Candida albicans is an opportunistic pathogen, which has recently been included in the high-priority list of pathogenic fungi by the World Health Organization (WHO). The scarce arsenal available to treat such invasive fungal infections makes the discovery of new antifungal targets an important task. This study utilizes DDA-MS technology to investigate both the phosphoproteomics and proteomics of C. albicans during its late-stage response to oxidative stress induced by H2O2, aiming to identify key proteins involved. Phosphorylation, as an important post-translational modification, plays a crucial role in the ability of C. albicans to survive oxidative stress. Our study enabled the identification and quantification of important changes in both protein abundance and phosphorylation events across multiple proteins following a 200 min 10 mM H2O2 treatment. The use of the DDA-MS approach allowed for the identification of new actors in the response to oxidative stress. Novel phosphorylation sites were identified in kinases and transcription factors. Regarding protein kinases, Cdc5-reduced phosphorylation may mediate a transient G2 cell cycle arrest, while Kis1─the regulatory β-subunit of Snf1 kinase─might play a role in ROS scavenging following oxidative stress. In terms of transcription factors, Gzf3-decreased phosphorylation was essential for cell survival and ROS detoxification after oxidative stress.

Colorectal cancer (CRC) is the third most prevalent malignancy in the gastrointestinal tract and the second leading cause of cancer-related deaths. Despite the identification of numerous biomarkers, their non-specific distribution across different cell types complicates the development of targeted therapies. Therefore, this study aims to identify specific biomarkers for CRC and utilize them for the development of targeted therapies.

Autophagy has been implicated in the pathophysiology of thyroid cancer and in determining the response of cancer cells to anticancer therapy. Dabrafenib, a BRAF inhibitor, has demonstrated efficacy and safety in several types of cancers. However, it is unknown whether Dabrafenib exerts a protective effect on autophagy in thyroid carcinoma cells. In the current study, our findings demonstrate that treatment with Dabrafenib reduced cell viability and promoted LDH release in SW579 thyroid carcinoma cells. Dabrafenib was then shown to promote autophagy by increasing the level of Beclin1 and the LC3-II/LC3-I ratio while reducing the level of p62. Additionally, exposure to Dabrafenib upregulated the expression of HMGB-1 at both mRNA and protein levels. Interestingly, silencing of HMGB-1 abrogated Dabrafenib-induced autophagy, suggesting that the effects of Dabrafenib are mediated by HMGB-1. Further study revealed that Dabrafenib activated the JAK1/STAT1 signaling pathway and that blockage of the JAK1/STAT1 signaling pathway with its inhibitor Pyridone 6 ameliorated Dabrafenib-induced HMGB-1 upregulation and autophagy, implicating the involvement of the JAK1/STAT1 signaling pathway in this process. Collectively, these findings demonstrate that Dabrafenib induces autophagy in thyroid carcinoma cells via the JAK1/STAT1/HMGB-1 axis. Notably, this effect occurs independently of BRAF V600E mutation status, suggesting a novel therapeutic mechanism.

Patients with ovarian high-grade serous carcinoma (OHGSC) gradually acquire resistance to standard chemotherapy following recurrence. In our previous study on OHGSC, histone deacetylase (HDAC) 6 upregulation led to a poor prognosis, and programmed death ligand-1 (PD-L1) expression was positively correlated with HDAC6 expression. We analyzed HDAC6 and PD-L1 expression before and after chemotherapy to investigate their association with chemotherapy resistance and patient survival. PD-L1 and HDAC6 expression were immunohistochemically analyzed using clinical samples from 54 patients with OHGSC before and after standard chemotherapy. High PD-L1 expression (≥ 5%) was detected in five and nine patients before and after chemotherapy, respectively. The mean PD-L1-positive rate after chemotherapy was 3.88%, which was significantly higher than the rate before chemotherapy (0.68%). The high HDAC6 expression frequency significantly increased from four patients before chemotherapy to 13 patients after. High PD-L1 expression after chemotherapy was significantly correlated with a chemotherapy response score of three, signifying a good chemo-response. High PD-L1 expression after chemotherapy was associated with poor progression-free survival and overall survival in patients who underwent complete surgical resection. In OHGSC, residual tumors after chemotherapy show enhanced HDAC6 and PD-L1 expression. Upregulated PD-L1 after neoadjuvant chemotherapy (NAC) has contradictory characteristics, indicating a good response to chemotherapy but unfavorable survival. It is a wolf in sheep's clothing, and physicians should not make an optimistic prognosis even if the patient shows a good response to NAC. HDAC6 and PD-L1 may be therapeutic targets and prognostic factors for residual tumors after chemotherapy in OHGSC.

