Cervical cancer is the leading type of primary malignancy in the uterus, causing significant morbidity and mortality, particularly in developing countries. Traditional treatments often result in severe side effects and recurrence, highlighting the need for safer alternatives. This study investigates the anticancer potential of Tetraselmis suecica, a green microalga known for its bioactive compounds.

Our study unravels a complex multi-layered molecular response of peanut roots to salinity, where reprograming of gene-expression is partly executed by changes in methylome via RdDM pathway and exerted through transcription factors. Peanut (Arachis hypogaea L.) is a major oilseed crop of global importance, whose production is severely impacted by salinity. Here, we have explored the transcriptional response of peanut roots to salinity stress using deep sequencing. Further, we have unravelled the salinity-induced changes in peanut root methylome. When peanut seedlings were grown under high-salt conditions for 7 days, their root and shoot growth was significantly impaired. A large-scale transcriptional reprogramming was recorded where 1926 genes were down- and 3260 genes were up-regulated due to salt stress in peanut roots. The molecular response of peanut root comprised several layers of regulators, which included the genes related to ion transport, osmolyte accumulation, signal transduction, and salt stress-responsive genes. Several negative regulators are also differentially expressed in peanut roots, which may contribute to its susceptibility. This response is regulated by a large number of transcription factors (TFs) and epigenetically by changes in DNA methylation. The DNA methylation changes in roots were highly complex and context dependent when exposed to salt stress. An inverse relationship between the changes in gene expression and methylation status was partially observed for several important gene sets and TFs. A treatment with 5'-azacytidine recovered the inhibitory impact of salt stress in peanut roots. Thus, a complex multilayered molecular response to salinity in peanut roots was observed. A part of this response may be modulated by the reprogramming of RNA-directed DNA methylation pathway. This investigation also serves as a resource for future gene-mining and methylation studies for improving peanut resistance to salt stress.

Phosphorus is an essential macronutrient for plant growth and development. Under phosphate (Pi) starvation conditions, plants activate a series of adaptive responses, among which reactive oxygen species (ROS) accumulation in root tissues represents a notable yet poorly characterized phenomenon. This study investigated the regulatory role of hydrogen peroxide (H2O2) in rice adaptation to Pi deficiency through pharmacological intervention using potassium iodide (KI), a specific H2O2 scavenger. Physiological analysis revealed that root-specific H2O2 depletion via KI treatment significantly impaired both Pi uptake and root growth under Pi-deficient conditions. Transcriptomic profiling demonstrated that H2O2 elimination substantially modulated the expression of 196 Pi starvation-responsive genes, particularly those involved in SPX-mediated phosphate sensing, extracellular acid phosphatases (APase) biosynthesis, high-affinity phosphate transporters, lipid metabolism enzymes, and redox homeostasis maintenance. Subsequent biochemical validation confirmed that both KI and diphenyleneiodonium (DPI) treatments suppressed Pi-starvation-induced APase activity and compromised Pi uptake ability. Notably, comparative analysis with the phr1/2/3 triple mutant revealed a 24% overlap in differentially expressed genes between H2O2 and PHR-deficient plants, with 90% of shared genes exhibiting congruent expression patterns. These findings collectively establish that H2O2 serves as a pivotal signaling mediator in the Pi starvation regulatory network, orchestrating metabolic reprogramming and developmental adaptation to Pi stress in rice.

