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From the onset of fertilization, the genome undergoes cell division and differentiation. All of these developmental transitions and differentiation processes include cell-specific signatures and gradual changes of the epigenome. Understanding what keeps stem cells in the pluripotent state and what leads to differentiation are fascinating and biomedically highly important issues. Numerous studies have identified genes, proteins, microRNAs and small molecules that exert essential effects. Notably, there exists a core pluripotency network that consists of several transcription factors and accessory proteins. Three eminent transcription factors, OCT4, SOX2 and NANOG, serve as hubs in this core pluripotency network. They bind to the enhancer regions of their target genes and modulate, among others, the expression levels of genes that are associated with Gene Ontology terms related to differentiation and self-renewal. Also, much has been learned about the epigenetic rewiring processes during these changes of cell fate. For example, DNA methylation dynamics is pivotal during embryonic development. The main goal of this review is to highlight an intricate interplay of (a) DNA methyltransferases controlling the expression levels of core pluripotency factors by modulation of the DNA methylation levels in their enhancer regions, and of (b) the core pluripotency factors controlling the transcriptional regulation of DNA methyltransferases. We discuss these processes both at the global level and in atomistic detail based on information from structural studies and from computer simulations.

The growing smooth talk in the field of natural compounds is due to the ancient and current interest in herbal medicine and their potentially positive effects on health. Dozens of antidiabetic natural compounds were reported and tested in vivo, in silico, and in vitro. The role of these natural compounds, their actions on the insulin signaling pathway, and the stimulation of the glucose transporter-4 (GLUT4) insulin-responsive translocation to the plasma membrane (PM) are all crucial in the treatment of diabetes and insulin resistance. In this review, we collected and summarized a group of available in vivo and in vitro studies which targeted isolated phytochemicals with possible antidiabetic activity. Moreover, the in silico docking of natural compounds with some of the insulin signaling cascade key proteins is also summarized based on the current literature. In this review, hundreds of recent studies on pure natural compounds that alleviate type II diabetes mellitus (type II DM) were revised. We focused on natural compounds that could potentially regulate blood glucose and stimulate GLUT4 translocation through the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway. On attempt to point out potential new natural antidiabetic compounds, this review also focuses on natural ingredients that were shown to interact with proteins in the insulin signaling pathway in silico, regardless of their in vitro/in vivo antidiabetic activity. We invite interested researchers to test these compounds as potential novel type II DM drugs and explore their therapeutic mechanisms.

Diabetes mellitus is a metabolic disease that predominates, nowadays. It causes hyperglycemia and consequently major health complications. Type II diabetes is the most common form and is a result of insulin resistance in the target tissues. To treat this disease, several mechanisms have been proposed. The most direct route is via inhibiting the intestinal enzymes, e.g., α-glucosidase and α-amylase, responsible for intestinal polysaccharide digestion that therefore would reduce the absorption of monosugars through the intestinal walls. In this study, we shed the light on this route by testing the inhibitory effect of Ocimum basilicum extract on the enzymes α-glucosidase and α-amylase in vitro and in silico. Experimental procedures were performed to test the effect of the O. basilicum methanol extract from aerial parts followed by the in silico docking. 500 μg/mL of the extract led to 70.2% ± 8.6 and 25.4% ± 3.3 inhibition on α-glucosidase and α-amylase activity, respectively. Similarly, the effect of caffeic acid, a major extract ingredient, was also tested, and it caused 42.7% ± 3.0 and 47.1% ± 4.0 inhibition for α-amylase and α-glucosidase, respectively. Docking experiments were performed to predict the phytochemicals responsible for this robust inhibitory activity in the O. basilicum extracts. Several compounds have shown variable levels of inhibition, e.g., caffeic acid, pyroglutamic acid, and uvasol. The results indicated that O. basilicum can be a potent antidiabetic drug.

Diabetes is a predominant metabolic disease nowadays due to the off-beam lifestyle of diet and reduced physical activity. Complications of the illness include the gene-environment interactions and the downstream genetic and epigenetic consequences, e.g., cardiovascular diseases, tumor progression, retinopathy, nephropathy, neuropathy, polydipsia, polyphagia, polyuria, and weight loss. This review sheds the light on the mechanistic insights of antidiabetic medicinal plants in targeting key organs and tissues involved in regulating blood glucose homeostasis including the pancreas, liver, muscles, adipose tissues, and glucose absorption in the intestine. Diabetes is also involved in modulating major epigenetic pathways such as DNA methylation and histone modification. In this respect, we will discuss the phytochemicals as current and future epigenetic drugs in the treatment of diabetes. In addition, several proteins are common targets for the treatment of diabetes. Some phytochemicals are expected to directly interact with these targets. We lastly uncover modeling studies that predict such plausible interactions. In conclusion, this review article presents the mechanistic insight of phytochemicals in the treatment of diabetes by combining both the cellular systems biology and molecular modeling.

