Search Results (183)

Objectives: High-calorie diets are linked to increased risks of chronic inflammation and immune dysfunction, yet their role in modulating pneumonia severity remains unclear. Focusing on the interactions among gut-originating short-chain fatty acids (SCFAs), neutrophil function, and histone deacetylases (HDACs), this research examined the exacerbating effects of a high-calorie diet on pneumonia in rats. Methods: Male Sprague-Dawley rats (3 weeks old, 110 ± 10 g) were allocated among four groups: normal diet (N), high-calorie diet (G), LPS-induced pneumonia (P), and high-calorie diet combined with lipopolysaccharide (LPS)-induced pneumonia (GP). LPS was administered via aerosolization for three days. Fecal, serum, and lung SCFA levels were quantified via GC-MS. Neutrophil extracellular traps (NETs) formation, neutrophil apoptosis, and HDAC activity were assessed using immunofluorescence, TUNEL assays, and qRT-PCR. Propionate supplementation and HDAC inhibitor (trichostatin A) interventions were applied to validate mechanistic pathways. Results: The group GP exhibited exacerbated lung inflammation, increased NETs release, and reduced neutrophil apoptosis compared to the group P. Propionate levels in feces, serum, and lung tissues decreased sharply in GP rats, correlating with elevated HDAC1/2/3/6 activity and reduced histone acetylation. Propionate supplementation or HDAC inhibition significantly attenuated lung injury, suppressed NETs, and restored neutrophil apoptosis. Conclusions: High-calorie diets exacerbate pneumonia by depleting gut-derived propionate, which drives HDAC-mediated NETs overproduction and impairs neutrophil apoptosis. Restoring propionate levels or targeting HDACs may offer therapeutic strategies for diet-aggravated respiratory diseases. Mechanistically, propionate-mediated HDAC inhibition demonstrates proof-of-concept efficacy in modulating H4 acetylation, warranting further investigation in disease-specific pneumonia models. Full article

Background/Objectives: Renal cell carcinoma (RCC) exhibits distinctive metabolic vulnerabilities that may be therapeutically targeted. This study investigates how tigecycline, an FDA-approved antibiotic that inhibits mitochondrial translation, affects RCC cells and explores potential combinatorial approaches to enhance its efficacy. Methods: We employed comprehensive metabolomic profiling, subcellular proteomics, and functional assays to characterize the effects of tigecycline on RCC cell lines, patient-derived organoids, and xenograft models. The synergistic potential of tigecycline with the histone deacetylase inhibitor entinostat was evaluated using combination index analysis. Results: Tigecycline selectively inhibited mitochondrial translation in RCC cells, reducing mitochondrially-encoded proteins while sparing nuclear-encoded components, profoundly disrupting mitochondrial bioenergetics and reducing tumor growth in xenograft models. Subcellular proteomic analyses revealed that tigecycline treatment triggered a significant accumulation of multiple histone variants concurrent with cell cycle arrest. Based on this discovery, combined treatment with tigecycline and entinostat demonstrated remarkable synergism across RCC cell lines and patient-derived. Conclusions: Our findings identify a promising therapeutic opportunity by targeting the crosstalk between mitochondrial function and epigenetic homeostasis in RCC, with the potential for rapid clinical translation given the established pharmacological profiles of both agents. Full article

As a major global health challenge, hepatocellular carcinoma (HCC) still faces substantial limitations in its treatment options. This study investigates the anti-HCC potential of ACY-1215, a selective Histone deacetylase 6 (HDAC6) inhibitor, and its mechanism targeting p53 regulation. In vitro studies conducted with HepG2 and SMMC-7721 cells revealed that ACY-1215 markedly inhibited HCC cell proliferation, migratory capacity, and invasive potential, as evidenced by CCK-8, colony formation, and Transwell assays. Furthermore, ACY-1215 induced caspase-dependent apoptosis. Mechanistically, ACY-1215 enhanced p53 acetylation by disrupting HDAC6-p53 interaction, thereby stabilizing p53 protein levels. Concurrently, it inhibited Murine Double Minute 2 (MDM2)-mediated ubiquitination, blocking proteasomal degradation and prolonging p53 half-life. This dual modulation restored p53 transcriptional activity, leading to the upregulation of downstream effector molecules associated with cell cycle regulation and apoptosis. Collectively, our findings reveal that ACY-1215 exerts potent anti-HCC effects through coordinated regulation of p53 acetylation and ubiquitination, offering a novel dual-targeting strategy for HCC therapy. Full article