In order to overcome the damage caused by phytopathogens, plants have evolved a complex defence system to protect themselves, such as the two-tiered innate immunity system. Chemical screening has led to the identification of plant immune-priming compounds, which facilitate the functional dissection of the plant immune system and contribute to chemical control for plant diseases. In this study, we identified decursin, a coumarin natural product, through high-throughput screening for activators of the expression of FLG22-INDUCED RECEPTOR KINASE 1 (FRK1). Decursin functions as a typical immune elicitor, triggering early immune responses, including a reactive oxygen species (ROS) burst, MAPK activation, and transcriptional reprogramming of defence genes. A targeted reverse genetic approach identified CERK1, a lysin motif receptor-like kinase (LysM-RLK), loss of function of which resulted in a significant reduction of decursin-induced immune responses. Moreover, decursin was demonstrated to be ineffective in eliciting immune activation in the lyk4 lyk5 mutant, a double mutant of two additional LysM-RLKs. Molecular docking studies predicted that decursin may bind to CERK1 and LYK5. Decursin has been demonstrated to possess potent antiphytopathogenic properties, exhibiting pronounced growth inhibitory effects against several important plant fungal pathogens in vitro and in vivo, thereby protecting plants from damage caused by these pathogens. It can be concluded that decursin exerts its function through two independent mechanisms to enhance plant disease resistance, providing a potent agrochemical in disease control.

The study investigates the anticancer effects of green silver nanoparticles (Ag-NPs) synthesized from Viola cornuta extract combined with papaverine on breast cancer cells. Ag-NPs were characterized using various analytical techniques, confirming their presence with UV-vis spectroscopy showing a peak at 413 nm and an average size of 42 nm via field emission scanning electron microscopy (FE-SEM) analysis. The particles demonstrated a face-centred cubic structure, with energy-dispersive X-ray spectroscopy (EDX) confirming elemental composition. Additionally, the zeta potential measurement of -6.75 mV indicated favourable electrostatic repulsion between nanoparticles, thereby confirming their stability. Antioxidant activity was significant, with an EC50 value of 38.78 μg/mL. The combination treatment of Ag-NPs and papaverine exhibited synergistic effects, lowering IC50 values to 2.8 + 112.7 μg/mL for MCF-7 cells and 6.2 + 112 μg/mL for MDA-MB-231 cells, without toxicity to normal cells. Flow cytometry revealed G0/G1 phase inhibition and increased sub-G1 populations, indicating cell cycle arrest, alongside increased reactive oxygen species generation and apoptosis. Notably, the experimental group showed altered expression of oncogenic and tumour suppressor microRNAs and apoptotic genes (p < .0001), underscoring the potential of this nanoparticle-papaverine combination as an effective anticancer strategy against breast cancer treatment resistance.

Notoginsenoside Ft1 (NFt1) is a bioactive compound derived from Panax notoginseng, a traditional medicinal herb that exhibits various pharmacological properties, including anti-inflammatory and anticancer effects. However, its effects on hepatocellular carcinoma (HCC) remain poorly understood. This study sought to investigate the anticancer effects of NFt1 and uncover its fundamental mechanisms in HCC cells. NFt1 treatment inhibited cell proliferation and promoted apoptosis by enhancing cell death markers. Transcriptome profiling using RNA-sequencing revealed that NFt1 treatment downregulated the expression of oncogenes (e.g., FOS, BRAF, RARA, MYC, and JUND), while upregulating lysosomal cell death-related genes (e.g., CTSB, CTSD, LAMP1, LAMP2, and TPP1). These effects are associated with PI3K/AKT/mTOR inhibition and increased transcriptional activity of transcription factor EB (TFEB). NFt1 treatment induced autophagic traits by suppressing the PI3K/AKT/mTOR pathway, thereby enhancing TFEB transactivity. These findings demonstrated the therapeutic promise of NFt1 in the effective management of HCC.