Lung cancer is one of the malignant tumors with the highest morbidity and mortality in China. Despite the use of some targeted therapies in lung cancer treatment, the prognosis remains suboptimal, highlighting the urgent need for new, effective drugs to enhance outcomes. Ticagrelor, a marketed anti-platelet drug, has been reported to have anti-tumor effects. This study primarily investigates the inhibitory effect of Ticagrelor on lung adenocarcinoma in both in vivo and in vitro models, as well as its molecular mechanisms. Firstly, the effects of ticagrelor on the proliferation (CCK-8 and Edu staining), migration (scratch test), and invasion (Transwell chamber) of lung adenocarcinoma cells were evaluated using a variety of lung adenocarcinoma cell models. Secondly, the efficacy of ticagrelor on lung adenocarcinoma in vivo was evaluated by A549, H1975 tumor-bearing mouse models. Finally, transcriptomic sequencing (RNA-Seq) and immunohistochemistry were used to explore the molecular mechanism of the intervention effect of ticagrelor on lung cancer. Ticagrelor significantly inhibits the proliferation, migration and invasion of various lung cancer cells in vitro, and markedly suppressed tumor growth in A549 and NCI-H1975 CDX model in vivo. The pathological results showed that the number of tumor cells in the intervention group was significantly reduced, with large area necrosis, and the expression of Ki-67 in the intervention group was significantly decreased by immunohistochemistry. RNA-seq sequencing results from NCI-H1975 xenograft showed that several integrin-related pathways were down-regulated in the Ticagrelor treatment group, along with a significant reduction in spleen tyrosine kinase (SYK), a pivotal protein related to integrin signaling. Furthermore, we demonstrated that ticagrelor inhibits lung adenocarcinoma by down-regulating SYK and regulating PI3K/AKT pathway using WB. Ticagrelor has obvious inhibitory effect on a variety of lung adenocarcinoma cell lines and cell line transplanted tumors, and its antitumor effect may be related to the inhibition of SYK signaling pathway and PI3K/AKT pathway.

Finding the molecular targets involved in the severity and drug resistance of Colorectal cancer (CRC) and applying targeted treatments against them is a promising approach. In this study, some candidate oncogenes related to disease severity and mortality were identified by extracting bioinformatics data, and the effect of Fe3O4@Glu-Cinnamon NPs on the survival of CRC cells (SW480) and the expression of these oncogenes was investigated. The NPs were characterized by FT-IR, XRD, DLS and zeta potential measurement, TEM and SEM imaging, EDS-mapping and VSM analysis. Cytotoxicity of the NPs was evaluated by the MTT assay and a flow cytometry analysis was done to investigate cell apoptosis/necrosis levels and cell cycle analysis of cancer cells. The Fe3O4@Glu-Cinnamon NPs with spherical morphology were correctly synthesized, containing no elemental impurities, with a size range of 26.8-60.2 nm, DLS of 213 nm, zeta potential of -15.4mV and maximum magnetization level of 20.33emu/g. Treatment of cancer cells with the NPs elevated primary and late apoptosis and cell necrosis levels to 20.85, 16.83 and 9.56% and treated cells were mainly arrested at the S and G2/M phases. The expression level of the oncogenes associated with mortality, SNAI1, THBS2 and INHBA reduced to 0.74, 0.66 and 0.7 folds, respectively. The magnetic properties of Fe3O4 NPs enable their potential use in targeted drug delivery, allowing for site-specific accumulation within tumors. This could minimize systemic toxicity while enhancing treatment efficacy.

The rise of drug-resistant fungal species, such as Candida auris, poses a serious threat to global health, with mortality rates exceeding 40% and resistance rates surpassing 90%. The limited arsenal of effective antifungal agents underscores the urgent need for novel strategies. Here, we systematically evaluate the role of histone H3 post-translational modifications in C. auris drug resistance, focusing on acetylation mediated by Gcn5 and Rtt109, and methylation mediated by Set1, Set2, and Dot1. Mutants deficient in these enzymes exhibit varying degrees of antifungal drug sensitivity. Notably, we discover that GCN5 depletion and the subsequent loss of histone H3 acetylation downregulates key genes involved in ergosterol biosynthesis and drug efflux, resulting in increased susceptibility to azoles and polyenes. Additionally, Gcn5 regulates cell wall integrity and echinocandin resistance through the calcineurin signaling pathway and transcription factor Cas5. In infection models using Galleria mellonella and immunocompromised mice, GCN5 deletion significantly reduces the virulence of C. auris. Furthermore, the Gcn5 inhibitor CPTH2 synergizes with caspofungin in vitro and in vivo without notable toxicity. These findings highlight the critical role of Gcn5 in the resistance and pathogenicity of C. auris, positioning it as a promising therapeutic target for combating invasive fungal infections.

