Numerous chemicals are associated with carcinogenesis through epigenetic alterations in cells. To detect global epigenetic changes induced by carcinogens, the housekeeping gene can serve as a reporter locus, offering a baseline for identifying shifts in epigenetic marks. To investigate this potential, we developed a simple, cost-effective, and quantitative reporter system to assess chemically induced epigenetic effects, utilizing the thymidine kinase (TK) gene mutation assay as a foundation. Using a standard genotoxicity test cell line, human lymphoblast TK6, we edited the CpG promoter loci of the endogenous TK gene using the CRISPR/dCas9-SunTag-DNMT3A system. This epi-genotoxicity assay, employing modified mTK6 cells, provides a simple method for quantifying chemically induced epigenetic effects. The assay successfully detects both increased TK reversion rates induced by DNMT inhibitors, such as 5-Aza-2'-deoxycytidine and GSK-3484862, and, for the first time, a significant reduction in TK revertant frequency caused by the non-genotoxic carcinogen 12-O-tetradecanoylphorbol-13-acetate (TPA). Chromatin immunoprecipitation and western blotting analyses revealed that TPA treatment led to a global decrease in H3K27Ac levels, likely driven by TPA-mediated inflammation. These results demonstrate the utility of the epi-genotoxicity assay as a valuable tool for evaluating dual-directional epigenetic changes triggered by chemical exposure.

Salmonella enterica is a clinically significant oro-fecal pathogen that causes a wide variety of illnesses and can lead to epidemics. S. enterica expresses a lot of virulence factors that enhance its pathogenesis in host. For instance, S. enterica employs a type three secretion system (T3SS) to translocate a wide array of effector proteins that could change the surrounding niche ensuring suitable conditions for the thrive of Salmonella infection. Many antimicrobials have been recently introduced to overcome the annoying bacterial resistance to antibiotics. Enoxacin is member of the second-generation quinolones that possesses a considerable activity against S. enterica. The present study aimed to evaluate the effect of enoxacin at sub-minimum inhibitory concentration (sub-MIC) on S. enterica virulence capability and pathogenesis in host. Enoxacin at sub-MIC significantly diminished both Salmonella invasion and intracellular replication within the host cells. The observed inhibitory effect of enoxacin on S. enterica internalization could be attributed to its ability to interfere with translocation of the T3SS effector proteins. These results were further confirmed by the finding that enoxacin at sub-MIC down-regulated the expression of the genes encoding for T3SS-type II (T3SS-II). Moreover, enoxacin at sub-MIC lessened bacterial adhesion to abiotic surface and biofilm formation which indicates a potential anti-virulence activity. Importantly, in vivo results showed a significant ability of enoxacin to protect mice against S. enterica infection and decreased bacterial colonization within animal tissues. In nutshell, current findings shed light on an additional mechanism of enoxacin at sub-MIC by interfering with Salmonella intracellular replication. The outcomes presented herein could be further invested in conquering bacterial resistance and open the door for additional effective clinical applications.

Lymphomas are complex malignancies of blood cells, characterized by the malignant transformation of lymphocytes. This transformation is partially driven by disruptions in epigenetic regulation, particularly the acetylation of histones. Among the key players in this process are histone deacetylases (HDACs), whose aberrant activity contributes significantly to lymphoma development. Consequently, targeting HDACs represents a promising pharmacotherapeutic approach. Several HDAC inhibitors (HDACis) have demonstrated significant anticancer effects, with four FDA-approved molecules-vorinostat, romidepsin, belinostat, and panobinostat-forming critical components of chemotherapy regimens for lymphoma treatment. These HDAC inhibitors exhibit their therapeutic efficacy through mechanisms that indirectly impact cellular memory and induce cancer cell death via apoptosis and cell cycle arrest. Their clinical effectiveness is particularly notable in various types of lymphomas, underscoring their therapeutic potential. The objective of this review is to provide a detailed analysis of FDA-approved HDACis, focusing on their molecular mechanisms of action and clinical applications in lymphoma treatment. Specifically, we aim to elucidate how these inhibitors modulate epigenetic regulation to achieve therapeutic efficacy, highlight their utility across different lymphoma subtypes, and examine their integration into combination therapies with other anticancer agents. Furthermore, this review seeks to identify gaps in current knowledge and propose directions for future research, including the development of next-generation HDAC inhibitors and strategies for optimizing their clinical use. By consolidating existing evidence, we strive to enhance the understanding of HDACis' role in lymphoma therapy and inspire advancements in their therapeutic potential.

