Search

Aldo-keto reductase family 1 member A (AKR1A) is an NADPH-dependent aldehyde reductase widely expressed in mammalian tissues. In this study induced differentiation of MC3T3-E1 preosteoblasts was found to increase AKR1A gene expression concomitantly increased N[O.sub.x]- (nitrite + nitrate), increased glucose uptake, increased [NAD[(P).sup.+]]/[NAD(P)H] and lactate production but decreased reactive oxygen species (ROS) without changes in endothelial nitric oxide synthase (eNOS) expression in differentiated osteoblasts (OBs). A study using gain- and loss-of-function MC3T3-E1 cells indicated that AKR1A is essential for modulating OB differentiation and gene expression of collagen 1 A1, receptor activator of nuclear factor kappa-B ligand, and osteoprotegerin in OBs. Immunofluorescence microscopy also revealed that changes in AKR1A expression altered extracellular collagen formation in differentiated OBs. Consistently analyses of alkaline phosphatase activity and calcium deposits of matrix mineralization by Alizarin Red S staining verified that AKR1A is involved in the regulation of OB differentiation and bone matrix formation. In addition, AKR1A gene alterations affected the levels of N[O.sub.x]-, eNOS expression, glucose uptake, [NAD[(P).sup.+]]/[NAD(P)H] dinucleotide redox couples, lactate production, and ROS in differentiated OBs. Herein, we report that AKR1A-mediated denitrosylation may play a role in the regulation of lactate metabolism as well as redox homeostasis in cells, providing an efficient way to quickly gain energy and to significantly reduce oxidative stress for OB differentiation. Key words: aldo-keto reductase family 1 member A (AKR1A), osteoblastogenesis, NADPH-dependent aldehyde reductase, alkaline phosphatase activity, Alizarin Red S staining L'aldéhyde réductase AKR1A (Aldo-keto reductase family 1 member A) est une aldéhyde réductase NADPH-dépendante largement exprimée dans les tissus des mammifères. Dans cette étude, les auteurs ont constaté que l'induction de la différenciation des préostéoblastes MC3T3-E1 accroissait l'expression du gène AKR1A, augmentait de façon concomitante les N[O.sub.x] - (nitrite + nitrate), augmentait l'absorption du glucose, augmentait la production de [NAD[(P).sup.+]]/[NAD(P)H] et de lactate, mais diminuait les dérivés réactifs de l'oxygène (DRO) sans modifier l'expression de l'eNOS (oxyde nitrique synthase endothéliale) dans les ostéoblastes différenciés. Une étude utilisant des cellules MC3T3-E1 avec gain ou perte de fonction indiquait que AKR1A est essentiel pour moduler la différenciation des OB et l'expression génique du collagène 1 Al, du récepteur de l'activateur du ligand du facteur nucléaire kappa (RANKL) et de l'ostéoprotégérine dans les OB. La microscopie par immunofluorescence a également révélé que les changements dans l'expression d'AKRIA modifiaient la formation de collagène extracellulaire dans les OB différenciés. De même, les analyses de l'activité de la phosphatase alcaline et des dépôts de calcium de la matrice minéralisée par coloration au rouge d'alizarine S confirmaient que AKR1A est impliqué dans la régulation de la différenciation des OB et de la formation de la matrice osseuse. En outre, les altérations du gène AKR1A affectaient les niveaux de N[O.sub.x]-, l'expression d'eNOS, l'absorption du glucose, les couples de dinucléotides redox [NAD[(P).sup.+]]/[NAD(P)H], la production de lactate et les DRO dans les OB différenciés. Les auteurs rapportent ici que la dénitrosylation médiée par AKR1A peut jouer un rôle dans la régulation du métabolisme du lactate ainsi que dans l'homéostasie redox dans les cellules, offrant ainsi un moyen efficace de gagner rapidement de l'énergie et de réduire significativement le stress oxydant pour la différenciation des OB. [Traduit par la Rédaction] Mots-clés : AKR1A, ostéoblastogenèse, aldéhyde réductase NADPH-dépendante, activité phosphatase alcaline, coloration rouge alizarine S, Introduction Aldo-keto reductase family 1 member A (AKR1A) is known to play roles in catalyzing intermediary metabolism, maintaining cellular redox homeostasis, and detoxifying toxic aldehydes (e.g., acrolein) due to its [...]

