is a proto-oncogene regulating a large number of genes involved in a plethora of cellular functions. Its deregulation results in activation of
gene expression and/or an increase in MYC protein ...stability.
overexpression is a hallmark of malignant growth, inducing self-renewal of stem cells and blocking senescence and cell differentiation. This review summarizes the latest advances in our understanding of MYC-mediated molecular mechanisms responsible for its oncogenic activity. Several recent findings indicate that MYC is a regulator of cancer genome and epigenome: MYC modulates expression of target genes in a site-specific manner, by recruiting chromatin remodeling co-factors at promoter regions, and at genome-wide level, by regulating the expression of several epigenetic modifiers that alter the entire chromatin structure. We also discuss novel emerging therapeutic strategies based on both direct modulation of MYC and its epigenetic cofactors.
Abstract
Background
Cancer cells are characterized by uncontrolled cell proliferation and impaired bioenergetics. Sirtuins are a family of highly conserved enzymes that play a fundamental role in ...energy metabolism regulation. SIRT1, in particular, drives many physiological stress responses and metabolic pathways following nutrient deprivation. We previously showed that SIRT1 activation using SCIC2.1 was able to attenuate genotoxic response and senescence. Here, we report that in hepatocellular carcinoma (HCC) cells under glucose-deprived conditions, SCIC2.1 treatment induced overexpression of SIRT1, SIRT3, and SIRT6, modulating metabolic response.
Methods
Flow cytometry was used to analyze the cell cycle. The MTT assay and xCELLigence system were used to measure cell viability and proliferation. In vitro enzymatic assays were carried out as directed by the manufacturer, and the absorbance was measured with an automated Infinite M1000 reader. Western blotting and immunoprecipitation were used to evaluate the expression of various proteins described in this study. The relative expression of genes was studied using real-time PCR. We employed a Seahorse XF24 Analyzer to determine the metabolic state of the cells. Oil Red O staining was used to measure lipid accumulation.
Results
SCIC2.1 significantly promoted mitochondrial biogenesis via the AMPK-p53-PGC1α pathway and enhanced mitochondrial ATP production under glucose deprivation. SIRT1 inhibition by Ex-527 further supported our hypothesis that metabolic effects are dependent on SIRT1 activation. Interestingly, SCIC2.1 reprogrammed glucose metabolism and fatty acid oxidation for bioenergetic circuits by repressing de novo lipogenesis. In addition, SCIC2.1-mediated SIRT1 activation strongly modulated antioxidant response through SIRT3 activation, and p53-dependent stress response via indirect recruitment of SIRT6.
Conclusion
Our results show that SCIC2.1 is able to promote energy homeostasis, attenuating metabolic stress under glucose deprivation via activation of SIRT1. These findings shed light on the metabolic action of SIRT1 in the pathogenesis of HCC and may help determine future therapies for this and, possibly, other metabolic diseases.
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Triple negative breast cancer (TNBC) is an invasive, metastatic, highly aggressive tumor. Cytotoxic chemotherapy represents the current treatment for TNBC. However, relapse and ...chemo-resistance are very frequent. Therefore, new therapeutic approaches that are able to increase the sensitivity to cytotoxic drugs are needed. Forskolin, a natural cAMP elevating agent, has been used for several centuries in medicine and its safeness has also been demonstrated in modern studies. Recently, forskolin is emerging as a possible novel molecule for cancer therapy. Here, we investigate the effects of forskolin on the sensitivity of MDA-MB-231 and MDA-MB-468 TNBC cells to doxorubicin through MTT assay, flow cytometry-based assays (cell-cycle progression and cell death), cell number counting and immunoblotting experiments. We demonstrate that forskolin strongly enhances doxorubicin-induced antiproliferative effects by cell death induction. Similar effects are observed with IBMX and isoproterenol cAMP elevating agents and 8-Br-cAMP analog, but not by using 8-pCPT-2′-O-Me-cAMP Epac activator. It is important to note that the forskolin-induced potentiation of sensitivity to doxorubicin is accompanied by a strong inhibition of ERK1/2 phosphorylation, is mimicked by ERK inhibitor PD98059 and is prevented by pre-treatment with Protein Kinase A (PKA) and adenylate cyclase inhibitors. Altogether, our data indicate that forskolin sensitizes TNBC cells to doxorubicin via a mechanism depending on the cAMP/PKA-mediated ERK inhibition. Our findings sustain the evidence of anticancer activity mediated by forskolin and encourage the design of future in-vivo/clinical studies in order to explore forskolin as a doxorubicin sensitizer for possible use in TNBC patients.