Osteosarcoma is a highly aggressive bone malignancy, particularly challenging in metastatic cases, with a 5-year survival rate remaining under 30%. Although doxorubicin (doxo) is a standard first-line chemotherapeutic agent, its clinical utility is often hindered by the development of drug resistance and associated systemic toxicity. Emerging evidence highlights the role of epigenetic alterations, particularly those involving histone deacetylases (HDACs), in promoting chemoresistance. In this context, the present study aimed to evaluate the therapeutic potential of combining doxo with the selective HDAC inhibitors, tasquinimod (Tas, targeting HDAC4) and PCI-34051 (PCI, targeting HDAC8), in SJSA-1 osteosarcoma cells. Utilizing both 2D and 3D in vitro models, the combination treatment (referred to as the T4 group) significantly reduced cell viability by 57.69% in 2D cultures and decreased spheroid volume by 35.19% in 3D models. The apoptotic response was markedly enhanced, with late apoptosis reaching 64.59% and necrosis at 32.07%, both surpassing the effects observed with doxo alone. Furthermore, wound healing assays demonstrated a 37.74% inhibition of migration, accompanied by a decreased expression of the matrix metalloproteinases MMP9 and MMP13. Mechanistically, the combination therapy led to the downregulation of protein kinase B (pAKT) and RUNX2, along with upregulation of apoptotic markers, including caspase 8, caspase 3, and cleaved caspase 3, indicating a disruption of key survival pathways. These findings suggest that dual HDAC inhibition with Tas and PCI can potentiate doxo efficacy by enhancing apoptosis, inhibiting proliferation, and reducing metastatic potential, thus offering a promising strategy to overcome chemoresistance in osteosarcoma. Further preclinical and clinical studies are required to validate these therapeutic benefits. Full article

Chitin deacetylase modifies chitin and has critical functions in the growth and development of insects; however, whether it has other roles is unclear. Laodelphax striatellus not only directly feeds on the phloem sap of rice but also transmits RSV, leading to significant losses in rice production. In this study, four CDA genes were identified based on SBPH genomic data and were classified into groups I and III based on a phylogenetic analysis. The expression of LsCDA1 and LsCDA2 in RSV-infected SBPH was increased by 282% and 159%, respectively, relative to the non-infected SBPH control. Additionally, RSV enhanced the expression of LsCDA1 (increased by 194%) in the ovaries. Yeast two-hybrid and glutathione-S-transferase pull-down assays demonstrated the interaction between LsCDA1 and RSV proteins NP and NS2. Furthermore, the knockdown of LsCDA1 expression decreased viral loads in RSV-infected SBPH and its ovaries by 66% and 72% relative to the dsGFP control. Silencing LsCDA1 significantly decreased VgR expression in SBPH and its ovaries and reduced fecundity. These results indicate that LsCDA1 positively regulates RSV accumulation in the ovaries and SBPH reproduction by modulating VgR expression, which offers a novel strategy for controlling both RSV and SBPH by targeting LsCDA1. Full article