Previous studies arguing for parental care in dinosaurs have been primarily based on fossil accumulations of adults and hatchlings, perinatal and post-hatchlings in nests and nest areas, and evidence of brooding, the majority of which date to the Late Cretaceous. Similarly, the general body proportions of preserved embryonic skeletons of the much older Early Jurassic Massospondylus have been used to suggest that hatchlings were unable to forage for themselves. Here, we approach the question of parental care in dinosaurs by using a combined morphological, chemical, and biomechanical approach to compare early embryonic and hatchling bones of the Early Jurassic sauropodomorph Lufengosaurus with those of extant avian taxa with known levels of parental care. We compare femora, the main weight-bearing limb bone, at various embryonic and post-embryonic stages in a precocious and an altricial extant avian dinosaur with those of embryonic and hatchling Lufengosaurus, and find that the rate and degree of bone development in Lufengosaurus is closer to that of the highly altricial Columba (pigeon) than the precocious Gallus (chicken), providing strong support for the hypothesis that Lufengosaurus was fully altricial. We suggest that the limb bones of Lufengosaurus hatchlings were not strong enough to forage for themselves and would likely need parental feeding. [ABSTRACT FROM AUTHOR]

Background: This study evaluated early childhood comorbidities of cerebral palsy (CP) in low birth weight (LBW) children and assessed the impact of maternal bio-psychosocial factors on CP risk in preterm infants of varying birth weights (BWs). Methods: Data from 15,181 preterm infants (2009–2013) and 151,810 controls were analyzed using Taiwan's National Health Insurance Research Database. CP prevalence and LBW-associated comorbidities were examined, and odds ratios (ORs) were calculated. Results: This study confirmed increasing prematurity and LBW rates in Taiwan, with LBW infants showing higher CP prevalence. Significant maternal risk factors included age extremes (<20 and >40 years). LBW infants exhibited higher risks for respiratory, circulatory, nervous system, and psycho-developmental comorbidities compared with controls, with the lowest BW having even higher ORs. Maternal factors such as family income, the number of hospital admissions, and length of hospital stay were remarkably correlated with BW and subsequent complications. Each additional gestational week crucially reduced the risk of complications in premature infants. Conclusions: LBW infants are at a higher risk for CP and various comorbidities, with maternal bio-psychosocial factors playing a critical role. Addressing these factors in prenatal care and interventions is essential to improve outcomes for premature infants. [ABSTRACT FROM AUTHOR]

Dravet syndrome (DS), also known as severe myoclonic epilepsy of infancy, is a rare and drug-resistant form of developmental and epileptic encephalopathies, which is both debilitating and challenging to manage, typically arising during the first year of life, with seizures often triggered by fever, infections, or vaccinations. It is characterized by frequent and prolonged seizures, developmental delays, and various other neurological and behavioral impairments. Most cases result from pathogenic mutations in the sodium voltage-gated channel alpha subunit 1 (SCN1A) gene, which encodes a critical voltage-gated sodium channel subunit involved in neuronal excitability. Precision medicine offers significant potential for improving DS diagnosis and treatment. Early genetic testing enables timely and accurate diagnosis. Advances in our understanding of DS's underlying genetic mechanisms and neurobiology have enabled the development of targeted therapies, such as gene therapy, offering more effective and less invasive treatment options for patients with DS. Targeted and gene therapies provide hope for more effective and personalized treatments. However, research into novel approaches remains in its early stages, and their clinical application remains to be seen. This review addresses the current understanding of clinical DS features, genetic involvement in DS development, and outcomes of novel DS therapies. [ABSTRACT FROM AUTHOR]

E7050 is an inhibitor of VEGFR2 with anti-tumor activity; however, its therapeutic mechanism remains incompletely understood. In the present study, we aim to evaluate the anti-angiogenic activity of E7050 in vitro and in vivo and define the underlying molecular mechanism. It was observed that treatment with E7050 markedly inhibited proliferation, migration, and capillary-like tube formation in cultured human umbilical vein endothelial cells (HUVECs). E7050 exposure in the chick embryo chorioallantoic membrane (CAM) also reduced the amount of neovessel formation in chick embryos. To understand the molecular basis, E7050 was found to suppress the phosphorylation of VEGFR2 and its downstream signaling pathway components, including PLCγ1, FAK, Src, Akt, JNK, and p38 MAPK in VEGF-stimulated HUVECs. Moreover, E7050 suppressed the phosphorylation of VEGFR2, FAK, Src, Akt, JNK, and p38 MAPK in HUVECs exposed to MES-SA/Dx5 cells-derived conditioned medium (CM). The multidrug-resistant human uterine sarcoma xenograft study revealed that E7050 significantly attenuated the growth of MES-SA/Dx5 tumor xenografts, which was associated with inhibition of tumor angiogenesis. E7050 treatment also decreased the expression of CD31 and p-VEGFR2 in MES-SA/Dx5 tumor tissue sections in comparison with the vehicle control. Collectively, E7050 may serve as a potential agent for the treatment of cancer and angiogenesis-related disorders. [ABSTRACT FROM AUTHOR]