Chlorogenic acid (CGA) is a very common dietary polyphenolic compound. CGA is becoming very attractive due to its potential use as preventive and therapeutic agent in many diseases, including cancer. ...Inorganic/organic hybrid materials are gaining considerable attention in the biomedical field. The sol-gel process provides a useful way to obtain functional organic/inorganic hybrids. The aim of this study was to synthesize silica/polyethylene glycol (PEG) hybrids with different percentages of CGA by sol-gel technique and to investigate their impact on the cancer cell proliferation. Synthesized materials have been chemically characterized through the FTIR spectroscopy and their bioactivity evaluated looking by SEM at their ability to produce a hydroxyapatite layer on their surface upon incubation with simulated body fluid (SBF). Finally, their effects on cell proliferation were studied in cell lines by direct cell number counting, MTT, flow cytometry-based cell-cycle and cell death assays, and immunoblotting experiments. Notably, we found that SiO₂/PEG/CGA hybrids exhibit clear antiproliferative effects in different tumor, including breast cancer and osteosarcoma, cell lines in a CGA dependent manner, but not in normal cells. Overall, our results increase the evidence of CGA as a possible anticancer agent and illustrate the potential for clinical applications of sol-gel synthesized SiO₂/PEG/CGA materials.
A large body of clinical and experimental evidence indicates that colorectal cancer is one of the most common multifactorial diseases. Although some useful prognostic biomarkers for clinical therapy ...have already been identified, it is still difficult to characterize a therapeutic signature that is able to define the most appropriate treatment. Gene expression levels of the epigenetic regulator histone deacetylase 2 (
) are deregulated in colorectal cancer, and this deregulation is tightly associated with immune dysfunction. By interrogating bioinformatic databases, we identified patients who presented simultaneous alterations in
, class II major histocompatibility complex transactivator (
, and beta-2 microglobulin (
) genes based on mutation levels, structural variants, and RNA expression levels. We found that
plays an important role in these alterations and that mutations in this gene are potentially oncogenic. The dysregulated mRNA expression levels of
were reported in about 5% of the profiled patients, while other specific alterations were described for
. By analyzing immune infiltrates, we then identified correlations among these three genes in colorectal cancer patients and differential infiltration levels of genetic variants, suggesting that
may have an indirect immune-related role in specific subgroups of immune infiltrates. Using this approach to carry out extensive immunological signature studies could provide further clinical information that is relevant to more resistant forms of colorectal cancer.
Epigenetic mechanisms finely regulate gene expression and represent potential therapeutic targets. Cambinol is a synthetic heterocyclic compound that inhibits class III histone deacetylases known as ...sirtuins (SIRTs). The acetylating action that results could be crucial in modulating cellular functions via epigenetic regulations. The main aim of this research was to investigate the effects of cambinol, and its underlying mechanisms, on cell differentiation by combining wet experiments with bioinformatics analyses and molecular docking simulations. Our in vitro study evidenced the ability of cambinol to induce the differentiation in MCF-7, NB4, and 3T3-L1 cell lines. Interestingly, focusing on the latter that accumulated cytoplasmic lipid droplets, the first promising results related to the action mechanisms of cambinol have shown the induction of cell cycle-related proteins (such as p16 and p27) and modulation of the expression of Rb protein and nuclear receptors related to cell differentiation. Moreover, we explored the inhibitory mechanism of cambinol on human SIRT1 and 2 performing in silico molecular simulations by protein-ligand docking. Cambinol, unlike from other sirtuin inhibitors, is able to better interact with the substrate binding site of SIRT1 than with the inhibition site. Additionally, for SIRT2, cambinol partially interacts with the substrate binding site, although the inhibition site is preferred. Overall, our findings suggest that cambinol might contribute to the development of an alternative to the existing epigenetic therapies that modulate SIRTs.
The use of
seeds in the culinary field or as aerial parts infusions in the pharmaceutical and cosmetic fields is widely reported. The biological activity of this plant, as demonstrated over the ...years, is closely related to its phytochemical content. This investigation focused on the comparative study of the same plants of
, one totally wild (
), while the other two, one with white flowers (
) and the other with blue flowers (
), were subject to cultivation, irrigation, and manual weeding. Using the potential of 1D and 2D-NMR spectroscopy, coupled with MS/MS spectrometric studies, the three methanolic extracts of
were investigated. Chemical studies have highlighted the presence of triterpene saponin compounds and various glycosylated flavonoids. Finally, the in vitro antiproliferative and antioxidant activities of the three individual extracts were evaluated. The antiproliferative activity performed on U-937, HL-60, and MCF-7 tumor cell lines highlighted a greater anticancer effect of the
and
extracts compared to the data obtained using
. The antioxidant activity, however, performed to quantify ROS generation is comparable among the extracts used.
