Diabetes mellitus is a chronic disease that impairs metabolism, and its prevalence has reached an epidemic proportion globally. Most people affected are with type 2 diabetes mellitus (T2DM), which is caused by a decline in the numbers or functioning of pancreatic endocrine islet cells, specifically the β-cells that release insulin in sufficient quantity to overcome any insulin resistance of the metabolic tissues. Genetic and epigenetic factors have been implicated as the main contributors to the T2DM. Epigenetic modifiers, histone deacetylases (HDACs), are enzymes that remove acetyl groups from histones and play an important role in a variety of molecular processes, including pancreatic cell destiny, insulin release, insulin production, insulin signalling, and glucose metabolism. HDACs also govern other regulatory processes related to diabetes, such as oxidative stress, inflammation, apoptosis, and fibrosis, revealed by network and functional analysis. This review explains the current understanding of the function of HDACs in diabetic pathophysiology, the inhibitory role of various HDAC inhibitors (HDACi), and their functional importance as biomarkers and possible therapeutic targets for T2DM. While their role in T2DM is still emerging, a better understanding of the role of HDACi may be relevant in improving insulin sensitivity, protecting β-cells and reducing T2DM-associated complications, among others.

Acetylresveratrol (AC-Res), to date, is a powerful stilbene phytoalexin generated organically or as a component of a plant's defensive system, is a significant plant phenolic chemical portion and is investigated as a therapy option for a number of disorders. Owing to its inadequate stabilisation and considerable conformation rigidity, the utility of AC-Res as a medication is limited.

Epigenetic modulations play a major role in gene expression and thus are responsible for various physiological changes including age-associated neurological disorders. Neurodegenerative diseases such as Alzheimer's (AD), Parkinson's (PD), Huntington's disease (HD), although symptomatically different, may share common underlying mechanisms. Most neurodegenerative diseases are associated with increased oxidative stress, aggregation of certain proteins, mitochondrial dysfunction, inactivation/dysregulation of protein degradation machinery, DNA damage and cell excitotoxicity. Epigenetic modulations has been reported to play a significant role in onset and progression of neurodegenerative diseases by regulating these processes. Previous studies have highlighted the marked antioxidant and neuroprotective abilities of polyphenols such as curcumin, by increased activity of detoxification systems like superoxide dismutase (SOD), catalase or glutathione peroxidase. The role of curcumin as an epigenetic modulator in neurological disorders and neuroinflammation apart from other chronic diseases have also been reported by a few groups. Nonetheless, the evidences for the role of curcumin mediated epigenetic modulation in its neuroprotective ability are still limited. This review summarizes the current knowledge of the role of mitochondrial dysfunction, epigenetic modulations and mitoepigenetics in age-associated neurological disorders such as PD, AD, HD, Amyotrophic Lateral Sclerosis (ALS), and Multiple Sclerosis (MS), and describes the neuroprotective effects of curcumin in the treatment and/or prevention of these neurodegenerative diseases by regulation of the epigenetic machinery.

Mercury is a well-known neurotoxicant for humans and wildlife. The epidemic of mercury poisoning in Japan has clearly demonstrated that chronic exposure to methylmercury (MeHg) results in serious neurological damage to the cerebral and cerebellar cortex, leading to the dysfunction of the central nervous system (CNS), especially in infants exposed to MeHg in utero. The occurrences of poisoning have caused a wide public concern regarding the health risk emanating from MeHg exposure; particularly those eating large amounts of fish may experience the low-level and long-term exposure. There is growing evidence that MeHg at environmentally relevant concentrations can affect the health of biota in the ecosystem. Although extensive in vivo and in vitro studies have demonstrated that the disruption of redox homeostasis and microtube assembly is mainly responsible for mercurial toxicity leading to adverse health outcomes, it is still unclear whether we could quantitively determine the occurrence of interaction between mercurial and thiols and/or selenols groups of proteins linked directly to outcomes, especially at very low levels of exposure. Furthermore, intracellular calcium homeostasis, cytoskeleton, mitochondrial function, oxidative stress, neurotransmitter release, and DNA methylation may be the targets of mercury compounds; however, the primary targets associated with the adverse outcomes remain to be elucidated. Considering these knowledge gaps, in this article, we conducted a comprehensive review of mercurial toxicity, focusing mainly on the mechanism, and genes/proteins expression. We speculated that comprehensive analyses of transcriptomics, proteomics, and metabolomics could enhance interpretation of "omics" profiles, which may reveal specific biomarkers obviously correlated with specific pathways that mediate selective neurotoxicity.

