Puerarin inhibits HDAC1-induced oxidative stress disorder by activating JNK pathway and alleviates acrolein-induced atherosclerosis.

OBJECTIVE: Atherosclerosis (AS) is a common pathogenesis of cardiovascular diseases. Puerarin (Pue) is a Chinese herbal remedy used to prevent and treat AS. Here, this research investigated the effect of Pue on AS progression. METHODS: ApoE-/- mice were induced with acrolein. Body weight, blood lipid index, inflammatory factors, mitochondrial oxidative stress, and lipid deposition were detected. IL-6 and TNF-α were detected by ELISA. Oil red staining and H&E staining were used to observe the aortic sinus plaque lesions. Serum expressions of inflammatory factors IL-6, TNF-a, SOD, GSH and MDA were detected by ELISA, the mRNA expression levels of HDAC1 in the aorta were detected by RT-qPCR, and IL-6 and TNF-α in the aorta were detected by immunohistochemistry. JNK, p-JNK, OPA-1, and HDAC1 were detected by Western blotting. RESULTS: Pue administration can effectively reduce lipid accumulation in AS mice induced by acrolein. Pue promoted the activity of SOD, GSH and MDA, and inhibited the formation of atherosclerotic plaques and the process of aortic histological changes. Pue reduced IL-6 and TNF-α. HDAC1 expression was down-regulated and p-JNK-1 and JNK protein expression was up-regulated. CONCLUSION: Pue reduces inflammation and alleviates AS induced by acrolein by mediating the JNK pathway to inhibit HDAC1-mediated oxidative stress disorder.

Endothelial histone deacetylase 1 activity impairs kidney microvascular NO signaling in rats fed a high-salt diet.

AIM: We aimed to test the hypothesis that a high-salt diet (HS) impairs NO signaling in kidney microvascular endothelial cells through a histone deacetylase 1 (HDAC1)-dependent mechanism. METHODS: Male Sprague Dawley rats were fed normal salt diet (NS; 0.49% NaCl) or HS (4% NaCl) for 2 weeks. NO signaling was assessed by measuring L-NAME induced vasoconstriction of the afferent arteriole using the blood perfused juxtamedullary nephron (JMN) preparation. In this preparation, kidneys were perfused with blood from a donor rat on a matching or different diet to that of the kidney donor. Kidney endothelial cells were isolated with magnetic activated cell sorting and HDAC1 activity was measured. RESULTS: We found HS-induced impaired NO signaling in the afferent arteriole. This was restored by inhibition of HDAC1 with MS-275. Consistent with these findings, HDAC1 activity was increased in kidney endothelial cells. We further found the loss of NO to be dependent upon the diet of the blood donor rather than the diet of the kidney donor and the plasma from HS-fed rats to be sufficient to induce impaired NO signaling. This indicates the presence of a humoral factor we termed plasma-derived endothelial dysfunction mediator (PDEM). Pretreatment with the antioxidants, PEG-SOD and PEG-catalase, as well as the NOS cofactor, tetrahydrobiopterin, restored NO signaling. CONCLUSION: We conclude that HS activates endothelial HDAC1 through PDEM leading to decreased NO signaling. This study provides novel insights into the molecular mechanisms by which a HS decreases renal microvascular endothelial NO signaling.

GSE1 promotes the proliferation and migration of lung adenocarcinoma cells by downregulating KLF6 expression.

Lung cancer is one of the most prevalent human cancers with a high lethality rate worldwide. In this study, we demonstrated that GSE1 (genetic suppressor element 1) expression is aberrantly upregulated in lung adenocarcinoma and that GSE1 depletion inhibits the proliferation and migration of both A549 and H1299 cells. Immunoprecipitation assays demonstrated that GSE1 interacts with histone deacetylase 1 (HDAC1) and other BRAF-HDAC complex (BHC) components in cells. The transcriptome of GSE1-knockdown A549 cells indicated that 207 genes were upregulated and 159 were downregulated based on a p-value < .05 and fold change ≥ 1.5. Bioinformatics analysis suggested that 140 differentially expressed genes harbor binding sites for HDAC1, including the tumor suppressor gene KLF6 (Kruppel-like factor 6). Indeed, quantitative reverse-transcription polymerase chain reaction and western blot analysis revealed that GSE1 could inhibit the transcription of KLF6 in lung cancer cells. In conclusion, GSE1 cooperates with HDAC1 to promote the proliferation and metastasis of non-small cell lung cancer cells through the downregulation of KLF6 expression.

