Disuse muscle atrophy secondary to acute illness or injury prolongs recovery and increases risk of permanent disability as a result of reduced muscle strength and myofiber damage upon reambulation. However, there are no pharmacotherapies to support muscle growth and repair following prolonged immobility. We propose that all-trans retinoic acid (ATRA) may support recovery of atrophied muscle via modulation of satellite cells and macrophages. Clinical application of ATRA is hindered by solubility, stability, and the need for high systemic doses. Therefore, in the current study, we developed poly(lactide-co-glycolide) (PLG) particles for local injection and extended release of ATRA (ATRA-PLG) and investigated the impact of ATRA-PLG on muscle recovery from disuse atrophy in adult mice following 10 days of hindlimb cast immobilization. A single administration of ATRA-PLG to the facia surrounding the calf muscle, at the time of cast removal, accelerates recovery of soleus muscle cross-sectional area. This is associated with decreased tissue damage, increased expression of macrophage scavenger receptors CD206 and CD163, and decreased CD68 and IL-6. Meanwhile, markers of muscle repair and growth are weakly impacted by ATRA-PLG. The data suggest that ATRA-PLG modulation of macrophages may limit inflammation and secondary injury to the atrophied muscle during the early stages of recovery, which then requires a lower repair response, and this translates to accelerated recovery of cross-sectional area. Our findings lay the foundation for future investigations of ATRA-PLG in populations that exhibit incomplete recovery from atrophy and dysregulated macrophage function, such as the elderly.NEW & NOTEWORTHY No pharmacotherapies exist to support muscle recovery from disuse. We developed particles for extended release of retinoic acid (ATRA-PLG) and investigated its impact on muscle recovery from cast immobilization. A single administration to the hindlimb, at the time of cast removal, accelerates soleus recovery and promotes macrophage polarization associated with repair. Our work supports ATRA-PLG as a clinical countermeasure to facilitate recovery from disuse and implicates modulation of inflammation as a mechanism of action.

Human cone photoreceptors differ from rods and serve as the retinoblastoma cell-of-origin, yet the developmental basis for their distinct behaviors is poorly understood. Here, we used deep full-length single-cell RNA-sequencing (scRNA-seq) to distinguish post-mitotic cone and rod developmental states and identify cone-specific features related to retinoblastomagenesis. The analyses revealed nascent, immediately post-mitotic cone and rod precursors characterized by higher THRB or NRL regulon activities, immature and maturing cone and rod precursors with concurrent cone- and rod-related gene and regulon expression, and distinct early and late cone and rod maturation states distinguished by maturation-associated declines in RAX regulon activity. Cell-state-specific gene expression features inferred from full-length scRNA-seq were consistent with past 3' scRNA-seq analyses. Beyond the cell state characterizations, full-length scRNA-seq revealed that both L/M cone and rod precursors co-expressed NRL and THRB RNAs yet differentially expressed functionally antagonistic NRL isoforms and prematurely terminated THRB transcripts. Moreover, early L/M cone precursors sequentially expressed several lncRNAs along with MYCN, which composed the seventh most L/M-cone-specific regulon, and SYK, which was implicated in the cone precursors' proliferative response to RB1 loss. These findings reveal previously unresolved photoreceptor precursor states and suggest a role for early cone-precursor-intrinsic SYK expression in retinoblastoma initiation.
© 2024, Shayler et al.

Insulin-like growth factor 1 (IGF1) plays a critical role in metabolism and aging, but its role in the brain remains unclear. This study examined whether hypothalamic neurons respond to IGF1 and how its actions are modulated. RT-qPCR and single-cell RNA sequencing indicated that Igf1r mRNA is expressed in neuropeptide Y/Agouti-related peptide (NPY/AgRP) neurons but has higher expression in pro-opiomelanocortin (POMC) neurons. IGF1 binding proteins Igfbp3 and Igfbp5 were significantly expressed, whereby Igfbp5 levels were modulated by fasting, nutrient availability, and circadian rhythms, implying that IGF1 signaling can be controlled by multiple mechanisms. In mouse and human models, IGF1 regulated Agrp, Npy, Pomc, Cartpt, Spx, Gal, and Fam237b expression, producing an overall anorexigenic profile. Hyperinsulinemia induced IGF1 resistance, accompanied by reduced IGF1R protein, as well as Igf1r and Irs2 mRNA expression via over-activation of phosphoinositide 3-kinase/forkhead box O1 (PI3K-FOXO1) signaling. Thus, hypothalamic neurons respond to IGF1 under physiological conditions, and hyperinsulinemia is a novel mechanism that drives cellular IGF1 resistance.
© The Author(s) 2025. Published by Oxford University Press on behalf of the Endocrine Society.

Choriocarcinoma is characterized by aggressive growth and metastasis, and integrins and matrix metalloproteinase-9 (MMP-9) play crucial roles in its progression. ATRA (All-trans retinoic acid) has been shown to have anti-tumor effects in various cancers, poses a 15-20% malignancy risk.  This study investigates the effects ATRA on MMP-9 activity and integrin expression in the choriocarcinoma cell line BeWo, and to explore the potential mechanisms underlying these effects.
This is an experimental study using choriocarcinoma cell line BeWo. Six treatment groups were established to varying concentrations of ATR and one group served as a control without ATRA exposure. The groups were labelled with fluorescence and performed with flowcytometry to determine MMP-9 and integrin expression. Data was presented as mean ± SD and analyzed using one-way ANOVA with post-hoc tests in which p-value <0.05.
ATRA at the doses of 100, 200, 400, and 800 μg/ml significantly decreased the MMP-9 activity compared to those in the control group. Furter, ATRA at the doses of 100, 200, 400, and 800 μg/ml significantly increased the integrin expression compared to those in the control group.
ATRA might decrease the MMP-9 activity as an invasive factor and increase integrin expression as an adhesive factor in the BeWo choriocarcinoma cell line that might play a role in the metastasis mechanism.

Alzheimer's disease (AD) is increasingly recognized as a metabolic disorder, often referred to as type 3 diabetes, due to its strong association with insulin resistance. Chronic exposure to aluminum, a known neurotoxin, has been identified as a significant risk factor in the development and progression of AD. This study explores the potential of metformin, a common anti-diabetic drug, to mitigate aluminum-induced neurotoxicity in an in vitro model of AD. Our findings reveal that metformin significantly reduces oxidative stress markers such as malonaldehyde, carbonyl groups, and reactive oxygen species while enhancing antioxidant defenses. Metformin modulates critical signaling pathways, including glycogen synthase kinase 3 beta (GSK3-β)/RAC-alpha serine/threonine protein kinase (RAC-alpha serine/threonine protein kinase (Akt1)/protein phosphatase 2A (PP2A) and Wnt/β-catenin, decreasing Tau protein levels and promoting neurogenesis. These results suggest that metformin may offer a novel therapeutic approach for AD, particularly in cases where aluminum exposure is a contributing factor.
© 2024 The Author(s). Journal of Applied Toxicology published by John Wiley & Sons Ltd.