Background/Objectives: Tartrazine (TRZ), a synthetic red azo dye derived from coal tar, is widely used as a food colorant in various food products, pharmaceuticals, and cosmetics. This study aims to investigate the impact of TRZ on the expression levels of DNA methyltransferases (DNMT1, DNMT3a, and DNMT3b) and histone deacetylases (HDAC5 and HDAC6). Additionally, we evaluate genomic DNA stability using the alkaline comet assay in three human cell lines: immortalized human keratinocyte (HaCaT), human hepatocellular carcinoma (HepG2), and human lung adenocarcinoma (A549). The research question focuses on whether TRZ exposure alters epigenetic regulation and DNA integrity, potentially implicating its role in carcinogenesis. Methods: The selected human cell lines were exposed to different concentrations of TRZ (20 µM, 40 µM, and 80 µM), with DMBA serving as a positive control. After treatment, we quantified the expression levels of DNMT1, DNMT3a, DNMT3b, HDAC5, and HDAC6 using quantitative real-time PCR. Additionally, we assessed DNA fragmentation via the alkaline comet assay to determine the extent of DNA damage resulting from TRZ exposure. Results: Our findings indicate that TRZ significantly upregulates the expression of HDAC5, HDAC6, DNMT1, DNMT3a, and DNMT3b in comparison to the control group. Furthermore, TRZ exposure leads to a notable increase in DNA damage, as evidenced by elevated tail moments across all examined human cell lines. Conclusions: These results suggest that TRZ may play a role in carcinogenesis and epigenetic modifications. The observed upregulation of DNMTs and HDACs, coupled with increased DNA damage, highlights the potential risks associated with TRZ exposure. Further research is necessary to explore these mechanisms and assess their implications for human health. Full article

It is well established that phenolic compounds from plant sources impact readouts of cell health such as reduced radical and reactive oxygen species. However, it is unclear if specific phenolic structures impact other cellular processes or proteins, such as the evolutionary conserved deacetylase Sirtuin 1 (SIRT1), and if phenolic combinations interact synergistically to do so. We observed that structurally diverse haskap berry phenolics (caffeic acid, cyanidin, kaempferol-3-O-glucoside, and gentisic acid) differentially impacted normal primary human fibroblast growth, which has been linked to SIRT1. These results were consistent with previous work from our lab indicating that haskap phenolic extracts/fractions impact human cell growth via SIRT1-dependent mechanisms. Therefore, we furthered the investigation into SIRT1 and phenolic structure and observed that the individual phenolics or their combinations had no observable impact on SIRT1 transcript abundance or cellular localization. We also observed that select phenolics decreased SIRT1 protein abundance and increased SIRT1 activity. The catechol-containing phenolics outperformed those that lack a catechol group, indicating potential structure-dependent impact(s). Potential synergy between the specific phenolics analyzed was observed in Western blot, and potential antagonism was identified in the SIRT1 activity assay. Results were concomitant with the presence of different phenolic structures, phenolic combinations, and cell type (sex and/or individual differences). These results highlight the possible significance of the catechol structure and indicate that phenolics have the potential to impact cell processes, which the authors hypothesize to be due to mechanisms that are independent of antioxidant activity. Full article

Background: In melanoma, multiligand drug strategies to disrupt cancer-associated epigenetic alterations and angiogenesis are particularly promising. Here, a novel dual-ligand with a single shared pharmacophore capable of simultaneously targeting histone deacetylases (HDACs) and sigma receptors (σRs) was synthesized and subjected to phenotypic in vitro screening. Methods: Tumor cell proliferation and spreading were investigated using immortalized human cancer and normal cell lines. Angiogenesis was also evaluated in mouse endothelial cells using a tube formation assay. Results: The dual-ligand compound exhibited superior potency in suppressing both uveal and cutaneous melanoma cell viability compared to other cancer cell types or normal cells. Melanoma selectivity reflected inhibition of the HDAC-dependent epigenetic regulation of tumor proliferative kinetics, without involvement of σR signaling. In contrast, the bifunctional compound inhibited the formation of capillary-like structures, formed by endothelial cells, and tumor cell spreading through the specific regulation of σ₁R signaling, but not HDAC activity. Conclusions: Together, the present findings suggest that dual-targeted HDAC/σ₁R ligands might efficiently and simultaneously disrupt tumor growth, dissemination and angiogenesis in melanoma, a strategy amenable to future clinical applications in precision cancer treatment. Full article