Identification of structural fingerprints among natural inhibitors of HDAC1 to accelerate nature-inspired drug discovery in cancer epigenetics.

Histone deacetylase 1 (HDAC1), a class I HDAC enzyme, is crucial for histone modification. Currently, it is emerged as one of the important biological targets for designing small molecule drugs through cancer epigenetics. Along with synthetic inhibitors different natural inhibitors are showing potential HDAC1 inhibitions. In order to gain insights into the relationship between the molecular structures of the natural inhibitors and HDAC1, different molecular modelling techniques (Bayesian classification, recursive partitioning, molecular docking and molecular dynamics simulations) have been applied on a dataset of 155 HDAC1 nature-inspired inhibitors with diverse scaffolds. The Bayesian study showed acceptable ROC values for both the training set and test sets. The Recursive partitioning study produced decision tree 1 with 6 leaves. Further, molecular docking study was processed for generating the protein ligand complex which identified some potential amino acid residues such as F205, H28, L271, P29, F150, Y204 for the binding interactions in case of natural inhibitors. Stability of these HDAC1-natutal inhibitors complexes has been also evaluated by molecular dynamics simulation study. The current modelling study is an attempt to get a deep insight into the different important structural fingerprints among different natural compounds modulating HDAC1 inhibition.Communicated by Ramaswamy H. Sarma.

Epigenetics.

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.

HDAC1 Promotes Mitochondrial Pathway Apoptosis and Inhibits the Endoplasmic Reticulum Stress Response in High Glucose-Treated Schwann Cells via Decreased U4 Spliceosomal RNA.

Dysfunction of Schwann cells, including cell apoptosis, autophagy inhibition, dedifferentiation, and pyroptosis, is a pivotal pathogenic factor in induced diabetic peripheral neuropathy (DPN). Histone deacetylases (HDACs) are an important family of proteins that epigenetically regulate gene transcription by affecting chromatin dynamics. Here, we explored the effect of HDAC1 on high glucose-cultured Schwann cells. HDAC1 expression was increased in diabetic mice and high glucose-cultured RSC96 cells, accompanied by cell apoptosis. High glucose also increased the mitochondrial pathway apoptosis-related Bax/Bcl-2 and cleaved caspase-9/caspase-9 ratios and decreased endoplasmic reticulum response-related GRP78, CHOP, and ATF4 expression in RSC96 cells (P < 0.05). Furthermore, overexpression of HDAC1 increased the ratios of Bax/Bcl-2, cleaved caspase-9/caspase-9, and cleaved caspase-3 and reduced the levels of GRP78, CHOP, and ATF4 in RSC96 cells (P < 0.05). In contrast, knockdown of HDAC1 inhibited high glucose-promoted mitochondrial pathway apoptosis and suppressed the endoplasmic reticulum response. Moreover, RNA sequencing revealed that U4 spliceosomal RNA was significantly reduced in HDAC1-overexpressing RSC96 cells. Silencing of U4 spliceosomal RNA led to an increase in Bax/Bcl-2 and cleaved caspase-9 and a decrease in CHOP and ATF4. Conversely, overexpression of U4 spliceosomal RNA blocked HDAC1-promoted mitochondrial pathway apoptosis and inhibited the endoplasmic reticulum response. In addition, alternative splicing analysis of HDAC1-overexpressing RSC96 cells showed that significantly differential intron retention (IR) of Rpl21, Cdc34, and Mtmr11 might be dominant downstream targets that mediate U4 deficiency-induced Schwann cell dysfunction. Taken together, these findings indicate that HDAC1 promotes mitochondrial pathway-mediated apoptosis and inhibits the endoplasmic reticulum stress response in high glucose-cultured Schwann cells by decreasing the U4 spliceosomal RNA/IR of Rpl21, Cdc34, and Mtmr11.

