibre was able to improve the weight reduction effects induced by a normocaloric diet. As a conclusion, soluble fibre supplementation compared to an energy reduction program, was the only treatment able to induce a significant additional effect in the improvement of weight loss and adipose tissue metabolism.
Subject(s)
Adipose Tissue , Diet, Reducing , Mitochondria , Obesity , Weight Loss , Adipose Tissue/metabolism , Adipose Tissue/pathology , Animals , Dietary Fats/adverse effects , Dietary Fats/pharmacology , Disease Models, Animal , Energy Intake/drug effects , Fish Oils/pharmacology , Male , Mice , Mitochondria/metabolism , Mitochondria/pathology , Obesity/chemically induced , Obesity/diet therapy , Obesity/metabolism , Obesity/pathology , Glycine maxABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Ginseng is a widely used ingredient in several traditional Chinese medicine formulation, mainly as a prophylactic and restorative agent. Ginseng's Chinese traditional formulations have shown protective effects against atherosclerosis, suggesting that ginseng may be useful for the treatment of metabolic disorders. AIM OF THE STUDY: To evaluate whether the supplementation with Panax ginseng (PG) has an effect on blood lipid profile in humans. MATERIALS AND METHODS: A meta-analysis and a systematic review were conducted to evaluate the effects of PG on blood lipid profile. RESULTS: A total of 18 studies met the inclusion criteria, from which 10 studies were performed in volunteers with at least one component of metabolic syndrome, 3 in postmenopausal women, 2 in healthy volunteers and 3 with other types of inclusion criteria. The doses employed ranged from 0.2 to 20â¯g/day (median 3â¯g/day, 95% CI 1.7, 5.8), while the treatment time ranged from 2 to 12 weeks (median 8 weeks, 95% CI 6, 9). Few studies reported the composition of the PG extract employed. The main ginsenosides reported were Rb1 and Rg1 (content ranging from Rb1 0.023-6.44â¯mg/g and Rg1 0.028-3.21â¯mg/g). Significant modification in blood profile was described in 7 studies, in which 5 studies observed a reduction in total cholesterol, 4 in LDL-cholesterol, and 2 in triacylglycerides. The meta-analysis of 10 studies in volunteers with parameters related with metabolic syndrome describes that PG may induce a mean difference compared to a placebo of -2.30 (95% CI -3.79,-0.80) and -1.47 (95% CI -1.90,-1.05) mg/dL per g/day of PG in the levels of total and LDL-cholesterol, with no significant effects in HDL-cholesterol and triacylglycerides. CONCLUSIONS: PG extract may induce an improvement in blood lipid profile mainly by a reduction in total and LDL-cholesterol levels.
Subject(s)
Lipids/blood , Panax , Plant Extracts/therapeutic use , Dietary Supplements , Humans , Phytotherapy , Randomized Controlled Trials as Topic , Treatment OutcomeABSTRACT
Soybean is recognized as rich source of bioactive compounds for the improvement of glucose homeostasis. However, the post-prandial mechanisms of action have not been extensively described. The aim of this study is to determine the changes in glucose homeostasis and related factors after acute intake of a soy beverage. Twenty-nine subjects (15 women and 14 men, with an average age of 19.5 ± 1.2) ingested 500 mL of water, glucose (20.5 g/500 mL) and soy beverage (20 g of carbohydrate) in three separate sessions. Capillary blood glucose was monitored every 15 min until 120 min post-prandial, and blood samples were collected at baseline and after 60 min for insulin, incretin, free amino acids, antioxidant capacity and inflammation marker analysis. The increase in capillary glucose after soy-beverage intake was negligible. This is explained in part by an increase in 83% in insulin levels than induced with glucose alone, which is mainly mediated by a low insulin degradation ratio (determined by c-peptide ratio), incretins and likely also by the modulation of the antioxidant environment. No associations were observed between the insulin levels and soy amino acid uptake. It could be concluded that the acute low glycaemic response of a soy beverage may involves a relationship between incretin and insulin secretion and insulin degradation.
Subject(s)
Amino Acids/blood , Blood Glucose/metabolism , C-Peptide/blood , Incretins/blood , Insulin/blood , Postprandial Period/physiology , Soy Milk , Adolescent , Cross-Over Studies , Female , Glycemic Index , Humans , Male , Young AdultABSTRACT
Biofortification is an effective and economical method to improve the micronutrient content of crops, particularly staples that sustain human populations in developing countries. Whereas conventional fortification requires artificial additives, biofortification involves the synthesis or accumulation of nutrients by plants at source. Little is known about the relative merits of biofortification and artificial fortification in terms of nutrient bioaccessibility and bioavailability, and much depends on the biochemical nature of the nutrient, which can promote or delay uptake, and determine how efficiently different nutrients are transported through the blood, stored, and utilized. Data from the first plants biofortified with minerals and vitamins provide evidence that the way in which nutrients are presented can affect how they are processed and utilized in the human body. The latest studies on the effects of the food matrix, processing and storage on nutrient transfer from biofortified crops are reviewed, as well as current knowledge about nutrient absorption and utilization.