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Abstract Objective This study aimed to investigate the function and mechanism of neddylation of HDAC1 underlying drug resistance of AML cells. Methods Evaluation experiments of effects of HDAC1 on drug resistance of AML cells were performed with AML cell transfected with constructs overexpressing HDAC1 or multi-drug resistance AML cells transfected with siRNA for HDAC1 through observing cell viability, percentage of apoptotic cell, doxorubicin-releasing index and multidrug resistance associated protein 1 (MRP1) expression. Neddylation or ubiquitination of HDAC1 was determined by immunoprecipitation or Ni2+ pull down assay followed by western blot. The role of HDAC1 was in vivo confirmed by xenograft in mice. Results HDAC1 was significantly upregulated in refractory AML patients, and in drug-resistant AML cells (HL-60/ADM and K562/A02). Intracellular HDAC1 expression promoted doxorubicin resistance of HL-60, K562, and primary bone marrow cells (BMCs) of remission AML patients as shown by increasing cell viability and doxorubicin-releasing index, inhibiting cell apoptosis. Moreover, HDAC1 protein level in AML cells was regulated by the Nedd8-mediated neddylation and ubiquitination, which further promoted HDAC1 degradation. In vivo, HDAC1 overexpression significantly increased doxorubicin resistance; while HDACs inhibitor Panobinostat markedly improved the inhibitory effect of doxorubicin on tumor growth. Furthermore, HDAC1 silencing by Panobinostat and/or lentivirus mediated RNA interference against HDAC1 effectively reduced doxorubicin resistance, resulting in the inhibition of tumor growth in AML bearing mice. Conclusion Our findings suggested that HDAC1 contributed to the multidrug resistance of AML and its function turnover was regulated, at least in part, by post-translational modifications, including neddylation and ubiquitination.

Non-drug strategy targeting adipocyte differentiation is critical for alleviating visceral obesity and its related diseases. However, whether and how low intensity pulsed ultrasound (LIPUS) could be used for inhibiting visceral adipocyte differentiation is not fully understood. In this study, we aim to investigate the effect and associated mechanism of LIPUS on primary visceral preadipocyte differentiation and explore its potential role for clinical visceral obesity management. The preadipocytes were daily exposed to LIPUS (0.5 MHz, 1.2 MPa) for 10 min. Adipogenic differentiation was estimated by the formation of lipid droplets and the levels of adipogenic transcriptional factors and representative markers. Mitogen-activated protein kinase (MAPK) member proteins and histone acetylation-related molecules were measured by western blotting. LIPUS stimulation with an average acoustic pressure of 1.2 MPa led to a prominent inhibition of adipogenic differentiation and expression of adipogenic markers. As a mechanism, LIPUS treatment increased the nuclear levels of histone deacetylase 1 (HDAC1) and decreased the acetylation of histone 3 and histone 4. Meanwhile, the inhibition of the HDAC1 could block the inhibitory effect of LIPUS on adipogenic differentiation via increasing AcH3 and AcH4 levels. Our study may provide an ultrasound-based promising strategy for clinical visceral obesity control.

Objective: Histone acetylation is an important mechanism in the regulation of gene expression and plays a crucial role in both cellular development and cellular response to external or internal stimuli. One key aspect of this form of regulation is that acetylation marks can be added and removed from sites of regulation very quickly through the activity of histone acetyltransferases (HATs) and histone deacetylases (HDACs). The activity of both HATs and HDACs has been shown to be important for both physiological hematopoiesis as well as during development of hematological neoplasia, such as lymphomas. In the present study we analyzed the effect of knockout of the two HDACs, Hdac1 and Hdac2 in cells expressing the fractalkine receptor (Cx3cr1) on lymphocyte development. Results: We report data showing a maturation defect in mice harboring a Cx3cr1 dependent knockout of Hdac1 and 2. Furthermore, we report that these mice develop a T-cell neoplasia at about 4–5 months of age, suggesting that a Cx3cr1 expressing subpopulation of immature T-cells gives rise to T-cell lymphomas in the combined absence of Hdac1 and Hdac2. [ABSTRACT FROM AUTHOR]

Background: Atherosclerosis (AS) is the most common type in cardiovascular disease. Due to its complex pathogenesis, the exact etiology of AS is unclear. circRNA has been shown to play an essential role in most diseases. However, the underlying mechanism of circRNA in AS has been not understood clearly. Methods: Quantitative Real-Time PCR assay was used to detect the expression of circRSF1, miR-135b-5p and histone deacetylase 1 (HDAC1). Western blot was applied to the measure of protein expression of HDAC1, B-cell lymphoma-2 (Bcl-2), BCL2-associated X (Bax), cleaved-caspase-3, vascular cell adhesion molecule 1 (VCAM1), intercellular cell adhesion molecule-1 (ICAM1) and E-selectin. MTT assay and flow cytometry were used to detect cell proliferation and apoptosis, respectively. Dual luciferase reporter assay and RIP assay was used to determine the relationship among circRSF1, miR-135b-5p and HDAC1. Besides, an ELISA assay was performed to measure the levels of IL-1β, IL-6, TNF-α and IL-8. Results: In this study, ox-LDL inhibited circRSF1 and HDAC1 expression while upregulated miR-135b-5p expression in Human umbilical vein endothelial cells (HUVECs). Importantly, ox-LDL could inhibit HUVECs growth. Moreover, promotion of circRSF1 or inhibition of miR-135b-5p induced cell proliferation while inhibited apoptosis and inflammation of ox-LDL-treated HUVECs, which was reversed by upregulating miR-135b-5p or downregulating HDCA1 in ox-LDL-treated HUVECs. More than that, we verified that circRSF1 directly targeted miR-135b-5p and HDAC1 was a target mRNA of miR-135b-5p in HUVECs. Conclusion: CircRSF1 regulated ox-LDL-induced vascular endothelial cell proliferation, apoptosis and inflammation through modulating miR-135b-5p/HDAC1 axis in AS, providing new perspectives and methods for the treatment and diagnosis of AS. [ABSTRACT FROM AUTHOR]

Exendin-4 has been found to have hypoglycemic effect and prevent bone loss in diabetic patients, but its mechanism of preventing bone loss is still unclear. In this study, high-fat diet combined with streptozotocin was used to establish type 2 diabetes mellitus (T2DM) mice, and bone marrow mesenchyme stem cells (BMSCs) were isolated for osteogenic induction in vitro. Alizarin red staining and ALP activity detection were used to observe the effect of exendin-4 on osteogenic differentiation of BMSCs. Western blot was used to detect the proteins expression in BMSCs. In vivo, the effects of exendin-4 treatment on body weight, blood glucose, bone density and bone quality of T2DM mice were observed by treatment with exendin-4. The results showed that exendin-4 promoted osteogenic differentiation of T2DM derived BMSCs, down-regulated histone deacetylase 1 (HDAC1) and p-β-Catenin proteins expression, and up-regulated Wnt3, β-Catenin and runt-related transcription factor 2 (Runx 2) proteins expression. In vivo, exendin-4 effectively suppressed the blood glucose and increased body weight of T2DM mice, and significantly improved bone density and bone quality of the right tibia. Interestingly, by over-expression of HDAC1 in BMSCs, the effect of exendin-4 on promoting osteogenic differentiation of BMSCs was attenuated, and the regulation of Wnt3a, β-Catenin, p-β-Catenin or Runx2 proteins were reversed. By injecting adenovirus containing HDAC1 into the right tibia of mice, the effect of exendin-4 on bone density and bone quality of T2DM mice was significantly attenuated. All above results suggest that the HDAC1-Wnt/β-Catenin signal axis is involved in the anti-diabetic bone loss effect of exendin-4, and HDAC1 may be the target of exendin-4. • Exendin-4 could prevent bone loss in diabetic patients. • Exendin-4 promotes differentiation of BMSCs derived from T2DM mice into osteoblasts. • Over-expression HDAC1 could attenuate the effects of exendin-4. • Exendin-4 targets HDAC1-Wnt/β-catenin signal axis to ameliorate diabetic osteoporosis. [ABSTRACT FROM AUTHOR]

