Differentiating Neuroblastoma: A Systematic Review of the Retinoic Acid, Its Derivatives, and Synergistic Interactions

A neuroblastoma (NB) is a solid paediatric tumour arising from undifferentiated neuronal cells. Despite the recent advances in disease management and treatment, it remains one of the leading causes of childhood cancer deaths, thereby necessitating the development of new therapeutic agents and regimens. Retinoic acid (RA), a vitamin A derivative, is a promising agent that can induce differentiation in NB cells. Its isoform, 13-cis RA or isotretinoin, is used in NB therapy; however, its effectiveness is limited to treating a minimal residual disease as maintenance therapy. As such, research focuses on RA derivatives that might increase the anti-NB action or explores the potential synergy between RA and other classes of drugs, such as cellular processes mediators, epigenetic modifiers, and immune modulators. This review summarises the in vitro, in vivo, and clinical data of RA, its derivatives, and synergising compounds, thereby establishing the most promising RA derivatives and combinations of RA for further investigation.

Effect of all-trans retinoic acid and pentagalloyl glucose on smooth muscle cell elastogenesis

BACKGROUND: The main objective of tissue engineering is to fabricate a tissue construct that mimics native tissue both biologically and mechanically. A recurring problem for tissue-engineered blood vessels (TEBV) is deficient elastogenesis from seeded smooth muscle cells. Elastin is an integral mechanical component in blood vessels, allowing elastic deformation and retraction in response to the shear and pulsatile forces of the cardiac system. OBJECTIVE: The goal of this research is to assess the effect of the vitamin A derivative all-trans retinoic acid (RA) and polyphenol pentagalloyl glucose (PGG) on the expression of elastin in human aortic smooth muscle cells (hASMC). METHODS: A polycaprolactone (PCL) and the gelatin polymer composite was electrospun and doped with RA and PGG. The scaffolds were subsequently seeded with hASMCs and incubated for five weeks. The resulting tissue-engineered constructs were evaluated using qPCR and Fastin assay for their elastin expression and deposition. RESULTS: All treatments showed an increased elastin expression compared to the control, with PGG treatments showing a significant increase in gene expression and elastin deposition.

Systematic Cell Line-Based Identification of Drugs Modifying ACE2 Expression

The COVID-19 pandemic caused by SARS-COV-2 has infected over 500,000 people causing over 25,000 deaths in the last 10 weeks. A key host cellular protein required for the virus entry is angiotensin-converting enzyme 2 (ACE2). Recent studies have reported that patients with hypertension and diabetes treated with ACE inhibitors or angiotensin receptor blockers might be at a higher risk of COVID-19 infection as these drugs have been reported to increase ACE2 expression. This has raised the need to systematically investigate the effect of different drugs including antihypertensives on modulating ACE2 expression. Here, we analyzed a publicly available CMAP dataset of pre/post transcriptomic profiles for drug treatment in cell lines for over 20,000 small molecules. We show that only one subclass of antihypertensives drugs - ACE inhibitors, are significantly enriched for drugs up-regulating ACE2 expression. Studying the effects of the 672 clinically approved drugs in CMAP, we chart the drug categories that affect ACE2 expression. Specifically, we find that panobinostat (an HDAC inhibitor) confers the highest up-regulation of ACE2 expression while isotretinoin (a vitamin A derivative) is its strongest down-regulator. Our results provide initial candidates guiding further in vitro and in vivo studies aimed at assessing drug effects on ACE2 expression.

Genu varum deformity due to premature epiphyseal closure after treatment with isotretinoin for neuroblastoma: A case report

Isotretinoin, a vitamin A derivative, is known to induce premature epiphyseal closure. We report the case of a 9-year-old boy with neuroblastoma who demonstrated premature epiphyseal closure after 1 year of isotretinoin treatment (72.3 mg/m2/day). A bone bridge developed on the bilateral proximal tibial growth plate resulting in genu varum. We performed hemiepiphysiodesis on the bilateral proximal tibia in anticipation of the spontaneous resolution of the bone bridge. Genu varum on the left side was corrected with the resolution of bone bridge. For the remaining bone bridge on the right side, arthroscopy-assisted physeal bar resection was performed, and genu varum on the right lower extremity was also corrected. A regular review of the alignment of the upper and lower limbs is necessary to provide timely intervention in patients using isotretinoin, considering the possibility of premature epiphyseal closure.

Isotretinoin-induced psychotic episode in a 17-year-old adolescent male

Isotretinoin, a synthetic vitamin A derivative, is primarily used in the management of severe nodulocystic acne. Since its introduction, isotretinoin has been linked with various psychiatric side effects. In particular, depression and suicidality have been extensively reported as side effects. This case report features a young male who developed a first psychotic episode within 3 months of starting isotretinoin therapy. The patient was hospitalized, and organic pathologies and use of psychoactive substances that could explain his presentation were ruled out. After stopping isotretinoin and starting olanzapine 10 mg, the psychotic symptoms remitted completely within 2 weeks. This case highlights the need for increased vigilance toward psychiatric manifestations of isotretinoin. In addition, it suggests that secondary psychosis should be considered as a differential diagnosis by clinicians, especially in patients with no past psychiatric history or family history of mental illness.

Structural biology of 11-cis-retinaldehyde production in the classical visual cycle

The vitamin A derivative 11-cis-retinaldehyde plays a pivotal role in vertebrate vision by serving as the chromophore of rod and cone visual pigments. In the initial step of vision, a photon is absorbed by this chromophore resulting in its isomerization to an all-trans state and consequent activation of the visual pigment and phototransduction cascade. Spent chromophore is released from the pigments through hydrolysis. Subsequent photon detection requires the delivery of regenerated 11-cis-retinaldehyde to the visual pigment. This trans–cis conversion is achieved through a process known as the visual cycle. In this review, we will discuss the enzymes, binding proteins and transporters that enable the visual pigment renewal process with a focus on advances made during the past decade in our understanding of their structural biology.

Variation in opsin transcript expression explains intraretinal differences in spectral sensitivity of the northern anchovy

Vertebrate retinal photoreceptors house visual pigments that absorb light to begin the process of vision. The light absorbed by a visual pigment depends on its two molecular components: protein (opsin) and chromophore (a vitamin A derivative). Although an increasing number of studies show intraretinal variability in visual pigment content, it is only for two mammals (human and mouse) and two birds (chicken and pigeon) that such variability has been demonstrated to underlie differences in spectral sensitivity of the animal. Here, we show that the spectral sensitivity of the northern anchovy varies with retinal quadrant and that this variability can be explained by differences in the expression of opsin transcripts. Retinal (vitamin A1) was the only chromophore detected in the retina, ruling out this molecular component as a source of variation in spectral sensitivity. Chromatic adaptation experiments further showed that the dorsal retina had the capacity to mediate color vision. Together with published results for the ventral retina, this study is the first to demonstrate that intraretinal opsin variability in a fish drives corresponding variation in the animal’s spectral sensitivity.

Modulation of spectral properties and pump activity of proteorhodopsins by retinal analogues

Microbial proteorhodopsins are light-driven proton pumps, using the vitamin A derivative retinal as chromophore. We show that retinal analogues can shift their absorbance band with preservation of functionality. This may provide attractive opportunities in biotechnology, optogenetics and as potential sensors.