Epigenetic modifier-induced biosynthesis of novel fusaric acid derivatives in endophytic fungi from Datura stramonium L.

The treatment of fungi with DNA methyltransferase(DNMT)and/or histone deacetylase(HDAC)inhibitors is a promising way to activate secondary metabolite biosynthetic pathways that are dormant under normal conditions.In this study,we included an HDAC inhibitor,suberoylanilide hydroxamic acid(SBHA),in the culture medium of endophytic fungi isolated from the medicinal plant Datura stramonium L.The production of two compounds was induced in the culture supplemented with SBHA,and their structures were determined to be the fusaric acid derivatives 5-butyl-6-oxo-1,6-dihydropyridine-2-carboxylic acid and 5-(but-9-enyl)-6-oxo-1,6-dihydropyridine-2-carboxylic acid.The result confirmed that the use of chemical epigenetic modifiers is an effective technique for promoting the expression of silent biosynthetic pathways to produce unique secondary metabolites.

Epigenetic regulation of targeted ferroptosis: A new strategy for drug development

Ferroptosis is a newly discovered form of cell death that is influenced by iron levels and is triggered by cellular metabolism and excessive lipid peroxidation.Epigenetic regulation plays a crucial role in the development and progression of diseases,making it essential to understand these mechanisms in order to identify potential targets for drug development and clinical treatment.The intersection of ferroptosis and epigenetics has opened up new avenues for research in drug development,offering innovative strategies for combating diseases.Recent studies have shown that epigenetic modifications can impact pathways related to ferroptosis,potentially leading to organ dysfunction.Despite the increasing focus on this relationship,the role of epigenetic regulation in drug development remains largely unexplored.This article explores current research on the interplay between epigenetic regulation and ferroptosis,delving into their regulatory mechanisms and discussing the effects of existing epigenetic modification regula-tors on diseases.Additionally,we highlight ongoing research on epigenetic factors involved in targeting ferroptosis in cancer,providing new insights for the development of cancer treatments.

Recent advances in targeted therapy for pancreatic adenocarcinoma

Pancreatic adenocarcinoma(PDAC)is a fatal disease with a 5-year survival rate of 8%and a median survival of 6 mo.In PDAC,several mutations in the genes are involved,with Kirsten rat sarcoma oncogene(90%),cyclin-dependent kinase inhibitor 2A(90%),and tumor suppressor 53(75%–90%)being the most common.Mothers against decapentaplegic homolog 4 represents 50%.In addition,the selfpreserving cancer stem cells,dense tumor microenvironment(fibrous accounting for 90%of the tumor volume),and suppressive and relatively depleted immune niche of PDAC are also constitutive and relevant elements of PDAC.Molecular targeted therapy is widely utilized and effective in several solid tumors.In PDAC,targeted therapy has been extensively evaluated;however,survival improvement of this aggressive disease using a targeted strategy has been minimal.There is currently only one United States Food and Drug Administration-approved targeted therapy for PDAC–erlotinib,but the absolute benefit of erlotinib in combination with gemcitabine is also minimal(2 wk).In this review,we summarize current targeted therapies and clinical trials targeting dysregulated signaling pathways and components of the PDAC oncogenic process,analyze possible reasons for the lack of positive results in clinical trials,and suggest ways to improve them.We also discuss emerging trends in targeted therapies for PDAC:combining targeted inhibitors of multiple pathways.The PubMed database and National Center for Biotechnology Information clinical trial website(www.clinicaltrials.gov)were queried to identify completed and published(PubMed)and ongoing(clinicaltrials.gov)clinical trials(from 2003-2022)using the keywords pancreatic cancer and targeted therapy.The PubMed database was also queried to search for information about the pathogenesis and molecular pathways of pancreatic cancer using the keywords pancreatic cancer and molecular pathways.

DNA methyltransferase inhibitor dramatically alters the secondary metabolism of Pestalotiopsis microspora

5-Azacytidine, a DNA methyltransferase inhibitor, led to significant changes in the secondary metabolism of the plant endophytic fungus, Pestalotiopsis microspora. Analysis of the culture broth extract led to the isolation of a new compound, 4＇-forrnamidophenyl-5-methoxybenzoate （1）, along with seven known polyketides, 4-hydroxybenzoic acid （2）, LL-P880ct （3）, 1＇-hydroxy-4-methoxy-6-pentyl-2H-pyran-2-one （4）, pestalotiollide B （5）, pestalotiopyrone G （6）, endocrocin （7） and 2＇-hydroxy- 6＇-hydroxymethyl-4＇-methylphenyl-2,6-dihydroxy-3-（2-isopentenyl）benzoate （8）. HPLC profiles revealed that all compounds except for 4 belonged to the newly induced secondary metabolites. In addition, all compounds were proved to be devoid of significant antifungal activity in the bioassays.