Histone Deacetylase Inhibitor Research Articles

Probing class I histone deacetylases (HDAC) with proteolysis targeting chimera (PROTAC) for the development of highly potent and selective degraders

Class I HDACs are considered promising targets for cancer due to their role in epigenetic modifications. The main challenges in developing a new, potent and non-toxic class I HDAC inhibitor are selectivity and appropriate pharmacokinetics. The PROTAC technique (Proteolysis Targeting Chimera) is a new method in drug development for the production of active substances that can degrade a protein of interest (POI) instead of inhibiting it. This technique will open the era to produce selective and potent drugs with a high margin of safety. Previously, we reported different inhibitors targeting class I HDACs functionalized with aminobenzamide or hydroxamate groups. In the current research work, we will employ PROTAC technique to develop class I HDAC degraders based on our previously reported inhibitors. We synthesized two series of aminobenzamide-based PROTACs and hydroxamate-based PROTACs and tested them in vitro against class I HDACs. To ensure their degradation, all of them were screened against HDAC2 as representative example of class I. The best candidates were evaluated at different concentrations at various HDAC subtypes. This resulted in the PROTAC (32a) (HI31.1) that degrades HDAC8 with a DC50 of 8.9 nM with a proper margin of selectivity against other isozymes. Moreover, PROTAC 32a is able to degrade HDAC6 with DC50 = 14.3 nM. Apoptotic study on leukemic cells (MV-4–11) displayed more than 50 % apoptosis took place at 100 nM. PROTAC 32a (HI31.1) showed a good margin of safety against normal cell line and proper chemical stability.

Histone deacetylase expression following cisplatin-induced acute kidney injury in male and female mice.

The chemotherapeutic agent cisplatin accumulates in the kidneys, leading to acute kidney injury (AKI). Preclinical and clinical studies have demonstrated sex-dependent outcomes of cisplatin-AKI. Deranged histone deacetylase (HDAC) activity is hypothesized to promote the pathogenesis of male murine cisplatin-AKI; however, it is unknown whether there are sex differences in the kidney HDACs. We hypothesized that there would be sex-specific Hdac expression, localization, or enzymatic activity, which may explain sexual dimorphic responses to cisplatin-AKI. In normal human kidney RNA samples, HDAC10 was significantly greater in the kidneys of women compared with men, whereas HDAC1, HDAC6, HDAC10, and HDAC11 were differentially expressed between the kidney cortex and medulla, regardless of sex. In a murine model of cisplatin-AKI (3 days after a 15 mg/kg injection), we found few sex- or cisplatin-related differences in Hdac kidney transcripts among the mice. Although Hdac9 was significantly greater in female mice compared with male mice, HDAC9 protein localization did not differ. Hdac7 transcripts were greater in the inner medulla of cisplatin-AKI mice, regardless of sex, and this agreed with a greater HDAC7 abundance. HDAC activity within the cortex, outer medulla, and inner medulla was significantly lower in cisplatin-AKI mice but did not differ between the sexes. In agreement with these findings, a class I HDAC inhibitor did not improve kidney injury or function. In conclusion, even though cisplatin-AKI was evident and there were transcript level differences among the different kidney regions in this model, there were few sex- or cisplatin-dependent effects on kidney HDAC localization or activity.NEW & NOTEWORTHY Kidney histone deacetylases (HDACs) are abundant in male and female mice, and the inner medulla has the greatest HDAC activity. A low dose of cisplatin caused acute kidney injury (AKI) in these mice, but there were few changes in kidney HDACs at the RNA/protein/activity level. A class I HDAC inhibitor failed to improve AKI outcomes. Defining the HDAC isoform, cellular source, and interventional timing is necessary to determine whether HDAC inhibition is a therapeutic strategy to prevent cisplatin-AKI in both sexes.

Remembering Hypoxia: Uncovering the Long-Term Effects of Transient Oxygen Deprivation on IFN Signaling and Progression of Breast Cancer.

