Melatonin integrates multiple biological pathways to enhance rice drought tolerance with cooperation of WRKY, bHLH, ERF, MYB and NAC transcription factors, and crosstalk of salicylic acid, ethylene and auxin. Drought is one of the primary environmental threats, and detrimentally affects plant growth and development, impeding crop yield and food quality worldwide. Melatonin has recently emerged as a multifunctional biomolecule with promising aspects in plant stress tolerance. However, the way in which melatonin improves drought tolerance in rice has not been investigated systematically. Here, we demonstrate that melatonin minimized drought effects on rice, resulting in improved germination rate and growth performance. Application of exogenous 200 and 400 µM melatonin can significantly inhibit the accumulation of reactive oxygen species in rice, by enhancing the activity of ROS scavenging enzymes. The accumulation of osmolytes was also stimulated by melatonin to endure with a better preservation of leaf water status in drought-stressed rice. Genome-wide expression profiling by RNA sequencing reveals an increase of oxidoreductase activity, iron ion binding, hydrolase activity, cell wall biogenesis, root development, while a decrease of nitrogen compound metabolism and cellular biosynthesis. Furthermore, melatonin could modulate rice drought response through the cooperation of WRKY, bHLH, ERF, MYB and NAC transcription factors, and modulates salicylic acid, ethylene and auxin pathways. Our finding provides new insights into melatonin-mediated drought tolerance in rice, and facilitates the rational applications in stress management for agricultural, horticultural, and floricultural plants.

Salt stress adversely impacts crop growth and development, resulting in stunted growth and diminished grain yield. Therefore, this study explores the synergetic effects of seed priming with iron nanoparticles (FeNPs) integrated with a genome-wide association study (GWAS) on the phenotypic, biochemical, and agronomic traits of 138 barley accessions under control, salinity stress, and seed iron priming treatments. A normal phenotypic distribution was observed across all accessions under the tested conditions, with significant natural phenotypic variation in response to the treatments. Remarkably, seed priming with FeNPs showed a significant enhancement in superoxide dismutase (SOD) activity and selective modulation of catalase (CAT) and glutathione reductase (GR) activities, indicating a targeted oxidative stress response. Compared to control and salinity stress conditions, priming with FeNPs showed substantial increases in all agronomic traits, including spike length (SL), number of spikelets per spike (NSS), number of grains per spike (NGS), weight of grains per spike (WGS), and thousand kernel weight (TKW), suggesting its potential to mitigate the adverse effects of salinity and promote better crop performance. Based on GWAS analysis, sixteen highly significant marker associations/candidate genes were detected to be associated with antioxidant components. Using quantitative real-time PCR analysis (RT-qPCR), FeNPs seed priming effectively modulates the plant's transcriptional response to salinity stress by balancing rapid gene activation with sustained stress adaptation. This approach mitigates excessive defense responses while promoting long-term stability through controlled upregulation of key genes, such as PP2C, Phosphotransferase, Terpene Synthase Putative, and RWP-RK. The findings support the potential of FeNPs as a biotechnological tool to enhance crop resilience and optimize agronomic performance under adverse environmental conditions.

Grey hair, a common ageing-associated phenomenon in humans, is mainly attributed to the damage of melanocytes and the absence of melanin. Grey hair has long been treated with traditional medicine, and new research has shown that various plant-derived monomers can increase tyrosinase activity and melanogenesis, indicating that they may have therapeutic value in curing grey hair. In this study, we outlined the role of melanin and pigmentation during hair growth and collected various medicinal plant monomers with the potential value of grey hair reversal. Many active ingredients from medicinal plants, such as fraxinol, tribuloside, morin and naringenin, can upregulate melanogenesis and tyrosinase activity through different signalling pathways. Some of them can promote melanosome quantity, maturation and transportation as well. Monomers isolated from medicinal plants may act as stimulators of melanogenesis. Many plant-derived monomers perform as activators that upregulate melanin synthesis and tyrosinase activity through different signalling pathways. They are of great research value for the treatment of hair greying. Moreover, to further improve experimental effect, safety and reliability, a systematic and comprehensive evaluation system needs to be established in the future before studying their clinical efficacy.

Understanding the molecular mechanisms underlying cold and methyl jasmonate (MeJA) responses is vital for improving the cold tolerance of grapes. This study treated 'Pinot noir' plantlets with MeJA, screened key genes in the regulatory pathway using transcriptomics and proteomics analyses, and investigated their regulatory mechanisms under cold stress. The results showed that 50 μmol L-1 MeJA significantly inhibited the growth of grape roots length, increased the endogenous MeJA content and antioxidant enzyme activities, and reduced membrane damage under cold stress. In addition, 50 μmol L-1 MeJA and cold stress treatment greatly increased the number of differential genes and metabolites in the phenylalanine synthesis and hormone signal transduction pathways. The results indicated that VvPAL10, an important gene in the phenylalanine synthesis pathway, significantly improved transgenic Arabidopsis thaliana and grapevine callus tissue tolerance to low temperatures.

