Epigenetic Action Research Articles

Jaboticaba Peel Extract Exerts Chemopreventive Effects in Transgenic Mouse Model of Prostate Cancer

Introduction: Angiogenesis, oxidative stress, and epigenetic alterations involved in prostate cancer (PCa) are associated with different risk factors, such as a high-fat diet (HFD), overweight, and obesity. Jaboticaba peel extract (PJE) has shown antiproliferative, antiangiogenic, and antioxidant activities in the prostate of senile mice. Method: This study aimed to evaluate the effect of PJE on the dorsolateral prostate microenvironment in male transgenic mice for the prostate adenocarcinoma model, considering different pathological alterations, changed or unchanged by HFD, focusing on histopathology, and molecules related to extracellular matrix (ECM), oxidative stress, angiogenesis, and Dact-1. Western blotting and immunohistochemistry were performed on Dact-1-associated tumor suppressor genes in transgenic mice. Mice were fed HFD and received patented jaboticaba peel extract (PJE) treatment. The plasma levels of systemic oxidative stress were evaluated. Results: Our results showed that PJE protected the dorsolateral prostate against proliferation and increased MMP9, TGFβ, and VEGF levels. PJE reduced oxidative stress and lipid peroxidation by modulating catalase, SOD 2, and 4HNE. PJE exhibited an epigenetic action, evidenced by increased Dact-1 gene expression in PCa. Conclusion: PJE could be a natural protector of PCa and prostate lesions associated with HFD intake.

Enzymatic TET-1 inhibition highlights different epigenetic behaviours of IL-1β and TNFα in tumour progression of OS cell lines

Osteosarcoma (OS) is the most frequent primary malignant bone tumour, whose heterogeneity represents a major challenge for common antitumour therapies. Inflammatory cytokines are known to be necessary for OS progression. Therefore, to optimise therapy, it is important to discover reliable biomarkers by identifying the mechanism generating OS and investigating the inflammatory pathways that support the undifferentiated state. In this work, we highlight the differences of epigenetic activities of IL-1β and TNFα, and the susceptibility of TET-1 enzymatic inhibition, in tumour progression of three different OS cell lines. Investigating DNA methylation of IL-6 promoter and determining its expression, we found that TET enzymatic inhibition influences proliferation induced by inflammatory cytokines in OS cell lines. Moreover, Bobcat 339 treatment blocks IL-1β epigenetic action on IL-6 promoter, while only partially those of TNFα as well as inhibits IL-1β-dependent epithelial–mesenchymal transition (EMT) process, but only partially those of TNFα. In conclusion, this work highlights that IL-1β and TNFα have different effects on DNA demethylation in OS cell lines, making DNA methylation a potential biomarker of disease. Specifically, in IL-1β treatment, TET-1 inhibition completely blocks tumour progression, while in TNFα actions, it is only partially effective. Given that these two inflammatory pathways can be therapeutic targets for treating these tumours, knowledge of their distinct epigenetic behaviours can be useful for developing precise and specific therapeutic strategies for this disease.

