Heparin-binding EGF-like growth factor via miR-126 controls tumor formation/growth and the proteolytic niche in murine models of colorectal and colitis-associated cancers.

MicroRNAs, including the tumor-suppressor miR-126 and the oncogene miR-221, regulate tumor formation and growth in colitis-associated cancer (CAC) and colorectal cancer (CRC). This study explores the impact of the epithelial cytokine heparin-binding epidermal growth factor (HB-EGF) and its receptor epidermal growth factor receptor (EGFR) on the pathogenesis of CAC and CRC, particularly in the regulation of microRNA-driven tumor growth and protease expression. In murine models of CRC and CAC, lack of miR-126 and elevated miR-221 expression in colonic tissues enhanced tumor formation and growth. MiR-126 downregulation in colon cells established a pro-tumorigenic proteolytic niche by targeting HB-EGF-active metalloproteinase-7, -9 (MMP7/MMP9), disintegrin, and metalloproteinase domain-containing protein 9, and modulating chemokine-mediated recruitment of HB-EGF-loaded inflammatory cells. Mechanistically, downregulation of HB-EGF and EGFR in the colon suppressed miR-221 and enhanced miR-126 expression via activating enhancer-binding protein 2 alpha. Reintroducing miR-126 reduced tumor development and HB-EGF expression. Combining miR-126 reintroduction, which targets specific HB-EGF-active proteases but not ADAM17, with MMP inhibitors like Batimastat or Marimastat effectively suppressed tumor growth. This combination normalized protease expression and balanced miR-126 and miR-221 levels in developing and growing tumors. These findings demonstrate that suppressing HB-EGF and EGFR1 shifts the balance from oncogenic miR-221 to tumor-suppressive miR-126 action. Consequently, normalizing miR-126 expression could open new avenues for treating patients with CAC and CRC, and this normalization is intertwined with the anticancer efficacy of MMP inhibitors.

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.

Synthesis and biological evaluation of ortho-phenyl phenylhydroxamic acids containing phenothiazine with improved selectivity for class IIa histone deacetylases.

Class IIa histone deacetylases (HDACs) have been linked to tumorigenesis in various cancers. Previously, we designed phenylhydroxamic acid LH4f as a potent class IIa HDAC inhibitor. However, it also unselectively inhibited class I and class IIb HDACs. To enhance the compound's selectivity towards class IIa HDACs, the ortho-phenyl group from the selective HDAC7 inhibitor 1 is incorporated into ortho position of the phenylhydroxamic acid in LH4f. Compared to LH4f, most resulting compounds displayed substantially improved selectivity towards the class IIa HDACs. Notably, compound 7 g exhibited the strongest HDAC9 inhibition with an IC50 value of 40 nM. Molecular modelling further identified the key interactions of compound 7 g bound to HDAC9. Compound 7 g significantly inhibited several human cancer cells, induced apoptosis, modulated caspase-related proteins as well as p38, and caused DNA damage. These findings suggest the potential of class IIa HDAC inhibitors as lead compounds for the development of cancer therapeutics.

Inhibition of HDAC8 mitigates AKI by reducing DNA damage and promoting homologous recombination repair.

Nephrotoxicity is a major side effect of platinum-based antineoplastic drugs, and there is currently no available therapeutic intervention. Our study suggests that targeting histone deacetylase 8 could be a potential treatment for cisplatin-induced acute kidney injury (AKI). In a murine model of AKI induced by cisplatin, the administration of PCI-34051, a selective inhibitor of HDAC8, resulted in significant improvement in renal function and reduction in renal tubular damage and apoptosis. Pharmacological inhibition of HDAC8 also decreased caspase-3 and PARP1 cleavage, attenuated Bax expression and preserved Bcl-2 levels in the injured kidney. In cultured murine renal epithelial cells (mRTECs) exposed to cisplatin, treatment with PCI-34051 or transfection with HDAC8 siRNA reduced apoptotic cell numbers and diminished expression of cleaved caspase-3 and PARP1; conversely, overexpression of HDAC8 intensified these changes. Additionally, PCI-34051 reduced p53 expression levels along with those for p21, p-CDK2 and γ-H2AX while preserving MRE11 expression in the injured kidney. Similarly, pharmacological and genetic inhibition of HDAC8 reduced γ-H2AX and enhanced MRE11 expression; conversely, HDAC8 overexpression exacerbated these changes in mRTECs exposed to cisplatin. These results support that HDAC8 inhibition attenuates cisplatin-induced AKI through a mechanism associated with reducing DNA damage and promoting its repair.