Hypoxia occurs in 90% of solid tumors and is strongly associated with an increased propensity for metastasis. Hypoxia induces tumor progression largely through inducing HIF-mediated transcription, resulting in alterations to tumor cell metabolism, as well as increases in migration and invasion. Hypoxia also results in a myriad of changes to the tumor microenvironment (TME). While many studies have examined the immediate effects of hypoxia on tumor cells and the associated TME, far fewer have focused on the long-term consequences of transient reductions in oxygen. In this issue of Cancer Research, Iriondo and colleagues examined whether short-term exposure to hypoxia leads to a "hypoxic memory" in the context of breast cancer. The authors used established cell lines and circulating tumor cell lines to demonstrate that these cells harbor a hypoxic memory that sustains downregulation of IFN signaling and antigen presentation (AP) pathways that contribute to tumor progression via alterations to tumor cells and the TME. The authors further showed that cells that have experienced hypoxia maintain the reduction in IFN signaling in vivo and are more aggressive. They determined that the hypoxic memory and reduction of IFN signaling can be reversed with a histone deacetylase inhibitor, entinostat, providing a potential means to reverse hypoxia-induced suppression of IFN signaling. As suppression of IFN signaling has the potential to influence both tumor cells and the TME, the identification of a strategy to inhibit long-term suppression of IFN signaling downstream of hypoxia could prove to be an effective means to target tumor progression. See related article by Iriondo et al., p. 3141.

Modeling high-risk Wilms tumors enables the discovery of therapeutic vulnerability

Wilms tumor (WT) is the most common pediatric kidney cancer treated with standard chemotherapy. However, less-differentiated blastemal type of WT often relapses. To model the high-risk WT for therapeutic intervention, we introduce pluripotency factors into WiT49, a mixed-type WT cell line, to generate partially reprogrammed cells, namely WiT49-PRCs. When implanted into the kidney capsule in mice, WiT49-PRCs form kidney tumors and develop both liver and lung metastases, whereas WiT49 tumors do not metastasize. Histological characterization and gene expression signatures demonstrate that WiT49-PRCs recapitulate blastemal-predominant WTs. Moreover, drug screening in isogeneic WiT49 and WiT49-PRCs leads to the identification of epithelial- or blastemal-predominant WT-sensitive drugs, whose selectivity is validated in patient-derived xenografts (PDXs). Histone deacetylase (HDAC) inhibitors (e.g., panobinostat and romidepsin) are found universally effective across different WT and more potent than doxorubicin in PDXs. Taken together, WiT49-PRCs serve as a blastemal-predominant WT model for therapeutic intervention to treat patients with high-risk WT.

Molecular Targets of Valeric Acid: A Bioactive Natural Product for Endocrine, Metabolic, and Immunological Disorders.

Postbiotics produced by gut microbiota have exhibited diverse pharmacological activities. Valeric acid, a postbiotic material produced by gut microbiota and some plant species like valerian, has been explored to have diverse pharmacological activities. This narrative review aims to summarise the beneficial role of valeric acid for different health conditions along with its underlying mechanism. In order to get ample scientific evidence, various databases like Science Direct, PubMed, Scopus, Google Scholar and Google were exhaustively explored to collect relevant information. Collected data were arranged and analyzed to reach meaningful a conclusion regarding the bioactivity profiling of valeric acid, its mechanism, and future prospects. Valeric acid belongs to short-chain fatty acids (SCFAs) compounds like acetate, propionate, butyrate, pentanoic (valeric) acid, and hexanoic (caproic) acid. Valeric acid has been identified as one of the potent histone deacetylase (HDAC) inhibitors. In different preclinical in -vitro and in-vivo studies, valeric acid has been found to have anti-cancer, anti-diabetic, antihypertensive, anti-inflammatory, and immunomodulatory activity and affects molecular pathways of different diseases like Alzheimer's, Parkinson's, and epilepsy. These findings highlight the role of valeric acid as a potential novel therapeutic agent for endocrine, metabolic and immunity-related health conditions, and it must be tested under clinical conditions to develop as a promising drug.

ClassIIb histone deacetylase participates in perioperative neurocognitive disorders in elderly mice via HSP90/GR signaling pathway.