This study aimed to explore the potential correlation between the metabolic intermediate L-2-hydroxyglutarate (L-2-HG) and T cell exhaustion, as well as the underlying mechanisms involved. In this study, we investigated the presence of exhausted T (Tex) cells in patients under certain conditions: HIV infection, chronic leukemia, and hepatocellular carcinoma. To gain insights into the epigenetic signatures and transcriptome changes in Tex cells, we employed a combination of RNA-seq and ATAC-seq analyses. To evaluate the impact of L-2-HG on mitochondrial function, differentiation, and antitumor capacity of Tex cells, we utilized in vitro cell culture experiments and animal tumor models. We observed mitochondrial depolarization and metabolic dysfunction in Tex cells, accompanied by a significant reduction in L-2-HG levels. Moreover, altered epigenetic characteristics were observed in Tex cells, including a substantial increase in H3K27me3 abundance. Culturing Tex cells with L-2-HG demonstrated improved mitochondrial metabolism, reduced H3K27me3 abundance, and enhanced memory T cell differentiation. In a mouse melanoma tumor model, L-2-HG-treated CD8+ T cells for adoptive therapy led to significantly reduced tumor volume and significantly enhanced effector function of T cells. The study revealed that L-2-HG acted as an immune metabolite through epigenetic modifications of Tex cells.

Embigin (EMB) is a transmembrane glycoprotein highly expressed in glioblastoma multiforme (GBM), yet its role in GBM progression remains unclear. In this study, we investigate the function of intracellular EMB in promoting GBM progression and evaluate the effect of Ganxintriol A, a traditional Chinese herbal extract, in GBM treatment.

Ovarian Cancer (OC) is the most lethal gynecological malignancy, characterized by peritoneal metastasis, directly linked to most OC-related deaths. Here, by interrogating CRISPR-Cas9 loss-of-function genetic screen data, we identified a list of genes essential for metastatic OC, including several well-known oncogenes (PAX8, CCNE1, WWTR1, WT1, KAT6A, MECOM, and SOX17) and others whose roles in OC have not yet been explored. Protein-protein interaction analysis of the selected genes revealed the presence of a protein network participating in the epigenetic regulation of gene expression. For one of the network components, BRPF1, we found that its increased expression correlates with OC progression and a poor prognosis for OC patients. Functional assays demonstrated that BRPF1 inhibition significantly reduces cellular migration and invasion, supporting its role in metastatic progression. Pharmacological blockade of BRPF1 using small molecule inhibitors resulted in reduced proliferation of high-grade serous OC cells through mechanisms involving the activation of programmed cell death, cell cycle deregulation, and enhanced DNA damage. Furthermore, analysis of transcriptional changes induced by BRPF1 targeting showed that the growth inhibitory effects may be mediated by the deregulation of PPARα signaling. The obtained results indicate that BRPF1 represents a novel potential therapeutic target for metastatic OC treatment.

The formation of biofilm by foodborne pathogens increases the risk of foodborne diseases, resulting in major health risks. Research on strategies for eliminating biofilm formation by foodborne pathogens is urgently needed. Therefore, the objective of this study was to construct a new technique for controlling foodborne bacteria and inhibiting the biosynthesis of biofilm via using natural products. The essential orange oil (EOO) and cell-free filtrate of Lactobacillus pentosus RS2 were used as antibacterial and antibiofilm agents against B. cereus RS1, the strongest biofilm-forming strain. The mixture of cell-free filtrate (CFF) and EOO (CFF/EOO) was the best antibiofilm agent under all tested conditions. The minimal inhibitory concentration (MIC) test revealed that 400 μl ml-1 CFF and 16 μl ml-1 EOO completely inhibited the growth of B. cereus. The treatment of three commercial surfaces with CFF/EOO resulted in a high reduction in biofilm synthesis, with adhesion percentages of 33.3, 36.3, and 40.8% on stainless steel, aluminum foil, and aluminum, respectively. The aluminum surface had the greatest adhesion with B. cereus RS1 among the three tested surfaces. These results were confirmed by expression analysis of three essential coding genes, sinR, calY, and spo0A, participating in biofilm formation in B. cereus. The biofilm-negative regulator gene sinR was overexpressed, whereas the biofilm-positive regulator genes calY and spo0A were down-expressed in B. cereus RS1 after treatment with antibiofilm agents, compared with those in the untreated sample. This study revealed that CFF/EOO was more effective at activating sinR (2.099 ± 0.167-fold increase) and suppressing calY and spo0A (0.314 ± 0.058 and0.238 ± 0.04-fold decrease, respectively) compared to control. This result confirmed the biochemical estimation of biofilm formation in B. cereus after treatment with all the experimental agents. The EOO and CFF of L. pentosus RS2 can be used as strong antibacterial and antibiofilm agents against foodborne bacteria. These products reduced the biofilm formation on trade surfaces affecting the expression of three essential biofilm regulatory genes. This study considered novel research concerning the potential antibiofilm activity of EOO combined with CFF of L. pentosus and the molecular analysis of genes regulating biofilm production under stress of CFF/EOO.

