Biology subjects

Narula, S.

Publications and source records attributed to Narula, S..

3 recordsLinked to original sources

bioRxiv2026

TR-107, a novel mitochondrial ClpP agonist, induces robust antitumor activity against preclinical models of adrenocortical carcinoma

AbstractAdrenocortical carcinoma (ACC) is a rare and highly aggressive endocrine malignancy originating from the adrenal cortex with limited effective treatment options. The underlying pathophysiology of ACC is uniquely characterized by abnormal steroid production and increased metabolic activity, highlighting the critical role of mitochondria in adrenal steroid hormone biosynthesis and tumor metabolism. In this study, we investigated the therapeutic potential of TR-107, a novel and highly selective small-molecule agonist targeting the mitochondrial protease ClpP. Pharmacologic hyperactivation of ClpP disrupts mitochondrial proteostasis and bioenergetics and has shown promising antitumor activity in various preclinical models. Our results demonstrated that TR-107 induces potent dose-dependent cytotoxic effects at nanomolar concentrations in ACC cell lines NCI-H295R and mACC3 as well as short-term ACC patient-derived organoid (PDO) models, markedly reducing cell viability and confluency in vitro. Metabolic analyses revealed that TR-107 significantly impaired oxygen consumption, indicating a disruption of oxidative phosphorylation and substantial attenuation of basal cellular respiration. Mechanistic studies showed dose-dependent increases in reactive oxygen species (ROS) levels and upregulation of proteins involved in mediating the ferroptotic rheostat. Pharmacokinetic assessment uncovered that TR-107 was not a substrate of the ABCB1 (MDR1/P-glycoprotein) efflux transporter, suggesting potential to overcome common multidrug resistance mechanisms. Given the importance of IGF-2 signaling in ACC, we further explored the combinatorial effects of TR-107 with IGF-1 receptor (IGF-1R) inhibitors and discovered that co-treatment produced synergistic reductions in cell viability across NCI-H295R, mACC3, and ACC PDOs. Collectively, these findings support the potential of mitochondrial ClpP hyperactivation as a promising therapeutic strategy for ACC and demonstrate that TR-107 exhibits significant antitumor activity as a monotherapy or in combination with IGF-1R inhibitors. These findings provide a strong rationale for advancing ClpP agonists into clinical development for the management of ACC.

cancer biology↗

bioRxiv2025

Pediatric cerebrospinal fluid immune profiling distinguishes pediatric-onset multiple sclerosis from other pediatric-onset acute neurological disorders

The cerebrospinal fluid (CSF) provides a unique glimpse into the central nervous system (CNS) compartment and offers insights into immune processes associated with both healthy immune surveillance as well as inflammatory disorders of the CNS. The latter include demyelinating disorders, such as multiple sclerosis (MS) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), that warrant different therapeutic approaches yet are not always straightforward to distinguish on clinical and imaging grounds alone. Here, we establish a comprehensive phenotypic landscape of the pediatric CSF immune compartment across a range of non-inflammatory and inflammatory neurological disorders, with a focus on better elucidating CNS-associated immune mechanisms potentially involved in, and discriminating between, pediatric-onset MS (MS) and other pediatric-onset suspected neuroimmune disorders, including MOGAD. We find that CSF from pediatric patients with non-inflammatory neurological disorders is primarily composed of non-activated CD4+ T cells, with few if any B cells present. CSF from pediatric patients with acquired inflammatory demyelinating disorders is characterized by increased numbers of B cells compared to CSF of both patients with other inflammatory or non-inflammatory conditions. Certain features, including particular increased frequencies of antibody-secreting cells (ASCs) and decreased frequencies of CD14+ myeloid cells, distinguish MS from MOGAD and other acquired inflammatory demyelinating disorders.

immunology↗

bioRxiv2024

Synovial fluid transcriptome dynamics in osteoarthritis progression: Implications in pathogenesis

BackgroundOsteoarthritis, a degenerative joint disease associated with various pathological manifestations in the joint including cartilage loss, alterations in subchondral bone and synovial inflammation. ObjectiveThis study aimed to elucidate the transcriptional and molecular changes in synovial fluid associated with OA progression, focusing on differential gene expression and pathway enrichment across OA grades. MethodologyPatients with different OA grades were recruited from PGIMER, Chandigarh, following the KL classification. Microarray analysis was conducted to study the transcriptional profiles in different OA grades using a fold-change (FC) cutoff of 2 and a p-value cutoff of 0.05, followed by pathway analysis performed using GSEA and STRING database. Selected genes from microarray and pathway analysis were validated using qRT-PCR. ResultsMicroarray analysis reveals distinct gene expression patterns corresponding to different OA stages (KL grade 2 to KL grade 4). Notably, the upregulation of AMTN and DKK2, alongside the downregulation of MSLN, highlighted their roles in pathological mineralization and disrupted bone remodeling in OA. Pathway enrichment analysis revealed significant changes in immune response, inflammation related pathways and cellular processes such as autophagy and programmed cell death, indicating their involvement in disease progression. Furthermore, mitochondrial dysfunction and impaired autophagy were linked to increased inflammation in advanced OA. ConclusionThese findings suggest that targeting mineralization and inflammatory pathways could offer novel therapeutic avenues for OA management.

pathology↗