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H3 histone methylation landscape in male urogenital cancers: from molecular mechanisms to epigenetic biomarkers and therapeutic targets.

During the last decades, male urogenital cancers (including prostate, renal, bladder and testicular cancers) have become one of the most frequently encountered malignancies affecting all ages. While their great variety has promoted the development of various diagnosis, treatment and monitoring strategies, some aspects such as the common involvement of epigenetic mechanisms are still not elucidated. Epigenetic processes have come into the spotlight in the past years as important players in the initiation and progression of tumors, leading to a plethora of studies highlighting their potential as

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… Demethylation, initially thought to be stable, is catalyzed by Lysine specific demethylase 1 (LSD1/KDM1A) which demethylates mono- or di-methylated histone lysine 4 (H3K4me1,2 - enhancer-associated histone marks), and interacts with histone deacetylases 1, 2 (HDAC1,2). … While JMJD6 can demethylate H3R2me2, PADIs are not necessarily able to demethylate, but they can block methylation by converting the arginine residue to citrulline ( Di Lorenzo and Bedford, 2011 ). 3 Prostate cancer (PCa) Prostate cancer is one of the most commonly diagnosed oncological conditions, …

Altered m6A RNA methylation contributes to hippocampal memory deficits in Huntington's disease mice.

N6-methyladenosine (m6A) regulates many aspects of RNA metabolism and is involved in learning and memory processes. Yet, the impact of a dys … ely, m6A is aberrantly regulated in an experience-dependent manner in the HD hippocampus leading to demethylation of important components of synapse organization. Notably, the levels of RNA demethylase (FTO) and methyltransferase (METTL14) were modulated after training in the hippocampus of WT mice but not in Hdh+/Q111 mice. Finally, inhibition of FTO expressio …

Epigenetic Drifts during Long-Term Intestinal Organoid Culture.

Organoids retain the morphological and molecular patterns of their tissue of origin, are self-organizing, relatively simple to handle and ac … rms of a mathematical model assuming that epigenetic changes during a long-term culture involve DNA demethylation that ceases if the metabolic adaptation is disturbed.

Gene Methylation and Silencing of WIF1 Is a Frequent Genetic Abnormality in Mantle Cell Lymphoma.

We have previously shown that the Wnt canonical pathway (WCP) is constitutively active in most cases of mantle cell lymphoma (MCL). Here, we … ne methylation of WIF1 in 4 of 5 cell lines (80%) and in 24 of 29 (82%) tumors. The addition of the demethylation agent 5-aza-2'-deoxycytidine to Mino and JeKo-1, two WIF1-negative cell lines, restored the expression of WIF1 mRNA in these cells. Gene transfection of WIF1 into JeKo-1 and Mino cells significantly reduced cell growth, and this finding correlated w …

QBD-driven HPLC method of eltrombopag olamine: Degradation pathway proposal, structure elucidation, and in silico toxicity prediction.

Eltrombopag olamine is prescribed for chronic immune (idiopathic) thrombocytopenic purpura (ITP). This work aims to investigate the formatio … chromatography with tandem mass spectrometry (LC-MS/MS), among the identified degradation pathways demethylation and decarboxylation are common reactions observed during oxidation resulted in majority of degradation products. All the degradation products are characterized with help of the daughter ions and product ion obtained upon LC-MS/MS analysis. The HPLC …

The Thioredoxin-Interacting Protein TXNIP Is a Putative Tumour Suppressor in Cutaneous T-Cell Lymphoma.

BACKGROUND: The thioredoxin-interacting protein (TXNIP) is involved in cellular metabolism and cell proliferation, and recently, deficient expression of TXNIP has been associated with progression and poor outcome for cancer patients. OBJECTIVES: To assess TXNIP expression and function in malignant T cells from cutaneous T-cell lymphoma (CTCL). METHODS: CTCL-derived malignant (MyLa2059, PB2B) and non-malignant (MyLa1850) cell lines were analysed by Western blotting and qPCR for TXNIP expression. Subsequently, the malignant CTCL cell lines were treated with GSK126 - an inhibitor of enhancer of

Histone lysine demethylase KDM5B maintains chronic myeloid leukemia via multiple epigenetic actions.