Environmental factors play an important role in anthocyanin biosynthesis, and potassium, an essential nutrient for blueberry growth, can act as an enzyme activator. However, few reports exist on the transcriptional and anthocyanin metabolic changes in blueberries regulated by potassium. The results indicated that potassium treatment significantly increased the contents of malvidin, petunidin, and delphinidin in blueberry fruits and accelerated early color development, particularly favoring the accumulation of darker pigments such as malvidin, petunidin, and delphinidin when applied at the young fruit stage. Transcriptome analysis identified 102 glucose metabolism-related genes and 12 differential potassium transport genes potentially involved in potassium-mediated anthocyanin synthesis and accumulation, with AKT1 and KUP potassium transporters being upregulated under potassium fertilization. In the anthocyanin biosynthesis pathway, 13 genes, including UFGT, F3H, CHI, HCT, C12RT1, DFR, and F3'5'H, were closely linked to flavonoid and anthocyanin metabolite synthesis regulated by potassium. Furthermore, potassium treatment markedly enhanced the activities of key enzymes, F3H, F3'5'H, and UFGT, in the anthocyanin synthesis pathway of blueberry fruits. Overall, these findings elucidate the influence of potassium application timing on anthocyanin synthesis and provide valuable insights into the molecular mechanisms governing anthocyanin biosynthesis in blueberries.

Immunotherapy (IO) is an effective treatment for various cancers; however, the benefits are modest for small cell lung cancer (SCLC). The poor response of SCLC to anti-PD-1/PD-L1 IO is due in part to the lack of cytotoxic T cells because of limited chemokine expression from SCLC tumors. Immunogenic radiosensitizers that enhance chemokine expression may be a promising strategy forward. Here, we show that the PARP inhibitors (PARPi), including olaparib, talazoparib and veliparib, in combination with radiotherapy (RT) enhance the immune activation and anti-tumor efficacy in SCLC cell lines, patient-derived xenograft (PDX) and syngeneic mouse models. The effect is further enhanced by continued delivery of adjuvant PARPi. The combination treatment (PARPi with RT) activates the cGAS-STING pathway and increases the mRNA levels of the T cell chemo-attractants CCL5 and CXCL10. In addition to upregulation of transcription, the combination treatment increases chemokine CXCL10 protein levels via stabilization of CXCL10 mRNA in an EIF4E2-dependent manner. The incorporation of anti-PD-L1 IO into the PARPi with RT combination therapy further improves the anti-tumor efficacy by increasing T cell infiltration and function. This study thus provides a proof of principle for the combination of PARP inhibitors, RT and anti-PD-L1 IO as a treatment strategy for SCLC.

Immune checkpoint blockade (ICB) therapy only induces durable responses in a subset of cancer patients. The underlying mechanisms of such selective efficacy remain largely unknown. By analyzing the expression profiles of immune checkpoint molecules in different statuses of murine tumors, we found that tumor progression generally randomly upregulated multiple immune checkpoints, thus increased the Heterogeneity of Immune checkpoint Signature (HIS) and resulted in immunotherapeutic resistance. Interestingly, overexpressing one pivotal immune checkpoint in a tumor hindered the upregulation of a majority of other immune checkpoint genes during tumor progression via suppressing interferon γ, resulting in HIS-low. Indeed, PD-L1 high-expression sensitized baseline large tumors to anti-PD1 therapy without altering the sensitivity of baseline small tumors. In line with these preclinical results, a retrospective analysis of a phase III study involving patients with non-small cell lung cancer (NSCLC) revealed that PD-L1 tumor proportion score (TPS) ≥ 50% more reliably predicted therapeutic response in NSCLC patients with baseline tumor volume (BTV)-large compared to patients with BTV-small. Notably, TPS combined with BTV significantly improved the predictive accuracy. Collectively, the data suggest that HIS reflects the dynamic features of tumor immune evasion and dictates the selective efficacy of ICB in a tumor size-dependent manner, providing a potential novel strategy to improve precision ICB. These findings highlight the application of ICB to earlier stages of cancer patients. The integration of PD-L1 with BTV may immediately improve patient stratification and prediction performance in the clinic.

