Biology subjects

Castro, J. C.

Publications and source records attributed to Castro, J. C..

3 recordsLinked to original sources

bioRxiv2026

Prefrontal cortex glucocorticoid receptors during fear memory consolidation shift the balance between salience and default-mode networks at retrieval in rats

Contextual fear memories become less specific as they age, modeling fear overgeneralization seen in post-traumatic stress disorder. Glucocorticoid receptor (GR) signaling in the dorsomedial prefrontal cortex (dmPFC) during the immediate post-learning period may govern both endocrine recovery from an aversive experience and the eventual specificity of the resulting memory, but this link remains untested. We infused vehicle or the GR antagonist mifepristone into the dmPFC of rats immediately after contextual fear conditioning, then measured corticosterone dynamics, fear expression at recent and remote time points, and c-Fos coactivation networks. Mifepristone accelerated corticosterone recovery without changing total hormone release, spared recent memory, and produced stronger, less context-specific freezing at the remote time point. This behavioral shift coincided with reorganization of the retrieval network from a salience-network-like to a default-mode-network-like configuration. These findings identify dmPFC glucocorticoid signaling as a mechanism constraining fear memory generalization as memories transition to a remote, cortically dependent state.

neuroscience↗

bioRxiv2025

microRNA-21 promotes dysregulated lipid metabolism and hepatocellular carcinoma

Backgrounds and AimsThe prevalence of hepatocellular carcinoma (HCC) is rising in parallel with increasing obesity and metabolic dysfunction-associated steatohepatitis (MASH). MicroRNAs are key post-transcriptional regulators of gene expression and are attractive targets for HCC therapy. Here we sought to identify and characterize dysregulated microRNAs in MASH-driven HCC (MASH-HCC). Approach and ResultsWe profiled microRNA expression in liver tissue from patients with MASH and/or MASH-HCC and in zebrafish HCC driven by activated {beta}-catenin (ABC), one of the most commonly mutated oncogenes in MASH-HCC. We found significant overlap between dysregulated human and zebrafish miRNAs, including miR-21, which was increasingly upregulated from normal liver to MASH to MASH-HCC. We generated transgenic zebrafish that overexpress or sponge (downregulate) miR-21. We found that miR-21 overexpression caused larval liver overgrowth and increased HCC while miR-21 sponge suppressed {beta}-catenin-driven larval liver overgrowth. By performing histologic and lipidomic analysis, we found that overexpression of miR-21, like ABC, suppressed lipid accumulation in response to a high cholesterol diet and increased accumulation of acylcarnitines. ConclusionsHere we characterize microRNA dysregulation in MASH and MASH-HCC in patients, identify miR-21 as increasingly dysregulated from MASH to MASH-HCC, and delineate the impacts of miR-21 overexpression on lipid metabolism and hepatocarcinogenesis in zebrafish {beta}-catenin-driven HCC. This study shows that miR-21, which is similarly dysregulated in human and zebrafish HCC, promotes lipid metabolic changes that may help drive hepatocarcinogenesis.

cancer biology↗

bioRxiv2022

Structural Characterization of L-Galactose Dehydrogenase: A Key Enzyme for Vitamin C Biosynthesis

In plants, it is well-known that ascorbic acid (vitamin C) can be synthesized via multiple metabolic pathways but there is still much to be learnt concerning their integration and control mechanisms. Furthermore, the structural biology of the component enzymes has been poorly exploited. Here we describe the first crystal structure for an L-galactose dehydrogenase (SoGDH from spinach), from the D-mannose/L-galactose (Smirnoff Wheeler) pathway which converts L-galactose into L-galactono-1,4-lactone. The kinetic parameters for the enzyme are similar to those from its homologue from camu-camu, a super-accumulator of vitamin C found in the Peruvian amazon. Both enzymes are monomers in solution, have a pH optimum of 7 and their activity is largely unaffected by high concentrations of ascorbic acid, suggesting the absence of a feedback mechanism acting via GDH. Previous reports may have been influenced by changes of the pH of the reaction medium as a function of ascorbic acid concentration. The structure of SoGDH is dominated by a ({beta}/)8 barrel closely related to aldehyde-keto reductases (AKRs). The structure bound to NAD+ shows that the lack of Arg279 justifies its preference for NAD+ over NADP+, as employed by many AKRs. This favours the oxidation reaction which ultimately leads to ascorbic acid accumulation. When compared with other AKRs, residue substitutions at the C-terminal end of the barrel (Tyr185, Tyr61, Ser59 and Asp128) can be identified to be likely determinants of substrate specificity. The present work contributes towards a more comprehensive understanding of structure-function relationships in the enzymes involved in vitamin C synthesis.

biophysics↗