Background: Sodium butyrate (NaBu), a short-chain fatty acid, modulates global gene expression through histone deacetylase (HDAC) inhibition, suppressing proliferation and inducing apoptosis in various cancers. Rutin (RUT), a polyphenolic flavonoid found in many plants, exhibits notable anticancer properties. Combining chemotherapeutic agents with natural polyphenols represents a promising strategy for cancer therapy. This study aims to evaluate, for the first time, the potential effects of NaBu and RUT combination therapy on metastatic castration-resistant prostate cancer (mCRPC) cells. Methods: PC-3 cells were treated with varying concentrations of NaBu, RUT, and their combinations. Cell viability was assessed using the WST-1 assay. Based on combination index values, selected treatments were further analyzed for apoptosis (Annexin V assay), intracellular reactive oxygen species (ROS) production, mRNA expression levels, and changes in cell and nuclear morphology. Results: The combined treatment of NaBu and RUT significantly reduced cell viability compared to individual treatments. Enhanced apoptotic induction and elevated ROS levels were observed in combination-treated cells, alongside notable changes in cellular and nuclear morphology and mRNA expression levels. Conclusions: NaBu and RUT combination therapy exhibits a synergistic anticancer effect in mCRPC cells by inhibiting cell viability, inducing apoptosis, and increasing ROS production. These findings suggest a promising therapeutic approach that warrants further investigation to elucidate the underlying molecular mechanisms and assess its potential in preclinical and clinical settings. Full article

Background: Emerging literature indicates that the microbiome and its byproducts, such as short-chain fatty acids (SCFAs), play an important role in childhood diseases such as allergies and asthma. Specifically, there is evidence suggesting that SCFAs play a critical role in fetal immunoprogramming during the late saccular phase of fetal lung development. An increase in acetate during the late saccular phase is known to play a critical role in inhibiting histone deacetylases (HDACs), resulting in a cascade of events, including Treg immune regulation, involved in fetal immunoprogramming, and reduction in the asthma phenotype. However, it is not known whether changes in SCFA levels, especially acetate, occurred during the canalicular or early saccular phase among pregnant women whose children did not develop asthma. Methods: In this research, we investigated this question using plasma samples obtained from mothers during the 20th and 28th weeks of pregnancy. Mothers whose children developed asthma were categorized as cases, while those whose children did not were categorized as controls. The specimens were assayed for a panel of SCFAs consisting of acetate, propionate, butyrate, valerate, isobutyrate, and isovalerate. Results: The resulting data indicated no significant differences between the cases and controls, either at week 20 or week 28, in any of the SCFAs measured, despite the vascularization during these phases. Conclusions: We did not find differences in measured SCFAs at week 20 or at week 28. A larger prospective study covering multiple time points is necessary to confirm the findings of this preliminary study. Such a study, together with the published literature regarding later time points, may help discover critical windows during pregnancy when simple manipulation of diet will result in healthier outcomes for infants. Full article

Patients carrying APOL1 risk alleles (G1 and G2) have a higher risk of developing Focal Segmental Glomerulosclerosis (FSGS); we hypothesized that escalated levels of miR193a contribute to kidney injury by activating renin–angiotensin system (RAS) in the APOL1 milieus. Differentiated podocytes (DPDs) stably expressing vector (V/DPD), G0 (G0/DPDs), G1 (G1/DPDs), and G2 (G2/DPDs) were evaluated for renin, Vitamin D receptor (VDR), and podocyte molecular markers (PDMMs, including WT1, Podocalyxin, Nephrin, and Cluster of Differentiation [CD]2 associated protein [AP]). G0/DPDs displayed attenuated renin but an enhanced expression of VDR and Wilms Tumor [WT]1, including other PDMMs; in contrast, G1/DPDs and G2/DPDs exhibited enhanced expression of renin but decreased expression of VDR and WT1, as well as other PDMMs (at both the protein and mRNA levels). G1/DPDs and G2/DPDs also showed increased mRNA expression for Angiotensinogen and Angiotensin II Type 1 (AT1R) and 2 (AT2R) receptors. Protein concentrations of Brain Acid-Soluble Protein [BASP]1, Enhancer of Zeste Homolog [EZH]2, Histone Deacetylase [HDAC]1, and Histone 3 Lysine27 trimethylated [H3K27me3] in WT1-IP (immunoprecipitated proteins with WT1 antibody) fractions were significantly higher in G0/DPDs vs. G1/DPD and G2/DPDs. Moreover, DPD-silenced BASP1 displayed an increased expression of renin. Notably, VDR agonist-treated DPDs showed escalated levels of VDR and a higher expression of PDMMs, but an attenuated expression of renin. Human Embryonic Kidney (HEK) cells transfected with increasing APOL1(G0) plasmid concentrations showed a corresponding reduction in renin mRNA expression. Bioinformatics studies predicted the miR193a target sites in the VDR 3′UTR (untranslated region), and the luciferase assay confirmed the predicted sites. As expected, podocytes transfected with miR193a plasmid displayed a reduced VDR and an enhanced expression of renin. Renal cortical section immunolabeling in miR193a transgenic (Tr) mice showed renin-expressing podocytes. Kidney tissue extracts from miR193aTr mice also showed reduced expression of VDR and PDMMs, but enhanced expression of Renin. Blood Ang II levels were higher in miR193aTr, APOLG1, and APOL1G1/G2 mice when compared to control mice. Based on these findings, miR193a regulates the activation of RAS and podocyte molecular markers through modulation of VDR and WT1 in the APOL1 milieu. Full article