Seed aging or deterioration can affect germination rate, vigor, and viability. Allium mongolicum seeds stored for different years were used to obtain germination indicators, physiological indicators, and proteomic and transcriptomic sequencing in seeds treated with spermidine (Spd). The germination ability of A. mongolicum seeds increased and then decreased with the extension of storage life. The germination rate was only about 40% after 6 years. Relative conductivity, malondialdehyde (MDA), and hydrogen peroxide (H2O2) content first decreased and then increased, while catalase activity (CAT), peroxidase activity (POD), superoxide dismutase activity (SOD), Ascorbate peroxidase activity (APX), and respiratory rate first increased and then decreased. Spd increased the seed germination rate, CAT, POD, SOD, and APX activity. However, it significantly reduced MDA, H2O2 content, and relative conductivity. Differentially expressed proteins were concentrated in energy metabolism pathways. Ten proteins related to the aging of A. mongolicum seeds were identified. The gene expression trend was basically consistent with the proteomic assay results. Energy metabolism is a key pathway in the aging of A. mongolicum seeds. Regulating the expression of genes involved in energy metabolism pathway can effectively alleviate A. mongolicum seed aging. The results enriched the molecular mechanism of the seed storability of A. mongolicum, providing theoretical bases for molecular marker-assisted breeding of its storability traits.

Adenosine kinase (ADK, EC: 2.7.1.20) is an evolutionarily ancient ribokinase, which acts as a metabolic regulator by transferring a phosphoryl group to adenosine to form AMP. The enzyme is of interest as a therapeutic target because its inhibition is one of the most effective means to raise the levels of adenosine and hence adenosine receptor activation. For these reasons, ADK has received significant attention in drug discovery efforts in the early 2000s for indications such as epilepsy, chronic pain, and inflammation; however, the report of adverse events regarding cardiovascular and hepatic function as well as instances of microhemorrhage in the brain of preclinical models prevented further development efforts. Recent findings emphasize the importance of compartmentalization of the adenosine system reflected by two distinct isoforms of the enzyme, ADK-S and ADK-L, expressed in the cytoplasm and the cell nucleus, respectively. Newly identified adenosine receptor independent functions of adenosine as a regulator of biochemical transmethylation reactions, which include DNA and histone methylation, identify ADK-L as a distinct therapeutic target for the regulation of the nuclear methylome. This newly recognized role of ADK-L as an epigenetic regulator points toward the potential disease-modifying properties of the next generation of ADK inhibitors. Continued efforts to develop therapeutic strategies to separate nuclear from extracellular functions of adenosine would enable the development of targeted therapeutics with reduced adverse event potential. This review will summarize recent advances in the discovery of novel ADK inhibitors and discuss their potential therapeutic use in conditions ranging from epilepsy to cancer.

Cancer stem-like cells (CSCs), a small subset of cells within the tumor microenvironment, favor tumor relapse and remain a major obstacle in cancer therapy. Hence, hyaluronan-based mesoporous silica nano-formulation with phloroglucinol (MSN-PG-HA) was employed in our study to address the cancer relapse by targeting CD44. Various in vitro cellular assays were conducted to assess the nano-formulation's effect on suppressing CSC characteristics in AGS, HCT-116 and SW-620. The CUA assay indicated increased uptake of FITC-labeled MSN-PG-HA by all GI cancer cell lines and no uptake by CD44- (3T3) cell line confirming the receptor-mediated endocytosis. Moreover, MSN-PG-HA nano-formulation has shown a significantly higher efficacy than free PG in other cellular assays by controlling cell migration, colony and spheroid formation, inducing apoptosis and suppressing the elevated MMP levels, for all the three GI cell lines with p ≤ 0.05, highlighting the nano-formulation's ability to target CSC. Further, the gene and protein expression analyses of hedgehog signaling pathway components, such as GLI1 and SMO, showed a 0.7 to 0.8-fold decrease in expression with MSN-PG-HA treated groups, proving that our nano-formulation could significantly target CSC-related proteins. Furthermore, the expression analysis utilizing inhibitors such as GANT-61 (GLI1 inhibitor) and Sonidegib (SMO inhibitor) have demonstrated that the MSN-PG-HA has shown a significant level of inhibition as that of GANT-61, indicating a similarity in their mechanism of action in inhibiting the cancer cell proliferation. Thus, our findings conclude that MSN-PG-HA could serve as a potential drug for targeting GI cancer stem cells.