We reported that high salt (HS) intake stimulates renal collecting duct (CD) endothelin (ET) type B receptor (ETBR)/nitric oxide (NO) synthase 1β (NOS1β)-dependent NO production inhibiting the epithelial sodium channel (ENaC) promoting natriuresis. However, the mechanism underlying the HS-induced increase of NO production is unclear. Histone deacetylase 1 (HDAC1) responds to increased fluid flow, as can occur in the CD during HS intake. The renal inner medulla (IM), in particular the IMCD, has the highest NOS1 activity within the kidney. Hence, we hypothesized that HS intake provokes HDAC1 activation of NO production in the IM. HS intake for 1 wk significantly increased HDAC1 abundance in the IM. Ex vivo treatment of dissociated IM from HS-fed mice with a selective HDAC1 inhibitor (MS-275) decreased NO production with no change in ET-1 peptide or mRNA levels. We further investigated the role of the ET-1/ETBR/NOS1β signaling pathway with chronic ETBR blockade (A-192621). Although NO was decreased and ET-1 levels were elevated in the dissociated IM from HS-fed mice treated with A-192621, ex vivo MS-275 did not further change NO or ET-1 levels suggesting that HDAC1-mediated NO production is regulated at the level or downstream of ETBR activation. In split-open CDs from HS-fed mice, patch clamp analysis revealed significantly higher ENaC activity after MS-275 pretreatment, which was abrogated by an exogenous NO donor. Moreover, flow-induced increases in mIMCD-3 cell NO production were blunted by HDAC1 or calcium inhibition. Taken together, these findings indicate that HS intake induces HDAC1-dependent activation of the ETBR/NO pathway contributing to the natriuretic response. [ABSTRACT FROM AUTHOR]

Background: Previous research has highlighted the ability of Homeobox A10 (HOXA10) to the promote proliferation, migration, and epithelial-mesenchymal transformation of various cancers, including lung adenocarcinoma (LAD), which is characterized by an aggressive disease course that exhibits rapid proliferation and migration, with studies suggesting histone deacetylase 1 (HDAC1) to be a downstream mediator of HOXA10. The current study aimed to investigate the mechanism by which HOXA10-mediated HDAC1 influences the development of LAD. Methods: The expression patterns of HOXA10, HDAC1, DNA methyltransferase 1 (DNMT1), and Kruppel-like factor 4 (KLF4) were determined. Additionally, the effect of HOXA10, HDAC1, or DNMT1 on invasive phenotypes of LAD was analyzed using depletion experiments. The interactions among HOXA10, HDAC1, DNMT1, and KLF4 were evaluated via chromatin immunoprecipitation, dual luciferase assay or co-immunoprecipitation. Furthermore, the tumorigenic ability of the LAD cells following HOXA10 silencing and/or HDAC1 overexpression in vivo was also investigated. Results: In the LAD tissues and cells, HOXA10, HDAC1, and DNMT1 all exhibited high levels of expression, while KLF4 was poorly expressed. HOXA10 silencing inhibited the expression of HDAC1, reduced LAD cell proliferation, migration, and invasion, and promoted the apoptosis. HDAC1 promoted DNMT1 expression through deacetylation, and DNMT1 inhibited the KLF4 expression through DNA methyltransferase. The in vitro findings were further attested through the use of in vivo assays. Conclusion: Taken together, the key observations of the current study highlight the role of HOXA10 and HDAC1 in promoting the proliferation and migration of LAD cells. HOXA10-induced upregulation of HDAC1 interacts with DNMT1-KLF4 axis, while the inhibition of HOXA10 or HDAC1 represents a promising anti-tumor therapy target for LAD. [ABSTRACT FROM AUTHOR]

Class I histone deacetylases, HDAC1, HDAC2, and HDAC3, represent potential targets for cancer treatment. However, the development of isoform-selective drugs for these enzymes remains challenging due to their high sequence and structural similarity. In the current study, we applied a computational approach to predict the selectivity profile of developed inhibitors. Molecular docking followed by MD simulation and calculation of binding free energy was performed for a dataset of 2-aminobenzamides comprising 30 previously developed inhibitors. For each HDAC isoform, a significant correlation was found between the binding free energy values and in vitro inhibitory activities. The predictive accuracy and reliability of the best preforming models were assessed on an external test set of newly designed and synthesized inhibitors. The developed binding free-energy models are cost-effective methods and help to reduce the time required to prioritize compounds for further studies.

Background: Cancer stem cells (CSCs) are the root of human cancer development and the major cause of treatment failure. Aberrant elevation of SOX4, a member of SOX (SRY-related HMG-box) family transcription factors, has been identified in many types of human cancer and promotes cancer development. However, the role of SOX4 in CSCs, especially at a proteome-wide level, has remained elusive. The aim of this study is to investigate the effect of SOX4 on the stemness of CSCs and reveal the underlying mechanisms by identification of SOX4-induced proteome changes through proteomics study. Results: Overexpression of SOX4 promotes sphere formation and self-renewal of colorectal cancer cells in vitro and in vivo and elevates the expression levels of CSCs markers. Through iTRAQ-based quantitative proteomics analysis, 215 differentially expressed proteins (128 upregulated, 87 downregulated) in SOX4-overexpressing HCT-116 spheres were identified. The bioinformatic analysis highlighted the importance of HDAC1 as the fundamental roles of its impacted pathways in stem cell maintenance, including Wnt, Notch, cell cycle, and transcriptional misregulation in cancer. The mechanistic study showed that SOX4 directly binds to the promoter of HDAC1, promotes HDAC1 transcription, thereby supporting the stemness of colorectal cancer cells. HDAC1 hallmarks colorectal cancer stem cells and depletion of HDAC1 abolished the stimulatory effect of SOX4. Furthermore, SOX4-HDAC1 axis is conserved in multiple types of cancer. Conclusions: The results of this study reveal SOX4-induced proteome changes in HCT-116 spheres and demonstrates that transcriptional activation of HDAC1 is the primary mechanism underlying SOX4 maintaining CSCs. This finding suggests that HDAC1 is a potential drug target for eradicating SOX4-driven human CSCs. [ABSTRACT FROM AUTHOR]

Nerve injury is an important reason of human disability and death. We studied the role of histone deacetylation in the response of the dorsal root ganglion (DRG) cells to sciatic nerve transection. Sciatic nerve transection in the rat thigh induced overexpression of histone deacetylase 1 (HDAC1) in the ipsilateral DRG at 1–4 h after axotomy. In the DRG neurons, HDAC1 initially upregulated at 1 h but then redistributed from the nuclei to the cytoplasm at 4 h after axotomy. Histone H3 was deacetylated at 24 h after axotomy. Deacetylation of histone H4, accumulation of amyloid precursor protein, a nerve injury marker, and GAP-43, an axon regeneration marker, were observed in the axotomized DRG on day 7. Neuronal injury occurred on day 7 after axotomy along with apoptosis of DRG cells, which were mostly the satellite glial cells remote from the site of sciatic nerve transection. Administration of sodium valproate significantly reduced apoptosis not only in the injured ipsilateral DRG but also in the contralateral ganglion. It also reduced the deacetylation of histones H3 and H4, prevented axotomy-induced accumulation of amyloid precursor protein, which indicated nerve injury, and overexpressed GAP-43, a nerve regeneration marker, in the axotomized DRG. Therefore, HDAC1 was involved in the axotomy-induced injury of DRG neurons and glial cells. HDAC inhibitor sodium valproate demonstrated the neuroprotective activity in the axotomized DRG. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To investigate the effect of microRNA-449 (miRNA-449) on cTnI and cardiac function and reveal the mechanism of Histone deacetylase 1 (HDAC1)-mediated histone deacetylation in cardiomyocytes. MATERIALS AND METHODS: First, we used biochemical analysis and Dual-Luciferase reporter gene assay to confirm that HDAC1 and miR-449 having the binding site. Then, the effect of miR-449 inhibited HDAC1 on cTnI gene transcription was observed. In vivo, the effect of histone acetylation on cTnI expression and cardiac function in heart was observed in elderly mice with low expression of cTnI through miR-449 agomiR intervention. RESULTS: This study revealed miR-449 can sponge with HDAC1. HDAC1-mediated histone deacetylation was involved in the regulation of cTnI gene expression by HDAC1-mediated acetylation of H3K4 and H3K9 in cTnI promoter regions. In addition, HDAC1-mediated histone deacetylation regulated the binding of the transcription factor GATA4 to the GATA element in the cTnI promoter region and improved cardiac function in elderly mice with low expression of cTnI CONCLUSIONS: MiR-449 can regulate the acetylation of the histones H3K4 and H3K9 of the GATA element in the cTnI promoter region, thereby recruiting the transcription factor GATA4 to the cTnI promoter region, upregulating the cTnI gene expression, and improving cardiac function in elderly mice with low expression of cTnI. [ABSTRACT FROM AUTHOR]