Background/Objectives: The incidence of head and neck squamous cell carcinoma (HNSCC), currently ~800,000 cases per year worldwide, is rising. Radiotherapy remains a mainstay for the treatment of HNSCC, although inherent radioresistance, particularly in human papillomavirus (HPV)-negative disease subtypes, remains a significant barrier to effective treatment. Therefore, combinatorial strategies using drugs or inhibitors against specific cellular targets are necessary to enhance HNSCC radiosensitivity to lead to an improvement in patient outcomes. Given that radiotherapy acts through targeting and damaging DNA, a common strategy is to focus on enzymes within DNA-dependent cellular pathways, such as DNA damage repair. Methods: Here, we have employed a 3D spheroid model of HNSCC (FaDu) in combination with a targeted drug screen to identify novel radiosensitisers that suppress tumour growth. Results: We identified that histone deacetylases (HDACs) were prominent candidates, and subsequently identified that the HDAC inhibitors mocetinostat and pracinostat, as well as the combined HDAC–epidermal growth factor receptor inhibitor CUDC-101, were effective at radiosensitising cell models of HNSCC (FaDu, A253, UMSCC11b) through their impact on both spheroid growth and clonogenic survival assays. We also demonstrated that this combinatorial strategy leads to inhibition of the repair of DNA double-strand breaks through the neutral comet assay and γH2AX foci analysis using immunofluorescence microscopy, providing a mechanism of action through which HDAC inhibition functions in HNSCC radiosensitisation. Conclusions: We believe that this approach should be further investigated in preclinical models, in order to realise the full therapeutic potential of HDAC inhibition for the radiosensitisation of HNSCC, eventually leading to improved patient treatment efficacy and outcomes. Full article

Objective: Previous drug repositioning studies have suggested that parthenolide may be a differentiation-inducing agent for glioma cells. This study aimed to experimentally verify the neuronal differentiation-inducing effects and proliferative impact of parthenolide on human glioma cells and explore its potential mechanisms. Methods: HE staining was used to observe the morphological changes in human glioma cell lines U87 and A172 induced by parthenolide. Immunocytochemistry was conducted to detect the expression of differentiation markers. The Ki-67 detection and CCK-8 assay were used to assess the effects of parthenolide on cell proliferation. The sphere formation assay was conducted to evaluate the self-renewal. Glioma stem cells (GSCs) derived from U87 cells were utilized to assess the ability of parthenolide to induce differentiation in GSCs. Western blot was used to detect the expression of histone deacetylase 1 (HDAC1). Bioinformatics analysis based on the CGGA database was conducted to evaluate the role of HDAC1 in glioma. Results: Parthenolide (4 μM) altered the morphology of U87 and A172 cells, as elongated cell projections were observed. Parthenolide induced glioma cells to express neuronal markers NeuN, MAP2, SYP, and NEFL, but not astrocyte or oligodendrocyte markers. Parthenolide significantly inhibited proliferation and self-renewal in glioma cells. Similar effects were observed in U87 GSCs. Furthermore, parthenolide downregulated HDAC1 expression in glioma cells, and the bioinformatics analysis revealed a potential relationship between neuronal characteristics and low expression of HDAC1 in glioma. Conclusion: Parthenolide induced neuronal differentiation and inhibited the cell proliferation in human glioma cells, which might be associated with the inhibition of HDAC1. Full article