Total Synthesis of Chalaniline A: An Aminofulvene Fused Chromone from Vorinostat-Treated Fungus Chalara sp. 6661.

Chalaniline A, an aminofulveno[1,2-b]chromone derivative previously isolated from a vorinostat-treated ascomycete Chalara sp., was prepared in nine steps from orcinol (3,5-dihydroxytoluene). In a key transformation, the tricyclic ring system of the target was generated by a pyrrolidine-catalyzed double annulation between α-(methylsulfinyl)-2,6-dihydroxy-4-methylacetophenone and the ketaldoester, methyl 2,5-dioxopentanoate. The resulting tertiary alcohol (coniochaetone H) was further converted to chalaniline A by operations including dehydration (to yield a hydroxyfulvene), Vilsmeier reaction, and enamine exchange.

Contilisant+Tubastatin A Hybrids: Polyfunctionalized Indole Derivatives as New HDAC Inhibitor-Based Multitarget Small Molecules with In Vitro and In Vivo Activity in Neurodegenerative Diseases.

Herein, we describe the design, synthesis, and biological evaluation of 15 Contilisant+Tubastatin A hybrids. These ligands are polyfunctionalized indole derivatives developed by juxtaposing selected pharmacophoric moieties of Contilisant and Tubastatin A to act as multifunctional ligands. Compounds 3 and 4 were identified as potent HDAC6 inhibitors (IC50 = 0.012 µM and 0.035 µM, respectively), so they were further evaluated in Drosophila and human cell models of Parkinson's disease (PD). Both compounds attenuated PD-like phenotypes, such as motor defects, oxidative stress, and mitochondrial dysfunction in PD model flies. Ligands 3 and 4 were also studied in the transgenic Caenorhabditis elegans CL2006 model of Alzheimer's disease (AD). Both compounds were nontoxic, did not induce undesirable animal functional changes, inhibited age-related paralysis, and improved cognition in the thrashing assay. These results highlight 3 and 4 as novel multifunctional ligands that improve the features of PD and AD hallmarks in the respective animal models.

Genetically Encoded Trensor Circuits Report HeLa Cell Treatment with Polyplexed Plasmid DNA and Small-Molecule Transfection Modulators.

HeLa cell transfection with plasmid DNA (pDNA) is widely used to materialize biologicals and as a preclinical test of nucleic acid-based vaccine efficacy. We sought to genetically encode mammalian transfection sensor (Trensor) circuits and test their utility in HeLa cells for detecting molecules and methods for their propensity to influence transfection. We intended these Trensor circuits to be triggered if their host cell was treated with polyplexed pDNA or certain small-molecule modulators of transfection. We prioritized three promoters, implicated by others in feedback responses as cells import and process foreign material and stably integrated each into the genomes of three different cell lines, each upstream of a green fluorescent protein (GFP) open reading frame within a transgene. All three Trensor circuits showed an increase in their GFP expression when their host HeLa cells were incubated with pDNA and the degraded polyamidoamine dendrimer reagent, SuperFect. We next experimentally demonstrated the modulation of PEI-mediated HeLa cell transient transfection by four different small molecules, with Trichostatin A (TSA) showing the greatest propensity to boost transgene expression. The Trensor circuit based on the TRA2B promoter (Trensor-T) was triggered by incubation with TSA alone and not the other three small molecules. These data suggest that mammalian reporter circuits could enable low-cost, high-throughput screening to identify novel transfection methods and reagents without the need to perform actual transfections requiring costly plasmids or expensive fluorescent labels.