Although much progress has been made in the diagnosis and treatment of thoracic aortic dissection (TAD), the overall morbidity and mortality rates of TAD are still high. Therefore, the molecular pathogenesis and etiology of TAD need to be elucidated. In this study, we found that histone deacetylase 1 (HDAC1) expression is dramatically higher in the aortic wall of patients with TAD (than that in a normal group) and negatively correlates with the levels of the vascular smooth muscle cell (SMC) contractile‐phenotype markers. Knockdown of HDAC1 upregulated both smooth muscle 22 α (SM22α) and α‐smooth muscle actin (α‐SMA) in platelet‐derived growth factor (PDGF)‐BB‐treated and ‐untreated SMCs. In addition, the knockdown of HDAC1 markedly decreased SMC viability and migration in contrast to the control group under the conditions of quiescence and PDGF‐BB treatment. We also showed that the expression of polycystic kidney disease 1 (PKD1) is decreased in the aortic wall of patients with TAD and negatively correlates with HDAC1 expression. Overexpressed PKD1 obviously increased SM22α and α‐SMA expression and reduced the viability and migration of SMCs, but these effects were attenuated by HDAC1. Furthermore, we demonstrated that HDAC1 serves as an important modulator of the migration and phenotypic switch of SMCs by suppressing the PKD1– mammalian target of the rapamycin signaling pathway. HDAC1 downregulation inhibited media degeneration and attenuated the loss of elastic–fiber integrity in a mouse model of TAD. Our results suggest that HDAC1 might be a new target for the treatment of a macrovascular disease such as TAD. [ABSTRACT FROM AUTHOR]

The effects of two lyophilized extracts obtained from the aerial parts of Thymus marschallianus Willd. and harvested from wild flora (TMW) and obtained from culture (TMC) were evaluated in Wistar rats with experimentally induced hyperglycemia. The hyperglycemia was induced by streptozotocin (STZ) administration and the obtained results were evaluated in comparison for TMW and TMC. The polyphenolic composition of extracts was evaluated by spectrophotometrical and LC-MS methods. In vitro antioxidant capacity assays (DPPH, FRAP, EPR) were performed in order to preliminary establish the ability of tested samples to protect against free radical induced damage. Afterwards, the effects of these extracts were assessed in vivo on rats with experimental-induced hyperglycemia. Oxidative stress biomarkers (e.g. malondialdehyde—MDA), phosphorylated transcription factor subunit of nuclear kappaB (NF-kB) p65, methyl CpG binding protein (MECP) 2 and histone deacetylase 1 (HDAC1) expressions in hippocampus and frontal lobe were assessed. Open Field Test (OFT) and Elevated Plus Maze (EPM) were conducted on tested animals. Malondialdehyde (MDA) levels and HDAC1and MeCP2 expressions increased significantly in hippocampus (p

Summary: UHRF1 is a key regulator in DNA methylation maintenance. It binds histone H3K9me2/3 and hemi-methylated DNA and recruits DNMT1 to DNA replication forks during S phase. However, the regulatory mechanism of hemi-methylated DNA binding activity of UHRF1 remains unknown. In this study, we reveal that acetylation of UHRF1 is regulated by PCAF and HDAC1. We show that UHRF1 acetylation at K490 attenuates its binding affinity to hemi-methylated DNA. We analyze genome-wide DNA methylation and gene-expression patterns using stable cell lines and discover that cells where the endogenous UHRF1 is replaced with an acetyl-mimetic (UHRF1 K490Q) mutant show deficiencies in inherited DNA methylation and show different gene-expression patterns in genes related to cell survival. These results reveal that precise regulation of UHRF1 acetylation is required to maintain DNA methylation during cell division and control cell survival.

Colistin has been considered as the last line of defense against Gram-negative bacterial infections, however, the potential nephrotoxicity limited its clinical use. 7-Hydroxycoumarin (7-HC) possesses many beneficial pharmacological activities. This study aimed to investigate the nephroprotective effects of 7-HC against colistin-induced kidney injury. In vivo experiments showed that 7-HC alleviated kidney injury induced by colistin, as indicated by lower levels of serum neutrophil gelatinase-associated lipocalin, blood urea nitrogen and creatinine levels. Both in vivo and in vitro results demonstrated that 7-HC alleviated oxidative stress and apoptosis induced by colistin, as shown by decreased malondialdehyde levels, decreased caspase-3 and caspase-9 activities, and increased superoxide dismutase and catalase activities. We also found that colistin significantly induced histone deacetylase (HDAC) 1 expression that deacetylated histone 3 at Lys27 acetylation (H3K27AC) of Nrf2 promoter region and hence inhibiting Nrf2 signaling. 7-HC treatment restored histone acetylation at the Nrf2 promoter region and hence promoted Nrf2 expression. These results suggested that 7-HC alleviates colistin-induced renal injury and this effect was achieved by enhancement of renal antioxidant capacity with the decreased level of HDAC1 and the activation of Nrf2 signaling pathway.

The mitotic deacetylase complex (MiDAC) is a recently identified histone deacetylase (HDAC) complex. While other HDAC complexes have been implicated in neurogenesis, the physiological role of MiDAC remains unknown. Here, we show that MiDAC constitutes an important regulator of neural differentiation. We demonstrate that MiDAC functions as a modulator of a neurodevelopmental gene expression program and binds to important regulators of neurite outgrowth. MiDAC upregulates gene expression of pro-neural genes such as those encoding the secreted ligands SLIT3 and NETRIN1 (NTN1) by a mechanism suggestive of H4K20ac removal on promoters and enhancers. Conversely, MiDAC inhibits gene expression by reducing H3K27ac on promoter-proximal and -distal elements of negative regulators of neurogenesis. Furthermore, loss of MiDAC results in neurite outgrowth defects that can be rescued by supplementation with SLIT3 and/or NTN1. These findings indicate a crucial role for MiDAC in regulating the ligands of the SLIT3 and NTN1 signaling axes to ensure the proper integrity of neurite development.

Quinoa peptides are the bioactive components obtained from quinoa protein digestion, which have been proved to possess various biological activities. However, there are few studies on the anticancer activity of quinoa peptides, and the mechanism has not been clarified. In this study, the novel quinoa peptides were obtained from quinoa protein hydrolysate and identified by liquid chromatography–tandem mass spectrometry (LC–MS/MS). The anticancer activity of these peptides was predicted by PeptideRanker and evaluated using an antiproliferative assay in colon cancer Caco-2 cells. Combined with the result of histone deacetylase 1 (HDAC1) inhibitory activity assay, the highly anticancer activity peptides FHPFPR, NWFPLPR, and HYNPYFPG were screened and further investigated. Molecular docking was used to analyze the binding site between peptides and HDAC1, and results showed that three peptides were bound in the active pocket of HDAC1. Moreover, real-time quantitative polymerase chain reaction (RT-qPCR), and Western blot showed that the expression of HDAC1, NFκB, IL-6, IL-8, Bcl-2 was significantly decreased, whereas caspase3 expression showed a remarkable evaluation. In conclusion, quinoa peptides may have the potential to protect against cancer development by inhibiting HDAC1 activity and regulating the expression of the cancer-related genes, which indicates that these peptides could be explored as functional foods to alleviate colon cancer.