The potential regulatory mechanisms of 100 μM melatonin (MT) treatment on proline accumulation in cantaloupe fruit under cold stress were investigated. The results showed that MT treatment increased the content of free proline in cold-stored cantaloupe fruit by upregulating the expressions of the Δ1-pyrroline-5-carboxylate synthase (P5CS) and ornithine δ-aminotransferase (OAT) genes and decreasing the transcripts and enzyme activity of proline dehydrogenase (ProDH). Furthermore, the yeast one-hybrid assay screened for CmDREB1A and CmDREB1E that bind CmP5CS, and electrophoretic mobility shift analysis and dual luciferase reporter gene verified that these two transcription factors could bind the CmP5CS promoter. Further experiments showed that CmDREB1A and CmDREB1E were involved in improving cold tolerance in cantaloupe by MT and regulating the expression of CmP5CS. Our study suggests that MT treatment promotes CmP5CS expression and positively regulates proline accumulation by activating CmDREB1A and CmDREB1E in cantaloupe, thereby improving fruit cold stress tolerance.

Endostar is a human recombinant endostatin which is an attractive anti-angiogenesis protein. Because inefficient antigen presenting MHC class I expression (which can be downregulated by HIF-1) is an important strategy for cancer immune evasion, besides its anti-angiogenesis effect, it remains unclear whether Endostar has an inhibitory effect on HIF-1 expression by upregulating MHC class I expression in cancer cells to facilitate immunotherapies, including PD-1/PD-L1 inhibitors. In this study, A549 and NCI-H1299 lung cancer cells were treated with Endostar (6.25 μg/ml, 12.5 μg/ml, and 25 μg/ml, respectively). HIF-1 expression was detected by Immunocytochemistry and Western blot. Proteins of the MHC class I α-heavy chain and β2 m light chain, STAT3 and pSTAT3 were detected by Western blot. The mRNAs of MHC class I α-heavy chain and β2 m light chain were detected by RT-qPCR. It was shown that decreased expression of HIF-1 and promotion of β2-microglobulin were observed after Endostar treatment. In addition, elevated levels of MHC class I α-heavy chain mRNA and protein, as well as downregulation of STAT3 and pSTAT3, were also observed following Endostar treatment. Endostar inhibited HIF-1 expression in A549 and NCI-H1299 lung cancer cells, upregulated expression of MHC class I α-heavy chain and β2 m light chain, with the upregulation of STAT3 and pSTAT3, suggesting involvement of STAT3 pathway. It is important because only in combination with MHC class I on target cells can tumor antigenic peptides be recognized by CD8+ CTLs which destroy target cells. However, MHC class I is frequently deficient in cancer cells.

Benign prostatic hyperplasia (BPH) poses a significant public health challenge, affecting a substantial portion of aging men worldwide. Current therapeutic options offer limited efficacy. The pathogenesis of BPH is multifactorial, involving ferroptosis, oxidative stress, and chronic inflammation. Hydroxycitric acid (HCA) is a natural compound with diverse pharmacological activities, including the inhibition of ferroptosis, anti-inflammatory, anti-oxidative stress, and anti-tumor effects. However, its role in BPH remains unexplored. This study aimed to investigate the effects of HCA on BPH and elucidate the underlying mechanisms, with the goal of providing novel therapeutic insights for BPH treatment.

Heteroresistance and persistence are examples of mechanisms that can allow otherwise drug-susceptible bacteria to survive and resume growth after antibiotic exposure. These temporary forms of antibiotic tolerance can be caused by the upregulation of stress response genes or a decrease in cell growth rate. However, it is not clear how the expression of multiple genes contributes to tolerance phenotypes. Using fluorescent reporters for stress-related genes, we conducted real-time measurements of expression prior to, during, and after antibiotic exposure. We first identified relationships between growth rate and reporter levels based on auto- and cross-correlation analysis, revealing consistent patterns where changes in growth rate were anticorrelated with fluorescence following a delay. We then used pairs of stress gene reporters and time-lapse fluorescence microscopy to measure the growth rate and reporter levels in cells that survived or died following antibiotic exposure. Using these data, we asked whether combined information about reporter expression and growth rate could improve our ability to predict whether a cell would survive or die following antibiotic exposure. We developed a Bayesian inference model to predict how the combination of dual reporter expression levels and growth rate impacts ciprofloxacin survival in Escherichia coli. We found clear evidence of the impact of growth rate and gadX promoter activity on survival. Unexpectedly, our results also revealed examples where additional information from multiple genes decreased prediction accuracy, highlighting an important and underappreciated effect that can occur when integrating data from multiple simultaneous measurements.IMPORTANCETransient increases in bacterial antibiotic tolerance can result in treatment failure despite an infection initially presenting as susceptible, presenting a significant challenge in antibiotic therapy. This phenomenon can also provide a window of opportunity for bacteria to acquire permanent genetic resistance mutations. Although understanding the underlying mechanisms of these antibiotic tolerance phenotypes is crucial for developing effective approaches to treatment, current approaches for studying these transient phenotypes have limitations. Here, we use fluorescent reporters to monitor the expression of genes involved in stress response over time, aiming to link expression with antibiotic survival outcomes. Our results reveal a counterintuitive finding: monitoring multiple gene reporters does not necessarily improve our ability to predict antibiotic survival outcomes compared to single gene reporters. This result emphasizes the need for a deeper mechanistic understanding of the relationship between stress response gene expression and antibiotic tolerance.

