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Pathogenic effects of Leu200Pro and Arg387His VRK1 protein variants on phosphorylation targets and H4K16 acetylation in distal hereditary motor neuropathy.

Rare recessive variants in the human VRK1 gene are associated with several motor neuron diseases (MND), such as amyotrophic lateral sclerosis, spinal muscular atrophy, or distal hereditary motor neuropathies (dHMN). A case with dHMN carrying two novel VRK1 gene variants, expressing Leu200Pro (L200P) and Arg387His (R387H) variant proteins, identified that these protein variants are functionally different. The Leu200Pro variant shares with several variants in the catalytic domain the loss of the kinase activity on different substrates, such as histones, p53, or coilin. However, the distal Arg387…

HDAC6 Deletion Decreases Pristane-induced Inflammation.

Systemic lupus erythematosus is an autoimmune disease characterized by excessive inflammation and production of pathogenic Abs. Histone deacetylase 6 (HDAC6) is a class IIb histone deacetylase. It has been reported that selective HDAC6 inhibition decreases inflammation in lupus mouse models. In this study, sex- and age-matched wild-type (WT) and HDAC6-/- mice on the C57BL/6 background were administered 0.5 ml of pristane or PBS i.p. at 8-12 wk of age and were euthanized 10 d later. At sacrifice, body weight and spleen weight were measured, sera were collected, and splenocytes and peritoneal ce

SIRT6 modulates lesion microenvironment in LPC induced demyelination by targeting astrocytic CHI3L1.

Demyelination occurs widely in the central nervous system (CNS) neurodegenerative diseases, especially the multiple sclerosis (MS), which with a complex and inflammatory lesion microenvironment inhibiting remyelination. Sirtuin6 (SIRT6), a histone/protein deacetylase is of interest for its promising effect in transcriptional regulation, cell cycling, inflammation, metabolism and longevity. Here we show that SIRT6 participates in the remyelination process in mice subjected to LPC-induced demyelination. Using pharmacological SIRT6 inhibitor or activator, we found that SIRT6 modulated LPC-induced

The role of chidamide in the treatment of B-cell non-Hodgkin lymphoma: An updated systematic review.

B-cell non-Hodgkin lymphoma (B-NHL) is a lymphoid malignancy derived from B-cells that remains difficult to treat. Moreover, relapses and refractory cases are common. Abnormalities in epigenetic mechanisms, such as imbalanced histone acetylation affecting certain genes, contribute to relapses and refractory cases. Chidamide (tucidinostat) is a novel histone deacetylase inhibitor that can reverse this epigenetic imbalance and has been approved for the treatment of T-cell malignancies. However, the use of chidamide for B-NHL remains limited, and the lack of relevant literature exacerbates this l

Endotheliitis and cytokine storm as a mechanism of clot formation in COVID-19 ischemic stroke patients: A histopathologic study of retrieved clots.

BackgroundStudies during the COVID-19 pandemic have demonstrated an association between COVID-19 virus infection and the development of acute ischemic stroke, particularly large vessel occlusion (LVO). Studying the characteristics and immunohistochemistry of retrieved stroke emboli during mechanical thrombectomy for LVO may offer insights into the pathogenesis of LVO in COVID-19 patients. We examined retrieved COVID-19 emboli from the STRIP, EXCELLENT, and RESTORE registries and compared their characteristics to a control group.MethodsWe identified COVID-positive LVO patients from the STRIP, R

SUV39H1 Inhibits Angiogenesis in Limb Ischemia of Mice.

Peripheral arterial disease (PAD), characterized by atherosclerosis of the peripheral arteries or even amputation, has threatened public life and health. However, the underlying mechanism remains largely obscure. SUV39H1, a histone methyltransferase, could specifically methylate lysine 9 of histone H3 and act as a repressor in transcriptional activity. The study aimed to investigate the role of SUV39H1 in limb ischemia. C57BL/6 male mice were randomly divided into Sham or Model groups to investigate the expression of SUV39H1 in the ischemic limbs. Then, pharmaceutical inhibition or genetic del

Epigenetic Regulation of Leukocyte Inflammatory Mediator Production Dictates Staphylococcus aureus Craniotomy Infection Outcome.