Synergistic Cytotoxicity of Histone Deacetylase and Poly-ADP Ribose Polymerase Inhibitors and Decitabine in Breast and Ovarian Cancer Cells: Implications for Novel Therapeutic Combinations.

Breast and ovarian cancers pose significant therapeutic challenges. We explored the synergistic cytotoxicity of histone deacetylase inhibitors (HDACis), poly(ADP-ribose) polymerase inhibitors (PARPis), and decitabine in breast (MDA-MB-231 and MCF-7) and ovarian (HEY-T30 and SKOV-3) cancer cell lines that were exposed to HDACi (panobinostat or vorinostat), PARPi (talazoparib or olaparib), decitabine, or their combinations. HDACi, PARPi, and decitabine combinations had synergistic cytotoxicity (assessed by MTT and clonogenic assays) in all cell lines (combination index < 1). Clonogenic assays confirmed the sensitivity of breast and ovarian cancer cell lines to the three-drug combinations (panobinostat, talazoparib, and decitabine; panobinostat, olaparib, and decitabine; vorinostat, talazoparib, and decitabine; vorinostat, olaparib, and decitabine). Cell proliferation was inhibited by 48-70%, and Annexin V positivity was 42-59% in all cell lines exposed to the three-drug combinations. Western blot analysis showed protein PARylation inhibition, caspase 3 and PARP1 cleavage, and c-MYC down-regulation. The three-drug combinations induced more DNA damage (increased phosphorylation of histone 2AX) than the individual drugs, impaired the DNA repair pathways, and altered the epigenetic regulation of gene expression. These results indicate that HDACi, PARPi, and decitabine combinations should be further explored in these tumor types. Further clinical validation is warranted to assess their safety and efficacy.

In vitro assay and inhibition of 9-cis-epoxycarotenoid dioxygenase (NCED) from Solanum lycopersicum and Zea mays.

The article reports methods for the expression and assay of 9-cis-epoxycarotenoid cleavage dioxygenase (NCED), an enzyme involved in the biosynthesis of phytohormone abscisic acid in plants. A method for the preparation of the unstable substrate 9'-cis-neoxanthin from fresh spinach is described. The inhibition of Solanum lycopersicum NCED by a series of aryl hydroxamic acid inhibitors is illustrated, and inhibitors D2 and D4 are assayed against NCED isozymes from Zea mays.

Development of Fragment-Based Inhibitors of the Bacterial Deacetylase LpxC with Low Nanomolar Activity.

In a fragment-based approach using NMR spectroscopy, benzyloxyacetohydroxamic acid-derived inhibitors of the bacterial deacetylase LpxC bearing a substituent to target the uridine diphosphate-binding site of the enzyme were developed. By appending privileged fragments via a suitable linker, potent LpxC inhibitors with promising antibacterial activities could be obtained, like the one-digit nanomolar LpxC inhibitor (S)-13j [Ki (EcLpxC C63A) = 9.5 nM; Ki (PaLpxC): 5.6 nM]. To rationalize the observed structure-activity relationships, molecular docking and molecular dynamics studies were performed. Initial in vitro absorption-distribution-metabolism-excretion-toxicity (ADMET) studies of the most potent compounds have paved the way for multiparameter optimization of our newly developed isoserine-based amides.

Matrix metalloproteinases mediate influenza A-associated shedding of the alveolar epithelial glycocalyx.

