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

Antioxidants ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1050
Author(s):  
Xing Li ◽  
Reem Hasaballah Alhasani ◽  
Yanqun Cao ◽  
Xinzhi Zhou ◽  
Zhiming He ◽  
...  
Keyword(s):  
Cell Death ◽  
Retinitis Pigmentosa ◽  
Network Pharmacology ◽  
Genetic Abnormality ◽  
Hub Genes ◽  
Zebrafish Model ◽  
Cone Cell ◽  
Antioxidant Genes ◽  
Rod Cells ◽  
Cone Cells

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.

Deletion of the Impg2 gene causes the degeneration of rod and cone cells in mice

2020 ◽  
Vol 29 (10) ◽  
pp. 1624-1634
Author(s):  
Huijuan Xu ◽  
Chao Qu ◽  
Li Gan ◽  
Kuanxiang Sun ◽  
Junkai Tan ◽  
...  
Keyword(s):  
Cell Death ◽  
Er Stress ◽  
Molecular Mechanisms ◽  
Histopathological Examination ◽  
Apoptotic Cell ◽  
Macular Dystrophy ◽  
Cone Cell ◽  
Rod Cells ◽  
Cone Cells

Abstract Variants in interphotoreceptor matrix proteoglycans (IMPG2) have been reported in retinitis pigmentosa (RP) and vitelliform macular dystrophy (VMD) patients. However, the underlying molecular mechanisms remain elusive due to a lack of suitable disease models. We developed two independent Impg2 knockout (KO) mouse models using the CRISPR/Cas9 technique to assess the in vivo functions of Impg2 in the retina. Impg2 ablation in mice recapitulated the RP phenotypes of patients, including an attenuated electroretinogram (ERG) response and the progressive degeneration of photoreceptors. The histopathological examination of Impg2-KO mice revealed irregularly arranged rod cells and mislocalized rhodopsin protein in the inner segment at 6 months of age. In addition to the pathological changes in rod cells, cone cells were also affected in KO retinas. KO retinas exhibited progressive cone cell death and impaired cone cell elongation. Further immunoblotting analysis revealed increased levels of endoplasmic reticulum (ER) stress-related proteins, including C/EBP homologous protein (CHOP), immunoglobulin heavy-chain-binding protein (BIP) and protein disulfide isomerase (PDI), in Impg2-KO mouse retinas. Increased gliosis and apoptotic cell death were also observed in the KO retinas. As autophagy is closely associated with ER stress, we then checked whether autophagy was disturbed in Impg2-KO mouse retinas. The results showed that autophagy was impaired in KO retinas, as revealed by the increased accumulation of SQSTM1 and other proteins involved in autophagy. Our results demonstrate the essential roles of Impg2 in the retina, and this study provides novel models for mechanistic investigations and development of therapies for RP caused by IMPG2 mutations.

scholarly journals Increased Expression of Catalase and Superoxide Dismutase 2 Reduces Cone Cell Death in Retinitis Pigmentosa

2009 ◽  
Vol 17 (5) ◽  
pp. 778-786 ◽  
Author(s):  
Shinichi Usui ◽  
Keiichi Komeima ◽  
Sun Young Lee ◽  
Young-Joon Jo ◽  
Shinji Ueno ◽  
...  
Keyword(s):  
Cell Death ◽  
Superoxide Dismutase ◽  
Retinitis Pigmentosa ◽  
Cone Cell ◽  
Superoxide Dismutase 2

Oxidative damage is a potential cause of cone cell death in retinitis pigmentosa

2005 ◽  
Vol 203 (3) ◽  
pp. 457-464 ◽  
Author(s):  
JiKui Shen ◽  
Xiaoru Yang ◽  
Aling Dong ◽  
Robert M. Petters ◽  
You-Wei Peng ◽  
...  
Keyword(s):  
Cell Death ◽  
Oxidative Damage ◽  
Retinitis Pigmentosa ◽  
Cone Cell

scholarly journals Antioxidants reduce cone cell death in a model of retinitis pigmentosa