Staphylococcus aureus is a common cause of surgical-site infections, including those arising after craniotomy, which is performed to access the brain for the treatment of tumors, epilepsy, or hemorrhage. Craniotomy infection is characterized by complex spatial and temporal dynamics of leukocyte recruitment and microglial activation. We recently identified unique transcriptional profiles of these immune populations during S. aureus craniotomy infection. Epigenetic processes allow rapid and reversible control over gene transcription; however, little is known about how epigenetic pathways influen

Characterization of K562 cells: uncovering novel chromosomes, assessing transferrin receptor expression, and probing pharmacological therapies.

Human erythroleukemic K562 cells represent the prototypical cell culture model of chronic myeloid leukemia (CML). The cells are pseudo-triploid and positive for the Philadelphia chromosome. Therefore, K562 cells have been widely used for investigating the BCR/ABL1 oncogene and the tyrosine kinase inhibitor, imatinib-mesylate. Further, K562 cells overexpress transferrin receptors (TfR) and have been used as a model for targeting cytotoxic therapies, via receptor-mediated endocytosis. Here, we have characterized K562 cells focusing on the karyotype of cells in prolonged culture, regulation of ex

Targeting the E2F1/Rb/HDAC1 axis with the small molecule HR488B effectively inhibits colorectal cancer growth.

Colorectal cancer (CRC), the third most common cancer worldwide, remains highly lethal as the disease only becomes symptomatic at an advanced stage. Growing evidence suggests that histone deacetylases (HDACs), a group of epigenetic enzymes overexpressed in precancerous lesions of CRC, may represent promising molecular targets for CRC treatment. Histone deacetylase inhibitors (HDACis) have gradually become powerful anti-cancer agents targeting epigenetic modulation and have been widely used in the clinical treatment of hematologic malignancies, while only few studies on the benefit of HDACis in

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… As an important epigenetic eraser, histone deacetylases (HDACs) remove acetyl groups from the N-acetylated lysine residues in the tail of histones, resulting in chromatin condensation and impacting gene expression [ 6 ]. … Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders. Nat Rev Drug Discov. 2014;13:673–91. doi: 10.1038/nrd4360. 7. Shvedunova M, Akhtar A. Modulation of cellular processes by histone and non-histone protein acetylation. …

Inhibition of Ezh2 redistributes bivalent domains within transcriptional regulators associated with WNT and Hedgehog pathways in osteoblasts.

Bivalent epigenomic regulatory domains containing both activating histone 3 lysine 4 (H3K4me3) and repressive lysine 27 (H3K27me3) trimethylation are associated with key developmental genes. These bivalent domains repress transcription in the absence of differentiation signals but maintain regulatory genes in a poised state to allow for timely activation. Previous studies demonstrated that enhancer of zeste homolog 2 (Ezh2), a histone 3 lysine 27 (H3K27) methyltransferase, suppresses osteogenic differentiation and that inhibition of Ezh2 enhances commitment of osteoblast progenitors in vitro a

Impact of DNA methylation of the human mesoderm-specific transcript (MEST) on male infertility.

Male infertility accounts for nearly 40%-50% of all infertile cases. One of the most prevalent disorders detected in infertile men is errors in the MEST differentially methylated region (DMR), which has been correlated with poor sperm indexes. The aim of our study was to characterize the methylation pattern of the MEST gene, along with assessing seminal factors and chromatin condensation in sperm samples from both infertile patients and fertile cases, all of whom were candidates for intracytoplasmic sperm injection. We collected forty-five semen specimens from men undergoing routine spermiogra

2,3,7,8-Tetrachlorodibenzo-p-dioxin induces multigenerational alterations in the expression of microRNA in the thymus through epigenetic modifications.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a potent AhR ligand, is an environmental contaminant that is known for mediating toxicity across generations. However, whether TCDD can induce multigenerational changes in the expression of microRNAs (miRs) has not been previously studied. In the current study, we investigated the effect of administration of TCDD in pregnant mice (F0) on gestational day 14, on the expression of miRs in the thymus of F0 and subsequent generations (F1 and F2). Of the 3200 miRs screened, 160 miRs were dysregulated similarly in F0, F1, and F2 generations, while 46 miRs w

In Vivo Genome-Wide PGR Binding in Pregnant Human Myometrium Identifies Potential Regulators of Labor.

The alterations in myometrial biology during labor are not well understood. The myometrium is the contractile portion of the uterus and contributes to labor, a process that may be regulated by the steroid hormone progesterone. Thus, human myometrial tissues from term pregnant in-active-labor (TIL) and term pregnant not-in-labor (TNIL) subjects were used for genome-wide analyses to elucidate potential future preventive or therapeutic targets involved in the regulation of labor. Using myometrial tissues directly subjected to RNA sequencing (RNA-seq), progesterone receptor (PGR) chromatin immunop

The comprehensive assessment of epigenetics changes during skin development.