Multiple factors contribute to the development of perioperative neurocognitive disorders (PND). This study was designed to investigate whether Histone Deacetylase 6 (HDAC6) was involved in the formation of postoperative cognitive dysfunction in elderly mice by regulating the degree of acetylation of heat shock protein (HSP90) and related protein functions and quantities. C57BL/6J male mice were randomly divided into six groups: control naive (group Control), anesthesia (group Anesthesia), splenectomy surgery (group Surgery), splenectomy surgery plus dissolvent (group Vehicles), splenectomy surgery plus the inhibitor ACY-1215 (group Ricolinostat), and splenectomy surgery plus the inhibitor RU-486(group Mifepristone). After the mice were trained for Morris Water Maze (MWM) test for five days, anesthesia and operational surgery were carried out the following day. Cognitive function was assessed on the 1st, 3rd and 7th days post-surgery. The hippocampi were harvested on days 1, 3, and 7 post-surgeries for Western blots and ELISA assays. Mice with the splenectomy surgery displayed the activation of the hypothalamic-pituitary-adrenal axis (HPA-axis), marked an increase in adrenocorticotropic hormone (ACTH), glucocorticoid, mineralocorticoid at the molecular level and impaired spatial memory in the MWM test. The hippocampus of surgical groups showed a decrease in acetylated HSP90, a rise in glucocorticoid receptor (GR)-HSP90 association, and an increase in GR phosphorylation and translocation. HDAC6 was increased after the surgical treated. Using two specific inhibitors, HDAC6 inhibitor Ricolinostat (ACY-1215) and GR inhibitor Mifepristone (RU-486), can partially mitigate the effects caused by surgical operation. Abdominal surgery may impair hippocampal spatial memory, possibly through the HDAC6-triggered increase in the function of HSP90, consequently strengthening the negative role of steroids in cognitive function. Targeting HDAC6- HSP90/GR signaling may provide a potential avenue for the treatment of the impairment of cognitive function after surgery.

DCas9-HDAC8-EGFP fusion enables epigenetic editing of breast cancer cells by H3K9 deacetylation

Epigenetic editing is thriving as a robust tool for manipulating transcriptional regulation and cell fate. Despite its regulatory role in gene downregulation, epigenetic editing with histone deacetylation has been sparsely studied, especially in the context of cancer. In this current study, we have reconstructed a dCas9-HDAC8-EGFP fusion to perform histone deacetylation on the promoter of the ESR1, TERT and CDKN1C genes for the first time in breast cancer cell lines MCF-7 and MDA-MB-231 as well as in HEK293T cells. Our results demonstrated that dCas9-HDAC8-EGFP in combination with appropriate gRNAs were able to downregulate the expression of the ESR1, TERT and CDKN1C genes transcriptionally by specifically depleting the H3K9ac level on the recruitment loci. The addition of histone deacetylase inhibitors was found to neutralize the outcomes of dCas9-HDAC8-EGFP-induced epigenetic editing. Furthermore, we observed a significant downregulation of full length ERα expression in epigenetically edited MCF-7 cells with consequential alteration in cellular response toward estradiol and tamoxifen treatment due to dCas9-HDAC8-EGFP mediated epigenetic editing of the ESR1 gene. Overall, dCas9-HDAC8-EGFP is a novel circuit that enabled downregulation of crucial genes with cellular outcome in breast cancer cells by preferentially inducing H3K9 deacetylation of specific promoter regions.

398 (PB386): High throughput screening identified the activity of histone deacetylase inhibitors in patient-derived models of undifferentiated pleomorphic sarcoma

398 (PB386): High throughput screening identified the activity of histone deacetylase inhibitors in patient-derived models of undifferentiated pleomorphic sarcoma

Hypoxic Memory Mediates Prolonged Tumor-Intrinsic Type I Interferon Suppression to Promote Breast Cancer Progression.