Platinum-based therapy is an integral part of the standard treatment for ovarian cancer. However, despite extensive research spanning several decades, the identification of dependable predictive biomarkers for platinum response in clinical practice has proven to be a formidable challenge. Recently, the development of single-cell technology has enabled more precise investigations into the heterogeneity of cancer. In this study, we isolated cancer cells from the single-cell transcriptomic data of platinum-sensitive and platinum-resistant patients with ovarian cancer. Differential gene analysis of platinum-sensitive and platinum-resistant cancer cells revealed that several of the differentially expressed genes had previously been reported in other studies to be associated with platinum resistant. Gene set enrichment analysis revealed the up-regulation of pathways involved in processes such as autophagy, cell cycle regulation, and DNA damage repair, which are known to promote platinum resistance in ovarian cancer. Based on these findings, we hypothesized that these differentially expressed genes could be used to predict the response of ovarian cancer patients to platinum-based chemotherapy. To validate this hypothesis, we explored 7 different machine learning models for predicting platinum chemotherapy response at varying feature gene counts. Ultimately, the random forest model performed the best, with 5 genes (PAX2, TFPI2, APOA1, ADIRF and CRISP3) and achieve an AUC of 0.993 in test cohort and 0.989 in GSE63885 independent validation cohorts. We named this model GPPS (Genes to Predict Platinum response Signature). Furthermore, we discovered that the GPPS model can also predict patient prognosis.

Potato (Solanum tuberosum L.) is one of the world's most important non-cereal food crops, with stolon development playing a crucial role in determining tuber yield. While some studies have examined the effects of sugars on potato stolon growth, their influence-particularly that of sucrose-on early stolon development remains unclear. Furthermore, the regulatory role of plant hormones in this process has yet to be established. Using a combination of in vitro culture, transcriptomics, gene expression analysis, and biochemical approaches, we investigated the contribution of sucrose (3% or 8%) on potato seedling stem nodes and stolon initials through phenotypic observation, RNA sequencing (RNA-seq), comparison of expression patterns, and hormone quantification. Firstly, compared to other types of sugars, we found that high concentrations of sucrose were the most effective in inducing stolon initial formation in potato seedlings. Furthermore, RNA-seq data showed that high sucrose levels significantly up-regulated the expression of genes involved in sugar metabolism and plant hormone metabolism. Additionally, the development of stem nodes and stolon initials under high sucrose conditions was also closely linked to hormone metabolism. Notably, high sucrose concentrations contributed to stem node and stolon initial development by modulating the IAA, CK, and GA signaling pathways. Based on the endogenous hormone measurement, and exogenous hormone application, together with heterologous overexpression of a potato Auxin response factor 9 (StARF9), we concluded that the early development of potato stolons was regulated by plant hormones, particularly auxin. In summary, this study elucidates the hormonal regulation of stolon initiation under high sucrose concentrations, offering a theoretical foundation and potential targets for in vitro culture and genetic improvement of potato.

Recent findings have indicated that pharmacological inhibition of the mTOR kinase can become a widely used experimental approach to generate dormant cancer cells in vitro. However, the suppression of mTOR, which is responsible for global translation, can significantly rewire basic cellular functions influencing the expression of housekeeping genes. To prevent incorrect selection of a reference gene in dormant tumor cells, we analyzed the expression stability of the widely used housekeeping genes GAPDH, ACTB, TUBA1A, RPS23, RPS18, RPL13A, PGK1, EIF2B1, TBP, CYC1, B2M, and YWHAZ in the T98G, A549, and PA-1 cancer cell lines treated with the dual mTOR inhibitor AZD8055. It has been revealed that the expression of the ACTB gene, encoding the cytoskeleton, and the RPS23, RPS18, and RPL13A genes, encoding ribosomal proteins, undergoes dramatic changes, and these genes are categorically inappropriate for RT-qPCR normalization in cancer cells treated with dual mTOR inhibitors. B2M and YWHAZ were determined to be the best reference genes in A549 cells, and the TUBA1A and GAPDH genes were the best reference genes in T98G cells. The optimal reference genes among the 12 candidate reference genes were not revealed in the PA-1 cell line. Validation of the stability of the 12 investigated genes demonstrated that the incorrect selection of a reference gene resulted in a significant distortion of the gene expression profile in dormant cancer cells.

This study investigates the effects of T-2 toxin metabolite HT-2 alone or combined with Akt1 on chondrocyte gene expression to elucidate their roles in Kashin-Beck disease (KBD) pathogenesis.

Cinnamaldehyde (CinA) is a phytochemical whose source plants are widely used as a medicine and food spice additive, but its vascular effect and mechanisms remain poorly understood.

