Biology subjects

Jagtap, U.

Publications and source records attributed to Jagtap, U..

3 recordsLinked to original sources

bioRxiv2024

miR-21: A therapeutic target for delaying severe liver disease and hepatocellular carcinoma in high-fat-diet-fed mice

Liver disease, including hepatocellular carcinoma (HCC), is a major global health concern, claiming approximately 2 million lives worldwide annually, yet curative treatments remain elusive. In this study, we aimed to investigate the role of microRNA-21-5p (miR-21) in metabolic dysfunction-associated steatotic liver disease (previously NAFLD), metabolic-associated steatohepatitis (previously NASH), and HCC within the context of a Western high-fat diet, without additional choline (HFD) and offering potential therapeutic insights. We found that reduced miR-21 levels correlated with liver disease progression in WT mice fed on HFD, while miR-21 knockout mice showed exacerbated metabolic dysfunction, including obesity, hepatomegaly, hyperglycemia, insulin resistance, steatosis, fibrosis, and HCC. Our study reveals that miR-21 plays a protective role in metabolic syndrome and in the progression of liver disease to cancer. MiR-21 directly targets Transforming growth factor beta-induced (Tgfbi), a gene also known to be significantly upregulated and a potential oncogene in HCC. Further, our study showed that intervention with the administration of a miR-21 mimic in WT livers effectively improves insulin sensitivity, steatosis, fibrosis, Tgfbi expression and tumor burden in HFD conditions. These findings indicate that miR-21 could serve as an effective strategy to delay or prevent liver disease in high-fat-diet environments. SignificanceOur study demonstrates in vivo that miR-21 has protective functions in the broad spectrum of high-fat diet-based, progressive liver disease and cancer, and we show potential therapeutic value of a microRNA-21 mimic. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=137 SRC="FIGDIR/small/613915v2_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@1915cd8org.highwire.dtl.DTLVardef@66887corg.highwire.dtl.DTLVardef@18a8e54org.highwire.dtl.DTLVardef@18631b0_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2022

BML-257, a small molecule that protects against drug induced liver injury in zebrafish

The use of many essential drugs is restricted due to their deleterious effects on the liver. Molecules that can prevent or protect the liver from drug induced liver injury (DILI) would be valuable in such situations. We used hepatocyte-specific expression of bacterial nitroreductase in zebrafish to cause temporally controlled liver damage. This transgenic line was used to run a whole organism based chemical screen in zebrafish larvae. In this screen we identified BML-257, a potent small molecule AKT inhibitor, that protected the liver against metronidazole-induced liver injury. BML-257 also showed potent prophylactic and pro-regenerative activity in this liver damage model. BML-257 also showed remarkable protective action in two independent toxicological models of liver injury caused by acetaminophen and Isoniazid. This suggests that BML-257 may have the potential to protect against multiple kinds of drug induced liver injury.

molecular biology↗

bioRxiv2019

A temporal map of gene expression pattern during zebrafish liver regeneration

Background & AimsZebrafish is increasingly being used to study liver injury and regeneration. However, very little is known about molecular players that respond to injury and participate in liver regeneration. Here we aim to generate a temporal map of gene expression changes at injury and during regeneration of the adult zebrafish liver.\n\nMethodsWe use a metronidazole-nitroreductase (MTZ-nfsb) based system to selectively ablate hepatocytes in adult zebrafish to create a model for liver injury and regeneration. Through RNA sequencing of liver samples at multiple time points we generate a comprehensive temporal map of gene expression changes during injury and regeneration.\n\nResultsGene expression reveals that soon after injury the immediate early transcription factor MYC induces a battery of genes that respond to the metronidazole-induced ROS by activating oxido-reductase pathways and apoptosis machinery. Upon injury, liver cells down regulate genes encoding complement proteins, bile acid and lipid biosynthesis pathway in a concerted manner. Midway through regeneration, we discover a spike of cholesterol biosynthesis and protein folding machinery genes suggesting an important role for these pathways in liver regeneration.\n\nConclusionsThe temporal transcriptomic map of liver regeneration would serve as a framework for further studies in understanding, and for screening for compounds that augment liver regeneration.\n\nGeneral significanceUsing a hepatocyte specific ablation of zebrafish liver, we create a model of adult liver regeneration. This model was used to generate a comprehensive transcriptomic map of gene expression trends during liver regeneration. This temporal map lays the groundwork to study important events in liver regeneration.\n\nHighlightsO_LIZebrafish is a valuable model for developing therapeutic strategies to augment liver regeneration\nC_LIO_LILiver regeneration in zebrafish is not well studied and pathways poorly understood\nC_LIO_LIWe develop a hepatocyte ablation model of liver injury and regeneration in adult zebrafish\nC_LIO_LIWe generate a comprehensive transcriptomic map of various stages of liver injury and regeneration\nC_LIO_LIWe discover a novel regulation of cholesterol biosynthesis pathways during liver regeneration\nC_LI\n\nGraphical abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=92 SRC=\"FIGDIR/small/677781v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (16K):\norg.highwire.dtl.DTLVardef@13a322corg.highwire.dtl.DTLVardef@1b40200org.highwire.dtl.DTLVardef@ef8f80org.highwire.dtl.DTLVardef@1b61e01_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