Flemingia macrophylla (Willd.) Merr. is commonly used as ethnic medicine in southwestern China, with genistein and genistin being the primary medicinal components. Magnesium has a significant impact on the growth, development, and accumulation of these active ingredients in F. macrophylla. To explore the effects of magnesium on the growth, development, and accumulation of active ingredients in F. macrophylla, tissue culture seedlings of F. macrophylla were treated with six different concentrations of magnesium, namely, T0 (0 g L-1), T0.5 (0.045 g L-1), T1 (0.09 g L-1), T2 (0.18 g L-1), T3 (0.27 g L-1), and T4 (0.36 g L-1), and then subjected to multi-omic analyses. Analysis of agronomic traits revealed that magnesium treatment significantly promoted rooting, whereas magnesium deficiency restricted root growth. Simultaneously, analysis of seedlings using high-performance liquid chromatography showed that 0.27 and 0.36 g L-1 magnesium significantly enhanced genistein synthesis and inhibited glycosylation (genistin). Furthermore, transcriptomic, proteomic, and metabolomic analyses indicated that differentially expressed genes and proteins under varying magnesium concentrations were primarily involved in phenylpropanoid, isoflavone, and flavonoid biosyntheses. Specifically, eight gene-protein pairs related to the synthesis of genistein and genistin were identified. Overall, our study identified essential genes/proteins involved in the synthesis of these two compounds and provided new ways to regulate genistein synthesis in medicinal plants.

Polycystic ovary syndrome (PCOS) is a common endocrine-metabolic disease in women of reproductive age. One of its core pathologies is ovarian granulosa cell (GC) dysfunction, and ferroptosis, as a novel cell death mode dependent on iron ions and lipid peroxidation, may be involved in the PCOS process, but the exact mechanism is unknown. Plumbagin (PLB) shows potential in PCOS treatment due to its antioxidant properties. The present study aimed to elucidate the molecular mechanisms by which PLB ameliorates mitochondrial dysfunction and ferroptosis in PCOS GCs through the YTH N6-methyladenosine RNA binding protein 1/L-type amino acid transporter 1 (YTHDF1/SLC7A5) axis.

Psoriasis is a common chronic inflammatory skin disease characterized by epidermal keratinocyte hyperproliferation and persistent immune activation. Histone deacetylase 3 (HDAC3), a member of the class I HDAC family, plays critical roles in regulating immunity and inflammation. However, its precise expression profile and functional contribution to psoriasis pathogenesis remain poorly defined.

Berbamine (BBM) has been reported to play an important role in the anti-inflammatory and anti-neoplastic activities. However, whether BBM mediates the anti-tumor efficacy in renal cell carcinoma (RCC) cells and the potential molecular mechanisms remain unclear.

Triple-negative breast cancer (TNBC) is associated with a poor prognosis due to insufficient molecular subtyping precision and limited actionable targets. Although metabolic reprogramming underlies TNBC chemotherapy resistance, establishing metabolic subtyping systems and investigating drug sensitivity across distinct metabolic subgroups could provide novel therapeutic avenues for breast cancer management. GSVA (Gene Set Variation Analysis) analysis of metabolic pathways reveals significant differences in TNBC (Triple-Negative Breast Cancer) patients. TNBC patients are classified into four metabolic subtypes through consensus clustering, based on their GSVA values of metabolic pathways. These subtypes are: MS_1, characterised by increased lipogenic activity; MS_2, characterised by increased carbohydrate and nucleotide metabolism; MS_3, a metabolism-active subtype with activation of all types of metabolism; and MS_4, characterised by suppressed metabolic activity across all types of metabolism. We next propose a novel method called MODIN (Multiomics-Driven Drug-Cell Interaction Network), which embeds multi-omics gene information (mRNA expression, copy number variation and DNA methylation) and drug SMILES data into a latent space, and then employs a multi-head attention-based interaction module to accurately predict the LN_IC50 values of 621 drugs in TNBC. Based on MODIN, noteworthy disparities in drug sensitivity emerge between the patient cohorts categorised as MS_2 and MS_3. MS_3 patients show a significantly higher sensitivity to chemotherapy regimens, especially for doxorubicin and docetaxel, while the MS_2 cohort displays marked resistance to these drugs. Our study reveals the metabolic heterogeneity of TNBC, and TNBC patients with increased carbohydrate and nucleotide metabolism exhibit the poorest prognoses and greater resistance to doxorubicin and docetaxel.