Diabetes has been recognized by ancient physicians and its main symptoms were known by the increased thirst, frequent urination, and tiredness. Medicinal plants were commonly used for treating these combined symptoms. In addition to several instructions for specific food consumption, a mild exercise was recommended. Currently, traditional medicine continues to be practiced in most Middle East, Asia, as well as developed countries. The current form of herbal medicine has historical roots in medieval Greco-Arab, ancient Egyptians, Chinese, and other ancient medicines. More than 800 plant species are reported as antidiabetic. Over 400 plants as well as 700 recipes and compounds have been scientifically evaluated for type 2 diabetes treatment. For instance, metformin, the most popular antidiabetic drug nowadays, was developed based on a biguanide compound isolated from French lilac. Medicinal herbs contain various bioactive compounds and thus can display multiple actions on insulin production as well as distinct insulin action mechanisms: insulin sensitizing, insulin mimicking, and inhibition of intestinal carbohydrate digestion and absorption. Herbal-derived insulin sensitizers act in a synergetic mechanism to increase glucose disposal and uptake by muscle, hepatic cells, and fat as well as those that control hepatic glycogen metabolism. This chapter provides a comprehensive overview on traditional herbal medicine including the historical background, medical innovations introduced by physicians and researchers, methods of therapies, and a state-of-the-art description of traditional herbal medicine.

Obesity is a global health problem affecting all age groups, leading to many complications such as type 2 diabetes, systemic hypertension, cardiovascular diseases, dyslipidemia, atherosclerosis, and stroke. Physiologically, obesity which arises from metabolic changes at tissue and organ levels results in an imbalance between energy intake and energy expenditure, which in turn results in increased fat accumulation in adipose tissue. Adipose tissue is an important endocrine organ, which secretes several hormones, including leptin and adiponectin and chemokines. These factors can regulate tumor behavior, inflammation, and the tumor microenvironment. Excessive adipose expansion during obesity causes adipose dysfunction and inflammation to increase systemic levels of pro-inflammatory factors. Cells from adipose tissue, such as cancer-associated adipocytes and adipose-derived stem cells, enter the cancer microenvironment to enhance pro-tumor effects. Dysregulated metabolism that stems from obesity including insulin resistance, hyperglycemia, and dyslipidemia can further affect tumor growth and development. Two different obesity treatment drugs are currently on the market: orlistat, which reduces intestinal fat absorption via inhibiting pancreatic lipase, and sibutramine, an anorectic or appetite suppressant. Both drugs have side effects, including increased blood pressure, dry mouth, constipation, headache, and insomnia. For this reason, a wide variety of natural materials has been explored for their obesity treatment potential. The present chapter focuses on the safety and efficacy of commonly used herbal medicines in the management of obesity through covering their beneficial effects and mechanism of action.

Diabetes and obesity have reached epidemic proportions globally, and they are a major contributor to the development of many pathological processes including hypertension, hyperlipidemia, cardiovascular diseases, and certain types of cancer. Increased consumption of more energy-dense, nutrient-poor diets with high levels of carbohydrates and saturated fats, combined with reduced physical activity, has led to currently observed high rates of diabetes and obesity. A strong relationship exists between diabetes and obesity, with fat tissue playing an important role in diabetes, a disease characterized by hyperglycemia, insulin hyposecretion, and insulin resistance. The resistance manifests primarily as impaired ability of the muscle tissue to take up glucose and of the liver to curb glucose output in response to insulin. Eventually, pancreatic beta cell insufficiency leads to overt diabetes.

The utilization of herb-based products to prevent/treat diseases is a therapeutic modality that has stood the test of long history of use and has played important roles in the development of conventional medicine. Indeed, many of the currently utilized pharmacological classes of drugs include a phytochemical prototype. Aspirin, atropine, codeine, ephedrine, digoxin, L-dopa, morphine, quinine, reserpine, taxol, and tubocurarine are a few examples of drugs, which were originally discovered through the study of medicinal plants and traditional knowledge of indigenous people. Black seeds, garlic, ginseng, ginger, ginkgo, olive oil, pomegranate, milk thistle, and St. John’s wort are a few examples of medicinal plants, which are gaining popularity among modern physicians and researcher, and this trend is likely to continue partly due to high cost involved in the development of patentable synthetic drugs. There is growing evidence to show that pharmacological effects of medicinal plants are potentiated through synergistic mechanisms and/or side effect-neutralizing combinations.