Targeting histone deacetylase 1 (HDAC1) in the bone marrow stromal cells revers imatinib resistance by modulating IL-6 in Ph + acute lymphoblastic leukemia.

Bone marrow stromal cells (BMSCs) can promote the growth of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). Histone deacetylases (HDACs) play essential roles in the proliferation and apoptosis resistance of Ph + ALL cells. In our previous study, inhibiting histone deacetylase 1 (HDAC1) decreases the proliferation of Ph + ALL cells. However, little is known regarding how HDAC1 in BMSCs of Ph + ALL patients affects the imatinib (IM) resistance. Therefore, the present work examined the roles of HDAC1 in BMSCs. Overexpression of HDAC1 was found in BMSCs of Ph + ALL patients with IM resistance. In addition, the Ph + ALL cell line SUP-B15 was co-cultured with BMSCs after lentivirus transfection for regulating HDAC1 expression. Knockdown of HDAC1 within BMSCs elevated the IM-mediated SUP-B15 cell apoptosis, while increasing HDAC1 expression had an opposite effect. IL-6 in BMSCs, which is an important factor for the microenvironment-associated chemoresistance, showed evident up-regulation in HDAC1-upregulated BMSCs and down-regulation in HDAC1-downregulated BMSCs. While recombinant IL-6 (rIL-6) can reversed the sensitivity of SUP-B15 cells to IM induced by downregulating HDAC1 expression in BMSCs. HDAC1 showed positive regulation on IL-6 transcription and secretion. Moreover, IL-6 secretion induced by HDAC1 in BMSCs might enhance IM resistance in Ph + ALL cells. With regard to the underlying molecular mechanism, NF-κB, an important signal responsible for IL-6 transcription in BMSCs, mediated the HDAC1-regulated IL-6 expression. Collectively, this study facilitated to develop HDAC1 inhibitors based not only the corresponding direct anti-Ph + ALL activity but also the regulation of bone marrow microenvironment.

MDM2 accelerated renal senescence via ubiquitination and degradation of HDAC1.

Senescence, an intricate and inevitable biological process, characterized by the gradual loss of homeostasis and declining organ functions. The pathological features of cellular senescence, including cell cycle arrest, metabolic disruptions, and the emergence of senescence-associated secretory phenotypes (SASP), collectively contribute to the intricate and multifaceted nature of senescence. Beyond its classical interaction with p53, murine double minute gene 2 (MDM2), traditionally known as an E3 ubiquitin ligase involved in protein degradation, plays a pivotal role in cellular processes governing senescence. Histone deacetylase (HDAC), a class of histone deacetylases mainly expressed in the nucleus, has emerged as a critical contributor to renal tissues senescence. In this study we investigated the interplay between MDM2 and HDAC1 in renal senescence. We established a natural aging model in mice over a 2-year period that was verified by SA-ß-GAL staining and increased expression of senescence-associated markers such as p21, p16, and TNF-α in the kidneys. Furthermore, we showed that the expression of MDM2 was markedly increased, while HDAC1 expression underwent downregulation during renal senescence. This phenomenon was confirmed in H2O2-stimulated HK2 cells in vitro. Knockout of renal tubular MDM2 alleviated renal senescence in aged mice and in H2O2-stimulated HK2 cells. Moreover, we demonstrated that MDM2 promoted renal senescence by orchestrating the ubiquitination and subsequent degradation of HDAC1. These mechanisms synergistically accelerate the aging process in renal tissues, highlighting the intricate interplay between MDM2 and HDAC1, underpinning the age-related organ function decline.

Blocking lncRNA HCG18 re-sensitizes Taxol resistant lung cancer cells to Taxol through modulating the miR-34a-5p/HDAC1 axis.