Hypoxia is a common feature of many solid tumors due to aberrant proliferation and angiogenesis that is associated with tumor progression and metastasis. Most of the well-known hypoxia effects are mediated through hypoxia-inducible factors (HIF). Identification of the long-lasting effects of hypoxia beyond the immediate HIF-induced alterations could provide a better understanding of hypoxia-driven metastasis and potential strategies to circumvent it. Here, we uncovered a hypoxia-induced mechanism that exerts a prolonged effect to promote metastasis. In breast cancer patient-derived circulating tumor cell lines and common breast cancer cell lines, hypoxia downregulated tumor-intrinsic type I IFN signaling and its downstream antigen presentation (AP) machinery in luminal breast cancer cells, via both HIF-dependent and HIF-independent mechanisms. Hypoxia induced durable IFN/AP suppression in certain cell types that was sustained after returning to normoxic conditions, presenting a "hypoxic memory" phenotype. Hypoxic memory of IFN/AP downregulation was established by specific hypoxic priming, and cells with hypoxic memory had an enhanced ability for tumorigenesis and metastasis. Overexpression of IRF3 enhanced IFN signaling and reduced tumor growth in normoxic, but not hypoxic, conditions. The histone deacetylase inhibitor entinostat upregulated IFN targets and erased the hypoxic memory. These results point to a mechanism by which hypoxia facilitates tumor progression through a long-lasting memory that provides advantages for circulating tumor cells during the metastatic cascade. Significance: Long-term cellular memory of hypoxia leads to sustained suppression of tumor-intrinsic type I IFN signaling and the antigen presentation pathway that facilitates tumorigenesis and metastasis. See related commentary by Purdy and Ford, p. 3125.

Histone Deacetylase Inhibitors for Peripheral T-Cell Lymphomas

Histone deacetylase inhibitors (HDACis) are being recognized as a potentially effective treatment approach for peripheral T-cell lymphomas (PTCLs), a heterogeneous group of aggressive malignancies with an unfavorable prognosis. Recent evidence has shown that HDACis are effective in treating PTCL, especially in cases where the disease has relapsed or is resistant to conventional treatments. Several clinical trials have demonstrated that HDACis, such as romidepsin and belinostat, can elicit long-lasting positive outcomes in individuals with PTCLs, either when used alone or in conjunction with conventional chemotherapy. They exert their anti-tumor effects by regulating gene expression through the inhibition of histone deacetylases, which leads to cell cycle arrest, induction of programmed cell death, and,the transformation of cancerous T cells, as demonstrated by gene expression profile studies. Importantly, besides clinical trials, real-world evidence indicated that the utilization of HDACis presents a significant and beneficial treatment choice for PTCLs. However, although HDACis showed potential effectiveness, they could not cure most patients. Therefore, new combinations with conventional drugs as well as new targeted agents are under investigation.

Discovery of organosulfur-based selective HDAC8 inhibitors with anti-neuroblastoma activity

Histone deacetylases (HDACs) are important epigenetic regulators of gene expression and various cellular processes, and are potential targets for anticancer therapy. In particular, HDAC8 is a promising therapeutic target for childhood neuroblastoma. To date, five HDAC inhibitors have been approved as anticancer drugs; however, all are non-selective HDAC inhibitors with various side effects. Furthermore, many promising HDAC inhibitors incorporate hydroxamic acid as a zinc binding group (ZBG), which may be associated with toxicity. Therefore, identification of isoform-selective HDAC inhibitors with novel ZBG is crucial. Here, a series of sulfur-based selective HDAC8 inhibitors featuring a novel ZBG were identified by modifying the early hit, ajoene, a component of garlic. Structure-activity relationship studies uncovered potent and selective HDAC8 inhibitors, and docking studies provided a structural rationale for HDAC8 inhibitory activity. One of the potent compounds, (Z)-1-phenyl-7-(4-methoxyphenyl)-2,3,7-trithiahepta-4-ene-7-oxide (15c), exhibited antiproliferative activity, with a GI50 of 2 µM, against neuroblastoma cell lines. 15c also showed significant in vivo efficacy in a neuroblastoma BE(2)-C xenograft model.

Histone deacetylase inhibition enhances extracellular vesicles from muscle to promote osteogenesis via miR-873-3p

