Biology subjects

Zhylkibayev, A.

Publications and source records attributed to Zhylkibayev, A..

3 recordsLinked to original sources

bioRxiv2024

Glucose-Sensing ChREBP Protein in the Pathogenesis of Diabetic Retinopathy

Glucose-sensing ChREBP and MondoA are transcriptional factors involved in lipogenic, inflammatory, and insulin signaling pathways implicated in metabolic disorders; however, limited ocular studies have been conducted on these proteins. We aimed to investigate the potential role of ChREBP in pathogenesis of diabetic retinopathy (DR). We used diabetic human and mouse retinal cryosections analyzed by immunohistochemistry. qRT-PCR was performed to quantify gene expression. To explore the role of ChREBP in rods, we generated caChREBPRP mice with constitutively active (ca) ChREBP. These mice underwent retinal function testing, followed by proteomic analysis using LC-MS. Furthermore, ARPE-19 cells were infected with lentiviral particles expressing human ChREBP (ARPE-19ChREBP) and subjected to global proteomics. Our results demonstrate that both pro-teins were expressed across the retina, although with distinct distribution patterns: MondoA was more prominently expressed in cones, while ChREBP was broadly expressed throughout the retina. Elevated expression of both proteins was observed in DR. This may have contributed to rod photo-receptor degeneration as we observed diminished scotopic ERG amplitudes detected in caChREB-PRP mice at P35. The retinal proteomic landscape indicated a decline in KEGG pathways associated with phototransduction, amino acid metabolism, and cell adhesion. Furthermore, rod-specific ca-ChREBP induced TXNIP expression. Consistent with altered retinal proteomics, ARPE-19ChREBP cells displayed a metabolic shift toward increased glyoxylate signaling, sugar metabolism, and lysosomal activation. Our study demonstrates that ChREBP overexpression causes significant metabolic reprograming triggering retinal functional loss in mice

cell biology↗

bioRxiv2024

Retinoid X Receptor as a Novel Drug Target to Treat Neurological Disorders Associated with α-Synucleinopathies.

This study investigated the therapeutic potential of the nuclear retinoid X receptor (RXR) in mitigating the progression of alpha-synucleinopathies (SNPs), particularly in Parkinsons disease (PD). PD-like pathology in mice was successfully induced through the co-delivery of AAV expressing human -synuclein (S) and S preformed fibrils (PFFs) into the substantia nigra pars compacta (SNpc). Significant increases in Lewy body (LB)-like inclusions, loss of tyrosine hydroxylase-positive (TH+) neurons, and reductions in dopamine (DA) levels in the striatum were observed. Additionally, diminished levels of PPAR and NURR1, along with elevated GFAP and Iba1, markers of neuroinflammation, microglial activation, and astrocytic gliosis were associated with PD pathogenesis. AAV-mediated overexpression of human RXR demonstrated preservation of TH+ neurons, prevention of DA decline and attenuation of S accumulation. Furthermore, RXR-treated PD brains showed a reduced number of GFAP+ and Iba1+ cells, decreased GFAP+ and Iba1+ immunoreactivity, and fewer and less widespread LB-like aggregates. RXR overexpression also enhanced the production of PPAR and NURR1, proteins critical for neuronal survival. These findings suggest that RXR activation promotes neuroprotection by mitigating SNPs and chronic neuroinflammation, a major contributor to PD progression. This research underscores the therapeutic potential of targeting nuclear receptors, such as RXR, in neurodegenerative diseases like PD

neuroscience↗

bioRxiv2023

Retinoid X Receptor activation prevents diabetic retinopathy in murine models.

Previously, the RXR agonist UAB126 demonstrated therapeutic potential to treat obese mice by controlling blood glucose levels (BGL) and altering the expression of genes associated with lipid metabolism and inflammatory response. The purpose of the study was to assess UAB126 effect in progression of diabetic retinopathy (DR) in rodent models of Type1 diabetes (T1D), streptozotocin-induced, and Type2 diabetes (T2D), the db/db mice. UAB126 treatment was delivered either by oral gavage for 6 weeks or by topical application of eye drops for 2 weeks. At the end of the treatment, the retinal function of diabetic mice was assessed by electroretinography (ERG), and their retinal tissue was harvested for protein and gene expression analyses. Bone-marrow cells were isolated and differentiated into bone marrow-derived macrophages (BMDMs). The glycolysis stress test and the 2-DG glucose uptake analysis were performed. Our results demonstrated that in the UAB126-treated diabetic BMDMs, the ECAR rate and the 2-DG uptake were improved as compared to untreated diabetic BMDMs. In UAB126-treated diabetic mice, hyperglycemia was reduced and associated with the preservation of ERG amplitudes and enhanced AMPK activity. Retinas from diabetic mice treated with topical UAB126 demonstrated an increase in Rxr and Ppar, and expression of genes associated with lipid metabolism. Altogether, our data indicate that RXR activation is beneficial to preclinical models of DR.

molecular biology↗