BACKGROUND: The alveolar epithelium is protected by a heparan sulfate-rich, glycosaminoglycan layer called the epithelial glycocalyx. It is cleaved in patients with acute respiratory distress syndrome (ARDS) and in murine models of influenza A (IAV) infection, shedding fragments into the airspace from the cell surface. Glycocalyx shedding results in increased permeability of the alveolar-capillary barrier, amplifying acute lung injury. The mechanisms underlying alveolar epithelial glycocalyx shedding in IAV infection are unknown. We hypothesized that induction of host sheddases such as matrix metalloproteinases (MMPs) during IAV infection results in glycocalyx shedding and increased lung injury. MATERIALS AND METHODS: We measured glycocalyx shedding and lung injury during IAV infection with and without treatment with the pan-MMP inhibitor Ilomastat (ILO) and in an MMP-7 knock out (MMP-7KO) mouse. C57BL/6 or MMP-7KO male and female mice were given IAV A/PR/8/34 (H1N1) at 30,000 PFU/mouse or PBS intratracheally. For some experiments, C56BL/6 mice were infected in the presence of ILO (100mg/kg) or vehicle given daily by IP injection. Bronchoalveolar lavage (BAL) and lung tissue were collected on day 1, 3, and 7 for analysis of glycocalyx shedding (BAL Syndecan-1) and lung injury (histology, BAL protein, BAL cytokines, BAL immune cell infiltrates, BAL RAGE). Expression and localization of the sheddase MMP-7 and its inhibitor TIMP-1 was examined by RNAScope. For in vitro experiments, MLE-12 mouse lung epithelial cells were cultured and treated with active or heat-inactivated heparinase (2.5 U/mL) prior to infection with IAV (MOI 1) and viral load and MMP-7 and TIMP-1 expression analyzed. RESULTS: IAV infection caused shedding of the epithelial glycocalyx into the BAL. Inhibition of MMPs with ILO reduced glycocalyx shedding by 36% (p = 0.0051) and reduced lung epithelial injury by 40% (p = 0.0404). ILO also reduced viral load by 68% (p = 0.027), despite having no significant effect on lung cytokine production. Both MMP-7 and its inhibitor TIMP-1 were upregulated in IAV infected mice: MMP-7 colocalized with IAV, while TIMP-1 was limited to cells adjacent to infection. However, MMP-7KO mice had similar glycocalyx shedding, epithelial injury, and viral load compared to WT littermates, suggesting redundancy in MMP sheddase function in the lung. In vitro, heparinase treatment before infection led to a 52% increase in viral load (p = 0.0038) without altering MMP-7 or TIMP-1 protein levels. CONCLUSIONS: Glycocalyx shedding and MMPs play key roles in IAV-induced epithelial injury, with significant impact on IAV viral load. Further studies are needed to understand which specific MMPs regulate lung epithelial glycocalyx shedding.

Nucleic acid binding affinity and antioxidant activity of N-m-Tolyl-4-Chlorophenoxyacetohydroxamicacid.

Hydroxamic acids represent a group of weak organic acids, both naturally occurring and synthetically derived, characterized by the general formula RC(= O)N(R'OH). In this study, we investigated the binding behavior of N-m-tolyl-4-chlorophenoxyaceto hydroxamic acid with calf thymus DNA (ct-DNA) and torula yeast RNA (t-RNA) through a combination of techniques including UV-visible spectroscopy, fluorescence emission analysis, viscometry, and computational simulations using AutoDock4 software. Our findings reveal that the mode of binding between the compound and the nucleic acids is consistent with intercalation. Competitive binding experiments demonstrated that the complex competes effectively with ethidium bromide (EB) for binding to ct-DNA/t-RNA, displacing EB from its binding sites. Additionally, the introduction of the compound into the DNA-EB system resulted in a quenching of fluorescence emission peaks. Analysis of absorption spectra indicated a red shift and hypochromic shift when the compound interacted with DNA, further supporting the intercalative binding mode. The calculated binding constant (Kb) value for the compound is 6.62 × 104 M-1 and 5.40 × 103 M-1 indicating a strong interaction with ct-DNA and t-RNA respectively. We determined the Stern-Volmer constants for ct-DNA and t-RNA as 9.96 × 104 M-1 and 8.13 × 105 M-1, respectively. The binding free energy values for ct-DNA/t-RNA were calculated to be - 3.741 × 107 and - 5.425 × 108 kcal/mol, respectively. Viscometric studies corroborated the UV results, showing a continuous increase in relative viscosity of ct-DNA/t-RNA solutions with the addition of the optimal hydroxamic acid concentration. Furthermore, we assessed the antioxidant activity of the compound using DPPH-radical scavenging and ß-carotene linoleic acid assays. Gel electrophoresis results demonstrated the compound's remarkable efficacy in preventing DNA damage. Collectively, all experimental evidence supports the conclusion that N-m-tolyl-4-chlorophenoxyaceto hydroxamic acid binds to ct-DNA/t-RNA through an intercalative mechanism, which is consistent with our molecular docking simulations.