Diabetes is one of the prominent metabolic disorders nowadays. It is associated with many complications, including polyuria, weight loss, polydipsia, polyphagia, blurred vision, retinopathy, neuropathy, and nephropathy. Ongoing research has advanced on the mechanisms accompanying the prevention and treatment of diabetes, and the vast majority of research papers in the field of drug design and pharmacokinetics concentrate on the mechanisms through which the homeostasis of serum glucose is achieved. Several organs are fundamental in the process of regulating blood glucose levels, namely, the pancreas, liver, muscles, and adipose tissues. On the one hand, pancreatic β-islets are responsible for insulin production. As such, some drugs are focused to augment the islet size, cell size and number, or insulin secretion levels. On the other hand, the liver is the most crucial organ to sense fluctuations in blood glucose concentration and respond via buffering mechanisms accordingly. Furthermore, muscle and adipose tissues play concomitant roles to withdraw extra glucose from the bloodstream. Several key enzymes (e.g., phosphofructokinase, phosphorylase, glucose-6-phosphatase, etc.), transporters (GLUT2, GLUT4, etc.), as well as cell surface receptors (IRS, TM7, and others) in the hepatic, muscular, and adipose tissues are major targets for antidiabetic drugs. Global control of blood glucose levels can be via insulin-dependent protein kinase B (PKB) or insulin-independent AMP-activated protein kinase (AMPK) signaling cascades. Additionally, several drugs target to soothe the cell damage associated with hyperglycemia. In this respect, antioxidants have invaluable effects that should not be ignored. Moreover, the simple routes for glycemic control are via the inhibition of glucose digestion and absorption. In this chapter, strategies to treat diabetes are discussed, with an emphasis on the phytochemical drugs used in the Middle East and their mechanisms of action.

Recent researches demonstrated the potential of phytochemicals to prevent and to counteract obesity. Multiple combinations of phytochemicals can result in a synergistic activity that increases their bioavailability and action on multiple molecular targets, offering advantages over chemical treatments. Herbal-derived compounds have potential for controlling appetite, inhibiting pancreatic lipase activity, stimulating thermogenesis and lipid metabolism, promoting lipolysis and adipogenesis, and inducing apoptosis in adipocytes. Appetite reduction and inhibiting pancreatic lipase activity represent the first line in the regulation of body weight. Stimulating lipolysis and thermogenesis represents an essential target for the development of anti-obesity drugs. Furthermore, targeting adipocyte life cycle using various dietary bioactives that affects different stages of adipocyte life cycle represents also an important target for the development of new anti-obesity drugs. In this regard, different stages of adipocyte development that are targeted by anti-obesity drugs can include preadipocytes, maturing preadipocytes, and mature adipocytes. Various herbal-derived active compounds, such as genistein, daidzein, cyanidin, proanthocyanidin, xanthohumol, apigenin and luteolin, kaempferol, myricetin, quercetin, epigallocatechin gallate, conjugated linoleic acid, docosahexaenoic acid, quercetin, resveratrol, and ajoene, affect adipocytes during specific stages of development, resulting in either the induction of apoptosis or inhibition of adipogenesis. Although numerous molecular targets that can be used for both treatment and prevention of obesity have been identified, targeted single cellular receptor or pathway has resulted in limited success. Therefore, targeting several cellular pathways simultaneously with multiple phytochemicals to achieve synergistic effects might be an appropriate approach in the management of obesity.

Because of their natural origin and reduced side effects, we are watching worldwide an extensive growth and increased popularity in the field of herbal mixtures. In contrast to synthetic pharmaceuticals based upon single compounds, many medicinal plants exert their beneficial pharmacological effects through synergistic or additive mechanisms of multiple active compounds acting at single or multiple cellular/tissue target sites associated with a physiological/pathological process. These additive or synergistic pharmacological effects are known to reduce or to eliminate side effects associated with the use of synthetic drugs. Synergistic effect of phytochemicals likely has its origin in their functional role in promoting plant survival. For instance, a mixture of active principles having additive or synergistic effects at multiple target sites would not only ensure effectiveness against a wide range of herbivores or phytopathogens but also decrease the chances of these organisms developing resistance or adaptive responses.

