Biology subjects

Nigam, N.

Publications and source records attributed to Nigam, N..

3 recordsLinked to original sources

bioRxiv2023

Angiopoietin-like protein 2 mediates vasculopathy driven fibrogenesis in a mouse model of systemic sclerosis

Vasculopathy is a common hallmark of various fibrotic disorders including systemic sclerosis (SSc), yet its underlying etiology and contribution to fibrogenesis remain ill-defined. In SSc the vasculopathy typically precedes the onset of fibrosis and we observed that this phenomenon is recapitulated in the Snail transgenic mouse model of SSc. The vascular anomalies manifest as deformed vessels, endothelial cell dysfunction and vascular leakage. Our investigation into the underlying mechanism of this phenotype revealed that Angiopoietin-like protein 2 (Angptl2), secreted by the Snail transgenic keratinocytes, is a principal driver of fibrotic vasculopathy. In endothelial cells, Angptl2 upregulates pro-fibrotic genes, downregulates the tight junction protein Claudin 5, and prompts the acquisition of mesenchymal characteristics. Inhibiting endothelial cell junctional instability and consequently vascular leakage with a synthetic analog of the microbial metabolite Urolithin A (UAS03) effectively mitigated the vasculopathy and inhibited fibrogenesis. Thus, Angptl2 emerges as a promising early biomarker of the disease and inhibiting the vasculopathy inducing effects of this protein with agents such as UAS03 presents an appealing therapeutic avenue to reduce disease severity. These insights hold the potential to revolutionize the approach to the treatment of fibrotic diseases by targeting the vascular defects.

pathology↗

bioRxiv2022

Epigenetic silencing by SMYD3 represses tumor intrinsic interferon response in HPV-negative squamous cell carcinoma of the head and neck.

Cancers often display immune escape, but the mechanisms and potential for reversibility are incompletely understood. Epigenetic dysregulation has been implicated in the immune escape of various cancer types. We have identified the epigenetic modifier SET and MYND-domain containing protein 3 (SMYD3) as a mediator of immune escape in human papilloma virus (HPV)- negative head and neck squamous cell carcinoma (HNSCC), an aggressive disease with poor prognosis and low response to immunotherapy with pembrolizumab, a programmed-death-1 (PD-1) targeting antibody. SMYD3 loss increased the sensitivity of HNSCC cancer cells to IFN-{beta}, resulting in upregulation of type I IFN response and antigen presentation machinery genes. We found that SMYD3 regulates the transcription of Ubiquitin-Like PHD And RING Finger Domain- Containing Protein 1 (UHRF1), a key epigenetic reader of trimethylated lysine 9 on histone H3 (H3K9me3), which binds to H3K9me3-enriched promoters of key immune-related genes and silences their expression. SMYD3 further maintains the repression of immune-related genes through the deposition of H4K20me3 within the gene body regions of these genes. In an anti-PD-1 immune checkpoint resistant syngeneic mouse model of HPV-negative HNSCC, Smyd3 depletion induced influx of CD8+ T-cells, upregulated PD-L1 and MHC class I molecules, and increased sensitivity to anti-PD-1 therapy. SMYD3 overexpression was associated with decreased CD8 T-cell infiltration in tumor samples from patients with HPV-negative HNSCC, and was associated with poor response to pembrolizumab. Overall, these data highlight a previously unreported function of SMYD3 as a master epigenetic regulator of anti-tumor immune response in HPV-negative HNSCC and provide a rationale for translational approaches combining SMYD3 depletion strategies with checkpoint blockade to overcome anti-PD-1 resistance in this devastating disease.

cancer biology↗

bioRxiv2021

The contributions of extracellular matrix and sarcomere properties to passive muscle stiffness in cerebral palsy

Cerebral palsy results from an upper motor neuron lesion and has significant effects on skeletal muscle stiffness throughout the body. The increased stiffness that occurs is partly a result of changes in the microstructural components of muscle. In particular, alterations in extracellular matrix, sarcomere length, fibre diameter, and fat content have been reported; however, experimental studies have shown wide variability in the degree to which each component is altered. Many studies have reported alterations in the extracellular matrix, while others have reported no changes. A consistent finding throughout the literature is increased sarcomere length in cerebral palsy muscle. Often more than one component is altered, making it difficult to determine the individual effects on stiffness. The purpose of this study is to use a modeling approach to isolate individual effects of microstructural alterations that typically occur during cerebral palsy on whole muscle behavior; in particular, the extracellular matrix volume fraction, stiffness, and sarcomere length. These microstructural effects can be captured using a three dimensional model of muscle. We found that the extracellular matrix volume fraction has a larger effect on stiffness compared to sarcomere length, even when coupled with decreased extracellular matrix stiffness. Additionally, the effects of sarcomere length in passive stiffness are mitigated by the increased extracellular matrix volume fraction. Using this model, we can achieve a better understanding of the possible combinations of microstructural changes that can occur during cerebral palsy. Developing these insights into diseased muscle tissue will help to direct future clinical and experimental procedures.

physiology↗