Related Experiment Video

Updated: Feb 7, 2026

siRNA Screening to Identify Ubiquitin and Ubiquitin-like System Regulators of Biological Pathways in Cultured Mammalian Cells

siRNA Screening to Identify Ubiquitin and Ubiquitin-like System Regulators of Biological Pathways in Cultured Mammalian Cells

Published on: May 24, 2014

δ-Tocotrienol feeding modulates gene expression of EIF2, mTOR, protein ubiquitination through multiple-signaling

Asaf A Qureshi¹, Dilshad A Khan², Shahida Mushtaq²

¹Department of Biomedical Science, School of Medicine, University of Missouri-Kansas City, 2411 Holmes Street, Kansas City, MO, 64108, USA. qureshia@umkc.edu.

Lipids in Health and Disease

|July 23, 2018

Abstract

Background:

δ-Tocotrienol is a naturally occurring proteasome inhibitor, which has the capacity to inhibit proliferation and induce apoptosis in several cancer cells obtained from several organs of humans, and other cancer cell lines. Moreover, results of plasma total mRNAs after δ-tocotrienol feeding to hepatitis C patients revealed significant inhibition in the expression of pro-inflammatory cytokines (TNF-α, VCAM1, proteasome subunits) and induction in the expression of ICAM1 and IFN-γ after post-treatment. This down-regulation of proteasome subunits leads to autophagy, apoptosis of immune cells and several genes. The present study describes RNA-sequence analysis of plasma total mRNAs obtained from δ-tocotrienol treatment of hepatitis C patients on gene expression regulated by proteasome.

Methods:

Pooled specimens of plasma total mRNAs of pre-dose versus post-dose of δ-tocotrienol treatment of hepatitis C patients were submitted to RNA-sequence analyses. The data based on > 1 and 8-fold expression changes of 2136 genes were uploaded into "Ingenuity Pathway Analyses (IPA)" for core analysis, which describes possible canonical pathways, upstream regulators, diseases and functional metabolic networks.

Results:

The IPA of "molecules" indicated fold change in gene expression of 953 molecules, which covered several categories of biological biomarkers. Out of these, gene expression of 220 related to present study, 12 were up-regulated, and 208 down-regulated after δ-tocotrienol treatment. The gene expression of transcription regulators (ceramide synthase 3 and Mohawk homeobox) were up-regulated, and gene expression of 208 molecules were down-regulated, involved in several biological functions (HSP90AB1, PSMC3, CYB5R4, NDUFB1, CYP2R1, TNFRF1B, VEGFA, GPR65, PIAS1, SFPQ, GPS2, EIF3F, GTPBP8, EIF4A1, HSPA14, TLR8, TUSSC2). IPA of "causal network" indicated gene regulators (676), in which 76 down-regulated (26 s proteasomes, interleukin cytokines, and PPAR-ligand-PPA-Retinoic acid-RXRα, PPARγ-ligand-PPARγ-Retinoic acid-RARα, IL-21, IL-23) with significant P-values. The IPA of "diseases and functions" regulators (85) were involved with cAMP, STAT2, 26S proteasome, CSF1, IFNγ, LDL, TGFA, and microRNA-155-5p, miR-223, miR-21-5p. The IPA of "upstream analysis" (934) showed 57 up-regulated (mainly 38 microRNAs) and 64 gene regulators were down-regulated (IL-2, IL-5, IL-6, IL-12, IL-13, IL-15, IL-17, IL-18, IL-21, IL-24, IL-27, IL-32), interferon β-1a, interferon γ, TNF-α, STAT2, NOX1, prostaglandin J2, NF-κB, 1κB, TCF3, and also miRNA-15, miRNA-124, miRNA-218-5P with significant activation of Z-Score (P < 0.05).

Conclusions:

This is first report describing RNA-sequence analysis of δ-tocotrienol treated plasma total mRNAs obtained from chronic hepatitis C patients, that acts via multiple-signaling pathways without any side-effects. These studies may lead to development of novel classes of drugs for treatment of chronic hepatitis C patients.

Insights

δ-Tocotrienol, a natural proteasome inhibitor, was studied in hepatitis C patients. RNA sequencing revealed significant changes in gene expression, suggesting potential for new hepatitis C therapies without side effects.

Area of Science:

Biochemistry
Molecular Biology
Hepatology

Background:

δ-Tocotrienol is a natural proteasome inhibitor with anti-cancer properties.
It affects proliferation and apoptosis in various cancer cell lines.
Previous studies showed δ-tocotrienol modulates pro-inflammatory cytokines and immune cell gene expression.

Purpose of the Study:

To analyze gene expression changes in plasma total mRNAs from hepatitis C patients treated with δ-tocotrienol.
To identify specific genes and pathways regulated by δ-tocotrienol in chronic hepatitis C.