This study elucidated how polyphenols from mango (Mangifera Indica L.) affect gut microbiota composition and SCFAs production in rats with DSS-induced colitis. Rats were administered either control or mango beverage for nine weeks, exposed to three cycles of 3% DSS with a 2-week recovery period. Mango intake caused a significant increase in tannase-producing bacteria Lactobacillus plantarum and Lactococcus lactis (p = 0.0494 and 0.0312, respectively), and butyrate-producing bacteria Clostridium butyrium (p = 0.0494). The concentrations of butyrate and valerate were increased by 150% and 119% in mango group. Mango beverage intake reduced HDAC1 activity, and induced the expressions of AMPK and the ratio of cleaved/total LC3A/B. The butyrate and pyrogallol production by mango intake may have contributed to the modulation of the HDAC1/AMPK/LC3 axis, confirmed in vitro. These results suggest mango intake mitigates inflammation in a DSS-induced colitis model partly by altering microbial composition and SCFAs production, and modulating the HDAC1/AMPK/LC3 axis.

MicroRNAs (miRNAs) are a class of small non-coding RNAs (ncRNAs) that regulate gene expression by repressing translation or triggering the degradation of complementary mRNA sequences. Certain miRNAs have been shown to function as integral components of the p53 and/or retinoblastoma (Rb) regulatory networks. As such, miRNA dysregulation can have a profound effect on cancer development. Previous studies have shown that miR-449a is down-regulated in human prostate cancer tissue and possesses potential tumor suppressor function. In the present study, we identify miR-449a-mediated growth arrest in prostate cancer cells is dependent on the Rb protein. We show that mutant Rb prostate cancer cells (DU- 145) are resistant to cell cycle arrest and cellular senescence induced by miR- 449a, while overexpression of wild-type Rb in DU-145 sublines (DU-1.1 and B5) restores miR-449a function. In silico analysis of 3'UTR regions reveal a putative miR-449a target site in the transcript of Cyclin D1 (CCND1); an oncogene involved in directly regulating Rb activity and cell cycle progression. Luciferase 3'UTR reporter constructs and inhibitory oligonucleotides confirm that Cyclin D1 is a direct downstream target of miR-449a. We also reveal that miR-449a suppresses Rb phosphorylation through the knockdown of Cyclin D1 and previously validated target HDAC1. By targeting genes involved in controlling Rb activity, miR- 449a regulates growth and senescence in an Rb-dependent manner. These data indicate that miR-449a is a miRNA component of the Rb pathway and its tumor suppressor-like effects, in part, depends on Rb status in prostate cancer cells.

Background/Aims: Cisplatin-based treatment is first-line chemotherapy for several cancers including ovarian cancer. The development of cisplatin resistance results in treatment failure, but the underlying mechanisms are not fully understood. Histone deacetylases (HDACs) are a large family of enzymes that deacetylate lysine residues on histones and non-histone proteins. High expression of HDAC1 is associated with poor outcomes in ovarian cancer. Furthermore, resistance to chemotherapeutic agents is associated with HDAC1 overexpression in ovarian cancer cells. The goals of this study were to determine whether targeting HDAC1 can sensitize ovarian cancer cells to cisplatin and to explore the underlying mechanisms. Methods: Small interfering RNA (siRNA)-targeting HDAC1 was designed to silence HDAC1 in the cisplatin-resistant ovarian cancer cell line A2780CDDP and its cisplatin-sensitive cell line A2780. The effects of targeting HDAC1 on cell viability assay, colony formation, and apoptosis were detected. c-Myc re-expression or miR-34a inhibitors were used to examine the relationship among HDAC1, c-Myc, and miR-34a expression, which was assessed by western blot analysis and quantitative reverse transcription PCR. We established stable transfectants of A2780CDDP/HDAC1 short hairpin RNA (shRNA) and A2780/HDAC1 shRNA. The therapeutic effectiveness of cisplatin in murine xenograft models was assessed following shRNA-mediated HDAC1 silencing in A2780CDDP and A2780 cells. The mechanism of cell death was studied in tumor sections obtained from different mouse tumors. Results: In cisplatin-resistant A2780CDDP cells, HDAC1 knockdown by siRNA suppressed cell proliferation, and increased apoptosis and chemosensitivity by downregulating c-Myc and upregulating miR-34a. In cisplatin-sensitive A2780 cells, HDAC1 knockdown did not affect cell proliferation and apoptosis. Cisplatin treatment activated HDAC1 and c-Myc and inactivated miR-34a. Inhibition of HDAC1 with siRNA reduced c-Myc expression, increased miR-34a expression, and sensitized A2780 cells to cisplatin-induced apoptosis. c-Myc re-expression or miR-34a targeting by miR-34a inhibitors protected cells from apoptosis or reversed cisplatin resistance following HDAC1 knockdown or/and cisplatin exposure. Finally, in vivo studies showed that targeting HDAC1 inhibited A2780CDDP-induced xenograft tumor growth but not A2780-induced xenograft tumor growth. Targeting HDAC1 sensitized both A2780- and A2780CDDP-induced xenograft tumors to cisplatin treatment. Conclusions: Upregulation of HDAC1 is a crucial event in the development of drug resistance to current treatments in ovarian cancer. Thus, targeting HDAC1 by enhancing c-Myc-dependent miR-34a expression might be an effective strategy for increasing the efficacy of cisplatin treatment.

Class I histone deacetylases (HDACs) are key regulators of cell proliferation and they are frequently dysregulated in cancer cells. We report here the synthesis of a novel series of class-I selective HDAC inhibitors (HDACi) containing a 2-aminobenzamide moiety as a zinc-binding group connected with a central (piperazin-1-yl)pyrazine or (piperazin-1-yl)pyrimidine moiety. Some of the compounds were additionally substituted with an aromatic capping group. Compounds were tested in vitro against human HDAC1, 2, 3, and 8 enzymes and compared to reference class I HDACi (Entinostat (MS-275), Mocetinostat, CI994 and RGFP-966). The most promising compounds were found to be highly selective against HDAC1, 2 and 3 over the remaining HDAC subtypes from other classes. Molecular docking studies and MD simulations were performed to rationalize the in vitro data and to deduce a complete structure activity relationship (SAR) analysis of this novel series of class-I HDACi. The most potent compounds, including 19f, which blocks HDAC1, HDAC2, and HDAC3, as well as the selective HDAC1/HDAC2 inhibitors 21a and 29b, were selected for further cellular testing against human acute myeloid leukemia (AML) and erythroleukemic cancer (HEL) cells, taking into consideration their low toxicity against human embryonic HEK293 cells. We found that 19f is superior to the clinically tested class-I HDACi Entinostat (MS-275). Thus, 19f is a new and specific HDACi with the potential to eliminate blood cancer cells of various origins.

The effects of two lyophilized extracts obtained from the aerial parts of Thymus marschallianus Willd. and harvested from wild flora (TMW) and obtained from culture (TMC) were evaluated in Wistar rats with experimentally induced hyperglycemia. The hyperglycemia was induced by streptozotocin (STZ) administration and the obtained results were evaluated in comparison for TMW and TMC. The polyphenolic composition of extracts was evaluated by spectrophotometrical and LC-MS methods. In vitro antioxidant capacity assays (DPPH, FRAP, EPR) were performed in order to preliminary establish the ability of tested samples to protect against free radical induced damage. Afterwards, the effects of these extracts were assessed in vivo on rats with experimental-induced hyperglycemia. Oxidative stress biomarkers (e.g. malondialdehyde—MDA), phosphorylated transcription factor subunit of nuclear kappaB (NF-kB) p65, methyl CpG binding protein (MECP) 2 and histone deacetylase 1 (HDAC1) expressions in hippocampus and frontal lobe were assessed. Open Field Test (OFT) and Elevated Plus Maze (EPM) were conducted on tested animals. Malondialdehyde (MDA) levels and HDAC1and MeCP2 expressions increased significantly in hippocampus (p<0.05) and frontal lobe (p<0.001) of diabetes group compared to the control group in parallel with decreasing of GSH/GSSG ratio. TMW and TMC administration reduced blood glucose levels and diminished lipid peroxidation, HDAC1 expression and enhanced antioxidant capacity in frontal lobe. TMW improved central locomotion of rats, increased phospho-NFkB p65 and diminished MECP2 expressions in hippocampus. Both tested samples exerted a beneficial effect by increasing the antioxidant defense. Our findings indicate that the administration of these extracts might represent a good option in the treatment of diabetes and its complications. [ABSTRACT FROM AUTHOR]