Lung cancer is one of the most frequently diagnosed cancers worldwide, associated with a poor survival rate. Taxol (Paclitaxel) is commonly used as a chemotherapeutic treatment for advanced lung cancers. While Taxol has improved clinical outcomes for lung cancer patients, a significant number of them develop resistance to Taxol, resulting in treatment failure. The role of the long noncoding RNA HCG18 in lung cancer and Taxol resistance has not yet been fully understood. To investigate this, we examined the expression of HCG18 and miR-34a-5p in lung tumors and normal lung tissues using qRT-PCR. We also assessed Taxol resistance through cell viability and apoptosis assays. Through the starBase online service, we analyzed the interactions between lncRNA and mRNA as well as miRNA and mRNA. We further validated the association between lncRNA and miRNA through luciferase and RNA pull-down assays. Our findings demonstrated that HCG18 was significantly upregulated in lung cancer tissues compared to normal lung tissues. Silencing HCG18 increased the sensitivity of lung cancer cells to Taxol. Additionally, our study established a Taxol-resistant cell line and observed a substantial upregulation of HCG18 in Taxol-resistant lung cancer cells. Bioinformatic analysis predicted that HCG18 could bind to miR-34a-5p, forming a competing endogenous RNA network, which was confirmed through luciferase assay. We found that miR-34a-5p was downregulated in lung cancer tissues and negatively correlated with Taxol resistance, as it directly bound to the 3'UTR region of HDAC1. Further results showed that inhibition of HCG18 significantly increased miR-34a-5p expression and sensitized lung cancer cells to Taxol. This sensitization could be reversed by inhibiting miR-34a-5p. Finally, we demonstrated in a xenograft mouse model that inhibition of HCG18 sensitized Taxol-resistant lung cancer cells to Taxol treatment by modulating the miR-34a-5p-HDAC1 axis. In conclusion, our in vitro and in vivo results uncover a novel molecular mechanism by which HCG18 promotes Taxol resistance through modulation of the miR-34a-5p/HDAC1 axis. These findings contribute to the diagnosis and treatment of chemo-resistant lung cancer.

HDAC1/2 and HDAC3 play distinct roles in controlling adult Meibomian gland homeostasis.

PURPOSE: To investigate the roles of HDAC1/2 and HDAC3 in adult Meibomian gland (MG) homeostasis. METHODS: HDAC1/2 or HDAC3 were inducibly deleted in MG epithelial cells of adult mice. The morphology of MG was examined. Proliferation, apoptosis, and expression of MG acinus and duct marker genes, meibocyte differentiation genes, and HDAC target genes, were analyzed via immunofluorescence, TUNEL assay, and RNA in situ hybridization. RESULTS: Co-deletion of HDAC1/2 in MG epithelium caused gradual loss of acini and formation of cyst-like structures in the central duct. These phenotypes required homozygous deletion of both HDAC1 and HDAC2, indicating that they function redundantly in the adult MG. Short-term deletion of HDAC1/2 in MG epithelium had little effect on meibocyte maturation but caused decreased proliferation of acinar basal cells, excessive DNA damage, ectopic apoptosis, and increased p53 acetylation and p16 expression in the MG. By contrast, HDAC3 deletion in MG epithelium caused dilation of central duct, atrophy of acini, defective meibocyte maturation, increased acinar basal cell proliferation, and ectopic apoptosis and DNA damage. Levels of p53 acetylation and p21 expression were elevated in HDAC3-deficient MGs, while the expression of the differentiation regulator PPARγ and the differentiation markers PLIN2 and FASN was downregulated. CONCLUSIONS: HDAC1 and HDAC2 function redundantly in adult Meibomian gland epithelial progenitor cells and are essential for their proliferation and survival, but not for acinar differentiation, while HDAC3 is required to limit acinar progenitor cell proliferation and permit differentiation. HDAC1/2 and HDAC3 have partially overlapping roles in maintaining survival of MG cells.

HOXA-AS2 Epigenetically Inhibits HBV Transcription by Recruiting the MTA1-HDAC1/2 Deacetylase Complex to cccDNA Minichromosome.