Syntheses of LSD1/HDAC Inhibitors with Demonstrated Efficacy against Colorectal Cancer: In Vitro and In Vivo Studies Including Patient-Derived Organoids.

Precedential evidence ascertaining the overexpression of LSD1 and HDACs in colorectal cancer spurred us to design a series of dual LSD1-HDAC inhibitors. Capitalizing on the modular nature of the three-component HDAC inhibitory model, tranylcypromine as a surface recognition motif was appended to zinc-binding motifs via diverse linkers. A compendium of hydroxamic acids was generated and evaluated for in vitro cytotoxicity against HCT-116 cells (human colorectal cancer cell lines). The most potent cell growth inhibitor 2 (GI50 = 0.495 µMm HCT-116 cells) shows promising anticancer effects by reducing colony formation and inducing cell cycle arrest in HCT-116 cells. It exhibits preferential inhibition of HDAC6, along with potent inhibition of LSD1 compared to standard inhibitors. Moreover, Compound 2 upregulates acetyl-tubulin, acetyl-histone H3, and H3K4me2, indicative of LSD1 and HDAC inhibition. In vivo, it demonstrates significant antitumor activity against colorectal cancer, better than irinotecan, and effectively inhibits growth in patient-derived CRC organoids.

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

OBJECTIVE: 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. METHODS: C57BL/6 J 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. RESULTS: 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. CONCLUSIONS: 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.

Differential expression and regulation of ADAD1, DMRTC2, PRSS54, SYCE1, SYCP1, TEX101, TEX48, and TMPRSS12 gene profiles in colon cancer tissues and their in vitro response to epigenetic drugs.

Colon cancer (CC) is a significant cause of death worldwide, particularly in Saudi Arabia. To increase the accuracy of diagnosis and treatment, it is important to discover new specific biomarkers for CC. The main objectives of this research are to identify potential specific biomarkers for the early diagnosis of CC by analyzing the expressions of eight cancer testis (CT) genes, as well as to analyze how epigenetic mechanisms control the expression of these genes in CC cell lines. Tissue samples were collected from 15 male patients with CC tissues and matched NC tissues for gene expression analysis. The expression levels of specific CT genes, including ADAD1, DMRTC2, PRSS54, SYCE1, SYCP1, TEX101, TEX48, and TMPRSS12, were assessed using quantitative techniques. To validate the gene expression patterns, we used publicly available CC statistics. To investigate the effect of inhibition of DNA methylation and histone deacetylation on CT gene expression, in vitro experiments were performed using HCT116 and Caco-2 cell lines. There was no detected expression of the genes neither in the patient samples nor in NC tissues, except for TEX48, which exhibited upregulation in CC samples compared to NC tissues in online datasets. Notably, CT genes showed expression in testis samples. In vitro, experiments demonstrated significant enhancement in mRNA expression levels of ADAD1, DMRTC2, PRSS54, SYCE1, SYCP1, TEX101, TEX48, and TMPRSS12 following treatment with 5-aza-2'-deoxycytidine and trichostatin A in HCT116 and Caco-2 cell lines. Epigenetic treatments modify the expression of CT genes, indicating that these genes can potentially be used as biomarkers for CC. The importance of conducting further research to understand and target epigenetic mechanisms to improve CC treatment cannot be overemphasized.

Tri-aryl antimony(V) hydroximato and hydroxamato complexes: Combining lipophilic Sb(III/V) and hydroxamic acids in combating Leishmania.