Chronic renal failure (CRF) is commonly associated with various adverse consequences including pathological vascular calcification (VC), which represents a significant clinical concern. Existing literature has suggested the involvement of histone deacetylases (HDACs) in the progression of CRF‐induced VC. However, the underlying molecular mechanisms associated with HDACs remain largely unknown. Therefore, we established the adenine‐induced CRF rat model and in vitro VC models based on vascular smooth muscle cells (VSMCs) to examine HDAC1/lysine demethylase 1A (LSD1)/SESN2 as a novel molecular pathway in CRF‐induced VC. Our initial results demonstrated that HDAC1 reduced the formation of VC in vivo and in vitro. HDAC1 was found to deacetylate LSD1, which subsequently led to impaired transcriptional activity in CRF‐induced VC. Moreover, our results illustrated that LSD1 diminished the enrichment of H3K4me2 at the SESN2 promoter. Autophagy was identified as a vasculo‐protective element against calcification in VC. Finally, we found that the inhibitory effects of HDAC1 overexpression on VC were partially abolished via over‐expressed LSD1 in adenine‐induced CRF model rats and in high phosphate‐induced VSMCs. Taken together, these results highlight the crucial role of HDAC1 as an antagonistic factor in the progression of VC in CRF, and also revealed a novel regulatory mechanism by which HDAC1 operates. These findings provide significant insight and a fresh perspective into promising novel treatment strategies by up‐regulating HDAC1 in CRF. [ABSTRACT FROM AUTHOR]

Colistin has been considered as the last line of defense against Gram-negative bacterial infections, however, the potential nephrotoxicity limited its clinical use. 7-Hydroxycoumarin (7-HC) possesses many beneficial pharmacological activities. This study aimed to investigate the nephroprotective effects of 7-HC against colistin-induced kidney injury. In vivo experiments showed that 7-HC alleviated kidney injury induced by colistin, as indicated by lower levels of serum neutrophil gelatinase-associated lipocalin, blood urea nitrogen and creatinine levels. Both in vivo and in vitro results demonstrated that 7-HC alleviated oxidative stress and apoptosis induced by colistin, as shown by decreased malondialdehyde levels, decreased caspase-3 and caspase-9 activities, and increased superoxide dismutase and catalase activities. We also found that colistin significantly induced histone deacetylase (HDAC) 1 expression that deacetylated histone 3 at Lys27 acetylation (H3K27AC) of Nrf2 promoter region and hence inhibiting Nrf2 signaling. 7-HC treatment restored histone acetylation at the Nrf2 promoter region and hence promoted Nrf2 expression. These results suggested that 7-HC alleviates colistin-induced renal injury and this effect was achieved by enhancement of renal antioxidant capacity with the decreased level of HDAC1 and the activation of Nrf2 signaling pathway. [ABSTRACT FROM AUTHOR]

Diabetic neuropathic pain is one of the most common complications of diabetes. Mechanisms underlying the central modulation are still unclear. Here, we investigated the role of the neuron-restricted silencing factor (NRSF/REST) in diabetic-related neuropathic pain. Mechanical allodynia and thermal hyperalgesia were assessed to evaluate painful behaviors. Our results found that in the anterior cingulate cortex (ACC) of db/db mice, NRSF/REST levels increased significantly. Reduction of NRSF/REST improved the painful sensation. Meanwhile, in vitro study found that high glucose and high palmitic acid treatment induced elevation of NRSF/REST and its cofactors (mSin3A, CoREST and HDAC1), whereas downregulation of GluR2 and NMDAR2B. Knockdown of NRSF/REST could attenuate the LDH release and partially reversed the expression changes of HDAC1 and NMDAR2B. Our results suggested that the elevation of NRSF/REST in the ACC area of db/db mice is one of the key mediators of diabetic neuropathic pain. • NRSF/REST level increases in diabetic mice or under high glucose and fatty acid treatment. • Knockdown of NRSF/REST in the ACC area alleviates diabetes painful neuropathy. • Knockdown of NRSF/REST reverses the expression changes of HDAC1 and NMDAR2B under high glucose and palmitic acid treatment. [ABSTRACT FROM AUTHOR]

Purpose: With the emerging knowledge about the impact of epigenetic alterations on behavior and brain disorders, the ability to measure epigenetic alterations in brain tissue in vivo has become critically important. We present the first in vivo/in vitro cross-validation of the novel positron emission tomography (PET) radioligand [11C]Martinostat in the pig brain with regard to its ability to measure histone deacetylase 1-3 (HDAC1-3) levels in vivo.Procedures: Nine female Danish landrace pigs underwent 121-min dynamic PET scans with [11C]Martinostat. We quantified [11C]Martinostat uptake using both a simple ratio method and kinetic models with arterial input function. By the end of the scan, the animals were euthanized and the brains were extracted. We measured HDAC1-3 protein levels in frontal cortex, cerebellum vermis, and hippocampus and compared the protein levels and regional outcome values to the [11C]Martinostat PET quantification.Results: [11C]Martinostat distributed widely across brain regions, with the highest uptake in the cerebellum vermis and the lowest in the olfactory bulbs. Based on the Akaike information criterion, the quantification was most reliably performed by Ichise MA1 kinetic modeling, but since the radioligand displayed very slow kinetics, we also calculated standard uptake value (SUV) ratios which correlated well with VT. The western blots revealed higher brain tissue protein levels of HDAC1/2 compared to HDAC3, and HDAC1 and HDAC2 levels were highly correlated in all three investigated brain regions. The in vivo SUV ratio measure correlated well with the in vitro HDAC1-3 levels, whereas no correlation was found between VT values and HDAC levels.Conclusions: We found good correlation between in vivo measured SUV ratios and in vitro measures of HDAC 1-3 proteins, supporting that [11C]Martinostat provides a good in vivo measure of the cerebral HDAC1-3 protein levels. [ABSTRACT FROM AUTHOR]

The transcription factor nuclear factor kappa B (NF- κ B) is activated in hepatocytes in the pathogenesis of hepatic steatosis. However, the action mechanism of NF- κ B remains to be established in the hepatic steatosis. In this study, the P50 subunit of NF- κ B was found to promote the hepatic steatosis through regulation of histone deacetylase 1 (HDAC1) in hepatocytes. The activity was supported by the phenotypes of P50 knockout (P50 -KO) mice and P65 knockout (P65 -KO) mice. Hepatic steatosis was reduced in the P50 -KO mice, but not in the P65 -KO mice. The reduction was a result of inhibition of HDAC1 activity in the P50 -KO cells. Knockdown of Hdac1 gene led to suppression of hepatocyte steatosis in HepG2 cells. A decrease in sterol-regulatory element binding protein 1c (SREBP1c) protein was observed in the liver of P50 -KO mice and in cell with Hdac1 knockdown. The decrease was associated with an increase in succinylation of SREBP1c protein. The study suggests that P50 stabilizes HDAC1 to support the SREBP1c activity in hepatic steatosis in the pathophysiological condition. Interruption of this novel pathway in the P50 -KO, but not the P65 -KO mice, may account for the difference in hepatic phenotypes in the two lines of transgenic mice. NF- κ B promotes hepatic steatosis through an impact of P50 subunit in HDAC1 protein. P50 stabilizes HDAC1 protein to keep succinylation of SREBP1c under control in favor of lipogenesis in the liver of wild type or P65 -KO mice. This pathway failed to operate in P50 -KO mice leading to reduction of hepatic steatosis. Image 1 [ABSTRACT FROM AUTHOR]