2006 ◽  
Vol 103 (30) ◽  
pp. 11300-11305 ◽  
Author(s):  
K. Komeima ◽  
B. S. Rogers ◽  
L. Lu ◽  
P. A. Campochiaro
Keyword(s):  
Cell Death ◽  
Retinitis Pigmentosa ◽  
Cone Cell

The mechanism of cone cell death in Retinitis Pigmentosa

2018 ◽  
Vol 62 ◽  
pp. 24-37 ◽  
Author(s):  
Peter A. Campochiaro ◽  
Tahreem A. Mir
Keyword(s):  
Cell Death ◽  
Retinitis Pigmentosa ◽  
Cone Cell

scholarly journals Blockade of neuronal nitric oxide synthase reduces cone cell death in a model of retinitis pigmentosa

2008 ◽  
Vol 45 (6) ◽  
pp. 905-912 ◽  
Author(s):  
Keiichi Komeima ◽  
Shinichi Usui ◽  
Jikui Shen ◽  
Brian S. Rogers ◽  
Peter A. Campochiaro
Keyword(s):  
Nitric Oxide ◽  
Cell Death ◽  
Nitric Oxide Synthase ◽  
Retinitis Pigmentosa ◽  
Neuronal Nitric Oxide Synthase ◽  
Cone Cell ◽  
Oxide Synthase

scholarly journals NADPH oxidase plays a central role in cone cell death in retinitis pigmentosa

2009 ◽  
Vol 110 (3) ◽  
pp. 1028-1037 ◽  
Author(s):  
Shinichi Usui ◽  
Brian C. Oveson ◽  
Sun Young Lee ◽  
Young-Joon Jo ◽  
Tsunehiko Yoshida ◽  
...  
Keyword(s):  
Cell Death ◽  
Retinitis Pigmentosa ◽  
Nadph Oxidase ◽  
Cone Cell

scholarly journals Studies on the Mechanism of Gegen Qinlian Decoction in Treating Diabetes Mellitus Based on Network Pharmacology

2021 ◽  
Vol 16 (1) ◽  
pp. 1934578X2098213
Author(s):  
Xiaodong Deng ◽  
Yuhua Liang ◽  
Jianmei Hu ◽  
Yuhui Yang
Keyword(s):  
Diabetes Mellitus ◽  
Molecular Docking ◽  
Protein Interaction ◽  
Protein Interaction Network ◽  
Interaction Network ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Network Pharmacology ◽  
Hub Genes ◽  
Topological Parameters

Diabetes mellitus (DM) is a chronic disease that is very common and seriously threatens patient health. Gegen Qinlian decoction (GQD) has long been applied clinically, but its mechanism in pharmacology has not been extensively and systematically studied. A GQD protein interaction network and diabetes protein interaction network were constructed based on the methods of system biology. Functional module analysis, Kyoto Encyclopedia of Genes and Genomes pathway analysis, and Gene Ontology (GO) enrichment analysis were carried out on the 2 networks. The hub nodes were filtered by comparative analysis. The topological parameters, interactions, and biological functions of the 2 networks were analyzed in multiple ways. By applying GEO-based external datasets to verify the results of our analysis that the Gene Set Enrichment Analysis (GSEA) displayed metabolic pathways in which hub genes played roles in regulating different expression states. Molecular docking is used to verify the effective components that can be combined with hub nodes. By comparing the 2 networks, 24 hub targets were filtered. There were 7 complex relationships between the networks. The results showed 4 topological parameters of the 24 selected hub targets that were much higher than the median values, suggesting that these hub targets show specific involvement in the network. The hub genes were verified in the GEO database, and these genes were closely related to the biological processes involved in glucose metabolism. Molecular docking results showed that 5,7,2', 6'-tetrahydroxyflavone, magnograndiolide, gancaonin I, isoglycyrol, gancaonin A, worenine, and glyzaglabrin produced the strongest binding effect with 10 hub nodes. This compound–target mode of interaction may be the main mechanism of action of GQD. This study reflected the synergistic characteristics of multiple targets and multiple pathways of traditional Chinese medicine and discussed the mechanism of GQD in the treatment of DM at the molecular pharmacological level.

