Cadmium (Cd) is a highly toxic heavy metal that substantially impacts crop productivity. Although γ-aminobutyric acid (GABA) has been shown to enhance plant resistance to abiotic stresses, the mechanism by which it mitigates Cd toxicity in maize (Zea mays L.) remains unclear. Using integrated physiological, transcriptomic, and metabolomic analyses, we found that exogenous GABA enhances maize seedling tolerance to Cd stress by simultaneously strengthening antioxidant defenses, regulating metal transport, and reinforcing cell walls. GABA significantly upregulates the activities of antioxidant enzymes, mitigating oxidative damage under Cd stress. Transcriptomic analysis confirmed induced expression of key antioxidant genes during the GABA-Cd interaction. Notably, Nramp and HMA transporter proteins were implicated in GABA-mediated suppression of Cd uptake and distribution. Transcriptional-metabolic co-analysis revealed that phenylpropanoid biosynthesis and the phenylalanine metabolism pathway, which are involved in cell wall biosynthesis, increase the GABA-mediated Cd tolerance. Exogenous GABA increased the activities of enzymes related to lignin synthesis. For example, the activity of phenylalanine lyase (PAL) increased by 41.48 % in roots at 4 days post-treatment, thus enhancing lignin deposition in the cell walls of maize roots. This structural reinforcement restricted Cd translocation from roots to shoots, thus reducing Cd accumulation in stem and leaf tissues. Conversely, pharmacological inhibition of endogenous GABA synthesis via 3-mercaptopropionic acid (3-MPA) decreased root lignin content and increased Cd shoot translocation, validating GABA's role in cell wall lignification. These findings clarify GABA's multifaceted role in mitigating Cd stress through coordinated physiological and molecular responses, highlighting its potential as a sustainable strategy to safeguard crop productivity under heavy metal contamination.

The purpose of this study is to explore the potential mechanism of Si-Wu-Tang (SWT) against esophageal squamous cell carcinoma (ESCC). Initially, 18 active molecules and 96 related targets of SWT obtained from publicly accessible databases. Through Genecards database queries and gene differential expression analysis combined with weighted gene correlation network analysis (WGCNA) on the GSE20347 dataset of ESCC, 3649 disease targets were identified. A subsequent analysis of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment was performed on 51 disease-drug intersection genes using the R language. Additionally, we identified 3 target hub genes (CDK1, NCOA1, and CHRM3) utilizing machine learning tools. Single-gene GSEA results suggested that hub genes may influence several signaling pathways and biological processes. Immune infiltration analysis demonstrated that SWT might impact the tumor immune microenvironment in ESCC by acting on hub targets. Molecular docking demonstrated the presence of affinity between target hub proteins and active compounds. This study revealed that SWT might exert its therapeutic effects on ESCC through multi-targets and multi-mechanisms.

A natural compound isobavachalcone (IBC) from Crotalaria junceaexhibited an excellent nematicidal effect against Meloidogyne incognita, with an LC50 value of 53.30 mg/L (24 h), which was validated through pot experiments. Further, a novel, multiple nematicidal mechanism of IBC was investigated. We discovered that it simultaneously induced oxidative stress and downregulated key lipid metabolism genes (e.g., fat-5, acox-1.2), leading to a significant reduction in triglyceride and fat content. Notably, IBC was also found to inhibit IRE-1/XBP-1 pathway of the endoplasmic reticulum unfolded protein response (UPRER), as evidenced by suppressed IRE-1 phosphorylation, blocked XBP-1 splicing, and reduced expression of the endoplasmic reticulum chaperone gene hsp-4. Moreover, molecular docking and dynamics simulations confirmed that IBC stably bound to the ATP-binding pocket of IRE-1. Importantly, the inhibition of IRE-1/XBP-1 pathway was revealed for the first time in nematode lethality. These findings indicate its potential for development as a novel nematicide.