Background: Since the discovery that Histone deacetylase inhibitors (HDCAi) could enhance radiation response, a number of HDACi, mainly pan-HDAC inhibitors, have been studied either as monotherapy or in combination with X-ray irradiation or chemotherapeutic drugs in the management of breast cancer. However, studies on the combination of HDACi and proton radiation remain limited. CUDC-101 is a multitarget inhibitor of Histone deacetylases (HDACs), epidermal growth factor receptor (EGFR), and human epidermal growth factor receptor 2 (HER-2). In this paper, the effectiveness of CUDC-101 in enhancing radiation response to both proton and X-ray irradiation was studied. Methods: MCF-7, MDA-MB-231, and MCF-10A cell lines were pre-treated with CUDC-101 and exposed to 148 MeV protons, and X-rays were used as reference radiation. Colony survival, γ-H2AX foci, apoptosis, and cell cycle analysis assays were performed. Results: γ-H2AX foci assays showed increased sensitivity to CUDC-101 in the MDA-MB-231 cell line compared to the MCF-7 cell line. In both cell lines, induction of apoptosis was enhanced in CUDC-101 pre-treated cells compared to radiation (protons or X-rays) alone. Increased apoptosis was also noted in CUDC-101 pre-treated cells in the MCF-10A cell line. Cell cycle analysis showed increased G2/M arrest by CUDC-101 mono-treatment as well as combination of CUDC-101 and X-ray irradiation in the MDA-MB-231 cell line. Conclusions: CUDC-101 effectively enhances response to both proton and X-ray irradiation, in the triple-negative MDA-MB-231 cell line. This enhancement was most notable when CUDC-101 was combined with proton irradiation. This study highlights that CUDC-101 holds potential in the management of triple-negative breast cancer as monotherapy or in combination with protons or X-ray irradiation. Full article

Background/Objectives: High fructose has been implicated as an important trigger of kidney inflammation in patients and experimental models. Magnolol, isolated from Magnolia officinalis, has an anti-inflammatory effect, but its protective role in podocytes remains underexplored. This study explored the protective effects and underlying mechanism of magnolol against high fructose-induced podocyte inflammation. Methods: The effects of magnolol on high fructose-induced podocyte inflammation were assessed in male Sprague Dawley rats administered 10% (w/v) fructose water for 12 weeks and heat-sensitive human podocyte cell lines (HPCs) exposed to 5 mM fructose. Podocyte foot processes were examined using transmission electron microscopy. The expression levels of nephrin, podocin, tumor necrosis factor-α (TNF-α), Notch1 intracellular domain (NICD1), triokinase/FMN cyclase (TKFC), specificity protein 1 (Sp1) and histone deacetylase 4 (HDAC4) were determined by Western blot, immunofluorescence and real-time quantitative polymerase chain reaction (qRT-PCR). The chromatin immunoprecipitation (ChIP) assay was performed to evaluate the interaction between Sp1 and the promoter region of HDAC4. Results: Magnolol mitigated the impairment of glomerular filtration function in high fructose-fed rats. Besides, it significantly alleviated the inflammatory responses in glomeruli and HPCs, evidenced by decreased protein levels of TNF-α and NICD1. Increased protein levels of TKFC, Sp1 and HDAC4 were observed in high fructose-stimulated HPCs and rat glomeruli. TMP195, an HDAC4 inhibitor, reduced TNF-α and NICD1 protein levels in high fructose-exposed HPCs. The increased Sp1 was shown to associate with the promoter region of HDAC4, promoting HDAC4 protein expression in high fructose-exposed HPCs. The knockdown of TKFC in HPCs by TKFC siRNA decreased Sp1, HDAC4 and NICD1 protein levels, alleviating podocyte inflammatory response. Furthermore, magnolol inhibited TKFC/Sp1/HDAC4/Notch1 activation in vivo and in vitro. Conclusions: Magnolol attenuated high fructose-induced podocyte inflammation possibly through the suppression of TKFC/Sp1/HDAC4/Notch1 activation, providing new evidence for its potential role in podocyte protection. Full article