Serum Acetylcarnitine as a Diagnostic Marker in Depression Episodes

Abstract Background: Depression is a serious public health concern due to its prevalence and associated discomfort, dysfunction, morbidity, and economic impact. Depression is more prevalent in women than in males. There is a need to investigate the course of depressive disorders in India to identify the necessity and duration of ongoing treatment. Studies should also assess cost-effective treatment strategies that can be easily implemented in primary care settings to successfully treat depression. Methods: This study aimed to estimate the Serum L-Acetyl Carnitine (LAC) levels in depressive episodes, mainly to find a correlation between the levels and depression and also to correlate the values to the severity of depression with a depression rating scale like Montgomery–Åsberg Depression Rating Scale (MADRS). LAC levels were estimated using an enzyme-linked immunosorbent assay kit. Results: A cross-sectional study was conducted with 60 individuals after obtaining their informed consent. This included 30 cases of diagnosed depression and 30 age and sex-matched normal controls. The diagnosed depressive episodes were rated in MADRS, and a score was assigned based on the same. The results were tabulated and statistically analyzed. The mean age of the case group was 41.37 ± 11.32 and control group was 41.50 ± 14.37. The incidence of depressive symptoms was higher in females (53%) than males (47%). The incidence of depressive symptoms was higher in the 41–50-year age group than in any other group. The acetyl carnitine-LAC levels were significantly decreased in patients with depressive episodes (950.7 ± 902.7) compared to the control (1799.6 ± 67.1), respectively. The Pearson’s correlation shows there is a strong negative correlation between the MADRS score and the levels of acetylcarnitine in the cases which was statistically significant, P < 0.001. Conclusions: LAC may have an important role in the pathophysiology of depression by its epigenetic action on metabotropic glutamate receptors and the decrease in the brain tissue may induce depressive symptoms, and consequently, their supplementation causes a rapid antidepressant effect. Hence, it could be a useful biochemical marker for the diagnosis of depression and also an effective for the treatment of depression.

Histone methyltransferases as a new target for the epigenetic action by vorinostat

Aberrant methylation and acetylation of histones are characteristic changes in the system of epigenetic regulation of gene expression accompanying the process of malignant transformation of the cell. Vorinostat is the epigenetic modulator that actively used in clinical oncology practice. The antitumor activity of vorinostat is considered to be associated with only with the inhibition of histone deacetylases. The effects of this drug on histone methylation have not been sufficiently studied. Using the HeLa TI test system, which allows evaluating the integral effect of epigenetically active compounds by activating the expression of the reporter gene GFP, and knockdown of genes by small interfering RNAs, we showed that the inhibitory effect of vorinostat is directed not only at HDAC1, but also at EZH2, SUV39H1, SUV39H2, SUV420H1. Using Western blotting, the ability of vorinostat to suppress the expression of enzymes EZH2, SUV39H1/2, SUV420H1 was confirmed and, in addition, its ability to inhibit the expression of enzymes SUV420H2 and DOT1L was revealed. The data obtained expand the understanding of the epigenetic effects of vorinostat and demonstrate the need for a large-scale analysis of its activity in relation to other epigenetic enzymes. A detailed understanding of the mechanism of epigenetic action of vorinostat will contribute to its more adequate use in the treatment of tumors with an aberrant epigenetic profile.

Histone Methyltransferases as a New Target for Epigenetic Action of Vorinostat

Epigenetic genome regulation during malignant cell transformation is characterized by the aberrant methylation and acetylation of histones. Vorinostat (SAHA) is an epigenetic modulator actively used in clinical oncology. The antitumor activity of vorinostat is commonly believed to be associated with the inhibition of histone deacetylases, while the impact of this drug on histone methylation has been poorly studied. Using HeLa TI cells as a test system allowing evaluation of the effect of epigenetically active compounds from the expression of the GFP reporter gene and gene knockdown by small interfering RNAs, we showed that vorinostat not only suppressed HDAC1, but also reduced the activity of EZH2, SUV39H1, SUV39H2, and SUV420H1. The ability of vorinostat to suppress expression of EZH2, SUV39H1/2, SUV420H1 was confirmed by Western blotting. Vorinostat also downregulated expression of SUV420H2 and DOT1L enzymes. The data obtained expand our understanding of the epigenetic effects of vorinostat and demonstrate the need for a large-scale analysis of its activity toward other enzymes involved in the epigenetic genome regulation. Elucidation of the mechanism underlying the epigenetic action of vorinostat will contribute to its more proper use in the treatment of tumors with an aberrant epigenetic profile.

