Current Drug Targets - Volume 21, Issue 11, 2020

Background: Endometriosis (EMS) is a gynecological disease defined by the translocation and growth of endometrial tissue in other tissues or organs outside the uterus. Its clinical manifestations are dysmenorrhea, irregular menstruation, and even infertility. Although EMS is a benign disease, it has the characteristics of malignant tumor and the potential of malignant transformation. Recent studies have found that EMS may involve epigenetic changes and that various epigenetic aberrations, especially aberrant DNA methylation may play an essential role in the pathogenesis of EMS. Previous studies have elucidated the epigenetic regulators of EMS and reported variations in epigenetic patterns of genes known to be associated with abnormal hormonal, immune, and inflammatory states of EMS. With the development of high-throughput sequencing and other biomolecular technologies, we have a better understanding of genome-wide methylation in EMS. Objective: This article will discuss the potentiality of targeting DNA methylation as the therapeutic approach for EMS. Results: This article reviews the role of DNA methylation in the pathophysiology of EMS and provides insight into a novel therapeutic approach for EMS by targeting DNA methylation modifiers. We also review the current progress in using DNA methylation inhibitors in EMS therapy and the potential promise and challenges ahead. Conclusion: Aberrant DNA methylation plays an essential role in the pathogenesis of EMS and epigenetic agents targeting DNA methyltransferases are expected to be the theoretical basis for the new treatment of EMS.

N6-methyladenine RNA modification (m6A) is an RNA methylation modification catalyzed by methyltransferase at the 6th position nitrogen atom of adenine (A), which is the most common chemical modification of eukaryotic messenger RNA (mRNA). Recently, m6A has been found to play an important role in the dynamic regulation of RNA, which is crucial for some physiological and pathophysiological processes such as adipogenesis, cell differentiation, and the immune/inflammatory response. Metabolic diseases are a series of chronic inflammatory disorders caused by metabolic dysfunction of proteins, glucose, and lipids. Emerging studies have shown that m6A plays an important role in the process of metabolic diseases such as obesity, type 2 diabetes mellitus (T2DM) and cardiovascular diseases (CVDs) via regulation of glucose/lipid metabolism and the immune/inflammatory response. In this review, we will summarize the role of m6A in metabolic diseases, which may provide new ideas for the prevention and treatment of metabolic diseases.

Epigenetic modifications ensure the maintenance of normal cellular functions, and their dysregulation is frequently found in many disease states, including cancer. Nowadays, the most studied epigenetic dysregulation associated with tumorigenesis, cancer progression and metastasis refers to the variations in DNA methylation, histone modification and chromatin structure. The development of novel agents targeting these processes has enabled us to open up new pathways for anti-cancer strategies. To date, many small molecules have been designed to target epigenetic modifiers, and some of them are currently in clinical trials for patients with haematologic malignancies and solid tumours. With this in mind, we elaborate on basic information on epigenetic modifications and potential epigenetic therapies for cancer treatment.

This review summarizes the epigenetic mechanisms of deoxyribonucleic acid (DNA) methylation, histone modifications in cancer and the epigenetic modifications in cancer therapy. Due to their undesired side effects, the use of epigenetic drugs as chemo-drugs in cancer therapies is limited. The drug delivery system opens a door for minimizing these side effects and achieving greater therapeutic benefits. The limitations of current epigenetic therapies in clinical cancer treatment and the advantages of using drug delivery systems for epigenetic agents are also discussed. Combining drug delivery systems with epigenetic therapy is a promising approach to reaching a high therapeutic index and minimizing the side effects.

Among the major components of green tea, epigallocatechin-3-gallate (EGCG) is the most effective for its anti-cancer characteristics. The bulk of studies provide the mechanisms of suppressive function of EGCG are involved in alteration of cancer cell cycle, development, and apoptosis through activation/inhibition of several signal pathways. Another mechanism that explains the multiple effects exerted by EGCG in cancer is the epigenetic change by DNA methylation or methyltransferases, histone acetylation or deacetylases, and no coding RNAs (micoRNAs). Furthermore, decontrolled expression of miRNA transcription has been tested to be directly regulated by oncogenic and tumor-suppressor transcription factors. Recently, several proteins have been identified as miRNA direct interactors by EGCG. However, the mechanisms explaining the action of miRNA being modulated by EGCG have not been completely understood yet. This review summarizes the state of epigenetic change being modulated by EGCG in a variety of cancers and oncogenic and tumor-suppressor transcription factors.

Leishmaniasis is one of the six entities on the list of most important diseases of the World Health Organization/Tropical Disease Research (WHO/TDR). After Malaria, it is one of the most prevalent and lethal parasitic diseases. VL is the fatal form of this disease, especially if left untreated. The drugs that are currently available for the treatment of VL are expensive, toxic, or no longer effective, especially in endemic regions. Currently, no vaccine has been developed to immunize humans against VL. The major problems with the current drugs are the development of resistance and their adverse effects. Therefore, there is a strong urge to research and design drugs that have better efficacies and low toxicities as compared to current chemotherapeutic drugs. Leishmania has various enzymes involved in its metabolic pathways, which are unique to either the same genus or trypanosomatids, making them a very suitable, attractive and novel target sites for drug development. One of the significant pathways unique to trypanosomatids is the thiol metabolism pathway, which is involved in the maintenance of redox homeostasis as well as protection of the parasite in the macrophage from oxidative stress-induced damage. In this review the several pathways, their essential enzymes as well as the proposed changes in the parasites due to drug resistance have been discussed to help to understand the most suitable drug target. The thiol metabolism pathway is discussed in detail, providing evidence of this pathway being the most favorable choice for drug targeting in VL.

Imidazole containing compounds have been a very much explored field since ancient times. Subsequently, it constitutes a significant moiety for the new drug development. A variety of compounds having imidazole moiety have been synthesized, evaluated and marketed for the treatment of various diseases such as antifungal, antiepileptic, ACE inhibitors and so on, as shown in the figure. The search for imidazole containing compounds with more selective biological potency with low side effects continues to be an active area of research in medicinal chemistry. This review is in an effort to highlight the marketed drugs with imidazole ring. The article also demonstrates the future prospective of marketed imidazoles as antifungal with potential activity targeting 14α-demethylase enzyme.