• One LncRNA HRCEG inhibits cell proliferation and EMT process in gastric cancer. • HRCEG was significantly connected with gastric cancer related pathways and were also highly involved in the EMT processes. • The expression of HRCEG is regulated by HDAC1. Recently, a number of long noncoding RNAs (lncRNAs) have been reported to play significant roles in human tumorigenesis. However, only few gastric cancer related lncRNAs have been well characterized. Here, we identified one lncRNA HRCEG, whose expression was decreased in the gastric cancer tissues compared with adjacent normal tissues. Overexpression of HRCEG significantly promoted cell apoptosis and inhibited cell proliferation. Importantly, we demonstrated that HRCEG levels inversely correlated with EMT process and HRCEG was regulated by the histone deacetylase 1 (HDAC1) in gastric cancer. These findings suggest that HRCEG might be regulated by HDAC1 to inhibit gastric cancer progress and metastatic capability via EMT pathway. [ABSTRACT FROM AUTHOR]

Stem cells are capable of sensing and processing environmental inputs, converting this information to output a specific cell lineage through signaling cascades. Despite the combinatorial nature of mechanical, thermal, and biochemical signals, these stimuli have typically been decoupled and applied independently, requiring continuous regulation by controlling units. We employ a programmable polymer actuator sheet to autonomously synchronize thermal and mechanical signals applied to mesenchymal stem cells (MSCs). Using a grid on its underside, the shape change of polymer sheet, as well as cell morphology, calcium (Ca2+) influx, and focal adhesion assembly, could be visualized and quantified. This paper gives compelling evidence that the temperature sensing and mechanosensing of MSCs are interconnected via intracellular Ca2+. Up-regulated Ca2+ levels lead to a remarkable alteration of histone H3K9 acetylation and activation of osteogenic related genes. The interplay of physical, thermal, and biochemical signaling was utilized to accelerate the cell differentiation toward osteogenic lineage. The approach of programmable bioinstructivity provides a fundamental principle for functional biomaterials exhibiting multifaceted stimuli on differentiation programs. Technological impact is expected in the tissue engineering of periosteum for treating bone defects. [ABSTRACT FROM AUTHOR]

Endothelial dysfunction is an earlier contributor to the development of atherosclerosis in chronic kidney disease (CKD), in which the role of epigenetic triggers cannot be ruled out. Endothelial protective strategies, such as defibrotide (DF), may be useful in this scenario. We evaluated changes induced by CKD on endothelial cell proteome and explored the effect of DF and the mechanisms involved. Human umbilical cord vein endothelial cells were exposed to sera from healthy donors (n = 20) and patients with end‐stage renal disease on haemodialysis (n = 20). Differential protein expression was investigated by using a proteomic approach, Western blot and immunofluorescence. HDAC1 and HDAC2 overexpression was detected. Increased HDAC1 expression occurred at both cytoplasm and nucleus. These effects were dose‐dependently inhibited by DF. Both the HDACs inhibitor trichostatin A and DF prevented the up‐regulation of the endothelial dysfunction markers induced by the uraemic milieu: intercellular adhesion molecule‐1, surface Toll‐like receptor‐4, von Willebrand Factor and reactive oxygen species. Moreover, DF down‐regulated HDACs expression through the PI3/AKT signalling pathway. HDACs appear as key modulators of the CKD‐induced endothelial dysfunction as specific blockade by trichostatin A or by DF prevents endothelial dysfunction responses to the CKD insult. Moreover, DF exerts its endothelial protective effect by inhibiting HDAC up‐regulation likely through PI3K/AKT. [ABSTRACT FROM AUTHOR]

OBJECTIVE: LncRNAs play a key role in the development and progression of prostate cancer. In this study, the effects of the lncRNA BLACAT1 in prostate cancer were investigated. PATIENTS AND METHODS: Real-time PCR was used to detect the expression of BLACAT1 and miR-361 in prostate cancer tissues and adjacent normal tissues (n=25). The function of BLACAT1 was detected through proliferation assay and apoptosis assay. The interaction between BLACAT1 and miR-361 in prostate cancer was studied by luciferase assay, RNA immunoprecipitation assay and chromatin immunoprecipitation analysis were performed to detect the BLACAT1 binding proteins. The xenograft mice experiment was performed to further confirm the functional significance of lncRNA BLACAT1 in vivo. RESULTS: In patient samples and prostate cancer cell lines, BLACAT1 was down-regulated and inversely proportional to DNMT1, HDAC1, EZH2, MDM2 and miR-361 expression. Treatment with 5-azacytidine and chidamide enhanced BLACAT1 expression and decreased the levels of miR-361. The BALCAT1 promoter was methylated in prostate cancer tissue and found to interact with miR-361 via luciferase assays. BLACAT1 bound to EZH2, DNMT1 and HDAC1. ChIP-seq analysis revealed that HDAC1 interacts with STAT3, while EZH2 interacts with the mitogen-activated protein kinase (MAPK) promoter. CONCLUSIONS: Two regulatory axes of BLACAT1-EZH2-MAPK and BLACAT1-HDAC1-STAT3 were identified to be associated with the progression of prostate cancer. Both chidamide and 5-azacytidine represent promising therapeutic options in prostate cancer treatment. [ABSTRACT FROM AUTHOR]

Mice naturally form social hierarchies, and their experiences as subordinate or dominant mice inform future behavioural strategies. To better understand the neural bases of social dominance, we investigated hippocampal gene and protein expression of histone deacetylase 2 (HDAC2), an epigenetic regulator that decreases expression of synaptic plasticity genes and reduces excitatory synaptic function. Hdac2 in hippocampus was associated with social status. The gene for a closely related histone deacetylase (Hdac1), and HDAC2 protein expression, were not associated with social rank in hippocampus. These findings suggest that Hdac2 expression in hippocampus is distinctly linked with social status. [ABSTRACT FROM AUTHOR]

A therapeutic approach for promoting neuroprotection and brain functional regeneration after strokes is still lacking. Histone deacetylase 1 (HDAC1), which belongs to the histone deacetylase family, is involved in the transcriptional repression of cell-cycle-modulated genes and DNA damage repair during neurodegeneration. Our previous data showed that the protein level and enzymatic activity of HDAC1 are deregulated in stroke pathogenesis. A novel compound named 5104434 exhibits efficacy to selectively activate HDAC1 enzymatic function in neurodegeneration, but its potential in stroke therapy is still unknown. In this study, we adopted an induced rat model with cerebral ischemia using the vessel dilator endothelin-1 to evaluate the potential of compound 5104434. Our results indicated compound 5104434 selectively restored HDAC1 enzymatic activity after oxygen and glucose deprivation, preserved neurite morphology, and protected neurons from ischemic damage in vitro. In addition, compound 5104434 attenuated the infarct volume, neuronal loss, apoptosis, DNA damage, and DNA breaks in cerebral ischemia rats. It further ameliorated the behavioral outcomes of neuromuscular response, balance, forepaw strength, and functional recovery. Collectively, our data support the efficacy of compound 5104434 in stroke therapy and contend that it can be considered for clinical trial evaluation.

Epigenetic therapy using histone deacetylase (HDAC) inhibitors has become an attractive project in new drug development. However, DNA methylation and histone acetylation are important epigenetic ways to regulate the occurrence and development of leukemia. Given previous studies, N-(2-aminophenyl)benzamide acridine (8a), as a histone deacetylase 1 (HDAC1) inhibitor, induces apoptosis and shows significant anti-proliferative activity against histiocytic lymphoma U937 cells. HDAC1 plays a role in the nucleus, which we confirmed by finding that 8a entered the nucleus. Subsequently, we verified that 8a mainly passes through the endogenous (mitochondrial) pathway to induce cell apoptosis. From the protein interaction data, we found that 8a also affected the expression of DNA methyltransferase 1 (DNMT1). Therefore, an experiment was performed to assess the binding of 8a to DNMT1 at the molecular and cellular levels. We found that the binding strength of 8a to DNMT1 enhanced in a dose-dependent manner. Additionally, 8a inhibits the expression of DNMT1 mRNA and its protein. These findings suggested that the anti-proliferative and pro-apoptotic activities of 8a against leukemia cells were achieved by targeting HDAC1 and DNMT1.

