Zebularine Ameliorates Imiquimod‐Induced Psoriasis by Inhibiting Oxidative Stress and Inflammation With Concomitant Inhibition of NF‐κB/MAPK and DNMT1

Article

Author: Sharma, Shivam ; Sood, Ankita ; Chintalapani, Srinidhi ; Tikoo, Kulbhushan

ABSTRACT:

In this study, we evaluated the impact of a potent DNA methyl transferase (DNMT) inhibitor zebularine on imiquimod‐induced psoriatic mice, revealing its efficacy in mitigating hyperproliferation and keratinocyte differentiation. Molecular analyses demonstrated a marked inhibition of p38, ERK, and JNK signaling pathways, accompanied by a notable reduction in proliferative markers such as Ki‐67. The crucial regulator of keratinocyte proliferation, Ki‐67, exhibited significant downregulation upon zebularine treatment. Moreover, significant anti‐inflammatory effects were evident through the suppression of the imiquimod‐induced p65 NF‐κB signaling cascade. This robust inhibition extended to the reduction in the cytokine storm associated with psoriasis‐like skin inflammation. Consequently, there was a restoration of the normal epidermal architecture, accompanied by a decrease in epidermal hyperplasia and splenomegaly. Importantly, zebularine's inhibition of DNMT1 underscores its role in modulating epigenetic pathways. By altering DNA methylation, zebularine might effectively inhibit the expression of genes responsible for both inflammation and proliferation, contributing to improved skin structure. These findings collectively highlight zebularine's potential as a therapeutic agent in the management of psoriasis, supported by its anti‐inflammatory effects and observed inhibition of DNMT1.

20 Jun 2025·CURRENT CANCER DRUG TARGETS

Elucidating the Potential of E-cadherin Re-expression along with Trichostatin A and Zebularine in Enhancing Tumour Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL)-Induced Apoptosis in Human Breast Adenocarcinoma Cells

Article

Author: Ngai, Siew Ching ; Fang, Chee Mun ; San, Ser Hui ; Wong, Sonia How Ming

Background::

Tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is an emerging anti-cancer therapy that targets and eliminates cancer cells without harming normal healthy cells. However, TRAIL therapy is limited by resistance. Notably, the depletion of the E-cadherin (CDH1) gene has been significantly associated with TRAIL re-sistance, particularly in triple-negative breast cancer (TNBC) cells like MDA-MB-231. How-ever, its re-expression has the potential to improve TRAIL-induced apoptosis.

Objectives::

This study focused on evaluating the potential of E-cadherin re-expression as the biomarker in sensitizing TRAIL-induced apoptosis and exploring the potential effects when E-cadherin is in combination with Trichostatin A (TSA), Zeb (Zeb), and TRAIL, which is a triple combinational treatment (TZT).

Methods::

This study utilized three cell models: E-MDA-MB-231, which represents MDA-MB-231 that re-expressed E-cadherin, the parental MDA-MB-231 that inherently lacks E-cadherin, and MCF-7 that naturally expresses E-cadherin. Following 48 hours of drug treat-ment, the cells were stained with Haematoxylin and Eosin (H&E), followed by flow cytomet-ric analysis of fluorescein isothiocyanate (FITC)-Annexin V/Propidium Iodide, reverse tran-scription-polymerase chain reaction (RT-PCR) for Bax/Bcl-2 ratio, and Western blot to deter-mine the cleavage of poly (ADP-ribose) polymerase (PARP).

Results::

All treatments, both single and combinational, induced significant apoptotic morphol-ogy changes, with TZT-treated more evident in all cell lines. Moreover, based on flow cy-tometric analysis, TZ caused the highest early apoptosis in E-MDA-MB-231 (7.43%) and MDA-MB-231 (10.67%), while TZT was shown effectiveness in MCF-7 (42.23%). Consistent with flow cytometry results, further RT-PCR analysis indicated that E-cadherin in combina-tion with TSA and Zeb (TZ) has the potential to improve the intrinsic apoptotic pathway, likely by increasing 1.5-fold of Bax/Bcl-2 ratio compared to the control, suggesting a shift toward a pro-apoptotic state. Finally, Western blot revealed that TZ, TRAIL, and TZT induced cleaved PARP in E-MDA-MB-231 and MDA-MB-231, suggesting apoptosis induction. Meanwhile in MCF-7 cells, cleaved PARP was observed only with TZ and TZT treatments. Notably, TRAIL treatment led to the highest cleaved PARP in E-MDA-MB-231 cells, while in MDA-MB-231, TZ treatment resulted in the most pronounced cleavage. This suggests that E-cadherin re-ex-pression enhances TRAIL sensitivity in E-MDA-MB-231 cells, whereas apoptosis is more effectively induced by TZ treatment in MDA-MB-231 cells.