Persistent transcription of HBV covalently closed circular DNA (cccDNA) is critical for chronic HBV infection. Silencing cccDNA transcription through epigenetic mechanisms offers an effective strategy to control HBV. Long non-coding RNAs (lncRNAs), as important epigenetic regulators, have an unclear role in cccDNA transcription regulation. In this study, lncRNA sequencing (lncRNA seq) is conducted on five pairs of HBV-positive and HBV-negative liver tissue. Through analysis, HOXA-AS2 (HOXA cluster antisense RNA 2) is identified as a significantly upregulated lncRNA in HBV-infected livers. Further experiments demonstrate that HBV DNA polymerase (DNA pol) induces HOXA-AS2 after establishing persistent high-level HBV replication. Functional studies reveal that HOXA-AS2 physically binds to cccDNA and significantly inhibits its transcription. Mechanistically, HOXA-AS2 recruits the MTA1-HDAC1/2 deacetylase complex to cccDNA minichromosome by physically interacting with metastasis associated 1 (MTA1) subunit, resulting in reduced acetylation of histone H3 at lysine 9 (H3K9ac) and lysine 27 (H3K27ac) associated with cccDNA and subsequently suppressing cccDNA transcription. Altogether, the study reveals a mechanism to self-limit HBV replication, wherein the upregulation of lncRNA HOXA-AS2, induced by HBV DNA pol, can epigenetically suppress cccDNA transcription.

An in silico drug repurposing approach to identify HDAC1 inhibitors against glioblastoma.

Despite considerable improvement in therapy and diagnosis, brain tumors remain a global public health concern. Among all brain tumors, 80% are due to Glioblastoma. The average survival rate of a patient once diagnosed with glioblastoma is 15 months. Lately, the role of peptidase enzymes, especially Neprilysin, a neutral endopeptidase, is gaining attention for its role in tumor growth regulation. Neprilysin expressions are positively correlated with several tumors including GBM and reduced expression of NEP protein is associated with the pathogenesis of multiple tumors. One of the main reasons for NEP protein downregulation is the action of Histone deacetylase (HDAC) enzymes, especially HDAC1. Additionally, studies have reported that increased levels of HDAC1 are responsible for downregulating NEP gene expression. Hence, HDAC1 inhibition can be a good target to elevate NEP levels, which can be a good therapeutic approach to GBM. This study utilizes the computational drug repurposing tool, Schrodinger Maestro to identify HDAC1 inhibitors from the ZINC15 database.1379 FDA-approved drugs from the ZINC15 database were screened through molecular docking. Based on docking score and ligand-protein interaction, the top ten molecules were selected which were then subjected to binding energy calculation and molecular dynamics (MD) simulations. The three most active drugs from the MD simulations- ZINC22010649 (Panobinostat), ZINC4392649 (Tasimelteon) and ZINC1673 (Melphalan), were tested on C6 and U87 MG glioblastoma cells for cytotoxicity and HDAC1 protein levels using western blot analysis. Among the three drugs, Panobinostat exhibited potent cytotoxic action and showed a significant reduction in the HDAC1 protein levels.Communicated by Ramaswamy H. Sarma.

Isobavachalcone alleviates ischemic stroke by suppressing HDAC1 expression and improving M2 polarization.