Butyrate restores the fat/lean mass ratio balance and energy metabolism and reinforces the tight junction-mediated intestinal epithelial barrier in prediabetic mice independently of its anti-inflammatory and epigenetic actions

Tissue/cellular actions of butyrate on energy metabolism and intestinal barrier in normal metabolic conditions or prediabetes are still unclear. In this work, we investigated the beneficial effect of dietary supplementation with sodium butyrate on energy metabolism, body mass composition, and intestinal epithelial barrier mediated by tight junction (TJ) in chow diet-fed normal and high-fat diet (HF)-fed prediabetic mice, considering the well-known butyrate action as an epigenetic and inflammatory regulator. Butyrate significantly reduced the fat/lean mass ratio, slightly ameliorated dyslipidemia, restored oral glucose tolerance, and increased basal energy expenditure in prediabetic HF-fed mice but had no effect on control animals. Such effects were observed in the absence of significant alterations in the hypothalamic expression of orexigenic and anorexigenic genes and motor activity. Also, butyrate suppressed the whitening effect of HF on brown adipose tissue but did not affect cell bioenergetics in immortalized UCP1-positive adipocytes in vitro. Butyrate reinforced the intestinal epithelial barrier in HF-fed mice and in Caco-2 monolayers, which involved higher trafficking of TJ proteins to the cell-cell contact region of the intestinal epithelia, without affecting TJ gene expression or the acetylation level of histones H3 and H4 in vivo. All metabolic and intestinal effects of butyrate in prediabetic mice occurred in the absence of detectable changes in systemic or local inflammation, or alterations in endotoxemia markers. Butyrate has no effect on chow diet-fed mice but, in the context of HF-induced prediabetes, it prevents metabolic and intestinal dysfunctions independently of its anti-inflammatory and epigenetic actions.

Role of vitamin C and SVCT2 in neurogenesis.

Different studies have established the fundamental role of vitamin C in proliferation, differentiation, and neurogenesis in embryonic and adult brains, as well as in in vitro cell models. To fulfill these functions, the cells of the nervous system regulate the expression and sorting of sodium-dependent vitamin C transporter 2 (SVCT2), as well as the recycling of vitamin C between ascorbic acid (AA) and dehydroascorbic acid (DHA) via a bystander effect. SVCT2 is a transporter preferentially expressed in neurons and in neural precursor cells. In developmental stages, it is concentrated in the apical region of the radial glia, and in adult life, it is expressed preferentially in motor neurons of the cerebral cortex, starting on postnatal day 1. In neurogenic niches, SVCT2 is preferentially expressed in precursors with intermediate proliferation, where a scorbutic condition reduces neuronal differentiation. Vitamin C is a potent epigenetic regulator in stem cells; thus, it can induce the demethylation of DNA and histone H3K27m3 in the promoter region of genes involved in neurogenesis and differentiation, an effect mediated by Tet1 and Jmjd3 demethylases, respectively. In parallel, it has been shown that vitamin C induces the expression of stem cell-specific microRNA, including the Dlk1-Dio3 imprinting region and miR-143, which promotes stem cell self-renewal and suppresses de novo expression of the methyltransferase gene Dnmt3a. The epigenetic action of vitamin C has also been evaluated during gene reprogramming of human fibroblasts to induced pluripotent cells, where it has been shown that vitamin C substantially improves the efficiency and quality of reprogrammed cells. Thus, for a proper effect of vitamin C on neurogenesis and differentiation, its function as an enzymatic cofactor, modulator of gene expression and antioxidant is essential, as is proper recycling from DHA to AA by various supporting cells in the CNS.

Exploring the Impact of Cyanidin-3-Glucoside on Inflammatory Bowel Diseases: Investigating New Mechanisms for Emerging Interventions.

