small molecules

2024-11-17 | Risk assessment of developmental and neurotoxicity by the flavoring agent perillaldehyde: NAC (N-acetylcysteine) mitigation of oxidative stress-mediated inhibition of the Nrf2 pathway.

Perillaldehyde (PAE), a prevalent flavoring agent, has raised safety concerns due to conflicting evidence regarding its toxicity. This study provides a comprehensive assessment of the developmental and neurotoxic effects of PAE in zebrafish, elucidating the underlying mechanisms of its toxicity. Results showed that PAE affected the viability and hatching rate of zebrafish at 96 h postfertilization with the 50 % lethal concentration (LC50) of 7.975 mg/L. Furthermore, exposed‌ to a non-lethal concentration of 4 mg/L PAE induced a spectrum of morphological abnormalities, such as pericardial edema, delayed yolk sac absorption, reduced body length, and microphthalmia. Behavioral observations revealed that PAE reduced motor ability, and was accompanied by an increase in spontaneous turning angle and angular velocity. Using the TG(elav13:EGFP) transgenic model, we observed the number of newborn neurons was reduced, indicating that PAE induced obvious neurotoxic effects. Additionally, this concentration facilitated the accumulation of reactive oxygen species (ROS) and malondialdehyde (MDA), concomitantly decreasing the activity of antioxidant enzymes. QRT-PCR analysis revealed that PAE down-regulated Nestin and Neurogenin1 gene expression, up-regulated Glipr1a and Nox1 gene expression, and inhibited the Nrf2/HO-1 pathway. Notably, co-administration of N-acetylcysteine (NAC), an inhibitor of oxidative stress, mitigated oxidative stress levels and partially ameliorated the neurotoxicity. These findings suggest that oxidative stress is the primary mediator of PAE-induced neurotoxicity. This study provides crucial insights for the safe application of PAE.

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2023-12-30 | Anti-Teratogenic Potential of Exogenously Applied Over-The-Counter L-Glutathione Supplement on Ethanol-Induced Teratogenesis in Zebrafish (Danio rerio)

Glutathione is the body’s most abundant endogenous non-enzymatic antioxidant and is used as a substrate for free radical scavenging in the body, especially during ethanol metabolism. This study aims to shift the paradigm of using glutathione as a whitening agent into a potent antioxidant for therapy, particularly for ethanol-induced teratogenesis in the Philippines. Zebrafish embryos were treated with glutathione at various time points of ethanol exposure and concentration. Pre-treatments, co-treatments, and post-treatments with 100 μM glutathione solution were done to assess the most appropriate time point for glutathione intake upon exposure of the embryo to ethanol. Eye diameter and otic vesicle diameter were chosen as morphological parameters because dysmorphogenesis of these organs resembles mammalian fetal alcohol syndrome disorders. For eye diameter, alleviation of microphthalmia by glutathione was seen in pre-treatment (1% ethanol only) and post-treatment (1% & 1.5%) while co-treatment did not exhibit rescue for eye diameter reduction. For otic vesicle diameter, pre- and co-treatment with glutathione did not exhibit any changes in size but post-treatment showed abnormal enlargement suggesting possible teratogenic effect across all ethanol concentrations. The 2,2-diphenylpicryl-1-hydrazine (DPPH) assay was used as a confirmatory test for the free radical scavenging activity (FRSA) of treated tissues. Pre-treatment with GSH at 1% ethanol showed the highest FRSA while post-treatment showed FRSA insignificantly different to controls. This study suggests that glutathione can alleviate oxidative stress in embryo development which may lead to dysmorphogenesis and that supplementation before and after ethanol exposure may be a viable form of therapy for ethanol-induced teratogenesis.

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2019-12-23 | Induction of Immune Surveillance of the Dysmorphogenic Lens.

The lens has been considered to be an immune privileged site not susceptible to the immune processes normally associated with tissue injury and wound repair. However, as greater insight into the immune surveillance process is gained, we have reevaluated the concept of immune privilege. Our studies using an N-cadherin lens-specific conditional knockout mouse, N-cadΔlens, show that loss of this cell-cell junctional protein leads to lens degeneration, necrosis and fibrotic change, postnatally. The degeneration of this tissue induces an immune response resulting in immune cells populating the lens that contribute to the development of fibrosis. Additionally, we demonstrate that the lens is connected to the lymphatic system, with LYVE(+) labeling reaching the lens along the suspensory ligaments that connect the lens to the ciliary body, providing a potential mechanism for the immune circulation. Importantly, we observe that degeneration of the lens activates an immune response throughout the eye, including cornea, vitreous humor, and retina, suggesting a coordinated protective response in the visual system to defects of a component tissue. These studies demonstrate that lens degeneration induces an immune response that can contribute to the fibrosis that often accompanies lens dysgenesis, a consideration for understanding organ system response to injury.

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proteins

2026-04-30 | DiseaseOntology/HumanDiseaseOntology: April 2026 Release

This release of the Human Disease Ontology includes 12,127 disease classes, 9,848 with textual definitions (81.2%). Translation files now include 11,825 labels (97.5%), 11,462 synonyms (58.6%), and 6,579 definitions (66.8%) in Spanish. Disease groups revised & expanded include Alport syndrome, glycogen storage disease, hydrocephalus, kidney disease, Meckel syndrome, neuropathies/HSANs, and viral encephalitis. While new subtypes have been added for Galloway-Mowat syndrome, Hermansky-Pudlak syndrome, Parkinson's disease, and retinitis pigmentosa. Additional new diseases include craniosynostosis-scoliosis syndrome; Davis-Wells syndrome; lobodontia; small fiber neuropathy; STAD syndrome; Zeitz-Han retinal dystrophy; Ebstein-Bezieau neurodevelopmental syndrome; Luo-Agrawal neurodevelopmental syndrome; neurodevelopmental disorder with congenital cardiac defects and variable renal and ocular abnormalities; neurodevelopmental disorder with seizures, hypotonia, and variable spasticity; neurodevelopmental disorder with spasticity, thin corpus callosum, and decreased brain white matter; X-linked neurodevelopmental disorder with poor or absent speech and behavioral abnormalities; and Yu-Kury neurodevelopmental syndrome. Additional revised diseases include autosomal recessive cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1; autosomal recessive nonsyndromic deafness subtypes; developmental and epileptic encephalopathy 25; early-onset obesity, adrenal insufficiency, and red hair; environmentally induced asthma; epidermolysis bullosa simplex & subtypes; isolated microphthalmia & syndromic microphthalmia 16; and spermatogenic failure. No terms changed obsoletion status in this release. Full Changelog: https://github.com/DiseaseOntology/HumanDiseaseOntology/compare/v2026-03-31...v2026-04-30

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2026-04-01 | Lenz Microphthalmia Syndrome ( See also NAA10 -Associated XLID)

Abstract This chapter provides pictures and clinical details of Lenz Microphthalmia syndrome, an XLID with microcephaly, microphthalmia, malformed or cupped ears, cleft lip and cleft palate, dental anomalies, urogenital anomalies, narrow shoulders, duplication of the thumbs or other digital malformations, and spinal curvature. Mutations in the NAA10 gene have been identified in families with Lenz Microphthalmia. Sloping shoulders, thinning of the lateral third of the clavicle, barrel chest, kyphoscoliosis, and gibbus anomaly are common. Some degree of cognitive impairment occurs in all cases, but considerable variation in severity has been reported. Carrier females may have short stature, microcephaly, and digital anomalies.

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