scholarly journals AnIn VivoZebrafish Model for Interrogating ROS-Mediated Pancreaticβ-Cell Injury, Response, and Prevention

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Abhishek A. Kulkarni ◽  
Abass M. Conteh ◽  
Cody A. Sorrell ◽  
Anjali Mirmira ◽  
Sarah A. Tersey ◽  
...  
Keyword(s):  
Cell Death ◽  
Caspase 3 ◽  
Cell Injury ◽  
Zebrafish Model ◽  
Chemical Genetic ◽  
Regulated Cell Death ◽  
Specific Manner ◽  
High Doses

It is well known that a chronic state of elevated reactive oxygen species (ROS) in pancreaticβ-cells impairs their ability to release insulin in response to elevated plasma glucose. Moreover, at its extreme, unmitigated ROS drives regulated cell death. This dysfunctional state of ROS buildup can result both from genetic predisposition and environmental factors such as obesity and overnutrition. Importantly, excessive ROS buildup may underlie metabolic pathologies such as type 2 diabetes mellitus. The ability to monitor ROS dynamics inβ-cells in situ and to manipulate it via genetic, pharmacological, and environmental means would accelerate the development of novel therapeutics that could abate this pathology. Currently, there is a lack of models with these attributes that are available to the field. In this study, we use a zebrafish model to demonstrate that ROS can be generated in aβ-cell-specific manner using a hybrid chemical genetic approach. Using a transgenic nitroreductase-expressing zebrafish line,Tg(ins:Flag-NTR)s950, treated with the prodrug metronidazole (MTZ), we found that ROS is rapidly and explicitly generated inβ-cells. Furthermore, the level of ROS generated was proportional to the dosage of prodrug added to the system. At high doses of MTZ, caspase 3 was rapidly cleaved,β-cells underwent regulated cell death, and macrophages were recruited to the islet to phagocytose the debris. Based on our findings, we propose a model for the mechanism of NTR/MTZ action in transgenic eukaryotic cells and demonstrate the robust utility of this system to model ROS-related disease pathology.

The Drosophila orphan nuclear receptor seven-up requires the Ras pathway for its function in photoreceptor determination

Development ◽  
1995 ◽  
Vol 121 (1) ◽  
pp. 225-235 ◽  
Author(s):  
G. Begemann ◽  
A.M. Michon ◽  
L. vd Voorn ◽  
R. Wepf ◽  
M. Mlodzik
Keyword(s):  
Cell Fate ◽  
Nuclear Receptor ◽  
Egf Receptor ◽  
Cell Transformation ◽  
Orphan Nuclear Receptor ◽  
Loss Of Function ◽  
Cone Cell ◽  
Ras Pathway ◽  
Protein Levels ◽  
Cone Cells

The Drosophila seven-up (svp) gene specifies outer photoreceptor cell fate in eye development and encodes an orphan nuclear receptor with two isoforms. Transient expression under the sevenless enhancer of either svp isoform leads to a dosage-dependent transformation of cone cells into R7 photoreceptors, and at a lower frequency, R7 cells into outer photoreceptors. To investigate the cellular pathways involved, we have taken advantage of the dosage sensitivity and screened for genes that modify this svp-induced phenotype. We show that an active Ras pathway is essential for the function of both Svp isoforms. Loss-of-function mutations in components of the Ras signal transduction cascade act as dominant suppressors of the cone cell transformation, whilst loss-of-function mutations in negative regulators of Ras-activity act as dominant enhancers. Furthermore, Svp-mediated transformation of cone cells to outer photoreceptors, reminiscent of its wild-type function in specifying R3/4 and R1/6 identity, requires an activated Ras pathway in the same cells, or alternatively dramatic increase in ectopic Svp protein levels. Our results indicate that svp is only fully functional in conjunction with activated Ras. Since we find that mutations in the Egf-receptor are also among the strongest suppressors of svp-mediated cone cell transformation, we propose that the Ras activity in cone cells is due to low level Egfr signaling. Several models that could account for the observed svp regulation by the Ras pathway are discussed.

Sign in / Sign up

Export Citation Format

Share Document