Conclusion::

In summary, H&E staining showed the positive effect of E-cadherin in sustaining apoptosis induced by TRAIL, especially in combination with TSA and Zeb. However, based on flow cytometry, RT-PCR, and Western blot results, TZ and TRAIL could potentially offer a more effective treatment option for E-MDA-MB-231. These findings suggest that TZ in-duced intrinsic apoptotic pathway via epigenetic modulation of CDH1 promoter while TRAIL-induced extrinsic apoptotic pathway via improved TRAIL signaling with E-cadherin re-ex-pression, indicating the potentiality of E-cadherin as a biomarker for TRAIL treatment in TNBC.

17 Jun 2025·JOURNAL OF EXPERIMENTAL BOTANY

Cytidine analogs in plant epigenetic research and beyond

Review

Author: Pecinka, Ales ; Dvořák Tomaštíková, Eva

Abstract:

Cytosine (DNA) methylation plays important roles in silencing transposable elements, plant development, genomic imprinting, stress responses, and maintenance of genome stability. To better understand the functions of this epigenetic modification, several tools have been developed to manipulate DNA methylation levels. These tools include mutants of DNA methylation writers and readers, targeted manipulation of locus-specific methylation, and the use of chemical inhibitors. Here, we summarize the effects of commonly used cytidine analog chemical inhibitors, represented by zebularine, 5-azacytidine, and their related compounds, on plants. These analogs are incorporated into chromosomal DNA, where they block the activity of the replicative CG DNA methyltransferase 1 (MET1). This leads to manifold alterations in the plant epigenome, modified developmental programs, or suppression of hybridization barriers. We also highlight the DNA-damaging effects of cytidine analogs, particularly the formation of stable DNA–protein crosslinks between DNA and MET1. This phenomenon sheds new light on specific phenotypes observed upon treatment with cytidine analogs. In conclusion, cytidine analogs are a vital tool for plant genome research and have the potential to open new promising avenues for applications in plant biotechnology and breeding.

News (Medical) associated with Zebularine

17 Aug 2023

·www.prnewswire.com

Sound Agriculture Releases Software Package to Democratize Epigenetic Data in Plant Breeding

EMERYVILLE, Calif., Aug. 17, 2023 /PRNewswire/ -- A team of researchers at Sound Agriculture has released a new software package, called sounDMR, designed to reveal epigenetic variation in plant populations. The findings, published today in Scientific Reports, showcase the potential of sounDMR to enable high-resolution epigenetic profiling of plants without the need for expensive equipment or complex library preparations, fostering new opportunities in plant breeding. Continue Reading Epigenetics is the study of heritable changes in gene expression that occur without changes to the underlying DNA sequence. DNA methylation is one of the key mechanisms through which epigenetic variation occurs. It plays an important role in regulating gene expression across all life forms, with a particular significance in plants. However, it is only recently that long and ultra-long read sequencing technologies have enabled the study of methylation patterns in complex genomic regions by accurately identifying 5mC methylation even in non-CG contexts. Using Oxford Nanopore technology, these methods can be applied to non-model organisms, such as crops, even in the absence of large sequencing facilities. New software called sounDMR democratizes the use of epigenetic data in plant breeding to improve agriculture outcomes. Tweet this The research team, led by Travis Bayer, PhD and Jack Colicchio, PhD, used sounDMR to effectively replicate findings from the established gold-standard method for methylation sequencing called whole genome bisulfite sequencing (WGBS). In addition, the team was able to expand on these findings by using Oxford Nanopore's "adaptive sampling," which allowed for the targeted sequencing of approximately 400 specific genome regions. This data revealed that the known demethylating agent, zebularine, decreased methylation across the Arabidopsis thaliana genome and induced epigenetic variation, improving the understanding of its effects. "There are epigenetic variations in all plant systems that haven't been considered in breeding because of the difficulty in identifying these nuances," said Travis Bayer, PhD, co-founder and CTO, Sound Agriculture. "With nanopore sequencing technology, we now have an added level of insight to support breeding decisions that can improve agriculture outcomes.""We are really pleased to see nanopore sequencing being used to improve outcomes in plant breeding. Oxford Nanopore technology offers more comprehensive genomic insights, especially in DNA methylation," said Gordon Sanghera, CEO Oxford Nanopore Technologies. "This is a great example of high-accuracy epigenetic insights in biological analyses being used to support new genomic discoveries for the benefit of agriculture."This work marks a milestone in the field of epigenetics by offering a comprehensive, affordable, and accessible approach to studying the complexities of plant populations at the epigenetic level. This advance will enable plant breeders and researchers to characterize epigenomic data in plant populations, leading to more accurate and faster development of desired crop varieties.For researchers interested in accessing the sounDMR software, visit Github to learn more. About Sound Agriculture Sound Agriculture develops nature-based solutions for sustainable crop production. Our breakthrough technology enables agriculture to adapt faster to climate change and evolving consumer preferences, creating healthier food that is also better for the planet. SOURCE, our flagship product, activates the microbiome to give crops access to more of the nutrients that exist in the field, reducing the need for synthetic nitrogen and phosphorus by 25 lbs per acre. Learn more at . CONTACT Michelle Yoshinaka VP Marketing Sound Agriculture 925-588-8242, m.yoshinaka@sound.ag SOURCE Sound Agriculture

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	United States	National Cancer Institute	01 Nov 1991

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