We previously showed that proliferating cell nuclear antigen (PCNA) interacts with androgen receptor (AR) through a PIP-box (PIP-box4) at the N-terminus of AR and regulates AR activity. In this study, we further investigated PCNA/AR interaction. We identified a second PIP-box (PIP-box592) in the DNA binding domain of AR and found that dihydrotestosterone enhances the binding of full-length AR (AR-FL) but not a constitutively active variant (AR-V7) to PCNA. Treatment with R9-AR-PIP, a PIP-box4-mimicking small peptide, inhibits the PCNA/AR interaction, AR occupancy at the androgen response element (ARE) in PSA and p21 genes, and expression of AR target genes, and induces cytotoxicity in AR-positive castration-resistant prostate cancer (CRPC) cells. R9-AR-PIP also significantly inhibits transcriptional activity of AR-FL upon dihydrotestosterone stimulation and the constitutive activity of AR-V7. Moreover, R9-AR-PIP and PCNA-I1S, a small molecule PCNA inhibitor, inhibit the ARE occupancy by AR-FL and AR-Vs in CCNA2 gene that encodes cyclin A2 and cyclin A2 expression. Finally, we found that cyclin A2 is overexpressed in all CRPC cells examined, suggesting that it may contribute to the development of CRPC. These data indicate that targeting PCNA/AR interaction inhibits both AR-FL- and AR-Vs-mediated signaling and implicates it could be a novel therapeutic strategy against CRPC.

Sulforaphane (SFN), a lipophilic small-molecule compound, can be rapidly and completely absorbed upon entering the body. It has garnered extensive research attention for its potential as an antiaging, anticancer, antidiabetic, and antibacterial agent. However, its role and mechanisms of SFN on skeletal muscle postinjury regeneration have not been reported. This research demonstrated that SFN enhanced the regeneration after skeletal muscle injury and up-regulated the proliferation of mouse C2C12 myoblasts. RNA-transcriptome sequencing data revealed that SFN increased Prl2C2 transcription and JAK/STAT signaling pathway activity. CHIP and dual-luciferase reporter gene assays verified that STAT3 binds to the Prl2C2 promoter and regulates its transcription. Consequently, SFN influenced the JAK2/STAT3 signaling activity. Finally, the transcription of Prl2C2 and the proliferation of mouse C2C12 myoblasts were detected by adding JAK2 inhibitor and SFN. The results showed that the JAK2 inhibitor blocked the up-regulation of SFN on the transcription of Prl2C2 and the proliferation of mouse C2C12 myoblasts. The discovery of this phenomenon and its mechanism offer guidance for treating skeletal muscle injuries and supporting animal nutrition research. SFN shows great potential in muscle repair, and future clinical trials could confirm its safety and efficacy, paving the way for new SFN-based treatments and providing new options for patients.

Stomach cancer has become one of the most common types of cancer, with its mortality rate ranking third in the world. Currently, the main treatments for gastric cancer are surgery, radiation therapy, and chemotherapy. Although current treatments can effectively prevent postoperative metastasis and recurrence of gastric cancer, they may also bring various adverse reactions in the gastrointestinal tract and side effects such as bone marrow suppression. Years of research have confirmed that traditional Chinese medicine treatment for gastric and other cancers has distinct characteristics and advantages. Combined treatment can increase the tumor inhibition rate, reduce the side effects of radiation and chemotherapy, improve patients' quality of life, and prolong the survival prognosis.