The histone lysine demethylase KDM5 family is implicated in normal development and stem cell maintenance by epigenetic modulation of histone … a small subset of the KDM5B targets showed differential expression in association with the histone demethylation activity. By characterizing the interacting proteins in K562 cells, we discovered that KDM5B recruits protein complexes involved in the mRNA processing machinery, implying an alternative epigenetic action mediated by KDM5B in gene regulation. Our st …

DNA methylation plays an important role in immune thrombocytopenia.

DNA methylation is the covalent addition of a methyl group to a DNA base, typically the cytosine of cytosine-phosphate-guanosine (CpG) dinucleotides. It is catalysed by methyltransferase enzymes using an S-adenosyl methionine donor, which is a heritable, stable and reversible DNA modification. Aberrant DNA methylation can influence gene expression without changing nucleotide sequences, inducing occurrence and development in autoimmune diseases, such as systemic lupus erythematosus and immune thrombocytopenia. Immune thrombocytopenia is an autoimmune disease characterised by bleeding and thromb

Investigation of GHSR methylation levels in thymomas from patients with Myasthenia Gravis.

BACKGROUND: Hypermethylation of the growth hormone secretagogue receptor gene (GHSR) is increasingly observed in human cancers, suggesting that it could represent a pan-cancer biomarker of clinical interest. However, little is still known concerning GHSR methylation levels in thymic epithelial tumors, and particularly in thymomas from patients with Myasthenia Gravis (TAMG). MATERIAL AND METHODS: In the present study we collected DNA samples from circulating lymphocytes and surgically resected tumor tissues of 65 TAMG patients, and from the adjacent healthy thymic tissue available from 43 of t

Imunofan-RDKVYR Peptide-Stimulates Skin Cell Proliferation and Promotes Tissue Repair.

Regeneration and wound healing are vital to tissue homeostasis and organism survival. One of the biggest challenges of today's science and m … ce significant transcriptional responses, such as enhanced activity of genes involved in active DNA demethylation (p < 0.05) in fibroblasts and activation of genes involved in immune responses, migration, and chemotaxis in adipose-derived stem cells derived from surgery donors. Experiments in a model of ear pinna injury in mice indicated that IM moderately prom …

Mitochondrial dysfunction and DNA damage accompany enhanced levels of formaldehyde in cultured primary human fibroblasts.

Formaldehyde (FA) is a simple biological aldehyde that is produced inside cells by several processes such as demethylation of DNA and proteins, amino acid metabolism, lipid peroxidation and one carbon metabolism (1-C). Although accumulation of excess FA in cells is known to be cytotoxic, it is unknown if an increase in FA level might be associated with mitochondrial dysfunction. We choose to use primary human fibroblasts cells in culture (foreskin, FSK) as a physiological model to gain insight into whether an increase in the level of FA might affect cellular physiology, especially with regard …

Ligand binding to a humanized anti-cocaine mAb measured by dye absorption spectroscopy.

Here we demonstrate that the antigen binding function of a humanized anti-cocaine mAb (h2E2) can be directly and easily determined using simple and inexpensive absorption spectroscopy and dyes commonly used for differential scanning fluorimetry, such as DASPMI and SYPRO Orange. Therapeutic monoclonal antibodies are commonly formulated in buffers which can interfere with necessary functional assays, containing additives and excipients such as mild detergents. Using the undiluted therapeutic product h2E2 mAb in its formulation buffer containing 0.01% polysorbate 80, the number of antigen/cocaine

Small Molecules Targeting H3K9 Methylation Prevent Silencing of Reactivated FMR1 Alleles in Fragile X Syndrome Patient Derived Cells.

In fragile X syndrome (FXS), expansion of a CGG repeat tract in the 5'-untranslated region of the FMR1 gene to >200 repeats causes transcriptional silencing by inducing heterochromatin formation. Understanding the mechanism of FMR1 silencing is important as gene reactivation is a potential treatment approach for FXS. To date, only the DNA demethylating drug 5-azadeoxycytidine (AZA) has proved effective at gene reactivation; however, this drug is toxic. The repressive H3K9 methylation mark is enriched on the FMR1 gene in FXS patient cells and is thus a potential druggable target. However, its c

High methylmercury uptake by green algae in Lake Titicaca: Potential implications for remediation.