Although it is believed that ubiquitin (Ub) modification is required for protein degradation in the proteasome system (UPS), several proteins are subject to Ub-independent proteasome degradation, and in many cases ubiquitin-like (UBL) modifications, including neddylation, FAT10ylation, SUMOylation, ISGylation, and urmylation, are essential instead. In this Review, we focus on UBL-dependent proteasome degradation (UBLPD), on proteasome regulators especially shuttle factors and receptors, as well as potential competition and coordination with UPS. We propose that there is a distinct UBL-proteasome system (UBLPS) that might be underestimated in protein degradation. Finally, we investigate the association of UBLPD with muscle wasting and neurodegenerative diseases in which the proteasome is abnormally activated and impaired, respectively, and suggest strategies to modulate UBLPD for disease therapy.

In cancer, synthetic lethality refers to the drug-induced inactivation of one gene and the inhibition of another in cancer cells by a drug, resulting in the death of only cancer cells; however, this effect is not present in normal cells, leading to targeted killing of cancer cells. Recent intensive epigenetic research has revealed that aberrant epigenetic changes are more frequently observed than gene mutations in certain cancers. Recently, numerous studies have reported various methylation synthetic lethal combinations involving DNA damage repair genes, metabolic pathway genes, and paralogs with significant results in cellular models, some of which have already entered clinical trials with promising results. This review systematically introduces the advantages of methylation synthetic lethality and describes the lethal mechanisms of methylation synthetic lethal combinations that have recently demonstrated success in cellular models. Furthermore, we discuss the future opportunities and challenges of methylation synthetic lethality in targeted anticancer therapies.

About 80 % of brain disorders have a genetic basis. The pathogenesis of most neurodegenerative diseases is associated with a myriad of genetic defects, epigenetic alterations (DNA methylation, histone/chromatin remodeling, miRNA dysregulation), and environmental factors. The emergence of new sequencing technologies and tools to study the epigenome has led to identifying predictive biomarkers for earlier diagnosis, opening up the possibility of prophylactical interventions. As a result, advances in pharmacogenetics and pharmacoepigenomics now allow for personalized treatments based on the profile of each patient and the specific genetic and epigenetic mechanisms involved. This Review highlights the complexity of neurodegenerative diseases and the variability in patient responses to pharmacotherapy, emphasizing the influence of genetic polymorphisms on the pharmacokinetics and pharmacodynamics of drugs used to treat those conditions. We specifically discuss the potential modulatory effect of several genetic polymorphisms associated with an increased risk of developing different neurodegenerative diseases. We explore genetic and genomic technologies and the potential of analyzing individual-specific drug metabolism to predict and influence drug response and associated clinical outcomes. We also provide insights into the mechanism of action of the drugs under investigation and their potential impact on disease-modifying pathways. Finally, the Review underscores the great potential of this field to enhance the effectiveness and safety of drug treatments through personalized medicine.