Six novel tri-aryl antimony(V) hydroximato complexes (3-8) with composition [SbAr3(O2NCR)] (3: Ar = Ph, R = o-(OH)Ph, 4: Ar = Ph, R = Me, 5: Ar = Ph, R = Ph; 6: Ar = Mes, R = Me, 7: Ar = Mes, R = Ph, 8: Ar = Mes, R = o-(OH)Ph (where Ph = phenyl, Me = methyl, Mes = mesityl)), were synthesised and evaluated for anti-parasitic activity towards Leishmania major (L. major) promastigotes and amastigotes. Complexes of the form [SbAr3(O2NCR)], with the dianionic hydroximato ligand binding O,O'-bidentate to the Sb(V) centre, exist in the solid-state for the mesityl-derived complexes. In contrast, the phenyl-ligated Sb(V) complexes crystallise as the hexacoordinate, hydroxamato species [SbPh3(O2NHC(OH))], with the OH ligand derived from entrained H2O in the crystallisation solvent. It is found that both the aryl and hydroximato ligands are found to influence the bioactivity of the Sb(V) complexes. Complexes 3-8 exhibited varied anti-promastigote activity with IC50 values ranging from 1.53 µM for 6 to 36.0 µM for 3, also reflected in varied anti-amastigote activity with a percentage infection range of 5.50% for 6 to 29.00% for 3 at a concentration of 10 µM. The complexes were relatively non-toxic to human fibroblasts with an IC50 value range of 59.3 µM (7) to ≥100 µM (3-6, 8), and exhibited varied toxicity towards J774.1 A macrophages (IC50: 3.97 (6) to ≥100 (8) µM). All complexes showed enhanced activity compared to the parent hydroxamic acids.

Isoalantolactone/hydroxamic acid hybrids as potent dual STAT3/HDAC inhibitors and self-assembled nanoparticles for cancer therapy.

Conventional chemotherapy, especially with natural anticancer drugs, usually suffers from poor bioavailability and low tumor accumulation. To address these limitations, we developed a novel approach for modifying natural products in which amphiphilic hydroxamic acid hybrids based on a natural product: isoalantolactone (IAL) were rationally designed. Compound 18 is identified as a highly potent dual signal transducer and activator of transcription 3 (STAT3)/histone deacetylases (HDAC) inhibitor and induces autophagy and apoptosis. 18 exhibits higher antitumor potency than IAL and the hydroxamic acid SAHA in vitro and in vivo. Furthermore, 18 self-assembled in water to form nanoparticles (18 NPs), which facilitated the accumulation of drugs in tumor tissues and promoted their cellular uptake, resulting in superior anticancer efficacy compared to free 18. Compared to drug-drug conjugates, hydroxamic acid hybrids have a smaller molecular weight and can synergize with various anticancer drugs. Overall, these findings indicate that 18 utilizing nanomedicines and dual-target drugs provide an efficient strategy for the rational design of dual-target drugs and the modification of natural products.

Histone deacetylase inhibitor, Trichostatin A mitigates ionizing radiation induced redox imbalance by regulating NRF2/GPX4/PINK1/PARKIN signaling in mice intestine.

BACKGROUND: Gastrointestinal-acute radiation syndrome (GI-ARS) caused by moderate to high doses of ionizing radiation exposure contribute to early death in humans. GI injury is also a common adverse effect seen in cancer patients undergoing abdominal/pelvic radiotherapy. Currently, no countermeasure agents have been approved for medical management of GI-ARS. The present study aims to evaluate the mechanism of action of Trichostatin A(TSA), a pan histone deacetylase inhibitor, against radiation-induced GI injury. METHODS: TSA (150 ng/kg bw) was administered to mice 1 h and 24 h after 15 Gy abdominal irradiation. Expression of various markers of oxidative stress, mitochondrial dysfunction, and apoptosis were checked in the jejunum, and their possible regulation through the Nrf2 signaling pathway was evaluated. RESULTS: TSA administered post-irradiation (15 Gy + TSA) elevated intestinal total antioxidant and glutathione levels by regulating the expression of Slc7A11 and antioxidant proteins, GCLC, GPX4, and TXNRD1. Improved mitochondrial membrane potential, ATP levels, downregulation of mitochondrial quality control proteins, (PINK1 and PARKIN), and differential regulation of the apoptotic proteins, (BAX, PUMA and BCL2) with reduced intestinal epithelial cell apoptosis in the TSA-adminstered group were observed. TSA also upregulated Nrf2 in the presence of its specific inhibitor, ML385, suggesting its involvement in regulating Nrf2 signaling during oxidative stress induced by radiation in intestine. H & E stained jejunum cross-sections revealed that TSA mitigated radiation-mediated intestinal injury in mice. CONCLUSIONS: Present findings indicate that TSA is beneficial in mitigating the damaging effects of ionizing radiation in the intestine.