Antimicrobial peptides (AMPs) possess vaccine adjuvant activity; however, their specific targets and molecular mechanisms remain incompletely understood, which hinders their clinical application. This study aimed to elucidate the key targets and pathways through which the antimicrobial peptide BSN-37 modulates immune responses in macrophages, providing evidence for its potential clinical translation. In this investigation, Balb/c mice were administered BSN-37 for 12 h, after which total RNA was extracted from peritoneal macrophages to assess the mRNA expression levels of cytokines and key molecules on the cell surface, followed by transcriptomic sequencing. The results demonstrated that BSN-37 significantly upregulated the mRNA expression of these molecules and cytokines. A total of 228 differentially expressed long non-coding RNAs (lncRNAs) (121 upregulated, 107 downregulated) and 149 differentially expressed mRNAs (104 upregulated, 45 downregulated) were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed significant enrichment of differentially expressed mRNAs in immune response pathways, PI3K-Akt signaling, and NOD-like receptor signaling. Differentially expressed lncRNA target genes were associated with T cell receptor signaling, PD-1 checkpoint regulation, and other immune regulatory pathways. Protein-protein interaction network analysis identified core genes such as CCchemokine receptor 1 (CCR1) and Toll Like Receptor 8 (TLR8). Molecular docking studies confirmed that BSN-37 exhibited strong binding affinity to TLR8 and CCR1, with binding energies less than - 5 kcal/mol. RT-qPCR validation confirmed the reliability of the sequencing data. These findings indicate that BSN-37 activates multiple immune response pathways in macrophages by targeting immune-related genes such as TLR8 and CCR1, offering theoretical support for the development of novel immune adjuvants.

Hepatocellular carcinoma (HCC) presents a significant global health challenge, marked by high mortality and recurrence. This study investigated the synergistic potential of cisplatin and palbociclib (C + P) against HCC cell lines. RT-qPCR revealed that C + P significantly downregulated HCC-related genes, including Hsp90, β-catenin, and components of the PI3K/AKT/mTOR pathway, compared to cisplatin alone and controls. Western blotting confirmed a reduction in phosphorylated AKT (P-AKT) with palbociclib and C + P, while PTEN, a tumor suppressor, was upregulated in the C + P group. Annexin V-FITC assays demonstrated a substantial increase in apoptosis in palbociclib and C + P treated cells. Cell cycle analysis indicated S and G0-G1 phase arrest with C + P, suggesting a combined cytotoxic effect. Scratch wound assays showed that both palbociclib and C + P significantly inhibited cell migration compared to cisplatin and controls. These findings suggest a promising synergistic effect of C + P in overcoming cisplatin resistance in HCC. However, further research is needed to fully elucidate the complex interactions between these drugs.

Despite Myc oncoproteins being major causal factors in human cancer, they remain "undruggable." The MYCN oncogene is one of the most powerful prognostic markers for the childhood cancer neuroblastoma and represents an important target for developing novel therapeutics. Here, we report the finding and characterization of M606, a selective small molecule inhibitor of MYCN, which was identified by screening a diverse chemical library. M606 reduced MYCN protein levels in neuroblastoma cell lines and upregulated hypoxia-inducible factor 1 alpha (HIF1A). Using siRNA-mediated knockdown of MYCN, c-Myc, or HIF1A in HepG2 and BE(2)-C cells followed by M606 treatment, we demonstrated that Myc downregulation and HIF1A upregulation were two independent effects of M606 treatment. M606 selectively targeted neuroblastoma cell lines expressing higher levels of MYCN protein and delayed neuroblastoma development in the TH-MYCN transgenic mouse model. Metabolomic analysis showed that M606 modulated glucose metabolism, consistent with a hypoxic response and iron deprivation. Biochemical characterization of M606 not only confirmed its iron-chelating properties but also revealed its ability to downregulate MYCN promoter activity, which could be rescued by the addition of iron. Luciferase assays identified the minimal MYCN promoter region required for the M606 response, which contained overlapping E2F transcription factor binding sites. Further evaluation defined a key role for E2F3 in the M606-mediated response. The finding of a potent cell-permeable iron chelator that can chelate iron to directly downregulate MYCN transcription via an E2F3-mediated response represents a potentially valuable therapeutic approach in the treatment of cancers overexpressing Myc oncoproteins.

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.

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.