Hydroxyurea (HU) is the most common drug therapy for sickle cell disease (SCD). The clinical benefits of HU derive from its upregulation of fetal hemoglobin (HbF), which reduces aggregation of the mutated sickle hemoglobin protein (HbS) and reduces SCD symptoms and complications. However, some individuals do not respond to HU, or stop responding over time. Unfortunately, current understanding of the mechanism of action of HU is limited, hindering the ability of clinicians to identify those patients who will respond to HU and to optimize treatment for those receiving HU. Given that epigenetic modifications are essential to erythropoiesis and HbF expression, we hypothesize that some effects of HU may be mediated by epigenetic modifications, specifically DNA methylation. However, few studies have investigated this possibility and the effects of HU on DNA methylation remain relatively understudied. In this review, we discuss the evidence linking HU treatment to DNA methylation changes and associated gene expression changes, with an emphasis on studies that were performed in individuals with SCD. Overall, although HU can affect DNA methylation, research on these changes and their clinical effects remains limited. Further study is likely to contribute to our understanding of hematopoiesis and benefit patients suffering from SCD.

Paraoxonase (PON) proteins have various hydrolytic activities. The PON family is able to detoxify oxidized low-density lipoprotein. Additionally, differentiation of monocytes into macrophages, as the first stage in the development of atherosclerosis, is suppressed by PON 1. The effects of polyphenols including curcumin on PON1 have been investigated in studies. In this study, our main goal is to investigate curcumin's effect on PON1 protein levels, gene expression, and enzyme activity in animal interventional studies.

Despite the tremendous progress in cancer research over the past few decades, effective therapeutic strategies are still urgently needed. Accumulating evidence suggests that immune checkpoints are the cause of tumor immune escape. PD-1/PD-L1 are among them. Posttranslational modification is the most critical step for protein function, and the regulation of PD-L1 by small molecules through posttranslational modification is highly valuable. In this review, we discuss the mechanisms of tumor cell immune escape and several posttranslational modifications associated with PD-L1 and describe examples in which small molecules can regulate PD-L1 through posttranslational modifications. Herein, we propose that the use of small molecule compounds that act by inhibiting PD-L1 through posttranslational modifications is a promising therapeutic approach with the potential to improve clinical outcomes for cancer patients.

Brominated flame retardants (BFRs) are synthetic chemicals incorporated into a wide variety of products, both for industrial applications and everyday use, with the primary aim of reducing their flammability or reducing the material burning rate. These compounds find widespread use in plastics, textiles, and electrical/electronic devices. However, BFRs can be released from products and, thus are determined in many environmental matrices such as soil, water and air.This review discuss the potential health implications of selected BFRs (PBDEs and TBBPA) exposure arising from their impact on the epigenetic mechanisms. Epigenetic modifications, such as DNA methylation and histone acetylation or methylation, as well as changes in miRNA pattern, play significant roles in gene expression and cell function and can be influenced by environmental factors.The studies indicate that PBDEs exposure can lead to global DNA hypomethylation, disrupting normal gene regulation and contributing to genomic instability. In animal models, PBDEs have been associated with adverse effects on neurodevelopment, including impairments in memory and learning. TBBPA exposure has also been linked to changes in DNA methylation patterns, alterations in histone posttranslational modifications and non-coding RNA expression. These epigenetic changes may contribute to health issues related to growth, development, and endocrine functions.The growing evidence of epigenetic modifications induced by BFRs exposure highlights the importance of understanding their potential risks to human health. Further investigations are needed to fully elucidate the long-term consequences of altered epigenetic marks and their impact on human health.

Alzheimer's disease (AD) is a progressive decline in cognitive ability and behavior which eventually disrupts daily activities. AD has no cure and the progression rate varies unlikely. Among various causative factors, heavy metals are reported to be a significant hazard in AD pathogenesis. Metal-induced neurodegeneration has been focused globally with thorough research to unravel the mechanistic insights in AD. Recently, heavy metals suggested to play an important role in epigenetic alterations which might provide evidential results on AD pathology. Epigenetic modifications are known to play towards novel therapeutic approaches in treating AD. Though many studies focus on epigenetics and heavy metal implications in AD, there is a lack of research on heavy metal influence on epigenetic toxicity in neurological disorders. The current review aims to elucidate the plausible role of cadmium (Cd), iron (Fe), arsenic (As), copper (Cu), and lithium (Li) metals on epigenetic factors and the increase in amyloid beta and tau phosphorylation in AD. Also, the review discusses the common methods of heavy metal detection to implicate in AD pathogenesis. Hence, from this review, we can extend the need for future research on identifying the mechanistic behavior of heavy metals on epigenetic toxicity and to develop diagnostic and therapeutic markers in AD.