Cyanidin-3-O-glucoside (C3G), the most widely distributed anthocyanin (ACN) in edible fruits, has been proposed for several bioactivities, including anti-inflammatory, neuro-protective, antimicrobial, anti-viral, anti-thrombotic and epigenetic actions. However, habitual intake of ACNs and C3G may vary widely among populations, regions, and seasons, among individuals with different education and financial status. The main point of C3G absorption occurs in the small and large bowel. Therefore, it has been supposed that the treating properties of C3G might affect inflammatory bowel diseases (IBD), such as ulcerative colitis (UC) and Crohn's disease (CD). IBDs develop through complex inflammatory pathways and sometimes may be resistant to conventional treatment strategies. C3G presents antioxidative, anti-inflammatory, cytoprotective, and antimicrobial effects useful for IBD management. In particular, different studies have demonstrated that C3G inhibits NF-κB pathway activation. In addition, C3G activates the Nrf2 pathway. On the other hand, it modulates the expression of antioxidant enzymes and cytoprotective proteins, such as NAD(P)H, superoxide dismutase, heme-oxygenase (HO-1), thioredoxin, quinone reductase-oxide 1 (NQO1), catalase, glutathione S-transferase and glutathione peroxidase. Interferon I and II pathways are downregulated by C3G inhibiting interferon-mediating inflammatory cascades. Moreover, C3G reduces reactive species and pro-inflammatory cytokines, such as C reactive protein, interferon-γ, tumor necrosis factor-α, interleukin (IL)-5, IL-9, IL-10, IL-12p70, and IL-17A in UC and CD patients. Finally, C3G modulates gut microbiota by inducing an increase in beneficial gut bacteria and increasing microbial abundances, thus mitigating dysbiosis. Thus, C3G presents activities that may have potential therapeutic and protective actions against IBD. Still, in the future, clinical trials should be designed to investigate the bioavailability of C3G in IBD patients and the proper therapeutic doses through different sources, aiming to the standardization of the exact clinical outcome and efficacy of C3G.

Probiotics and Commensal Bacteria Metabolites Trigger Epigenetic Changes in the Gut and Influence Beneficial Mood Dispositions.

The effect of the intestinal microbiome on the gut-brain axis has received considerable attention, strengthening the evidence that intestinal bacteria influence emotions and behavior. The colonic microbiome is important to health and the pattern of composition and concentration varies extensively in complexity from birth to adulthood. That is, host genetics and environmental factors are complicit in shaping the development of the intestinal microbiome to achieve immunological tolerance and metabolic homeostasis from birth. Given that the intestinal microbiome perseveres to maintain gut homeostasis throughout the life cycle, epigenetic actions may determine the effect on the gut-brain axis and the beneficial outcomes on mood. Probiotics are postulated to exhibit a range of positive health benefits including immunomodulating capabilities. Lactobacillus and Bifidobacterium are genera of bacteria found in the intestines and so far, the benefits afforded by ingesting bacteria such as these as probiotics to people with mood disorders have varied in efficacy. Most likely, the efficacy of probiotic bacteria at improving mood has a multifactorial dependency, relying namely on several factors that include the agents used, the dose, the pattern of dosing, the pharmacotherapy used, the characteristics of the host and the underlying luminal microbial environment (e.g., gut dysbiosis). Clarifying the pathways linking probiotics with improvements in mood may help identify the factors that efficacy is dependent upon. Adjunctive therapies with probiotics for mood disorders could, through DNA methylation molecular mechanisms, augment the intestinal microbial active cohort and endow its mammalian host with important and critical co-evolutionary redox signaling metabolic interactions, that are embedded in bacterial genomes, and that in turn can enhance beneficial mood dispositions.

Effectiveness of apabetalone and some other indirect epigenetic-oriented drugs in the treatment of heart failure

