Biology subjects

Ghazizadeh, S.

Publications and source records attributed to Ghazizadeh, S..

5 recordsLinked to original sources

bioRxiv2026

Targeting therapy-induced senescence across multiple breast cancer subtypes in a metastatic bone-like microenvironment

Chemotherapeutic treatment of breast cancer with Doxorubicin (DOX) can induce tumor and stromal cell senescence leading to therapy-resistance. Senescence-associated secretory phenotype (SASP) promotes secretion of pro-inflammatory and tumorigenic factors causing systemic inflammation. Combined, this can result in immune suppression, tumor growth and secondary spread of cancer. Targeting and removing senescent and cancerous cells using a combination of chemotherapeutic and senolytic drugs may reduce systemic inflammation, improve therapeutic efficacy, and prevent metastasis. Exposure of triple-negative breast cancer (MDA-MB-231), hormone-responsive (MCF-7) and HER2+ (MDA-MB-453) cells, and primary spine osteoblasts to DOX showed significant induction of p21-positive senescent cells. DOX and senolytics (RG-7112, o-Vanillin) treatment of co-culture spheroids showed a significant additive effect in reducing tumor sphere viability and growth, indicating reduced metastatic potential. This was correlated with reduced SASP in triple-negative and hormone responsive lines and decreased levels of senescent cells in all subtypes and primary stromal cells, while proliferation was decreased, and apoptosis increased across all breast cancer subtypes. Future chemotherapeutic treatment in breast cancer models may be optimized by adding senolytic drugs to more effectively clear senescent tumor and stromal cells, reducing risk for relapse and metastatic potential, while allowing for tissue regeneration in the bone metastatic environment. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/724653v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@c4cb8forg.highwire.dtl.DTLVardef@105219org.highwire.dtl.DTLVardef@17e0517org.highwire.dtl.DTLVardef@802bd2_HPS_FORMAT_FIGEXP M_FIG C_FIG Senolytics selectively eliminate senescent cancer and stromal cells and enhance Doxorubicin efficacy in a 3D bone-like tumor microenvironment model.

cancer biology↗

bioRxiv2025

Senolytic Therapy as a Preventive Strategy for Low Back Pain

Cell senescence drives inflammation and tissue breakdown and is a key hallmark of aging. Low back pain is strongly linked to age-related degeneration of spine tissues, and with an accumulation of senescent. Here we show that preventive administration of the senolytic agents o-vanillin and RG-7112 prevent the development of pain-related behaviour in young sparc-/- mice. Treated mice exhibit a reduction of senescence markers in the intervertebral discs, vertebral endplates, vertebral bone, and spinal cord, alongside a dampening of pro-inflammatory senescence-associated secretory factors in these tissues. This early senolytic intervention also preserves intervertebral disc volume and vertebral bone microarchitecture, indicating protection against structural degeneration of the spine. These findings demonstrate that targeting cellular senescence at an early stage can mitigate degenerative changes and pain, supporting senolytic therapy as a promising preventive strategy for musculoskeletal decline.

cell biology↗

bioRxiv2025

Beyond miRNA cargo profiles: anti-inflammatory roles of extracellular vesicle-enriched miRNAs derived from human intervertebral disc cells unveiled by functional testing

Intervertebral disc (IVD) degeneration is a leading cause of chronic low back pain and a major contributor to global disability. Understanding the molecular mechanisms underlying this condition is essential for developing targeted therapies. Among these mechanisms, microRNAs (miRNAs) have emerged as critical post-transcriptional regulators of gene expression in IVD cells, influencing key processes such as extracellular matrix (ECM) homeostasis, inflammatory signalling, and cellular senescence. Extracellular vesicles (EVs), which transport miRNAs between cells, represent a promising avenue for therapeutic intervention. However, the composition of their miRNA cargo across different stages of disc degeneration remains inadequately characterized. We isolated EVs from primary human IVD cells derived from non-degenerate, mildly-degenerate, and severely degenerate tissues, and performed small RNA sequencing to profile their miRNA content. Bioinformatic analyses revealed enrichment in pathways related to ECM-receptor interaction, focal adhesion, inflammation, and cell cycle regulation. Notably, let-7b-5p and miR-100-5p were among the most abundant miRNAs and were significantly lower in EVs from degenerate discs. Functional assays demonstrated that transfection of IVD cells with let-7b-5p or miR-100-5p mimics individually suppressed IL-1{beta} expression at both mRNA and protein levels, confirming their anti-inflammatory roles. Strikingly, co-delivery of both miRNAs enhanced suppression of pro-inflammatory mediators, reduced senescence-associated p16 expression, and upregulated TIE2 mRNA, indicating synergistic effects in promoting a regenerative cell phenotype. These findings highlight the regulatory roles of EV-enriched let-7b-5p and miR-100-5p in modulating inflammation and senescence in IVD cells, and underscore the potential of miRNA-loaded EVs as cell-free regenerative therapies for disc degeneration.

cell biology↗

bioRxiv2024

Senolytic Treatment for Low Back Pain.

Senescent cells (SnCs) accumulate due to aging and external cellular stress throughout the body. They adopt a senescence-associated secretory phenotype (SASP) and release inflammatory, and degenerative factors that actively contribute to age-related diseases such as low back pain (LBP). The senolytics, o-Vanillin and RG-7112, remove senescent human intervertebral (IVD) cells and reduce SASP release, but it is not known if they can treat LBP. sparc-/- mice, with LBP, were treated orally with o-Vanillin and RG-7112 as single or combination treatments. Treatment reduced LBP and SASP factor release and removed SnCs from the IVD and spinal cord. Treatment also lowered degeneration score in the IVDs, improved vertebral bone quality, and reduced the expression of pain markers in the spinal cord. The result indicates that RG-7112 and o-Vanillin with the combination treatment providing the strongest effect are potential disease-modifying drugs for LBP and other painful disorders where cell senescence is implicated. One Sentence Summary: Senolytics drugs can reduce back pain

cell biology↗

bioRxiv2020

Diverse Epithelial Cell Populations Contribute to Regeneration of Secretory Units in Injured Salivary Glands

Salivary glands exert exocrine secretory function to provide saliva for lubrication and protection of the oral cavity. Its epithelium consists of several differentiated cell types including acinar, ductal and myoepithelial cells that are maintained in a lineage-restricted manner during homeostasis or after mild injuries. Glandular regeneration following a near complete loss of secretory cells, however, may involve cellular plasticity, although the mechanism and extent of such plasticity remain unclear. Here, by combining lineage-tracing experiments with a model of severe glandular injury in the mouse submandibular gland, we show that de novo formation of secretory units involves induction of cellular plasticity in multiple non-acinar cell populations. Fate-mapping analysis revealed that although ductal stem cells marked by cytokeratin K14 and Axin2 undergo a multipotency switch, they do not make a significant contribution to acinar regeneration. Intriguingly, more than 80% of regenerated acini derive from differentiated cells including myoepithelial and ductal cells that dedifferentiate to a progenitor-like state before redifferentiation to acinar cells. The potential of diverse cell populations serving as a reserve source for acini widens the therapeutic options for hyposalivation. SummarySalivary glands rely in recruitment of committed and fully differentiated cell populations as well as stem cells to ensure rapid regeneration and recovery of secretory cells.

cell biology↗