Brown fat is known to provide non-shivering thermogenesis through mitochondrial uncoupling mediated by uncoupling protein 1 (UCP1). Non-shivering is not dependent on UCP2, UCP4, and BMCP1/UCP5 genes, which are distinct from UCP1 in a way that they are not constitutive uncouplers. Although they are susceptible to free fatty acid and free radical activation, their functioning has a significant impact on the performance of neurons.

Angiotensin-converting enzyme 2 (ACE2) is a key enzyme in the renin-angiotensin system (RAS), also serving as an amino acid transporter and a receptor for certain coronaviruses. Its primary role is to protect the cardiovascular system via the ACE2/Ang (1-7)/MasR cascade. Given the critical roles of ACE2 in regulating numerous physiological functions, molecules that can upregulate or activate ACE2 show vast therapeutic value. There are only a few ACE2 activators that have been reported, a wide range of molecules, including food-derived compounds, have been reported as ACE2 up-regulators. Effective doses of bioactive peptides range from 10 to 50 mg/kg body weight (BW)/day when orally administered for 1 to 7 weeks. Protein hydrolysates require higher doses at 1000 mg/kg BW/day for 20 days. Phytochemicals and vitamins are effective at doses typically ranging from 10 to 200 mg/kg BW/day for 3 days to 6 months, while Traditional Chinese Medicine requires doses of 1.25 to 12.96 g/kg BW/day for 4 to 8 weeks. ACE2 activation is linked to its hinge-bending region, while upregulation involves various signaling pathways, transcription factors, and epigenetic modulators. Future studies are expected to explore novel roles of ACE2 activators or up-regulators in disease treatments and translate the discovery to bedside applications.

Breast cancer stands as the most prevalent form of cancer among women globally, influenced by a combination of genetic and environmental factors. Recent studies have investigated changes in microRNAs (miRNAs) during breast cancer progression and the potential impact of environmental chemicals on miRNA expression. This review aims to provide an updated overview of miRNA alterations in breast cancer and to explore their potential association with environmental chemicals. We will discuss the current knowledge on dysregulated miRNAs in breast cancer, including both upregulated and downregulated miRNAs. Additionally, we will review the influence of environmental chemicals, such as endocrine-disrupting compounds, heavy metals, and air pollutants, on miRNA expression and their potential contribution to breast cancer development. This review aims to advance our understanding of the complex molecular mechanisms underlying miRNA dysregulation in breast cancer by comprehensively examining miRNA alterations and their association with environmental chemicals. This knowledge is crucial for the development of targeted therapies and preventive measures. Furthermore, identifying specific miRNAs affected by environmental chemicals may allow the prediction of individual susceptibility to breast cancer and the design of personalized intervention strategies.

The advancement of novel technologies, coupled with bioinformatics, has led to the discovery of additional genes, such as long noncoding RNAs (lncRNAs), that are associated with drug resistance. LncRNAs are composed of over 200 nucleotides and do not possess any protein coding function. These lncRNAs exhibit lower conservation across species, are typically expressed at low levels, and often display high specificity towards specific tissues and developmental stages. The LncRNA MALAT1 plays crucial regulatory roles in various aspects of genome function, encompassing gene transcription, splicing, and epigenetics. Additionally, it is involved in biological processes related to the cell cycle, cell differentiation, development, and pluripotency. Recently, MALAT1 has emerged as a novel mechanism contributing to drug resistance or sensitivity, attracting significant attention in the field of cancer research. This review aims to explore the mechanisms through which MALAT1 confers resistance to chemotherapy and radiotherapy in cancer cells.