Regular physical activity is widely recognized for reducing the risk of various disorders, with skeletal muscles playing a key role by releasing biomolecules that benefit multiple organs and tissues. However, many individuals, particularly the elderly and those with clinical conditions, are unable to engage in physical exercise, necessitating alternative strategies to stimulate muscle cells to secrete beneficial biomolecules. Histone acetylation and deacetylation significantly influence exercise-induced gene expression, suggesting that targeting histone deacetylases (HDACs) could mimic some exercise responses. In this study, we explored the effects of the HDAC inhibitor Trichostatin A (TSA) on human skeletal muscle myoblasts (HSMMs). Our findings showed that TSA-induced hyperacetylation enhanced myotube fusion and increased the secretion of extracellular vesicles (EVs) enriched with miR-873-3p. These TSA-EVs promoted osteogenic differentiation in human bone marrow mesenchymal stem cells (hBMSCs) by targeting H2 calponin (CNN2). In vivo, systemic administration of TSA-EVs to osteoporosis mice resulted in significant improvements in bone mass. Moreover, TSA-EVs mimicked the osteogenic benefits of exercise-induced EVs, suggesting that HDAC inhibition can replicate exercise-induced bone health benefits. These results demonstrate the potential of TSA-induced muscle-derived EVs as a therapeutic strategy to enhance bone formation and prevent osteoporosis, particularly for individuals unable to exercise. Given the FDA-approved status of various HDAC inhibitors, this approach holds significant promise for rapid clinical translation in osteoporosis treatment.

IDH1/MDH1 deacetylation promotes NETosis by regulating OPA1 and autophagy

BackgroundAs a heterogeneous and life-threatening disease, the pathogenesis of acute liver failure (ALF) is complex. Our previous study has shown that IDH1/MDH1 deacetylation promotes ALF by regulating NETosis (a novel mode of cell death). In this article, we explore the manners of IDH1/MDH1 deacetylation regulates NETosis. MethodsIn vitro experiments, the formation of NETs was detected by immunofluorescence staining and Western blotting. LC3 fluorescence staining was used to detect autophagosome formation. To observe mitochondrial morphology, cells were stained by Mito-Tracker Red. Western blotting was used to detect the levels of autophagy protein and mitochondrial dynamin. In vivo experiments, the ALF model in mouse was established with LPS/D-gal, and the formation of NETs was detected by immunofluorescence staining and Western blotting. The autophagy levels were detected by Western blotting in liver samples. ResultsIn dHL-60 cells, Western blotting results showed that the expression of OPA1 was higher in the IDH1/MDH1 deacetylated group compared with the IDH1/MDH1 WT group. And histone deacetylase inhibitor 6 (HDAC6i, ACY1215) decreased the expression level of OPA1 in IDH1/MDH1 deacetylated group. IDH1/MDH1 deacetylation increased the expression levels of both LC3B-II and Beclin 1, while decreasing the expression level of P62. It was reversed by ACY1215. Combined with our previous experiments, IDH1/MDH1 deacetylation upregulated autophagy concomitant with the increased expression of the markers of NETs formation. In a mouse model of ALF, ACY1215 further decreased the expression levels of LC3B-II and Beclin 1, while increasing the expression level of P62 in IDH1/MDH1 deacetylated mice. ConclusionsIDH1/MDH1 deacetylation promoted NETosis by regulating autophagy and OPA1 in vitro. The regulation of neutrophil autophagy on NETosis during IDH1/MDH1 deacetylation might be masked in mice. ACY1215 might attenuate NETosis by regulating neutrophil autophagy, which alleviated ALF aggravated by IDH1/MDH1 deacetylation.

Cytotoxicity of bendamustine, alone and in combination with novel agents, toward adult T-cell leukemia cells.

Adult T-cell leukemia/lymphoma (ATL) develops from the infection of T cells with human T lymphotropic virus type 1 (HTLV-1). There are an estimated 5-20 million HTLV-1 carriers worldwide and the patients are frequently observed in subtropical Africa, the Caribbean, Middle East, South America, and South West Japan. The prognosis of ATL remains dismal due to rapid acquired resistance to treatment with cytotoxic chemotherapeutic agents. In particular, the development of novel therapies for relapsed or refractory (R/R) ATL is an unmet need. Previous clinical trials revealed that bendamustine (BDM) was effective as the first-line treatment for indolent lymphoma and R/R cases of diffuse large B-cell lymphoma. Its major advantage is that it has few side effects such as hair loss and peripheral neuropathy, and does not impair the quality of life. However, its efficacy has not been verified for ATL in pre-clinical or clinical studies. In this study, we have shown the cytotoxicity of BDM alone and in combination with novel agents including the histone deacetylase (HDAC) inhibitor tucidinostat, the enhancer of zeste homolog 1/2 (EZH1/2) dual inhibitor valemetostat, and the Bcl2 family inhibitor ABT-737. The combined in vitro effects of BDM and tucidinostat were reproduced in a murine model without any obvious hematological toxicity. Our present results suggest that the combination of tucidinostat and BDM could additively prolong the survival of patients with R/R progressive ATL. The efficacy and safety of this combination are thus worthy of investigation in clinical settings.

