Biology subjects

Ahmad, S. T.

Publications and source records attributed to Ahmad, S. T..

5 recordsLinked to original sources

bioRxiv2026

Epigallocatechin Gallate (EGCG) as a Protective Agent Against Enzymatic Stromal Degradation in Caprine and Ovine Corneas: Towards Novel Therapeutics for Keratoconus

PurposeKeratoconus (KC) is a progressive corneal ectatic disorder marked by stromal thinning, enzymatic degradation, and oxidative stress. Conventional corneal collagen cross-linking (CXL) therapy poses risks. Epigallocatechin gallate (EGCG), a catechin found in green tea, has been shown to cross-link collagen, inhibit proteases, and modulate inflammation, suggesting its potential as an alternative therapy for KC. This study aimed to (1) evaluate the protective effects of EGCG against collagenase-mediated stromal degradation in caprine and ovine corneas and (2) investigate the use of caprine and ovine cornea as viable ex vivo models for corneal ectasia research. MethodsGoat (n=4) and sheep (n=8) corneoscleral buttons were cultured in an air-liquid interface (ALI). Tissue viability was monitored by transparency grading and histology. The corneal ectasia environment was induced by collagenase type I digestion. An EGCG-rich extract was utilized for the treatments. ResultsGoat and sheep corneas remained intact for 7 days in MEM-based medium, though transparency decreased, with edema (whitening) by Day 7. Histology confirmed stromal loosening and reduced keratocyte cell density but preserved architecture sufficient for enzymatic digestion. EGCG pre-treatment and post-treatment exposure were associated with greater resistance to enzymatic digestion, with greater stromal preservation of quadrants in the EGCG pre-treated quadrant than in PBS pre-treated controls. ConclusionsThis study provides proof of concept that EGCG extract confers protection against enzymatic degradation in goat and sheep corneas, highlighting its potential as a protective agent for corneal ectatic disorders like Keratoconus. Additionally, goat and sheep corneas can represent practical and ethical ex vivo models for short-term ocular research. Future work should focus on cytotoxicity, biomechanical validation, optimized culture conditions, and in vivo studies.

pathology↗

bioRxiv2024

Loss of the Familial Dysautonomia gene Elp1 in cerebellar granule cell progenitors leads to ataxia in mice

Familial Dysautonomia (FD) is an autosomal recessive disorder caused by a splice site mutation in the gene ELP1, which disproportionally affects neurons. While classically characterized by deficits in sensory and autonomic neurons, neuronal defects in the central nervous system have been described. ELP1 is highly expressed in the normal developing and adult cerebellum, but its role in cerebellum development is unknown. To investigate the cerebellar function of Elp1, we knocked out Elp1 in cerebellar granule cell progenitors (GCPs) and examined the outcome on animal behavior and cellular composition. We found that GCP-specific conditional knockout of Elp1 (Elp1cKO) resulted in ataxia by 8 weeks of age. Cellular characterization showed that the animals had smaller cerebella with fewer granule cells. This defect was already apparent 7 days after birth, when Elp1cKO animals also exhibited fewer mitotic GCPs and shorter Purkinje dendrites. Through molecular characterization, we found that loss of Elp1 was associated with an increase in apoptotic cell death and cell stress pathways in GCPs. Our study demonstrates the importance of ELP1 within the developing cerebellum, and suggests that Elp1 loss in the GC lineage may also play a role in the progressive ataxia phenotypes of FD patients.

neuroscience↗

bioRxiv2020

SMPD3-mediated extracellular vesicle biogenesis inhibits oligodendroglioma growth