Bacillus Calmette-Guérin (BCG) treatment for non-muscle invasive bladder cancer (NMIBC) is an established immunotherapeutic, however, a significant portion of patients do not respond to treatment. Despite extensive research into the therapeutic mechanism of BCG, gaps remain in our understanding. This review specifically focuses on the epigenomic contributions in the immune microenvironment, in the context of BCG treatment for NMIBC. We also summarise the current understanding of NMIBC epigenetic characteristics, and discuss how future targeted strategies for BCG therapy should incorporate epigenomic biomarkers in conjunction with genomic biomarkers.

Epitranscriptomics, the field of post-translational RNA modifications, is a burgeoning domain of research that has recently received significant attention for its role in multiple diseases, including cancer. N6-methyladenosine (m6A) is the most prominent post-translational RNA modification and plays a critical role in RNA transcription, processing, translation, and metabolism. The m6A modification is controlled by three protein classes known as writers (methyltransferases), erasers (demethylases), and readers (m6A-binding proteins). Each class of m6A regulatory proteins has been implicated in cancer initiation and progression. As such, many of these proteins have been identified as potential targets for anti-cancer chemotherapeutics. In this work, we provide an overview of the role m6A-regulating proteins play in cancer and discuss the current state of small molecule therapeutics targeting these proteins.

Advances in understanding gene expression regulation through epigenetic mechanisms have contributed to elucidating the regulatory mechanisms of noncoding RNAs as pharmacological targets in several diseases. MicroRNAs (miRs) are a class of evolutionarily conserved, short, noncoding RNAs regulating in a concerted manner gene expression at the post-transcriptional level by targeting specific sequences of the 3'-untranslated region of mRNA. Conversely, mechanisms of cardiovascular disease (CVD) remain largely elusive due to their life-course origins, multifactorial pathophysiology, and co-morbidities. In this regard, CVD treatment with conventional medications results in therapeutic failure due to progressive resistance to monotherapy, which overlooks the multiple factors involved, and reduced adherence to poly-pharmacology approaches. Consequently, considering its role in regulating complete gene pathways, miR-based drugs have appreciably progressed into preclinical and clinical testing. This review summarizes the current knowledge about the mechanisms of miRs in cardiovascular disease, focusing specifically on describing how clinical chemistry and physics have improved the stability of the miR molecule. In addition, a comprehensive review of the main miRs involved in cardiovascular disease and the clinical trials in which these molecules are used as active pharmacological molecules is provided.

The natriuretic peptide system (NPS) is the key driving force of the heart's endocrine function. Recent developments in NPS-targeted therapies have been found promising and effective against cardiovascular diseases, including hypertension. Notably, after discovering crosstalk between NPS and the renin-angiotensin-aldosterone system (RAAS), various combinations such as neprilysin/angiotensin II receptor type 1 AT1 receptor inhibitors and neprilysin/renin inhibitors have been preclinically and clinically tested against various cardiac complications. However, the therapeutic effects of such combinations on the pathophysiology of hypertension are poorly understood. Furthermore, the complicated phenomena underlying NPS regulation and function, particularly in hypertension, are still unexplored. Mounting evidence suggests that numerous regulatory mechanisms modulate the expression of NPS, which can be used as potential targets against hypertension and other cardiovascular diseases. Therefore, this review will specifically focus on epigenetic and other regulators of NPS, identifying prospective regulators that might serve as new therapeutic targets for hypertension. More importantly, it will shed light on recent developments in NPS-targeted therapies, such as M-atrial peptides, and their latest combinations with RAAS modulators, such as S086 and sacubitril-aliskiren. These insights will aid in the development of effective therapies to break the vicious cycle of high blood pressure during hypertension, ultimately addressing the expanding global heart failure pandemic.