Ischemic stroke is a serious cerebrovascular condition. Isobavachalcone (ISO) has been documented to exhibit an anti-inflammatory effect across a variety of diseases; however, its protective impact on ischemic stroke remains unexplored. In this study, we evaluated the influence of ISO in both transient middle cerebral artery occlusion/reperfusion (tMCAO/R) rat models and oxygen-glucose deprivation/reperfusion (OGD/R) cell models. We observed that pretreatment with 50 mg/kg ISO diminished the volume of brain infarction, reduced brain edema, and ameliorated neurological deficits in rats. A reduction in Nissl bodies was noted in the tMCAO/R group, which was reversed following treatment with 50 mg/kg ISO. TUNEL/NeuN double staining revealed a decrease in TUNEL-positive cells in tMCAO/R rats treated with ISO. Furthermore, ISO treatment suppressed the expression of cleaved caspase-3 and BAX, while elevating the expression of BCL-2 in tMCAO/R rats. The levels of CD86 and iNOS were elevated in tMCAO/R rats; conversely, ISO treatment enhanced the expression of CD206 and Arg-1. Additionally, the expression of TNF-α, IL-6, and IL-1ß was elevated in tMCAO/R rats, whereas ISO treatment counteracted this effect. ISO treatment also increased the expression of TGF-ß and IL-10 in the ischemic penumbra of tMCAO/R rats. It was found that ISO treatment hindered microglial M1 polarization and favored M2 polarization. Histone Deacetylase 1 (HDAC1) is the downstream target protein of ISO, with ISO treatment resulting in decreased HDAC1 expression in both tMCAO/R rats and OGD/R-induced cells. Overexpression of HDAC1 was shown to promote microglial M1 polarization and inhibit M2 polarization in OGD/R+ISO cells. Overall, ISO treatment mitigated brain damage following ischemic stroke by promoting M2 polarization and attenuated ischemic injury by repressing HDAC1 expression.

A novel potent class I HDAC inhibitor reverses the STAT4/p66Shc apoptotic defect in B cells from chronic lymphocytic leukemia patients.

Chronic Lymphocytic Leukemia (CLL) patients have a defective expression of the proapoptotic protein p66Shc and of its transcriptional factor STAT4, which evoke molecular abnormalities, impairing apoptosis and worsening disease prognosis and severity. p66Shc expression is epigenetically controlled and transcriptionally modulated by STAT4; epigenetic modifiers are deregulated in CLL cells and specific histone deacetylases (HDACs) like HDAC1, are overexpressed. Reactivation of STAT4/p66Shc expression may represent an attractive and challenging strategy to reverse CLL apoptosis defects. New selective class I HDAC inhibitors (HDACis, 6a-g) were developed with increased potency over existing agents and preferentially interfering with the CLL-relevant isoform HDAC1, to unveil the role of class I HDACs in the upregulation of STAT4 expression, which upregulates p66Shc expression and hence normalizes CLL cell apoptosis. 6c (chlopynostat) was identified as a potent HDAC1i with a superior profile over entinostat. 6c induces marked apoptosis of CLL cells compared with SAHA, which was associated with an upregulation of STAT4/p66Shc protein expression. The role of HDAC1, but not HDAC3, in the epigenetic upregulation of STAT4/p66Shc was demonstrated for the first time in CLL cells and was validated in siRNA-induced HDAC1/HDAC3 knock-down EBV-B cells. To sum up, HDAC1 inhibition is necessary to reactivate STAT4/p66Shc expression in patients with CLL. 6c is one of the most potent HDAC1is known to date and represents a novel pharmacological tool for reversing the impairment of the STAT4/p66Shc apoptotic machinery.

Cisplatin-resistance induces lung squamous carcinoma cell growth by nicotine-mediated α7nAchR/HDAC1/Cyclin D1/pRb cell cycle activation.