Although SIN3A is required for the survival of early embryos and embryonic stem cells (ESCs), the role of SIN3A in the maintenance and establishment of pluripotency remains unclear. Here, we find that the SIN3A/HDAC corepressor complex maintains ESC pluripotency and promotes the generation of induced pluripotent stem cells (iPSCs). Members of the SIN3A/HDAC corepressor complex are enriched in an extended NANOG interactome and function in transcriptional coactivation in ESCs. We also identified a critical role for SIN3A and HDAC2 in efficient reprogramming of somatic cells. Mechanistically, NANOG and SIN3A co-occupy transcriptionally active pluripotency genes in ESCs and also co-localize extensively at their genome-wide targets in pre-iPSCs. Additionally, both factors are required to directly induce a synergistic transcriptional program wherein pluripotency genes are activated and reprogramming barrier genes are repressed. Our findings indicate a transcriptional regulatory role for a major HDAC-containing complex in promoting pluripotency.

Background: Recent studies have shown that activated pyroptosis in atopic dermatitis (AD) switches inflammatory processes and causes abnormal cornification and epidermal barrier dysfunction. Little research has focused on the interaction mechanism between pyroptosis-related genes and human keratinocyte differentiation., Methods: The AD dataset from the Gene Expression Omnibus (GEO) was used to identify differently expressed pyroptosis-related genes (DEPRGs). Hub genes were identified and an enrichment analysis was performed to select epithelial development-related genes. Lesions of AD patients were detected via immunohistochemistry (IHC) to verify the hub gene. Human keratinocytes cell lines, gasdermin D (GSDMD) overexpression, Caspase1 siRNA, Histone Deacetylase1 (HDAC1) siRNA, and HDAC1 overexpression vectors were used for gain-and-loss-of-function experiments. Regulation of cornification protein was determined by qPCR, western blot (WB), immunofluorescence (IF), dual-luciferase reporter assay, co-immunoprecipitation (Co-IP), and chromatin immunoprecipitation (ChIP)., Results: A total of 27 DEPRGs were identified between either atopic dermatitis non-lesional skin (ANL) and healthy control (HC) or atopic dermatitis lesional skin (AL) and HC. The enrichment analysis showed that these DEPRGs were primarily enriched in the inflammatory response and keratinocytes differentiation. Of the 10 hub genes identified via the protein-protein interaction network, only GSDMD was statistically and negatively associated with the expression of epithelial tight junction core genes. Furthermore, GSDMD was upregulated in AD lesions and inhibited human keratinocyte differentiation by reducing filaggrin (FLG) expression. Mechanistically, GSDMD activated by Caspase1 reduced FLG expression via HDAC1. HDAC1 decreased FLG expression by reducing histone acetylation at the FLG promoter. In addition, GSDMD blocked the interaction of Potassium Channel Tetramerization Domain Containing 6 (KCTD6) and HDAC1 to prohibit HDAC1 degradation., Conclusion: This study revealed that GSDMD was upregulated in AD lesions and that GSDMD regulated keratinocytes via epigenetic modification, which might provide potential therapeutic targets for AD., Competing Interests: The authors declare that they have no competing interests., (© 2024 Zhong et al.)

Epigenetics is the study of heritable changes to the genome and gene expression patterns that are not caused by direct changes to the DNA sequence. Examples of these changes include posttranslational modifications to DNA-bound histone proteins, DNA methylation, and remodeling of nuclear architecture. Collectively, epigenetic changes provide a layer of regulation that affects transcriptional activity of genes while leaving DNA sequences unaltered. Sequence variants or mutations affecting enzymes responsible for modifying or sensing epigenetic marks have been identified in patients with congenital heart disease (CHD), and small-molecule inhibitors of epigenetic complexes have shown promise as therapies for adult heart diseases. Additionally, transgenic mice harboring mutations or deletions of genes encoding epigenetic enzymes recapitulate aspects of human cardiac disease. Taken together, these findings suggest that the evolving field of epigenetics will inform our understanding of congenital and adult cardiac disease and offer new therapeutic opportunities., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Notch signaling plays a critical role in cell fate decisions in all cell types. Furthermore, gain-of-function mutations in NOTCH1 have been uncovered in many human cancers. Disruption of Notch signaling has recently emerged as an attractive disease treatment strategy. However, the nuclear interaction landscape of the oncoprotein NOTCH1 remains largely unexplored. We therefore employed here a proximity-dependent biotin identification approach to identify in vivo protein associations with the nuclear Notch1 intracellular domain in live cells. We identified a large set of previously reported and unreported proteins that associate with NOTCH1, including general transcription and elongation factors, DNA repair and replication factors, coactivators, corepressors, and components of the NuRD and SWI/SNF chromatin remodeling complexes. We also found that Notch1 intracellular domain associates with protein modifiers and components of other signaling pathways that may influence Notch signal transduction and protein stability such as USP7. We further validated the interaction of NOTCH1 with histone deacetylase 1 or GATAD2B using protein network analysis, proximity-based ligation, in vivo cross-linking and coimmunoprecipitation assays in several Notch-addicted cancer cell lines. Through data mining, we also revealed potential drug targets for the inhibition of Notch signaling. Collectively, these results provide a valuable resource to uncover the mechanisms that fine-tune Notch signaling in tumorigenesis and inform therapeutic targets for Notch-addicted tumors., Competing Interests: Conflicts of interest Sanford Research has licensed BioID reagents developed by K. J. R. to BioFront Technologies. The remaining authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Chronic pancreatitis (CP) as a progressive inflammatory disorder, remains untreatable. The novel treatment strategy for CP is imperative. We attempted to explore the therapeutic biomarkers for CP. The single-cell sequencing data were retrieved from Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) in idiopathic CP were identified, followed by function and pathway annotation, and PPI network established. DEGs of interest were verified in human tissue samples. The function of candidate biomarker was determined in the murine model with CP. A total of 208 genes were specially differentially expressed in idiopathic patients. Functional enrichment analysis showed DEGs were mainly enriched in glycogen catabolic process, RNA splicing, and glucagon signaling pathway. A PPI network centered on HDAC1 was constructed. HDAC1 was overexpressed in CP patients. The murine model with CP was induced by repetitive cerulein treatment. Silencing sh-HDAC1 treatment reversed cerulein-induced inflammatory cells accumulation, high expression of TGF-β1, and collagen 1 in pancreas in vivo. HDAC1 might be served as potential biomarker for CP. The present study provided insights into the molecular mechanism of CP that may be useful in further investigations., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Skeletal development requires precise extrinsic and intrinsic signals to regulate processes that form and maintain bone and cartilage. Notch1 is a highly conserved signaling receptor that regulates cell fate decisions by controlling the duration of transcriptional bursts. Epigenetic molecular events reversibly modify DNA and histone tails by influencing the spatial organization of chromatin and can fine-tune the outcome of a Notch1 transcriptional response. Histone deacetylase 1 and 2 (HDAC1 and HDAC2) are chromatin modifying enzymes that mediate osteoblast differentiation. While an HDAC1-Notch interaction has been studied in vitro and in Drosophila, its role in mammalian skeletal development and disorders is unclear. Osteosclerosis is a bone disorder with an abnormal increase in the number of osteoblasts and excessive bone formation., Methods: Here, we tested whether Hdac1/2 contribute to the pathogenesis of osteosclerosis in a murine model of the disease owing to conditionally cre-activated expression of the Notch1 intracellular domain in immature osteoblasts., Results: Importantly, selective homozygous deletions of Hdac1/2 in osteoblasts partially alleviate osteosclerotic phenotypes (Col2.3kb-Cre; TG RosaN1ICD/+ ; Hdac1 flox/flox ; Hdac2 flox/flox ) with a 40% decrease in bone volume and a 22% decrease in trabecular thickness in 4 weeks old when compared to male mice with heterozygous deletions of Hdac1/2 (Col2.3 kb-Cre; TG RosaN1ICD/+ ; Hdac1 flox/+ ; Hdac2 flox/+ ). Osteoblast-specific deletion of Hdac1/2 in male and female mice results in no overt bone phenotype in the absence of the Notch1 gain-of-function (GOF) allele., Conclusions: These results provide evidence that Hdac1/2 contribute to Notch1 pathogenic signaling in the mammalian skeleton. Our study on epigenetic regulation of Notch1 GOF-induced osteosclerosis may facilitate further mechanistic studies of skeletal birth defects caused by Notch-related GOF mutations in human patients, such as Adams-Oliver disease, congenital heart disease, and lateral meningocele syndrome., (© 2023 Wiley Periodicals LLC.)