Epigenetic therapy for cardiovascular disease (CVD) has received increased attention from the medical community in recent years. Evidence of this is the fact that more and more controlled clinical trials evaluate the beneficial effects of: 1) direct epigenetic drugs, for example, apabetalone, and 2) repurposed drugs with possible indirect epigenetic action, for example, metformin, statins, sodium-glucose transport protein 2 (SGLT2) inhibitors and omega-3 polyunsaturated fatty acids (PUFAs) in CVD, including heart failure (HF) with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). Apabetalone is the first and unique direct-acting epigenetic drug tested in patients with CVD, and the BETonMACE study showed a reduction in first hospitalization for HF (at any EF) and CVD mortality in patients with type 2 diabetes (T2D) and recent acute coronary syndrome, suggesting a possible role for this drug in secondary prevention. Patients with HFpEF appear to benefit from the addition of metformin and SGLT2 inhibitors to standard statin therapy due to their ability to reduce the death risk. In contrast, hydralazine with or without isosorbide dinitrate produced no beneficial effects. In HFrEF, metformin and SGLT2 inhibitors may reduce the risk of HF and death, while clinical trials with statins have mixed results. PUFA supplementation was associated with a significant reduction in car­diovascular risk in both HFrEF and HFpEF. However, definitive data on the benefits of direct and indirect epigenetic therapy for CVD can only be obtained from large clinical trials in the future. The purpose of this review was to provide updated information on epigenetic therapy for CVD obtained from clinical trials.

How SARS-CoV-2 Alters the Regulation of Gene Expression in Infected Cells.

Nonstructural accessory proteins in viruses play a key role in hijacking the basic cellular mechanisms, which is essential to promote the virus survival and evasion of the immune system. The immonuglobulin-like open reading frame 8 (ORF8) protein expressed by SARS-CoV-2 accumulates in the nucleus and may influence the regulation of the gene expression in infected cells. In this contribution, by using microsecond time-scale all-atom molecular dynamics simulations, we unravel the structural bases behind the epigenetic action of ORF8. In particular, we highlight how the protein is able to form stable aggregates with DNA through a histone tail-like motif, and how this interaction is influenced by post-translational modifications, such as acetylation and methylation, which are known epigenetic markers in histones. Our work not only clarifies the molecular mechanisms behind the perturbation of the epigenetic regulation caused by the viral infection but also offers an unusual perspective which may foster the development of original antivirals.

LepRb+ cell-specific deletion of Slug mitigates obesity and nonalcoholic fatty liver disease in mice.

Leptin exerts its biological actions by activating the long-form leptin receptor (LepRb). LepRb signaling impairment and leptin resistance are believed to cause obesity. The transcription factor Slug - also known as Snai2 - recruits epigenetic modifiers and regulates gene expression by an epigenetic mechanism; however, its epigenetic action has not been explored in leptin resistance. Here, we uncover a proobesity function of neuronal Slug. Hypothalamic Slug was upregulated in obese mice. LepRb+ cell-specific Slug-knockout (SlugΔLepRb) mice were resistant to diet-induced obesity, type 2 diabetes, and liver steatosis and experienced decreased food intake and increased fat thermogenesis. Leptin stimulated hypothalamic Stat3 phosphorylation and weight loss to a markedly higher level in SlugΔLepRb than in Slugfl/fl mice, even before their body weight divergence. Conversely, hypothalamic LepRb+ neuron-specific overexpression of Slug, mediated by AAV-hSyn-DIO-Slug transduction, induced leptin resistance, obesity, and metabolic disorders in mice on a chow diet. At the genomic level, Slug bound to and repressed the LepRb promoter, thereby inhibiting LepRb transcription. Consistently, Slug deficiency decreased methylation of LepRb promoter H3K27, a repressive epigenetic mark, and increased LepRb mRNA levels in the hypothalamus. Collectively, these results unravel what we believe to be a previously unrecognized hypothalamic neuronal Slug/epigenetic reprogramming/leptin resistance axis that promotes energy imbalance, obesity, and metabolic disease.

Prospective Epigenetic Actions of Organo-Sulfur Compounds against Cancer: Perspectives and Molecular Mechanisms.