Although bacterial cells typically contain a single chromosome, some species are naturally polyploid and carry multiple copies of their chromosome. Polyploid chromosomes can be identical or heterogeneous, the latter giving rise to bacterial heterozygosity. Although the benefits of heterozygosity are well studied in eukaryotes, its consequences in bacteria are less understood. Here, we examine this question in the context of antibiotic resistance to understand how bacterial genomic heterozygosity affects bacterial survival. Using a cell-wall-deficient model system in the actinomycete Kitasatospora viridifaciens, we found that heterozygous cells that contain different chromosomes expressing different antibiotic resistance markers persist across a broad range of antibiotic concentrations. Recombinant cells containing the same resistance genes on a single chromosome also survive these conditions, but these cells pay a significant fitness cost due to the constitutive expression of these genes. By contrast, heterozygous cells can mitigate these costs by flexibly adjusting the ratio of their different chromosomes, thereby allowing rapid responses in temporally and spatially variable environments. Our results provide evidence that bacterial heterozygosity can increase adaptive plasticity in bacterial cells in a similar manner to the evolutionary benefits provided by multicopy plasmids in bacteria.

The current study evaluated the effects of dietary supplementation of Triphala (TR) on yellow perch (Perca flavescens) growth performance, immune response, related gene expression, and intestinal histological structure. The experimental design included four groups: one control group (0% TR/ kg diet) and three TR-supplemented groups with 2, 4, and 6%/kg diet for four weeks and each group was allocated in triplicates with 30 fish each. Sampling included three fish from each replicate for evaluating immune response and gene expression. Findings showed that Triphala markedly improved growth performance, Immunoglobulin M (IgM) levels, lysozyme activity, and Nitric Oxide (NO) activity with the most significant (p < 0.05) results for 6% TR/kg diet group. The TR groups also showed significantly decreased glucose and cortisol concentrations with the lowest values for the 6% TR/kg diet group. Moreover, TR-incorporated groups revealed significantly upregulated expression (p < 0.05) of growth [Insulin-Like Growth Factor-1 (IGF-1)] and immune [Alpha 2 Macroglobulin (A2M), Serum Amyloid A (SAA) and Complement Component C3 (CCC3)] genes in incorporated groups, specially the 6% TR group. Moreover, the intestinal morphometric histological analysis revealed that villus length was increased in a dose-dependent manner, coping with other enhanced parameters. Current results endorse the positive effects of Triphala incorporation on yellow perch farming as a safe alternative option to enhance growth performance, immune response, related gene expression, and intestinal histology.

Endocrine resistance remains a significant therapeutic challenge in estrogen receptor-positive (ER+) breast cancer, the most common subtype, contributing to increased morbidity and mortality. The interaction between ER and HER family receptors, particularly HER2 and epidermal growth factor receptor (EGFR), drives resistance to standard therapies such as tamoxifen and trastuzumab by activating key signaling pathways, including PI3K/AKT and RAS/MAPK. Dysregulated miRNAs, which are non-coding gene expression regulators, have been linked to therapy response.