Regorafenib, a multi‑kinase inhibitor, has limited efficacy in hepatocellular carcinoma (HCC) due to dose‑-dependent toxicity. The present study explored whether low‑dose Regorafenib combined with Nifuroxazide exerts enhanced anti‑tumor effects in HCC models. In vitro experiments with HepG2 cells showed the combination inhibited cell viability, proliferation and migration, induced apoptosis and reduced expression of key proteins, including phosphorylated signal transducer and activator of transcription 3 (STAT3). In vivo, H22 tumor‑bearing mice treated with the combination exhibited suppressed tumor growth without systemic toxicity, along with changes in apoptotic proteins, enhanced tumor‑infiltrating immune cells and improved systemic immune responses. These findings indicated that the combination exerts enhanced suppression of HCC by inhibiting STAT3 and remodeling anti‑tumor immunity, providing preclinical evidence for a safe and effective strategy.

Following the publication of the above paper, it was drawn to the Editor's attention by a concerned reader that the β‑actin blots for the MGC‑803 cell line in Fig. 4A were strikingly similar to the blots on the right‑hand side of the gel intended to show the caspase‑9 experiments in Fig. 7A; moreover, the blots shown for caspase‑3 for the MGC‑803 cell line in Fig. 4A were remarkably similar to blots that subsequently appeared in another article featuring one of the named authors (Tao Sun) in the same journal about a year later. In addition, a number of duplicated blots were noted comparing the flow cytometric plots in Figs. 3 and 6, including one blot which subsequently reappeared in a paper published in the journal Molecular Medicine Reports that was written by different authors. The authors were contacted by the Editorial Office to offer an explanation for the apparent duplications of data both within the paper, and the subsequently published ones. Owing to the fact that the Editorial Office has been made aware of potential issues surrounding the scientific integrity of this paper, we are issuing an Expression of Concern to notify readers of this potential problem while the Editorial Office continues to investigate this matter further. [Molecular Medicine Reports 34: 227‑234, 2015; DOI: 10.3892/or.2015.3994].

Multiple myeloma (MM) is an incurable hematologic malignancy characterized by the clonal expansion of plasma cells in the bone marrow. Despite advances in therapeutic agents, including proteasome inhibitors, immunomodulatory drugs and immunotherapies, relapse driven by treatment resistance remains a major clinical challenge. This underscores the critical need to elucidate additional molecular mechanisms that drive MM pathogenesis and therapeutic failure. The emerging field of epitranscriptomics, which studies post‑transcriptional RNA modifications, offers a promising perspective. Among these modifications, N6‑methyladenosine (m6A), the most abundant internal mRNA modification, has been implicated in regulating nearly every aspect of RNA metabolism. Growing evidence indicates that dysregulation of the m6A modification machinery plays a pivotal role in MM heterogeneity, disease progression and drug resistance. The present review synthesized current knowledge on how specific m6A regulators contribute to MM oncogenesis by modulating key signaling pathways, interactions with the bone marrow microenvironment and responses to therapy. It also discussed the potential of targeting m6A pathways as a therapeutic strategy to overcome treatment resistance and improve patient outcomes. By highlighting recent advances and future directions, the present review underscored m6A modification as an important frontier in the battle against MM.

Papillary thyroid cancer (PTC) is the most common type of endocrine malignancy caused by genetic mutations, hormonal imbalances, and environmental factors. However, recurrent infections, and metastasis in PTC patients remain challenged due to complexity of traditional methods. Baicalein (BA) is a kind of natural flavonoid that exhibits the anti-cancer, anti-inflammatory, anti-tumor, and anti-viral activities. The molecular mechanism of baicalein in pathogenesis of PTC remains unclear. This study was designed to explore the inhibitory effects of BA against PTC by mediating the Golgi apparatus reprogramming via PLAU and suppressing the TPL2/MEK2/ERK2 pathway.