Feed is very important for fish farming. The appropriate composition and proportion of feed ingredients can promote the growth of fish, maintain normal physiology and behavior, and even improve the resistance ability to disease and stress, etc. The core of artificial compound feed (ACF) is the composition and proportion of lipid, protein, and carbohydrate, which are also the main nutritional components required by fish. Appropriate levels and ratios can promote fish growth and save costs, and the improper would affect the biological clock systems of fish, leading to metabolic abnormalities. This study explored the preparation of ACF for H. kuda. The composition and proportion of the three main nutrients in ACF were screened based on the synchronicity between six pairs of clock genes (Clock, Bmal1, Per1, Per2, Per3, Cry1, and Cry2) in the central and peripheral clock systems, as well as the expression of eight lipid-metabolism genes (Hmgcr, Mvk, Mvd, Lss, Fdps, Cetp, Scap, Srebp1, Srebp2) in the liver and their synergy with liver clock genes. The results showed that, based on several parameters such as gene expression cycle, relative expression level, and top phase appearance time, the best synergy between the central and peripheral circadian clock systems was observed in ACF with crude fat content of 8.80%, crude protein content more than 38.4%, and carbohydrate content of 23.5%. Based on the expression relationship between lipid metabolism genes and circadian clock genes in the liver, it was further clarified that the optimal levels of fat, protein, and carbohydrate were determined with 8.80%, 38.4%, and 23.5%, respectively. After 4 weeks of breeding validation, compared with frozen Mysis, the screened ACF fed for H. kuda showed significant advantages in body length specific growth rate (SGRL), body weight specific growth rate (SGRW), and feed conversion rate (FCR).

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal sarcomas of the upper digestive tract. Imatinib is the first-line therapy for patients with metastatic or unresectable GISTs. However, the majority of GIST patients eventually develop imatinib resistance.

BCR::ABL1-targeting tyrosine kinase inhibitors (TKIs) dominate the treatment of chronic myeloid leukemia (CML) over the past decades. In this study, we reported an unexpected role of neddylation inhibitors in desensitizing the therapeutic efficacy of BCR::ABL1-targeting TKIs in CML. Unlike their function in reducing drug resistance in many solid tumors, we revealed that neddylation inhibitors counteracted the cytotoxicity of TKIs against CML cells, both in cellular experiments and in animal model. Conversely, neddylation agonist sensitized the function of TKIs. RNA sequencing data revealed that neddylation inhibitor reversed the transcriptomic changes induced by TKI. Co-immunoprecipitation (co-IP) assay identified ABL1 kinase domain as a novel substrate for neddylation. Furthermore, an artificial intelligence (AI) 3-Dimensional spatial structure binding technology was employed to predict the impact of neddylation on the structure of ABL1 kinase domain. Finally, we provided potential evidence showing that TKI therapy decreased the expression of neddylation enzymes in the bone marrow of CML patients. Hence, our study offers new insights into the post-translational modification (PTM)-mediated drug resistance, and highlights the potential clinical benefits of neddylation agonists in improving the responsiveness of BCR::ABL1 TKIs in CML.

Environmental factors may affect gene expression through epigenetic modifications of histones and transcription factors. Here, we report that cellular uptake of sorbate, a common food preservative, induces lysine sorbylation (Ksor) in mammalian cells and tissue mediated by the noncanonical activities of class I histone deacetylases (HDAC1-3). We demonstrated that HDAC1-3 catalyze sorbylation upon sorbate uptake and desorbylation in the absence of sorbate both in vitro and in cells. Sorbate uptake in mice livers significantly induced histone Ksor, correlating with decreased expressions of inflammation-response genes. Accordingly, sorbate treatment in macrophage RAW264.7 cells upon lipopolysaccharide (LPS) stimulation dose-dependently down-regulated proinflammatory gene expressions and nitric oxide production. Proteomic profiling identified RelA, a component of the NF-κB complex, and its interacting proteins as bona fide Ksor targets and sorbate treatment significantly decreased NF-κB transcriptional activities in response to LPS stimulation in RAW264.7 cells. Together, our study demonstrated a noncanonical mechanism of sorbate uptake in regulating epigenetic histone modifications and inflammatory gene expression.

The cGAS-STING pathway is a central signalling mechanism in inflammatory responses and can be activated by cisplatin. Increased autophagic activity has been linked to cisplatin resistance in non-small cell lung cancer (NSCLC); however, how autophagy-STING interactions influence the cisplatin response remains unclear. This study investigates how autophagy modulation affects STING expression and cisplatin sensitivity in NSCLC cells with different basal STING levels. Autophagy was inhibited using chloroquine and induced by serum starvation in Calu-1 and H2030 cells. In Calu-1 cells, cisplatin treatment increased STING expression, activated the cGAS-STING pathway, and induced interferon responses correlated with cisplatin concentration. Autophagy inhibition reduced STING expression and interferon activation while enhancing cisplatin sensitivity. Conversely, autophagy induction caused fluctuations in STING expression and decreased cisplatin sensitivity, with ISG15 expression being selectively increased under serum starvation. In contrast, H2030 cells exhibited low basal STING expression and showed minimal responses to cisplatin or autophagy modulation. These findings suggest that STING expression levels critically influence autophagy-mediated responses to DNA-damaging chemotherapy in NSCLC.