Drought stress imposes severe challenges on agriculture by impacting crop performance. Understanding drought responses in plants at a cellular level is a crucial first step toward engineering improved drought resilience. However, the molecular responses to drought are complex as they depend on multiple factors, including the severity of drought, the profiled organ, its developmental stage or even the cell types therein. Thus, deciphering the transcriptional responses to drought is especially challenging. In this study, we investigated tissue-specific responses to mild drought (MD) in young Arabidopsis thaliana (Arabidopsis) leaves using single-cell RNA sequencing (scRNA-seq). To preserve transcriptional integrity during cell isolation, we inhibited RNA synthesis using the transcription inhibitor actinomycin D, and demonstrated the benefits of transcriptome fixation for studying mild stress responses at a single-cell level. We present a curated and validated single-cell atlas, comprising 50 797 high-quality cells from almost all known cell types present in the leaf. All cell type annotations were validated with a new library of reporter lines. The curated data are available to the broad community in an intuitive tool and a browsable single-cell atlas (http://www.single-cell.be/plant/leaf-drought). We show that the mesophyll contains two spatially separated cell populations with distinct responses to drought: one enriched in canonical abscisic acid-related drought-responsive genes, and another one enriched in genes involved in iron starvation responses. Our study thus reveals a dual adaptive mechanism of the leaf mesophyll in response to MD and provides a valuable resource for future research on stress responses.

Isorhamnetin (ISO), a dietary flavonoid, has been shown to possess antioxidant, anti-cancer, and anti-inflammatory properties. Cancer-associated fibroblasts (CAFs), found in the tumor microenvironment of several types of cancer including pancreatic ductal adenocarcinoma (PDAC) impact the tumor growth and development of chemoresistance. Thus, modulating CAFs is an attractive mean to increase the efficacy of therapies targeting cancer cells. In this study, the anti-proliferative effect of ISO and the underlying transcriptomic profile of ISO-treated PDAC-derived CAFs were investigated. ISO treatment showed a time- and concentration-dependent decrease in cell viability with a slight increase in apoptotic cells. Microarray and cell cycle analyses revealed ISO induced downregulation of pathways in cell cycle and DNA replication; and G2/M checkpoint. Cell cycle analysis showed cells in the G2/M phase were increased. In response to the treatment, hallmark for p53 pathway genes, known to regulate cell cycle checkpoints, were highly upregulated. Moreover, ISO-treated cells had an increased area of the mitochondrial network, but lower mitochondrial membrane potential accompanied by a decrease of ATP production, measured by oxygen consumption rate. Inflammatory gene expression of IL1A1, IL6, CXCL1, and LIF were significantly inhibited in ISO-treated CAFs. Taken together, our results demonstrated that the cytostatic effect of ISO on human CAFs was mediated by inducing cell cycle arrest at G2/M phase associated with activation of p21, impaired mitochondrial homeostasis, and inhibition of inflammatory mediators gene expression, warranting further investigation for its use in combinatorial therapy that target both the cancer and the tumor microenvironment as a whole.

RNA guanine (G)-quadruplexes (rG4) are unique noncanonical structures composed of stacked guanine quadruplexes that play diverse roles in regulating gene expression, from transcription to protein synthesis. This study proposes a new splice-switching therapy using G-quadruplex-inducing antisense oligonucleotides (G-ASOs) to reinstate dystrophin expression in Duchenne muscular dystrophy (DMD) models. G-ASOs consist of two functionally independent domains that enable the formation of RNA/DNA hetero-G-quadruplex (hG4) structures. The antisense domain binds to complementary sequences within the target RNA, while the G-rich domain, which contains a sequence of continuous guanines (G-tract), interacts with the G-rich region of target RNA to form an hG4 structure. This precise binding forms an hG4 structure that effectively interrupts alternative splicing. In contrast to the traditional methods that block sterically, this technique employs steric hindrance by forming hG4 structures. Significantly, our findings show that hG4 structures can still form effectively even when the G-rich region of the target RNA and the antisense sequence are as much as 70 nucleotides apart. To address the challenges associated with G-quadruplex formation via G-ASO self-assembly, we developed bulge-containing G-ASOs. This enhancement improves both the efficiency of hG4 formation and the induction of exon-skipping therapy. In summary, this study highlights the potential of G-ASOs in gene therapy, specifically DMD, and marks significant progress in the development of novel therapeutic strategies. These findings highlight the effectiveness of G-ASOs in exon-skipping therapy and demonstrate the advancements in RNA structural manipulation.

Gansui [Euphorbia kansui T. N. Liou ex S.B.Ho (Euphorbiaceae)] has been reported to inhibit the proliferation of non-small cell lung cancer (NSCLC) cells; however, its underlying pharmacological mechanism remains unclear.