The majority of adenocarcinoma lung cancer is found in nonsmokers. A history of tobacco use is more common in squamous cell carcinoma of the lung. The aim of this study is to identify the cisplatin (CDDP)-resistance that promotes lung squamous carcinoma cell growth through nicotine-mediated HDAC1/7nAchR/E2F/pRb cell cycle activation. Squamous cell carcinoma (NCI-H520 and NCI-H157) cells were examined after cisplatin and nicotine treatment by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assay, cell migration assay, immunofluorescence staining, western blot analysis, and immunoprecipitation analysis. Consequently, CDDP is released from DNA and Rb phosphorylated pRb as a result of nicotine-induced cancer cell proliferation through 7nAchR, which then triggers the opening of the HDAC1 cell cycle. The cell cycle is stopped when CDDP adducts are present. Nicotine exerts cancer cytoprotective effects by allowing HDAC1 repair mechanisms to re-establish E2F promoting DNA stimulation cell cycle integrity in the cytosol and preventing potential CDDP and HDAC1 suppressed in the nuclear. Concentration expression of nicotine causes squamous carcinoma cell carcinogens to emerge from inflammation. COX2, NF-KB, and NOS2 increase as a result of nicotine-induced squamous carcinoma cell inflammation. Nicotine enhanced the cell growth-related proteins such as α7nAchR, EGFR, HDAC1, Cyclin D, Cyclin E, E2F, Rb, and pRb by western blot analysis. It also induced cancer cell inflammation and growth. As a result, we suggest that nicotine will increase the therapeutic resistance effects of CDDP. This has the potential to interact with nicotine through α7nAchR receptors and HDAC1/Cyclin D/E2F/pRb potentially resulting in CDDP therapy resistance, as well as cell cycle-induced cancer cell growth.

Butyrate alleviates alcoholic liver disease-associated inflammation through macrophage regulation and polarization via the HDAC1/miR-155 axis.

BACKGROUND: We recently found that butyrate could ameliorate inflammation of alcoholic liver disease (ALD) in mice. However, the exact mechanism remains incompletely comprehended. Here, we examined the role of butyrate on ALD-associated inflammation through macrophage (Mψ) regulation and polarization using in vivo and in vitro experiments. METHODS: For in vivo experiments, C57BL/6J mice were fed modified Lieber-DeCarli liquid diets supplemented with or without ethanol and sodium butyrate (NaB). After 6 weeks of treatment, mice were euthanized and associated indicators were analyzed. For in vitro experiments, lipopolysaccharide (LPS)-induced inflammatory murine RAW264.7 cells were treated with NaB or miR-155 inhibitor/mimic to verify the anti-inflammatory effect and underlying mechanism. RESULTS: The administration of NaB alleviated pathological damage and associated inflammation, including LPS, tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1ß levels in ALD mice. NaB intervention restored the imbalance of macrophage polarization by inhibiting inducible nitric oxide synthase (iNOS) and elevating arginase-1 (Arg-1). Moreover, NaB reduced histone deacetylase-1 (HDAC1), nuclear factor kappa-B (NF-κB), NOD-like receptor thermal protein domain associated protein 3 (NLRP3), and miR-155 expression in ALD mice, but also increased peroxisome proliferator-activated receptor-γ (PPAR-γ). Thus, MiR-155 was identified as a strong regulator of ALD. To further penetrate the role of miR-155, LPS-stimulated RAW264.7 cells co-cultured with NaB were treated with the specific inhibitor or mimic. Intriguingly, miR-155 was capable of negatively regulated inflammation with NaB intervention by targeting SOCS1, SHIP1, and IRAK-M genes. CONCLUSION: Butyrate suppresses the inflammation in mice with ALD by regulating macrophage polarization via the HDAC1/miR-155 axis, which may potentially contribute to the novel therapeutic treatment for the disease.

Securin acetylation prevents precocious separase activation and premature sister chromatid separation.

Lysine acetylation of non-histone proteins plays crucial roles in many cellular processes. In this study, we examine the role of lysine acetylation during sister chromatid separation in mitosis. We investigate the acetylation of securin at K21 by cell-cycle-dependent acetylome analysis and uncover its role in separase-triggered chromosome segregation during mitosis. Prior to the onset of anaphase, the acetylated securin via TIP60 prevents its degradation by the APC/CCDC20-mediated ubiquitin-proteasome system. This, in turn, restrains precocious activation of separase and premature separation of sister chromatids. Additionally, the acetylation-dependent stability of securin is also enhanced by its dephosphorylation. As anaphase approaches, HDAC1-mediated deacetylation of securin promotes its degradation, allowing released separase to cleave centromeric cohesin. Blocking securin deacetylation leads to longer anaphase duration and errors in chromosome segregation. Thus, this study illustrates the emerging role of securin acetylation dynamics in mitotic progression and genetic stability.