Major epigenetic alterations, such as chromatin modifications, DNA methylation, and miRNA regulation, have gained greater attention and play significant roles in oncogenesis, representing a new paradigm in our understanding of cancer susceptibility. These epigenetic changes, particularly aberrant promoter hypermethylation, abnormal histone acetylation, and miRNA dysregulation, represent a set of epigenetic patterns that contribute to inappropriate gene silencing at every stage of cancer progression. Notably, the cancer epigenome possesses various HDACs and DNMTs, which participate in the histone modifications and DNA methylation. As a result, there is an unmet need for developing the epigenetic inhibitors against HDACs and DNMTs for cancer therapy. To date, several epigenetically active synthetic inhibitors of DNA methyltransferases and histone deacetylases have been developed. However, a growing body of research reports that most of these synthetic inhibitors have significant side effects and a narrow window of specificity for cancer cells. Targeting tumor epigenetics with phytocompounds that have the capacity to modulate abnormal DNA methylation, histone acetylation, and miRNAs expression is one of the evolving strategies for cancer prevention. Encouragingly, there are many bioactive phytochemicals, including organo-sulfur compounds that have been shown to alter the expression of key tumor suppressor genes, oncogenes, and oncogenic miRNAs through modulation of DNA methylation and histones in cancer. In addition to vitamins and microelements, dietary phytochemicals such as sulforaphane, PEITC, BITC, DADS, and allicin are among a growing list of naturally occurring anticancer agents that have been studied as an alternative strategy for cancer treatment and prevention. Moreover, these bioactive organo-sulfur compounds, either alone or in combination with other standard cancer drugs or phytochemicals, showed promising results against many cancers. Here, we particularly summarize and focus on the impact of specific organo-sulfur compounds on DNA methylation and histone modifications through targeting the expression of different DNMTs and HDACs that are of particular interest in cancer therapy and prevention.

Contexto, ser humano y epigenética

The discovery of the whole sequence of the human genome in 2001 promised to be a revolution in terms of dealing with diseases and understanding what makes us a “different” species from other animals. However, the scope of this promising discovery was more limited than expected. The information carried by DNA is complex and, furthermore, it does not explain the vast repertoire of functions and dysfunctions that organisms present. For this reason, it began to be thought that it was necessary to change the focus to understand how individuals are formed and develop, and turn the attention paid to DNA to what surrounds that DNA: the environment of the organism (both internal and external). In this way, the studies began to focus on the influence of the context to which organisms are exposed to understand the characteristics of the body and its actions. In thinking about the concept of the body in development, this renewed focus in the environmental influence allows an understanding of it as a permeable and complex system, where dysregulations (diseases) may also be triggered by exogenous events and not only from the endogenous factors. Therefore, in a recursive way, the influence of the human being on the environment transforms the environment that returns to influence the human being. Here is the history of mankind. There are contexts that offer a healthy framework for the growth of its inhabitants and there are others that make life vulnerable and produce lifetime consequences. However, while some people are and feel vulnerable to contexts of adversity, other people are resilient and manage to positively live and growth despite the difficulties that might appear throughout life. Epigenetics has been proposed as one of the molecular mechanisms that explain how those contexts “get under the skin” and trigger phenotypic characteristics. Although the regulation of gene expression by epigenetic mechanisms occurs naturally and constantly in the developing organism, it can also be influenced by environmental factors, such as age, lifestyle, health conditions or social relationships. Epigenetics is sensitive to environmental changes allowing organisms to adapt their physiology and behavior. Unlike the changes that occur in the DNA sequence, epigenetic processes are reversible. One of the most known examples of epigenetic action in determining phenotypes according to the environment is the stress response through the hypothalamus-pituitary-adrenal (HPA) axis. The functioning of the HPA axis and the response to stress can be related to the concepts of vulnerability and trauma. If an emotionally sensitive event is disturbing, it becomes a stressful situation, with the activation of the HPA axis, flooding the bloodstream with cortisol. This allostatic process is the basis of the mechanism of adaptability of humans to traumatic impacts. But if the situation continues to impact, allostasis is systematized and generates an allostatic circuit that produces a residual charge that ends up creating dysfunction in the organism. In this article the involvement of epigenetics in this regulation is discussed and some seminal studies in rodents and humans are presented. The last few years of scientific research have seen an explosive growth of studies linking situations of vulnerability (particularly, during early life) with the development of psychopathologies. Epigenetics was established as an interesting factor that allows to relate, from a biological point of view, the context in which people develop with their emotional states. This article proposes a review of some of these works in order to integrate them into a complex conception of the human being, which understands it as a system of relationships between various dimensions, including genetics, epigenetics, neurology, emotions, social interactions, cognition, and socio-culture, framed in a particular context. https://doi.org/10.16888/interd.2023.40.1.5