Isocitrate dehydrogenase (IDH) mutant gliomas, including oligodendroglioma (IDH-O) and astrocytoma (IDH-A), have signature slow-growth rates that are poorly understood. Here, we reveal that SMPD3, a ceramide-producing sphingomyelinase implicated as a tumor suppressor gene and involved in extracellular vesicle biogenesis, suppresses IDH-mutant tumor growth via autocrine and paracrine actions. In patients with IDH-mutant gliomas, higher SMPD3 expression levels correlate with longer survival, consistent with ceramide acting as an anti-oncometabolite. SMPD3 knock-down in patient-derived IDH-O cells enhances proliferation cell-autonomously in 2D-culture and 3D-human cerebral organoids, and accelerates tumor growth in mouse orthotopic xenografts. Supporting paracrine actions, IDH-O-derived extracellular vesicles, enriched in ribosomal proteins, induce astrocytic death in vitro. Furthermore, non-neoplastic glia in IDH-O tumors proliferate abnormally yet undergo apoptosis, concomitant with the acquisition of a translation-enriched transcriptional signature by tumor-associated oligodendrocytes. SMPD3 thus suppresses IDH-mutant glioma growth cell-autonomously and phenotypically alters normal glia via extracellular vesicle biogenesis and paracrine actions.

cancer biology↗

bioRxiv2019

Loss of CIC promotes mitotic dysregulation and chromosome segregation defects

CIC encodes a transcriptional repressor and MAPK signalling effector that is inactivated by loss-of-function mutations in several cancer types, consistent with a role as a tumour suppressor. Here, we used bioinformatic, genomic, and proteomic approaches to investigate CICs interaction networks. We observed both previously identified and novel candidate interactions between CIC and SWI/SNF complex members, and also observed novel interactions between CIC and cell cycle regulators and RNA processing factors. We found that CIC loss is associated with an increased frequency of mitotic defects in human cell lines and an in vivo mouse model and with dysregulated expression of mitotic regulators. We also observed aberrant splicing in CIC-deficient cell lines predominantly at 3 and 5 untranslated regions of genes, including genes involved in MAPK signalling, DNA repair, and cell cycle regulation. Our study thus characterises the complexity of CICs functional network and describes the effect of its loss on cell cycle regulation, mitotic integrity, and transcriptional splicing, thereby expanding our understanding of CICs potential roles in cancers. In addition, our work exemplifies how multi-omic, network-based analyses can be used to uncover novel insights into the interconnected functions of pleiotropic genes/proteins across cellular contexts. Simple summaryCapicua (CIC) is a gene that is frequently mutated in several cancer types, including stomach cancers and certain subtypes of brain tumours and sarcomas. CIC, the protein encoded by the CIC gene, has been shown to play a multitude of roles in both normal and cancer cell functions; however, most studies exploring these roles focus on a single aspect of CIC function and may therefore overlook complex interconnected activities in which CIC is involved. In this study, we have used multiple complementary approaches to obtain a broader view of CICs complex functional networks. We observed novel interactions (genetic or physical) between CIC and genes/proteins involved in various aspects of cellular function, including regulation of cell division and processing of RNA molecules. Altogether, our work characterises the complexity of CICs functional network and expands our understanding of its potential roles in cancer.

cancer biology↗

bioRxiv2018

Regulation of neural stem cell fate by the transcriptional repressor Capicua

Capicua (Cic) is a transcriptional repressor mutated in the brain cancer oligodendroglioma. Despite its cancer link, little is known of Cics function in the brain. Here, we investigated the relationship between Cic expression and cell type specification in the brain. Cic is strongly expressed in astrocytic and neuronal lineage cells but is more weakly expressed in stem cells and oligodendroglial lineage cells. Using a new conditional Cic knockout mouse, we show that forebrain-specific Cic deletion increases proliferation and self-renewal of neural stem cells. Furthermore, Cic loss biases neural stem cells toward glial lineage selection, expanding the pool of oligodendrocyte precursor cells (OPCs). These proliferation and lineage selection effects in the developing brain are dependent on de-repression of Ets transcription factors. In patient-derived oligodendroglioma cells, CIC re-expression or ETV5 blockade decreases lineage bias, proliferation, self-renewal and tumorigenicity. Our results identify Cic is an important regulator of cell fate in neurodevelopment and oligodendroglioma, and suggest that its loss contributes to oligodendroglioma by promoting proliferation and an OPC-like identity via Ets overactivity.

cancer biology↗