In this paper, a two-dimensional numerical investigation on a prototypal solar chimney system integrated with an absorbing capacity wall in a south facade of a building is presented. The capacity ...wall is composed of a high absorbing plate and an assigned thickness of phase change material in metal foam. The chimney consists of a converging channel with one vertical absorbing wall and the glass plate inclined of 2°. The channel height inside the chimney is equal to 4.0 m, whereas the channel gap is at the inlet equal to 0.34 m and at the outlet it is 0.20 m. The thermal energy storage system is 4.0 m high. The numerical analysis was intended to evaluate the thermal and fluid dynamic behaviors of the solar chimney integrated with a latent thermal energy storage system. The investigation has shown that in all cases PCM has not fully melted during the day and the presence of aluminum foam inside the box attenuates the variation of temperatures during the day. The results show that the three different thickness of the thermal storage system present very similar fluid dynamic and thermal behaviors. For the analyzed configurations, the phase change material does not reach a total melting during the considered day.
Cardiovascular diseases (CVDs) remain a leading global cause of morbidity and mortality. These diseases have a multifaceted nature being influenced by a multitude of biochemical, genetic, ...environmental, and behavioral factors. Epigenetic modifications have a crucial role in the onset and progression of CVD. Epigenetics, which regulates gene activity without altering the DNA’s primary structure, can modulate cardiovascular homeostasis through DNA methylation, histone modification, and non-coding RNA regulation. The effects of environmental stimuli on CVD are mediated by epigenetic changes, which can be reversible and, hence, are susceptible to pharmacological interventions. This represents an opportunity to prevent diseases by targeting harmful epigenetic modifications. Factors such as high-fat diets or nutrient deficiencies can influence epigenetic enzymes, affecting fetal growth, metabolism, oxidative stress, inflammation, and atherosclerosis. Recent studies have shown that plant-derived bioactive compounds can modulate epigenetic regulators and inflammatory responses, contributing to the cardioprotective effects of diets. Understanding these nutriepigenetic effects and their reversibility is crucial for developing effective interventions to combat CVD. This review delves into the general mechanisms of epigenetics, its regulatory roles in CVD, and the potential of epigenetics as a CVD therapeutic strategy. It also examines the role of epigenetic natural compounds (ENCs) in CVD and their potential as intervention tools for prevention and therapy.
The Stachys L. genus has been used in traditional medicine to treat skin inflammations, stomach disorders, and stress. The aim of this study was to investigate the chemical profile and biological ...activity of the methanolic extract of Stachys spreitzenhoferi Heldr. (Lamiaceae) aerial parts, collected on the island of Kythira, South Greece. The analysis by liquid chromatography coupled with electrospray ionization and high-resolution mass spectrometry LC-(−)ESI/HRMSn of the methanol extract revealed the occurrence of thirty-six compounds - flavonoids, phenylethanoid glycosides, iridoids, quinic acid derivatives, aliphatic alcohol glycosides, and oligosaccharides – highlighting the substantial presence, as main peaks, of the iridoid melittoside (2) along with flavonoid compounds such as 4′-O-methylisoscutellarein mono-acetyl-diglycoside/chrysoeriol mono-acetyl-diglycoside (24), trimethoxy- (35) and tetramethoxyflavones (36). This extract was tested for its antimicrobial properties against Gram-positive and negative pathogenic strains. The extract was not active against Gram-negative bacteria tested, but it possessed a good dose-dependent antimicrobial activity towards S. aureus (MIC: 1.0 mg/mL) and L. monocytogenes (MIC: 1.0 mg/mL) Gram-(+) strains. Furthermore, this extract has been tested for its possible antioxidant activity in vitro. In particular, it has been shown that these molecules cause a decrease in DPPH, ABTS, and H2O2 radicals. The extract of S. spreitzenhoferi exhibited anti-DPPH activity (IC50: 0.17 mg/mL), anti-H2O2 activity (IC50: 0.125 mg/mL), and promising antiradical effect with an IC50 value of 0.18 mg/mL for anti-ABTS activity. S. spreitzenhoferi extract caused a decrease in ROS (at the concentration of 200 μg/mL) and an increase in the activity of the antioxidant enzymes SOD, CAT, and GPX in OZ-stimulated PMNs. Furthermore, it exhibited antiproliferative activity against acute myeloid leukemia (U937 cell), causing 50% of cell death at the 0.75 mg/mL.
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•Chemical profile and biological activity of the aerial parts of Stachys spreitzenhoferi Heldr. (Lamiaceae).•S. spreitzenhoferi extract exhibits different biological activities.•It showed a selective antibacterial action against Gram-positive strains.•It caused a decrease in DPPH, ABTS, and H2O2 radicals.•It exhibited antiproliferative activity against cancer cells.
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