Anthropogenic pressure in the high altitude lakes such as Titicaca and Uru (Bolivia) may favor the production of methylmercury (MeHg) known to accumulate in trophic chains. Periphyton associated with emerged aquatic plants (totoras) from the lake shores accumulates and demethylates MeHg providing a potential cost-effective water treatment technique. In this laboratory study, we measured the MeHg uptake kinetics of a consortium of green algae isolated from Lake Titicaca totora's periphyton. The most abundant algal consortium, composed of Oedogonium spp., Chlorella spp., Scenedesmus spp., was ex

Phase II clinical trial of pazopanib in patients with acute myeloid leukemia (AML), relapsed or refractory or at initial diagnosis without an intensive treatment option (PazoAML).

We evaluated pazopanib (800 mg orally QD) in patients not eligible for intensive treatment with relapsed/refractory AML or at initial diagnosis. Patients receiving pazopanib for > 14 days were analyzed for safety, tolerability, and efficacy. Co-primary endpoints were cumulative response rate and reduction of bone marrow microvessel density. Twenty patients (median age 76 years, range 52-86) were treated. Fifteen had relapsed/refractory and five had newly diagnosed AML. Median ECOG performance status was 1 (range 1-3). Four patients had adverse, 15 intermediate, and 1 patient favorable cytogene

Profiling and comparison of the metabolites of diosmetin and diosmin in rat urine, plasma and feces using UHPLC-LTQ-Orbitrap MSn.

Diosmin (diosmetin-7-O-rutinoside) and its aglycone diosmetin, natural bioflavonoids distributing in a variety of citrus fruits and Chinese … tes and 64 diosmin metabolites were respectively identified in rat biological samples. Methylation, demethylation, hydroxylation, glycosylation, glucuronidation, diglucuronidation and sulfation were common metabolic pathways of diosmetin and diosmin, while demethoxylation, decarbonylation, dihydroxylation and dehydroxylation were particular metabolic pathways o …

Selenium and stable mercury isotopes provide new insights into mercury toxicokinetics in pilot whales.

High exposures of mammalian species to inorganic mercury (HgII) and methylmercury (MeHg) have been associated with adverse effects on behavior and reproduction. Different mammalian species exhibit varying responses to similar external exposure levels, reflecting potential differences in Hg toxicokinetics. Here, we use Hg stable isotopes, total Hg, MeHg and selenium (Se) concentrations measured in multiple tissues of North Atlantic pilot whales (Globicephala melas) to investigate processes affecting the distribution and accumulation of HgII and MeHg. We find that simple mixing of two distinct i

Lysine demethylase 3a in craniofacial and neural development during Xenopus embryogenesis.

Epigenetic modifier lysine demethylase 3a (Kdm3a) specifically demethylates mono‑ and di‑methylated ninth lysine of histone 3 and belongs to the Jumonji domain‑containing group of demethylases. Kdm3a serves roles during various biological and pathophysiological processes, including spermatogenesis and metabolism, determination of sex, androgen receptor‑mediated transcription and embryonic carcinoma cell differentiation. In the present study, physiological functions of Kdm3a were evaluated during embryogenesis of Xenopus laevis. Spatiotemporal expression pattern indicated that kdm3a exhibited i

Clinical significance of PCDH10 promoter methylation in diffuse large B-cell lymphoma.

BACKGROUND: PCDH10, one of the non-clustered protocadherins, is identified as a tumor suppressor gene in many tumors. Recently, promoter methylation of PCDH10 was found in diffuse large B-cell lymphoma (DLBCL) but not in normal lymph nodes, suggesting that its epigenetic aberrance is essential to the lymphomagenesis. However, there are few studies on the clinicopathological relevance and prognostic significance of PCDH10 methylation status in DLBCL. METHODS: One hundred-seven cases of DLBCL between Jan 2009 and Jul 2010 were selected to extract genomic DNA and perform bisulfite modification.

Metabolic profiling of five flavonoids from Dragon's Blood in human liver microsomes using high-performance liquid chromatography coupled with high resolution mass spectrometry.

Although much is known about the pharmacological activities of Dragon's Blood (DB, a traditional Chinese herb), its metabolism in human live … Sn data. The metabolic profile of the five flavonoids in HLMs involved hydroxylation, oxidation and demethylation. Among them, hydroxylation was the predominant biotransformation of the five flavonoids in HLMs, occurring in combination with other metabolic reactions. Assay with recombinant P450s revealed that CYP2C9 and CYP2C19 played an important role in the h …