Nanostructured lipid carrier formulation for delivering poorly water-soluble ITF3756 HDAC inhibitor

Histone deacetylases (HDACs) are enzymes that play crucial roles in cellular processes by hydrolyzing acetyl-L-lysine side chains in core histones, thereby regulating gene expression and maintaining homeostasis. Histone deacetylase inhibitors (HDACi) have emerged as promising agents, particularly in cancer treatment, due to their ability to induce cytotoxic and pro-apoptotic effects. Selective HDAC6 inhibitors, such as ITF3756, have shown low off-target toxicity and promising pharmacological activities, but their poor water solubility limits their application in nanoparticulate drug delivery systems. Here, we optimized a nanostructured lipid carrier (NLC) formulation for delivering ITF3756 using the design of experiments (DOE) and response surface methodology (RSM). An interaction between the factor surfactant and formulation volume was observed, thus demonstrating that the surfactant concentration impacts the NLC size. It can be speculated that the higher the amount of the drug in the formulation, the lower the polydispersion index (PDI), thus resulting in more stable nanostructures. The optimized ITF3756-NLC demonstrated a size of 51.1 ± 0.3 nm, 8.85 ± 4.71 mV charge, and high entrapment efficiency (EE%), maintaining stability for 60 days. Moreover, ITF3756-NLC enhanced α-tubulin acetylation in melanoma, lung, and brain cancer cell lines, indicating retained or improved bioactivity. The ITF3756-NLC formulation offers a viable approach for enhancing the bioavailability and therapeutic efficacy of HDAC6 inhibitors, demonstrating potential for clinical applications in cancer immunotherapy.

PET imaging assist investigation of HDAC6 expression change in MDD and evaluating antidepressant efficacy of a newly developed HDAC6 inhibitor

The histone deacetylase 6 (HDAC6) is closely related to the pathogenesis of depression in epigenetic regulation. However, it remains unclear how HDAC6 expression changes in depression pathophysiology and whether it is a target for antidepressant treatment. Herein, we investigate the expression change of HDAC6 in major depressive disorder (MDD) and evaluate the efficacy of a novel HDAC6 inhibitor, PB200, using positron emission tomography (PET) imaging. PET imaging studies with an HDAC6 PET probe [18F]Bavarostat allied with in vitro experiments demonstrated significantly increased HDAC6 expression in the brains of MDD mice. To investigate if pharmacological inhibition of HDAC6 can exert antidepressant effects, a series of naphthyridine-based HDAC6 inhibitors were designed and synthesized, among which PB200 demonstrated high selectivity and inhibitory activity against HDAC6, favorable metabolic stability, and excellent brain uptake. Moreover, PB200 exhibited significant antidepressant effects by restoring abnormal HDAC6 expression level and alleviating neuroinflammation. These results imply that targeting HDAC6 shows promise as a therapeutic strategy for depression, and PB200 is a potential therapeutic option for treating MDD.

Therapeutic role of histone deacetylase inhibition in an in vitro model of Graves' orbitopathy.

Graves' orbitopathy (GO), a manifestation of Graves' disease, is characterized by orbital fibroblast‑induced inflammation, leading to fibrosis or adipogenesis. Histone deacetylase (HDAC) serves a central role in autoimmune diseases and fibrosis. The present study investigated HDAC inhibition in orbital fibroblasts from patients with GO to evaluate its potential as a therapeutic agent. Primary cultured orbital fibroblasts were treated with an HDAC inhibitor, panobinostat, under the stimulation of IL‑1β, TGF‑β or adipogenic medium. Inflammatory cytokines, and fibrosis‑ and adipogenesis‑related proteins were analyzed using western blotting. The effects of panobinostat on HDAC mRNA expression were measured in GO orbital fibroblasts, and specific HDACs were inhibited using small interfering RNA transfection. Panobinostat significantly reduced the IL‑1β‑induced production of inflammatory cytokines and TGF‑β‑induced production of fibrosis‑related proteins. It also suppressed adipocyte differentiation and adipogenic transcription factor production. Furthermore, it significantly attenuated HDAC7 mRNA expression in GO orbital fibroblasts. In addition, the silencing of HDAC7 led to anti‑inflammatory and anti‑fibrotic effects. In conclusion, by inhibiting HDAC7 gene expression, panobinostat may suppress the production of inflammatory cytokines, profibrotic proteins and adipogenesis in GO orbital fibroblasts. The present in vitro study suggested that HDAC7 could be a potential therapeutic target for inhibiting the inflammatory, adipogenic and fibrotic mechanisms of GO.