Epigenetic regulation is critical to multiple physiological and pathological processes. However, little is known regarding the epigenetic changes during neonatal skin development and skin aging, and in response to ultraviolet (UV) exposure. The transcriptomes of human skin samples from different ages or irradiated with different types and doses of UV light were analyzed using R (version 4.0.3) software. The epigenetic landscape of the skin, including histone modifications, genetic imprinting and m6A modification, which are mainly involved in collagen formation, extracellular matrix organizatio

Inflammasome activation in neutrophils of patients with severe COVID-19.

Infection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) engages the inflammasome in monocytes and macrophages and leads to the cytokine storm in COVID-19. Neutrophils, the most abundant leukocytes, release neutrophil extracellular traps (NETs), which have been implicated in the pathogenesis of COVID-19. Our recent study shows that activation of the NLRP3 inflammasome is important for NET release in sterile inflammation. However, the role of neutrophil inflammasome formation in human disease is unknown. We hypothesized that SARS-CoV-2 infection may induce inflammasome acti

Epigenetic Mechanisms as Emerging Therapeutic Targets and Microfluidic Chips Application in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a disease that progress over time and is defined as an increase in pulmonary arterial pressure and pulmonary vascular resistance that frequently leads to right-ventricular (RV) failure and death. Epigenetic modifications comprising DNA methylation, histone remodeling, and noncoding RNAs (ncRNAs) have been established to govern chromatin structure and transcriptional responses in various cell types during disease development. However, dysregulation of these epigenetic mechanisms has not yet been explored in detail in the pathology of pulmonary arterial h

Shaking up the silence: consequences of HMGN1 antagonizing PRC2 in the Down syndrome brain.

Intellectual disability is a well-known hallmark of Down Syndrome (DS) that results from the triplication of the critical region of human chromosome 21 (HSA21). Major studies were conducted in recent years to gain an understanding about the contribution of individual triplicated genes to DS-related brain pathology. Global transcriptomic alterations and widespread changes in the establishment of neural lineages, as well as their differentiation and functional maturity, suggest genome-wide chromatin organization alterations in trisomy. High Mobility Group Nucleosome Binding Domain 1 (HMGN1), exp

Antenatal Dexamethasone Exposure Impairs Vascular Contractile Functions via Upregulating IP3 Receptor 1 and Cav1.2 in Adult Male Offspring.

BACKGROUND: Administration of antenatal glucocorticoids remains common practice for treating preterm delivery. Antenatal glucocorticoid exposure increased the risk of developing vascular diseases in later life, but the precise mechanisms remain unclear. This study aimed to explore the effects and mechanisms of antenatal exposure to clinically relevant doses of dexamethasone (synthetic glucocorticoids) on vascular functions in adult male offspring. METHODS: Pregnant Sprague-Dawley rats received dexamethasone or vehicle during the last week of pregnancy. Male offspring were killed at gestationa

Increased MYBL2 expression in aggressive hormone-sensitive prostate cancer.

Loss of the histone demethylase KDM5D (lysine-specific demethylase 5D) leads to in vitro resistance of prostate cancer cells to androgen deprivation therapy (ADT) with and without docetaxel. We aimed to define downstream drivers of the KDM5D effect. Using chromatin immunoprecipitation sequencing (ChIP-seq) of the LNCaP cell line (androgen-sensitive human prostate adenocarcinoma) with and without silenced KDM5D, MYBL2-binding sites were analyzed. Associations between MYBL2 mRNA expression and clinical outcomes were assessed in cohorts of men with localized and metastatic hormone-sensitive prost

HDAC inhibitors Panobinostat and Romidepsin enhance tax transcription in HTLV-1-infected cell lines and freshly isolated patients' T-cells.

The viral transactivator Tax plays a key role in HTLV-1 reactivation and de novo infection. Previous approaches focused on the histone deacetylase inhibitor (HDACi) Valproate as a latency-reversing agent to boost Tax expression and expose infected cells to the host's immune response. However, following treatment with Valproate proviral load decreases in patients with HAM/TSP were only transient. Here, we hypothesize that other compounds, including more potent and selective HDACi, might prove superior to Valproate in manipulating Tax expression. Thus, a panel of HDACi (Vorinostat/SAHA/Zolinza,