The Multiple Functions of Melatonin: Applications in the Military Setting.

The aim of this review is to provide the reader with a general overview on the rationale for the use of melatonin by military personnel. This is a technique that is being increasingly employed to manage growing psycho-physical loads. In this context, melatonin, a pleotropic and regulatory molecule, has a potential preventive and therapeutic role in maintaining the operational efficiency of military personnel. In battlefield conditions in particular, the time to treatment after an injury is often a major issue since the injured may not have immediate access to medical care. Any drug that would help to stabilize a wounded individual, especially if it can be immediately administered (e.g., per os) and has a very high safety profile over a large range of doses (as melatonin does) would be an important asset to reduce morbidity and mortality. Melatonin may also play a role in the oscillatory synchronization of the neuro-cardio-respiratory systems and, through its epigenetic action, poses the possibility of restoring the main oscillatory waves of the cardiovascular system, such as the Mayer wave and RSA (respiratory sinus arrhythmia), which, in physiological conditions, result in the oscillation of the heartbeat in synchrony with the breath. In the future, this could be a very promising field of investigation.

DNA Methylation: An Approach to Forensic Age Prediction by Molecular Mechanism

Epigenetic processes have an important role in gene expression which is affected by living environments conditions. Occurrence of epigenetics is conciliated by two major molecular mechanisms which includes histone modification and DNA methylation. DNA methylation is an epigenetic channel action, this is a natural process where transmission of a methyl group on the C5 position of the cytosine to form 5-methylcytosine at genome. So, epigenetic change is normal and continual fact that may be influenced by many factors including age, the environment / lifestyle, and disease state. The normal process of aging causes a span of transformation of tissues and organs which gathered over life time. Now this could be possible to be examined through molecular based method. In view of this methylation levels of age associated marker have been used for highly accurate age prediction in this area and depicted that an age associated methylation marker on specific gene location found to be useful with marginal lapse. In Indian scenario there are no such study published on epigenetic markers for age estimation. In future for forensic cases work Molecular biomarkers may be significant to estimate age.

The Binomial "Inflammation-Epigenetics" in Breast Cancer Progression and Bone Metastasis: IL-1β Actions Are Influenced by TET Inhibitor in MCF-7 Cell Line.

The existence of a tight relationship between inflammation and epigenetics that in primary breast tumor cells can lead to tumor progression and the formation of bone metastases was investigated. It was highlighted how the induction of tumor progression and bone metastasis by Interleukin-1 beta, in a non-metastatic breast cancer cell line, MCF-7, was dependent on the de-methylating actions of ten-eleven translocation proteins (TETs). In fact, the inhibition of their activity by the Bobcat339 molecule, an inhibitor of TET enzymes, determined on the one hand, the modulation of the epithelial-mesenchymal transition process, and on the other hand, the reduction in the expression of markers of bone metastasis, indicating that the epigenetic action of TETs is a prerequisite for IL-1β-dependent tumor progression and bone metastasis formation.

Epigenetic Mechanisms Involved in Inflammaging-Associated Hypertension.