Main Methods:

Plasma total mRNAs from hepatitis C patients before and after δ-tocotrienol treatment were analyzed using RNA sequencing.
Data from over 2136 genes were analyzed using Ingenuity Pathway Analysis (IPA) for pathway and network analysis.

Main Results:

IPA revealed significant changes in 953 molecules, with 220 related to the study; 12 were upregulated and 208 downregulated.
Key downregulated genes included proteasome subunits and inflammatory cytokines.
Upstream analysis identified significant activation of microRNAs and downregulation of key inflammatory and immune regulators.

Conclusions:

This is the first report on RNA-sequence analysis of δ-tocotrienol treated plasma mRNAs in chronic hepatitis C patients.
δ-Tocotrienol acts through multiple signaling pathways with no observed side effects.
These findings may facilitate the development of novel therapeutic agents for chronic hepatitis C.

Read full analysis

Keywords:

Canonical pathways Causal network Chronic hepatitis C Diseases and functions Gene expression of biomarkers RNA-sequence Up-stream regulators δ-Tocotrienol

More Related Videos

Detection of Protein Ubiquitination

Detection of Protein Ubiquitination

Published on: August 19, 2009

Using an Automated Cell Counter to Simplify Gene Expression Studies: siRNA Knockdown of IL-4 Dependent Gene Expression in Namalwa Cells

Using an Automated Cell Counter to Simplify Gene Expression Studies: siRNA Knockdown of IL-4 Dependent Gene Expression in Namalwa Cells

Published on: April 14, 2010

Related Concept Videos

PI3K/mTOR/AKT Signaling Pathway

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast, mTORC2 consists of a...

Regulation of Expression Occurs at Multiple Steps

Regulation of Expression Occurs at Multiple Steps

Gene expression can be regulated at almost every step from gene to protein. Transcription is the step that is most commonly regulated. This involves the binding of proteins to short regulatory sequences on the DNA. This association can either promote or inhibit the transcription of a gene associated with the respective sequence.
Transcription results in the generation of precursor (pre-mRNA) that consists of both exons and introns, which needs further processing before being translated to a...

mTOR Signaling and Cancer Progression

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...

What is Gene Expression?

What is Gene Expression?

Overview
Gene expression is the process in which DNA directs the synthesis of functional products, that is, proteins. Cells can regulate gene expression at various stages. It allows organisms to generate different cell types and enables cells to adapt to internal and external factors.
Genetic Information Flows from DNA to RNA to Protein
A gene is a stretch of DNA that serves as the blueprint for functional RNAs and proteins. Since DNA is made up of nucleotides and proteins consist of amino...

mRNA Stability and Gene Expression

mRNA Stability and Gene Expression

The structure and stability of mRNA molecules regulates gene expression, as mRNAs are a key step in the pathway from gene to protein. In eukaryotes, the half-life of mRNA varies from a few minutes up to several days. mRNA stability is essential in growth and development. The absence of the proteins regulating its stability, such as tristetraprolin in mice, can cause systemic issues, including bone marrow overgrowth, inflammation, and autoimmunity.
Cis-acting Elements involved in mRNA stability

Proteins: From Genes to Degradation

Proteins: From Genes to Degradation

Within a biological system, the DNA encodes the RNA, and the nucleotide sequence in the RNA further defines the amino acid sequence in the protein. This is referred to as “The Central Dogma of Molecular Biology” - a term coined by Francis Crick. Central dogma is a firm principle in biology that defines the flow of genetic information within any life form. The two fundamental steps in central dogma are - transcription and translation.
Transcription is the synthesis of RNA...

Articles linked to this work by shared authors, journal, and citation graph.

Prognostic Associations of Molecular MRD and Genomic Features in ZNF384-Rearranged B-ALL Undergoing Allo-HSCT.

Transplantation and cellular therapy·2026

Antibiotic- and inducer-free biosynthesis of indican from crude glycerol using engineered probiotic Escherichia coli Nissle 1917.

Bioresources and bioprocessing·2026

Gemtuzumab Ozogamicin-Containing Salvage Strategies as a Bridge to Second Allogeneic Hematopoietic Stem Cell Transplantation in Post-transplant Relapsed AML.

Transplantation and cellular therapy·2026

Cell Surface Engineering with DNA Nanotechnology: From Molecular Design to Biological Application.

The journal of physical chemistry. B·2026

Aggregation and propagation of TAF15 trigger neurodegeneration.

Neuron·2026

Mapping Neuroanatomical Heterogeneity of Brain Aging Within a Clinically Defined Aging Reference Cohort.

Bioengineering (Basel, Switzerland)·2026

See all related articles