Gypenosides Alleviate Cone Cell Death in a Zebrafish Model of Retinitis Pigmentosa

Abstract

Retinitis pigmentosa (RP) is a group of visual disorders caused by mutations in over 70 genes. RP is characterized by initial degeneration of rod cells and late cone cell death, regardless of genetic abnormality. Rod cells are the main consumers of oxygen in the retina, and after the death of rod cells, the cone cells have to endure high levels of oxygen, which in turn leads to oxidative damage and cone degeneration. Gypenosides (Gyp) are major dammarane-type saponins of Gynostemma pentaphyllum that are known to reduce oxidative stress and inflammation. In this project we assessed the protective effect of Gyp against cone cell death in the rpgrip1 mutant zebrafish, which recapitulate the classical pathological features found in RP patients. Rpgrip1 mutant zebrafish were treated with Gyp (50 µg/g body weight) from two-months post fertilization (mpf) until 6 mpf. Gyp treatment resulted in a significant decrease in cone cell death compared to that of untreated mutant zebrafish. A markedly low level of reactive oxygen species and increased expression of antioxidant genes were detected in Gyp-incubated mutant zebrafish eyes compared to that of untreated mutant zebrafish. Similarly, the activities of catalase and superoxide dismutase and the level of glutathione were significantly increased in Gyp-treated mutant zebrafish eyes compared to that of untreated mutant zebrafish. Gyp treatment also decreased endoplasmic reticulum stress in rpgrip1 mutant eyes. Expression of proinflammatory cytokines was also significantly decreased in Gyp-treated mutant zebrafish eyes compared to that of untreated mutant zebrafish. Network pharmacology analysis demonstrated that the promotion of cone cell survival by Gyp is possibly mediated by multiple hub genes and associated signalling pathways. These data suggest treatment with Gyp will benefit RP patients.

Longitudinal genotype-phenotype analysis in 86 patients with PAX6-related aniridia

“…Typical aniridia phenotypes are usually associated with loss-of-function heterozygous PAX6 mutations, which result in haploinsufficiency ( 13 – 17 ), with nearly 70% (i.e., nonsense, frameshift from insertion-deletion, and most intronic/splicing variants) leading to the introduction of a premature termination codon (PTC). Other variants causing PAX6 haploinsufficiency include whole-gene deletions or mutations in the PAX6 3′ regulatory region ( 18 , 19 ). Mutations leading to the C-terminal extension (CTE) of PAX6 protein are less common, with some reports linking these variants to more severe aniridia phenotypes, comparable to PTCs ( 3 , 20 , 21 ).…”

“…In contrast, missense PAX6 variants are usually linked to milder aniridia cases or, more frequently, to nonaniridia-related phenotypes, such as microphthalmia and ocular coloboma (OMIM 120430 and 120200) or foveal hypoplasia 1 (OMIM 136520; refs. 18 , 22 – 24 ).…”

“…Both conditions involve deletions of the PAX6 gene as well as WT1 (WAGR) or WT1 and BDNF (WAGRO; ref. 18 ).…”

Comparative gene pathway analysis during adolescent binge-EtOH exposure, withdrawal, and following abstinence

“…Rpgrip1 encodes RPGR interacting protein 1 and is not well characterized outside of the eye. It is thought to function as a scaffolding protein, be involved with the function of non-motile cilium, and has been implicated the development of immune-related autosomal recessive congenital blindness (Roepman et al, 2005) due to the increased production of reactive oxygen species and inflammation (Li et al, 2021).…”

“…Table 1. The Molecular Signatures Database (MSigDB) was originally developed for use with GSEA (Liberzon et al, 2015, Liberzon et al, 2011, Köhler et al, 2020, Godec et al, 2016. The latest version of MSigDB consists of seven collections C1-C7 grouped by their location in the human genome.…”