Epigenetic modulators in combination with proapoptotic drugs have become the standard of care treatment in hematological malignancies. Conversely, these combinations have failed to demonstrate clinical efficacy in solid tumors. To address this discrepancy, we conducted a comprehensive analysis of the anti-tumor activity of epigenetic inhibitors in combination with BH3 mimetics that block anti-apoptotic proteins BCL-XL, BCL2 or MCL1 in a large set of solid tumor cell lines derived from patients and mouse models. Treatment with epigenetic drugs targeting DNA methyltransferase, histone methyltransferase, and histone deacetylase enzymes in combination with a BCL-XL inhibitor resulted in marked synergistic in vitro responses both in human and mouse solid tumor cell lines. This unique BCL-XL dependency was in clear contrast to hematological malignancies, which are largely dependent on BCL2 or MCL1 inhibition under epigenetic drug treatment. Mechanistically, co-targeting of epigenetic regulators and BCL-XL induced expression of endogenous retroelements that led to immunogenic cell death. We thus hypothesized that this response may sensitize tumor cells to immune checkpoint blockade (ICB). Accordingly, treatment with a triple combination of epigenetic and BCL-XL inhibitors with an anti-PD-1 monoclonal antibody in vivo reduced tumor growth and prolonged overall survival in a panel of murine syngeneic and orthotopic models of lung, colorectal and breast carcinomas, melanoma, and glioblastoma, as well as in an immunocompetent human colon cancer model. Using flow cytometry and single-cell RNA sequencing of the tumor microenvironment, we found that the broad activity of the triple therapy relied on the expansion of T and NK cells with cytotoxic potential, an increase in the M1/M2 macrophage ratio, and a reduction of immunosuppressive Treg cells, dendritic cells, and B lymphocytes. In conclusion, we report a novel regimen combining epigenetic and BCL-XL inhibitors with ICB that produces potent anti-tumor responses in multiple preclinical models of solid tumors.

Isorhapontigenin is an effective active ingredient in Rheum officinale, which has been reported to have anti-tumor effects. However, its effect and molecular mechanism on non-small cell lung cancer are still unclear. Firstly, potential therapeutic targets of Isorhapontigenin against non-small cell lung cancer were obtained through network pharmacology analysis. Secondly, bioinformatics analysis was conducted to identify key targets and potential signaling pathway mechanisms based on the obtained potential targets. Then, evaluated the binding ability between Isorhapontigenin and key targets by using molecular docking strategies. Finally, in vitro cell experiments were conducted to verify the effects and related targets of Isorhapontigenin on non-small cell lung cancer cells. 104 drug targets and 6688 disease targets were acquired from SwissTarget prediction, BATMAN-TCM, STITCH and Genecards databases.79 potential therapeutic targets were identified through analysis based on online Venn website and PPI interaction analysis was performed on these targets to ultimately obtain 55 key targets. GO and KEGG analysis revealed that Isorhapontigenin targets non-small cell lung cancer mainly through regulation of cell proliferation, cell cycle dynamics, and the PI3K/RELA/cell cycle axis. Molecular docking confirmed that Isorhapontigenin can bind to cell proliferation, cycle related proteins (CCND1, CDK2, PIK3CA, RELA). CCK-8 detection revealed that Isorhapontigenin significantly inhibited the proliferation of PC9 lung cancer cells, Moreover, RT-qPCR detection showed that Isorhapontigenin downregulated the expression of CCND1, CDK2, PIK3CA and RELA genes. CCND1, CDK2, PIK3CA and RELA are highly expressed in NSCLC tissues. Overall survival analysis of patients indicated that key genes in the PIK3CA and NF-κBp65 signaling pathway significantly affected overall survival. Our research has found that Isorhapontigenin can effectively against non-small cell lung cancer, and this effect may be achieved by inhibiting cell proliferation and cycle progression mediated by the PIK3CA/NF-KB signaling pathway. Isorhapontigenin is a new potential therapeutic agent for lung cancer.

Marsdenia tenacissima extract (MTE) from the stem of the Traditional Chinese herbal medicine of Marsdenia tenacissima (Roxb.) Wight et Arn. has been used as an anticancer remedy for decades.