This review summarizes the involvement of inflammaging in vascular damage with focus on the epigenetic mechanisms by which inflammaging-induced hypertension is triggered. Inflammaging in hypertension is a complex condition associated with the production of inflammatory mediators by the immune cells, enhancement of oxidative stress, and tissue remodeling in vascular smooth muscle cells and endothelial cells. Cellular processes are numerous, including inflammasome assembly and cell senescence which may involve mitochondrial dysfunction, autophagy, DNA damage response, dysbiosis, and many others. More recently, a series of noncoding RNAs, mainly microRNAs, have been described as possessing epigenetic actions on the regulation of inflammasome-related hypertension, emerging as a promising therapeutic strategy. Although there are a variety of pharmacological agents that effectively regulate inflammaging-related hypertension, a deeper understanding of the epigenetic events behind the control of vessel deterioration is needed for the treatment or even to prevent the disease onset.

Sulforaphane inhibits histone deacetylase causing cell cycle arrest and apoptosis in oral squamous carcinoma cells

BackgroundBiologic compounds have recently generated interest in cancer chemoprevention. Sulforaphane (SFN), an isothiocyanate from cruciferous vegetables, has profound epigenetic actions. Since epigenetic aetiology is crucial for oral cancer, this study evaluated the role of SFN in oral cancer prevention. MethodsOral squamous cell carcinoma cells (UPCI-SCC-172) were treated with SFN in three concentrations: 10 μM, 20 μM and 30 μM for two time periods: 24 h and 48 h. MTT assay assessed cell proliferation. Histone deacetylase (HDAC) enzyme activity was colorimetrically estimated in the nuclear extracts. Flow cytometry determined cell cycle stages, reactive oxygen species (ROS) generation and mitochondrial membrane potential (MMP) changes. Extrinsic and intrinsic apoptotic pathways were evaluated from caspase enzyme assays. ResultsCell proliferation and HDAC activity (44% in 24 h and 40% in 48 h) were significantly inhibited (p < 0.01). For 10 μM concentration, G2/M cell cycle arrest was found with a reduction in G1 phase cell population at 24 h and 48 h. Concentrations of 20 μM and 30 μM SFN presented cells in apoptosis marked by increased sub G1 cells at 48 h. Concentrations of 10 μM and 20 μM SFN showed a 1.3 to 2.8-fold increase in ROS generation at 24 h and 48 h. The concentration of 30 μM SFN showed a drop in ROS production, denoting cells already in apoptosis. Fall in MMP was also dose- and time-dependent. Caspase enzyme assays (p < 0.001) demonstrated activation of both extrinsic and intrinsic apoptotic pathways. ConclusionInhibitory action of SFN on oral cancer cell proliferation and HDAC activity led to cell cycle arrest and apoptosis. These effects marked by increase in ROS, a decrease in MMP and activation of apoptotic pathways offer exciting therapeutic options.

Butyrate, a typical product of gut microbiome, affects function of the AhR gene, being a possible agent of crosstalk between gut microbiome, and hepatic drug metabolism

Modulation of gut microbiome composition seems to be a promising therapeutic strategy for a wide range of pathologic states. However, these microbiota-targeted interventions may affect production of microbial metabolites, circulating factors in the gut-liver axis influencing hepatic drug metabolism with possible clinical relevance. Butyrate, a short-chain fatty acid produced through microbial fermentation of dietary fibers in the colon, has well established anti–inflammatory role in the intestine, while the effect of butyrate on the liver is unknown. In this study, we have evaluated the effect of butyrate on hepatic AhR activity and AhR-regulated gene expression. We have showed that AhR and its target genes were upregulated by butyrate in dose-dependent manner in HepG2-C3 as well as in primary human hepatocytes. The involvement of AhR has been proved using specific AhR antagonists and siRNA–mediated AhR silencing. Experiments with AhR reporter cells have shown that butyrate regulates the expression of AhR target genes by modulating the AhR activity. Our results suggest also epigenetic action by butyrate on AhR and its repressor (AHRR) presumably through mechanisms based on HDAC inhibition in the liver. Our results demonstrate that butyrate may influence the drug-metabolizing ability of liver enzymes e.g., through the interaction with AhR-dependent pathways.