DNA methylation plays a major role in organismal development and the regulation of gene expression. Methylation of cytosine bases and the cellular roles of methylated cytosine in eukaryotes are well established, as well as methylation of adenine bases in bacterial genomes. Still lacking, however, is a general mechanistic understanding, in structural and thermodynamic terms, of how proteins recognize methylated DNA. Toward this aim, we present the results of molecular dynamics simulations, alchemical free energy perturbation, and MM-PBSA calculations to explain the specificity of the R.DpnI enzyme from Streptococcus pneumonia in binding to adenine-methylated DNA with both its catalytic and winged-helix domains. We found that adenine-methylated DNA binds more favorably to the catalytic subunit of R.DpnI (−4 kcal mol−1) and to the winged-helix domain (−1.6 kcal mol−1) than non-methylated DNA. In particular, N6-adenine methylation is found to enthalpically stabilize binding to R.DpnI. In contrast, C5-cytosine methylation entropically favors complexation by the MBD domain of the human MeCP2 protein with almost no contribution of the binding enthalpy.

DNA methylation plays a major role in organismal development and the regulation of gene expression. Methylation of cytosine bases and its cellular roles in eukaryotes are well established, as well as methylation of adenine bases in bacterial genomes. Here, we present results from molecular dynamics simulations, alchemical free energy perturbation, and MM-PBSA calculations to explain the specificity of the R.DpnI enzyme for binding to adenine-methylated DNA in both its catalytic and winged-helix domains. We find that adenine-methylated DNA binds more favorably to the catalytic subunit of R.DpnI (−4 kcal/mol) and to the winged-helix domain (−1.6 kcal/mol) than unmethylated DNA.In particular, N6-adenine methylation is found to enthalpically stabilize binding to R.DpnI. In contrast, C5-cytosine methylation stabilizes binding to the MBD domain of the MeCP2 entropically with almost no difference in binding enthalpy.

Adenine and cytosine methylation are two important epigenetic modifications of DNA sequences at the levels of the genome and transcriptome. To characterize the differential roles of methylating adenine or cytosine with respect to their hydration properties, we performed conventional MD simulations and free energy perturbation calculations for two particular DNA sequences, namely the brain-derived neurotrophic factor (BDNF) promoter and the R.DpnI-bound DNA that are known to undergo methylation of C5-methyl cytosine and N6-methyl adenine, respectively. We found that a single methylated cytosine has a clearly favorable hydration free energy over cytosine since the attached methyl group has a slightly polar character. In contrast, capping the strongly polar N6 of adenine with a methyl group gives a slightly unfavorable contribution to its free energy of solvation. Performing the same demethylation in the context of a DNA double-strand gave quite similar results for the more solvent-accessible cytosine but much more unfavorable results for the rather buried adenine. Interestingly, the same demethylation reactions are far more unfavorable when performed in the context of the opposite (BDNF or R.DpnI target) sequence. This suggests a natural preference for methylation in a specific sequence context. In addition, free energy calculations for demethylating adenine or cytosine in the context of B-DNA vs. Z-DNA suggest that the conformational B-Z transition of DNA transition is rather a property of cytosine methylated sequences but is not preferable for the adenine-methylated sequences investigated here.

Cytosine methylation plays an important role in the epigenetic regulation of eukaryotic gene expression. The methyl-CpG binding domain (MBD) is common to a family of eukaryotic transcriptional regulators. How MBD, a stretch of about 80 amino acids, recognizes CpGs in a methylation dependent manner, and as a function of sequence, is only partly understood. Here we show, using an Escherichia coli cell-free expression system, that MBD from the human transcriptional regulator MeCP2 performs as a specific, methylation-dependent repressor in conjunction with the BDNF (brain-derived neurotrophic factor) promoter sequence. Mutation of either base flanking the central CpG pair changes the expression level of the target gene. However, the relative degree of repression as a function of MBD concentration remains unaltered. Molecular dynamics simulations that address the DNA B fiber ratio and the handedness reveal cooperative transitions in the promoter DNA upon MBD binding that correlate well with our experimental observations. We suggest that not only steric hindrance, but also conformational changes of the BDNF promoter as a result of MBD binding are required for MBD to act as a specific inhibitory element. Our work demonstrates that the prokaryotic transcription machinery can reproduce features of epigenetic mammalian transcriptional regulatory elements.