Gemcitabine (GEM) is used as a first-line therapy for patients diagnosed with any stage of pancreatic cancer (PC); however, patient survival is poor because of GEM resistance. Thus, new approaches to overcome GEM resistance in PC are urgently needed. Here, we aimed to establish an in vivo drug-resistant PC model and identify genes involved in GEM resistance. We focused on one of these factors, CITED4, and elucidated its mechanisms of action in GEM resistance in PC.

Recent research indicates that programmed death 1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors show promise in treating triple-negative breast cancer (TNBC), but their efficacy is lower than anticipated, especially when used alone. Therefore, enhancing the anti-tumor immune response strategy for TNBC is crucial. Ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), involved in tumor cell regulation and a potential therapeutic target, has an undefined role in TNBC immunotherapy. In this study, we explored the inverse correlation between UCH-L1 and PD-L1 in TNBC patient tissues. Through in vitro experiments, we found that UCH-L1 negatively regulates PD-L1 by stabilizing the E3 ubiquitin ligase ariadne-1 homolog (ARIH1), which promotes PD-L1 ubiquitination and degradation. Further analysis in Balb/c mice xenograft tumors showed that UCH-L1 correlates with GZMB+/CD8+ T cell infiltration in TNBC, suggesting potential synergistic effects when combining UCH-L1 inhibitors with PD-L1 antibodies. Overall, in TNBC, UCH-L1 stabilizes ARIH1, leading to low PD-L1 expression, which may explain the limited effectiveness of immunotherapy in TNBC patients. Our mouse experiments showed improved therapeutic effects when combining UCH-L1 inhibitors with PD-L1 antibodies. These findings offer a new avenue for immunotherapy in TNBC patients.

(R)-β-homoserine (RBH) is a structural analogue of β-aminobutyric acid (BABA) that can enhance plant resistance to a wide range of pathogens. Here, we investigated the regulatory role of VvTCP7 on the RBH-induced priming response against Botrytis cinerea in grapes. The results showed that RBH primed a defense mechanism in grape berries and enhanced their response to fungal infection. RBH upregulated the expression of a group of genes involved in SA synthesis, thus inducing SA accumulation in grapes. VvTCP7 has high homology to AtCHE in Arabidopsis thaliana and is recognized to be a nucleus-localized protein that promotes SA synthesis. Notably, RBH elevated VvTCP7 expression in harvested grape berries, which was accompanied by enhanced expression of VvNPR1, a master regulator of SAR, as well as the SA-responsive PR genes. Additionally, Y1H, EMSA and DLR assays confirmed that VvTCP7 has the ability to bind directly to the GGNCCC motif within the VvICS promoter to induce VvICS transcription and SA synthesis. Overexpression of VvTCP7 in Arabidopsis led to a marked increase in the transcription of PR genes, enhancing defensive response to B. cinerea. However, the VvTCP7 knockout led to a decrease in PR gene expression and increased susceptibility to the fungus. Collectively, the data suggest that VvTCP7 contributes to RBH-induced SAR priming by activating the SA synthesis and resultant enhances SAR defenses to combat fungal invasion.

We demonstrate that exposure to the AB5 subtilase cytotoxin (SubAB) induces the unfolded protein response (UPR) in human peripheral blood mononuclear cells, concomitant with a proinflammatory response across distinct cell subsets. Notably, SubAB selectively induces type-I interferon (IFN) expression in plasmacytoid dendritic cells, acting synergistically with Toll-like receptor 7 stimulation. The induction of type-I IFN in response to SubAB relies on stimulator of interferon genes (STING) activation, coupled with protein synthesis inhibition mediated by protein kinase R-like endoplasmic reticulum kinase (PERK) and phosphorylation of the eukaryotic translation initiation factor 2 subunit-alpha. By impeding mRNA translation through the integrated stress response, SubAB precipitates the downregulation of the negative innate signaling feedback regulator Tax1-binding protein 1. This downregulation is necessary to unleash TANK-binding kinase 1 signaling associated with STING activation. These findings shed light on how UPR-inducing conditions may regulate the immune system during infection or pathogenesis.