Zn 2+ -dependent histone deacetylases (HDACs) are enzymes that regulate gene expression by removing acetyl groups from histone proteins. These enzymes are essential in all living systems, playing key roles in cancer treatment and as potential pesticide targets. Previous phylogenetic analyses of HDAC in certain species have been published. However, their classification and evolutionary origins across biological kingdoms remain unclear, which limits our understanding of them. In this study, we collected the HDAC sequences from 1451 organisms and performed analyses. The HDACs are found to diverge into three classes and seven subclasses under divergent selection pressure. Most subclasses show species specificity, indicating that HDACs have evolved with high plasticity and diversification to adapt to different environmental conditions in different species. In contrast, HDAC1 and HDAC3, belonging to the oldest class, are conserved and crucial in major kingdoms of life, especially HDAC1. These findings lay the groundwork for the future application of HDACs.

Splicing factor proline/glutamine-rich (SFPQ) is expressed in induced pluripotent stem cells (iPSCs), which are reported to orchestrate hypoxic injury responses and release extracellular vesicles (EVs). Therefore, this study sought to explore the role of iPSC-derived EVs carrying SFPQ in hypoxia-induced injury to retinal Müller cells. We induced oxygen-glucose deprivation/reoxygenation (OGD/R) in Müller cells. SFPQ was overexpressed or knocked down in iPSCs, from which EVs were extracted. Müller cells were co-cultured with EVs, and the results indicated that SFPQ protein was transferred into retinal Müller cells by iPSC-derived EVs. We identified an interaction of SFPQ with HDAC1 in retinal Müller cells. Specifically, SFPQ recruited HDAC1 to downregulate HIF-2α by regulating its acetylation. The in vitro studies suggested that iPSC-derived EVs, SFPQ or HDAC1 overexpression, or HIF-2α silencing diminished cell injury and apoptosis but elevated proliferation in retinal Müller cells. The in vivo studies indicated that iPSC-derived EVs containing SFPQ curtailed apoptosis of retinal Müller cells, thus alleviating retinal ischemia/reperfusion (I/R) injury of rat model. Taken together, iPSC-derived EVs containing SFPQ upregulated HDAC1 to attenuate OGD/R-induced Müller cell injury via downregulation of HIF-2α., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Aberrant expression or dysfunction of cyclin-dependent kinase 7(CDK7) and histone deacetylase 1 (HDAC1) are associated with the occurrence and progression of various cancers. In this study, we developed a series of dual-target inhibitors by designing and synthesizing compounds that incorporate the pharmacophores of THZ2 and SAHA. The most potent dual-target inhibitor displayed robust inhibitory activity against several types of cancer cells and demonstrated promising inhibitory effects on both CDK7 and HDAC1. After further mechanistic studies, it was discovered that this inhibitor effectively arrested HCT-116 cells at the G2 phase and induced apoptosis. Additionally, it also significantly hindered the migration of HCT-116 cells and exhibited notable anti-tumor effects. These findings offer strong support for the development of dual-target inhibitors of CDK7 and HDAC1 and provide a promising avenue for future cancer therapy., (© 2023 Wiley-VCH GmbH.)

Objective: To study the relationship between clock genes and Major Depressive Disorder (MDD)., Methods: GEO database was used to obtain the chip data and clinical information of datasets GSE98793, GSE39653 and GSE52790. The differentially expressed clock genes were found through the analysis of the differentially expressed genes between MDD and healthy controls. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes Pathway (KEGG) enrichment analysis were performed on the differential expressed clock genes. Lasso Regression and Support Vector Machine (SVM) method were used for screening the differential expressed clock genes. Logistic regression was used to establish a diagnostic model for depression with the screened genes. Receiver Operating Characteristic (ROC) Curve was used to verify the model. Gene differential expression analysis was performed for MDD with high scores and MDD with low scores in the diagnostic model. Gene Set Enrichment Analysis (GSEA) enrichment analysis was performed for differentially expressed genes. Single-gene GSEA was used to analyze each gene in the model separately. Cibersort method was used to analyze the immune infiltration of MDD and healthy controls, and the correlation between immune cells and clock genes was analyzed. Cytoscape was used to analyze the clock gene interaction network. The DGIdb website was used to predict potentially effective therapeutic drugs for clock genes closely related to MDD., Results: Six genes were identified by differential expression analysis of clock genes between MDD and healthy controls. GO and KEGG enrichment analysis of 6 genes showed that their pathways were concentrated such as circadian rhythm, rhythmic process, TGF - beta signaling pathway, longevity regulating pathway-multiple species, adipocytokine signaling pathway and so on. Lasso regression and SVM were used to screen out 5 clock genes (HDAC1, ID3, NFIL3, PRKAA1, TNF) for MDD. The diagnostic model of depression was established according to the 5 clock genes. The area under the curve (AUC) of the established depression diagnostic model was 0.686. Gene difference analysis was performed between MDD patients with high score of clock gene diagnostic model and MDD patients with low score. GSEA was performed for the differential genes showed that the most enriched pathways were:adipocytokine signaling pathway, TGF beta signaling pathway, oxidative phosphorylation, primary immunodeficiency, and so on. The single gene GSEA showed that the most enriched pathways were Toll like receptor signaling pathway, glucolipid metabolism, amino acid metabolism, neuroactive ligand receptor interaction, and so on. The results of immune infiltration analysis showed that NK cells resting and Macrophages M2 were different between MDD and control groups. In MDD, the gene closely related to NK cells resting was HDAC1, and the genes closely related to Macrophages M2 were HDAC1 and NFIL3. The RNA interactions network of clock genes shows that the regulation process is complex, which can provide a reference for subsequent related research. Potential therapeutic drugs predict display, among the 5 clock genes, TNF, HDAC1, and PRKAA1 may have potential effective therapeutic drugs., Conclusion: Among all CLOCK genes, HDAC1, ID3, NFIL3, PRKAA1, TNF are closely related to MDD. Among them, TNF, HDAC1, and PRKAA1 may have potential effective therapeutic drugs., Competing Interests: Declaration of competing interest The authors have stated that they have no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

• Tnc controls microglial phagocytosis at postnatal age partially via TLR4. • Tnc-KO microglia exhibit reduced HDAC1 protein levels at postnatal age. • Tnc induces HDAC1 expression in cultured microglia in part via TLR4. • Tnc regulates microglial cytokines, chemotaxis, phagocytosis via TLR4 in vitro. Tenascin C (Tnc) is an extracellular matrix glycoprotein, expressed in the CNS during development, as well as in the setting of inflammation, fibrosis and cancer, which operates as an activator of Toll-like receptor 4 (TLR4). Although TLR4 is highly expressed in microglia, the effect of Tnc on microglia has not been elucidated to date. Herein, we demonstrate that Tnc regulates microglial phagocytic activity at an early postnatal age (P4), and that this process is partially dependent on microglial TLR4 expression. We further show that Tnc regulates proinflammatory cytokine/chemokine production, chemotaxis and phagocytosis in primary microglia in a TLR4-dependent fashion. Moreover, Tnc induces histone-deacetylase 1 (HDAC1) expression in microglia, such that HDAC1 inhibition by MS-275 decreases Tnc-induced microglial IL-6 and TNF-α production. Finally, Tnc −/− cortical microglia have reduced HDAC1 expression levels at P4. Taken together, these findings establish Tnc as a regulator of microglia function during early postnatal development. [ABSTRACT FROM AUTHOR]