Studies have shown that essential oils not only increase cell viability but also affect lipid metabolism in mammals. However, the extent to which these effects are realized in goose liver has not yet been fully elucidated. The object of research is to investigate the effects of four essential oil mixtures (juniper oil, mint oil, thyme oil, rosemary oil) on lipid metabolic gene expressions in goose. We measured mRNA levels of metabolic genes (ACSBG2, ELOVL1, ELOVL2, CYP2Cl9, CYP2K1), antioxidative gene (SOD1) and very low-density lipoprotein triglyceride (VLDL) synthesis genes (APOB, FOXO1, MTTP), in goose (Anser anser) liver. Search groups were formed as C (control; no additives), EK1 (0.4 mL/L essential oil mixture supplemented) and EK2 (0.8 mL/L essential oil mixture supplemented). The relative expression levels of genes in the liver were measured using RT-qPCR. β-Actin was used as reference gene control for normalization of qPCR data. As a result, essential oil supplementation downregulated metabolic genes compared to the control group. APOB gene among VLDL genes was significantly downregulated. Antioxidative effect gene was downregulated in parallel with the others. This indicates that essential oil intake with drinking water downregulates the genes involved in lipid metabolism in goose liver. Our data show that essential oils have a significant effect on the regulation of genes and pathways involved in hepatic lipid metabolism.

Trigonelline (TGN), an alkaloid identified in medicinal plants such as coffee (Coffea spp.) and fenugreek (Trigonella foenum-graecum), has demonstrated significant anticancer properties across various malignancies, yet its efficacy in bladder cancer (BLCA) remains underappreciated. This study investigates TGN's role in modulating cancer stem cells (CSCs) and the tumor microenvironment (TME), two key contributors to BLCA progression and chemoresistance. Through comprehensive bioinformatics analyses of BLCA patient datasets, a TGY signature (TGFβ3, GLI2, YAP1) was identified as a critical signaling hub associated with poor prognosis, therapeutic resistance, and CSC generation. Computational docking studies revealed TGN's high binding affinity to the TGY signature, TGFβ3 (ΔG = -3.9 kcal/mol), GLI2 (ΔG = -4.2 kcal/mol), YAP1 (ΔG = -3.4 kcal/mol), suggesting its potential to disrupt this signaling axis. In vitro experiments demonstrated that TGN effectively inhibited BLCA cell proliferation, colony formation, and tumorspheroid growth while significantly enhancing cisplatin sensitivity in resistant cell lines. Notably, TGN reduced the transformation of fibroblasts into cancer-associated fibroblasts (CAFs) through the downregulation of α-SMA and FAP (Fibroblast activation protein) expression, indicating its capacity to normalize the TME. Real-time PCR analysis revealed that TGN treatment significantly reduced markers of epithelial-mesenchymal transition and stemness pathways. Our preclinical mouse study demonstrated that combining TGN and cisplatin significantly reduced tumorigenesis in cisplatin-resistant bladder tumoroids harboring CAFs. Importantly, this combination therapy showed no apparent systematic toxicity, suggesting a favorable safety profile. Our findings reveal novel molecular targets of TGN in bladder cancer; TGN acts as a potent disruptor of the TGY signaling axis and a normalizer of the TME by reducing CAF transformation. In sum, our findings advocate for TGN's further exploration as a candidate for combination therapy in drug-resistant BLCA, with the potential to improve patient outcomes by simultaneously targeting both CSCs and the TME, serving as a foundation for future clinical trials.

Oral squamous cell carcinoma (OSCC), one of the most common cancers in Taiwan, needs new therapeutic agents and treatments. The aim of this study was to investigate the anti-proliferative activity of {N-[3-chloro-4-[5-[3-[[[4-[(cyclopropylcarbonyl)-amino]3-(trifluoromethyl)phenylamino]carbonyl]amino]phenyl]-1,2,4-oxadiazol-3-yl]phenyl]-3-pyridine-carboxamide} (COC), a synthetic molecule, in OSCC cells. COC exhibits potent tumor-suppressive efficacy with IC50 values of 195 nM and 204 nM toward SCC2095 and SCC4 OSCC cells, respectively. Our data revealed that COC caused caspase-dependent apoptosis and downregulated the MAPK signaling pathway. In addition, COC modulated the levels of E-cadherin and β-catenin and inhibited migration. COC also decreased p-STAT3 levels, and the overexpression of STAT3 partially attenuated COC-induced cytotoxicity. Therefore, our findings suggest the use of COC as a new approach to oral cancer treatment.