Modulation of Stemness and Differentiation Regulators by Valproic Acid in Medulloblastoma.

Changes in epigenetic processes such as histone acetylation are proposed as key events influencing cancer cell function and the initiation and progression of pediatric brain tumors. Valproic acid (VPA) is an antiepileptic drug that acts partially by inhibiting histone deacetylases (HDACs) and could be repurposed as an epigenetic anticancer therapy. Here, we show that VPA reduced medulloblastoma (MB) cell viability and led to cell cycle arrest. These effects were accompanied by enhanced H3K9 histone acetylation (H3K9ac) and decreased expression of the MYC oncogene. VPA impaired the expansion of MB neurospheres enriched in stemness markers, and reduced MYC while increasing TP53 expression in these spheres. In addition, VPA induced morphological changes consistent with neuronal differentiation and increased expression of differentiation marker genes TUBB3 and ENO2. Expression of stemness genes SOX2, NES, and PRTG was differentially affected by VPA in MB cells with different TP53 status. VPA increased H3K9 occupancy of the promoter region of TP53. Among genes regulated by VPA, stemness regulators MYC and NES showed association with patient survival in specific MB subgroups. Our results indicate that VPA may exert antitumor effects in MB by influencing histone acetylation, which may result in modulation of stemness, neuronal differentiation, and expression of genes associated with patient prognosis in specific molecular subgroups. Importantly, the actions of VPA in MB cells and neurospheres include a reduction in expression of MYC and increase in TP53.

Electroacupuncture Promotes the Generation of Intestinal Treg Cells After Ischemic Stroke by Foxp3 Acetylation Regulation.

Electroacupuncture (EA) has been shown to ameliorate brain injury and protect against intestinal injury after ischemic stroke. These protective effects are closely associated with the enhancement of regulatory T (Treg) cell numbers and function in the intestine, as well as the inhibition of intestinal γδ T cell production and their migration to the brain. This study aimed to elucidate the potential mechanism by which EA regulates intestinal Treg cell differentiation after stroke. Sprague-Dawley rats were divided into three groups: the sham group, the middle cerebral artery occlusion (MCAO) group, and the MCAO plus EA (MEA) group. The MCAO model was generated by occluding the middle cerebral artery. EA was applied to Baihui (GV20) acupoint once daily. Samples were collected 3days after reperfusion. Our results showed that EA reduced the inflammatory response in the brain and intestine after ischemic stroke. EA treatment increased the percentage of Treg cells in the small intestine of rats. EA increased the levels of SCFAs, while also inhibiting histone deacetylase activity (HDAC). Additionally, acetylated Foxp3 protein in the small intestine was increased after EA treatment. These results suggest that EA at GV20 alleviates brain and intestinal inflammatory injury in stroke rats, potentially through the enhancement of SCFA-mediated Foxp3 acetylation in Treg cells.

Pharmacological regeneration of sensory hair cells restores afferent innervation and vestibular function.

The sensory cells that transduce the signals for hearing and balance are highly specialized mechanoreceptors called hair cells that reside in the sensory epithelia of the inner ear. Loss of hair cells from toxin exposure and age can cause balance disorders and is essentially irreversible due to the inability of mammalian vestibular organs to regenerate physiologically active hair cells. Here, we show substantial regeneration of hair cells in a mouse model of vestibular damage by treatment with a combination of glycogen synthase kinase 3β and histone deacetylase inhibitors. The drugs stimulated supporting cell proliferation and differentiation into hair cells. The new hair cells were reinnervated by vestibular afferent neurons, rescuing otolith function by restoring head translation-evoked otolith afferent responses and vestibuloocular reflexes. Drugs that regenerate hair cells thus represent a potential therapeutic approach to the treatment of balance disorders.