LMK-235 suppresses osteoclastogenesis and promotes osteoblastogenesis by inhibiting HDAC4.

Osteoblasts and osteoclasts play an important role in maintaining the structural integrity of bone tissue, in which osteoclasts degrade bone structure and osteoblasts restore bone tissue. The imbalance of osteoblast and osteoclast function can lead to many bone-related diseases, such as osteoporosis and inflammatory osteolysis. The drug that can both promote bone formation and inhibit bone loss will be able to treat those diseases. In this study, it was found that LMK-235, an selective HDAC4/5 inhibitor, inhibited the differentiation and maturation of osteoclasts by regulating NF-κB and p-Smad2/3 signaling pathways via inhibition of HDAC4. At the same time, we found that LMK-235 promoted osteoblast mineralization by upregulating Runx2 expression via inhibition of HDAC4. In vivo, LMK-235 was able to alleviate lipopolysaccharide (LPS)-induced calvarial osteolysis and promote the repair of bone defects. Taken together, LMK-235 suppresses osteoclast differentiation and promotes osteoblast formation by inhibiting HDAC4. This may provide a valuable treatment for bone diseases caused by abnormal osteoclast bone resorption and osteoblast bone regeneration.

Analysis of the effect of HDAC inhibitors on the formation of the HIV reservoir.

The HIV reservoir is more dynamic than previously thought with around 70% of the latent reservoir originating from viruses circulating within 1 year of the initiation of antiretroviral therapy (ART). In an ex vivo model system of HIV latency, it was reported that early exposure to class I histone deacetylase (HDAC) inhibitors might prevent these more recently infected cells from entering a state of stable viral latency. This finding raises the possibility that co-administration of HDAC inhibitors at the time of ART initiation may prevent the establishment of much of the HIV reservoir. Here, we tested the effects of the HDAC inhibitors suberoylanilide hydroxamic acid (SAHA) and panobinostat co-administered at the time of ART initiation on the formation of the viral reservoir in HIV-infected humanized mice. As previously shown, SAHA and panobinostat were well tolerated in humanized mice. Unexpectedly, co-administration of SAHA resulted in an increase in the frequency of CD4+ cells carrying HIV DNA but did not alter the frequency of cell-associated HIV RNA in HIV-infected, ART-treated humanized mice. Co-administration of panobinostat did not alter levels of cell-associated HIV DNA or RNA. Our in vivo findings indicate that co-administration of HDAC inhibitors initiated at the same time of ART treatment does not prevent recently infected cells from entering latency.IMPORTANCECurrent antiretroviral therapy (ART) does not eradicate cells harboring replication-competent HIV reservoir. Withdrawal of ART inevitably results in a rapid viremia rebound. The HIV reservoir is more dynamic than previously thought. Early exposure to class I histone deacetylase (HDAC) inhibitors inhibit these more recently infected cells from entering a state of stable viral latency in an ex vivo model of latency, raising the possibility that co-administration of HDAC inhibitors at the time of ART initiation may reduce much of the HIV reservoir. Here, we tested the effects of the HDAC inhibitors suberoylanilide hydroxamic acid or panobinostat during ART initiation on the formation of the viral reservoir in HIV-infected humanized mice. Our in vivo study indicates that in contrast to in vitro observations, the co-administration of HDAC inhibitors at the same time of ART initiation does not prevent recently infected cells from entering latency.