Mechanism of HDAC1 Regulating Iron Overload-Induced Neuronal Oxidative Damage After Cerebral Hemorrhage.

Iron overload is associated with brain edema in the context of intracerebral hemorrhage (ICH). Here, we investigated the role of histone deacetylase 1 (HDAC1) in mediating oxidative damage induced by iron overload after ICH. Utilizing ICH mouse models and FeCl2-induced HT-22 cell models, we assessed HDAC1 expression and its impact on iron overload and oxidative damage. We examined the levels of Kruppel like factor 4 (KLF4), RAN binding protein 9 (RANBP9), as well as the acetylation levels of HDAC1 and histones H3 and H4 in the KLF4 promoter, and the KLF4 level in the RANBP9 promoter. Additionally, we investigated the binding relationships between KLF4 and the RANBP9 promoter, HDAC1 and miR-129-5p. Our results demonstrated elevated HDAC1 expression in ICH mice and FeCl2-induced HT-22 cells. HDAC1 silencing improved neurological function in mice, reduced brain edema, and alleviated iron overload and oxidative damage in vitro. HDAC1 downregulated KLF4 expression by reducing acetylation levels in the KLF4 promoter, leading to decreased KLF4 enrichment in the RANBP9 promoter and increased RANBP9 expression. Furthermore, upstream miR-129-5p inhibited HDAC1, and the downregulation of miR-129-5p mitigated the protective effect of HDAC1 silencing. Collectively, our findings highlight the significant role of HDAC1 in exacerbating iron overload-induced oxidative damage following ICH and its regulation by miR-129-5p.

ZNF787 and HDAC1 Mediate Blood-Brain Barrier Permeability in an In Vitro Model of Alzheimer's Disease Microenvironment.

The permeability of the blood-brain barrier (BBB) is increased in Alzheimer's disease (AD). This plays a key role in the instigation and maintenance of chronic inflammation during AD. Experiments using AD models showed that the increased permeability of the BBB was mainly caused by the decreased expression of tight junction-related proteins occludin and claudin-5. In this study, we found that ZNF787 and HDAC1 were upregulated in ß-amyloid (Aß)1-42-incubated endothelial cells, resulting in increased BBB permeability. Conversely, the silencing of ZNF787 and HDAC1 by RNAi led to reduced BBB permeability. The silencing of ZNF787 and HDAC1 enhanced the expression of occludin and claudin-5. Mechanistically, ZNF787 binds to promoter regions for occludin and claudin-5 and functions as a transcriptional regulator. Furthermore, we demonstrate that ZNF787 interacts with HDAC1, and this resulted in the downregulation of the expression of genes encoding tight junction-related proteins to increase in BBB permeability. Taken together, our study identifies critical roles for the interaction between ZNF787 and HDAC1 in regulating BBB permeability and the pathogenesis of AD.

PADI4 negatively regulates RIG-I-mediated antiviral response through deacetylation of IFN-ß promoter via HDAC1.

The production of type I interferon (IFN) is precisely modulated by host to protect against viral infection efficiently without obvious immune disorders. Elucidating the tight control towards type I IFN production would be helpful to get insight into natural immunity and inflammatory diseases. As yet, however, the mechanisms that regulate IFN-ß production, especially the epigenetic regulatory mechanisms, remain poorly explored. This study elucidated the potential function of Peptidylarginine deiminases (PADIs)-mediated citrullination in innate immunity. We identified PADI4, a PADIs family member that can act as an epigenetic coactivator, could repress IFN-ß production upon RNA virus infection. Detailed experiments showed that PADI4 deficiency increased IFN-ß production and promoted antiviral immune activities against RNA viruses. Mechanistically, the increased PADI4 following viral infection translocated to nucleus and recruited HDAC1 upon binding to Ifnb1 promoter, which then led to the deacetylation of histone H3 and histone H4 for repressing Ifnb1 transcription. Taken together, we identify a novel non-classical role for PADI4 in the regulation of IFN-ß production, suggesting its potential as treatment target in inflammatory or autoimmune diseases.