The side effects and non-specific targeting of healthy organs associated with conventional cancer therapies necessitate the design and fabrication of novel nanomaterial-based drug delivery systems. In this study, we successfully fabricated a novel two-dimensional (2D) covalent organic framework (COF) nanomaterial. This COF was loaded with tamoxifen (TMX) and surface-modified with folic acid (FA) to achieve effective targeting for breast cancer therapy. The resulting construct, TMX@COF-FA, was characterized using PXRD, FTIR, ¹³C NMR, CHNS analysis, BET surface area analysis, TGA, UV-Vis spectroscopy, SEM, and EDX analysis. The COF carrier demonstrated a high drug encapsulation efficiency of approximately 82%. Furthermore, it exhibited a pH-responsive drug release profile, with a significantly higher release rate at pH 5.4 compared to pH 7.4, which is ideal for the acidic tumor microenvironment. Cell viability studies revealed that TMX@COF-FA induced about 90% cell death in MCF-7 breast cancer cells, while showing minimal cytotoxicity in L929 fibroblast cells. The mechanism of cell death was investigated using AO/EtBr dual staining, ROS detection assays, flow cytometry (FACS), and qRT-PCR. Collectively, our findings demonstrate that the FA-conjugated COF can efficiently deliver TMX to MCF-7 cells via folate receptor-mediated endocytosis, leading to potent cancer cell destruction. This study underscores the potential of functionalized COFs as promising targeted drug delivery platforms for breast cancer treatment.

Regucalcin (RGN) is a multifunctional regulator of intracellular calcium signaling, implicated in cellular homeostasis and stress responses. While aberrant RGN activity has been associated with diabetic kidney disease (DKD), existing studies have primarily focused on its role in proximal tubular cells. Whether RGN is expressed in podocytes and how its expression responds to diabetic-like stimuli remain largely unexplored. Podocyte injury under diabetic conditions is a critical event in DKD pathogenesis. Therefore, in this study, we aimed to investigate whether podocytes express RGN and how its expression is affected under high-glucose (HG) conditions. To address these questions, we employed quantitative real-time PCR, Western blotting, fluorescence-based protein staining, and immunohistochemical analysis of renal sections. Our results confirmed RGN expression in podocytes and revealed its dysregulation at both the mRNA and protein levels under HG conditions. Additionally, we identified the subcellular localization of RGN and a significant association with sarco/endoplasmic reticulum calcium ATPase (SERCA), a key enzyme regulating endoplasmic reticulum (ER) calcium storage and the ER stress response. Altered RGN expression in podocytes exposed to HG concentrations may contribute to the progression of DKD, possibly through the disruption of intracellular calcium homeostasis.

The uterus is a dynamic organ in which the endometrium undergoes cyclic processes of proliferation, shedding, and regeneration under the influence of estrogen and progesterone. In particular, estrogen regulates the proliferation and differentiation of the endometrium and plays an important role in the development of gynecological diseases such as endometrial cancer. Farnesyl diphosphate synthase (FDPS) is a key enzyme involved in the mevalonate pathway, catalyzing the synthesis of farnesyl pyrophosphate (FPP), which plays an essential role in cholesterol biosynthesis and protein prenylation. In this study, we demonstrated using an in vivo mouse model that the expression of FDPS is regulated by estrogen. FDPS expression was specifically elevated during the proestrus stage of the estrous cycle and subsequently decreased. In ovariectomized (OVX) mice, FDPS expression was significantly increased 24 h after estrogen treatment, whereas this response was suppressed by treatment with the estrogen receptor alpha (ERα) antagonist, ICI 182,780. Although FDPS expression has been reported in various cancers, its role in endometrial cancer remains unclear. Histological and cellular analyses revealed that FDPS is highly expressed in human endometrial cancer tissues and in the endometrial cancer cell line Ishikawa, where it contributes to cell proliferation. These findings suggest that FDPS may play a role in the survival and growth of endometrial cancer cells. This study provides new insights into the potential function of FDPS in the uterus and suggests that targeting FDPS may represent a promising therapeutic strategy for endometrial cancer.

Cancer is a heterogeneous disease at the cellular level and analyzing the genetic and molecular profile is essential for targeted therapy. Cancer cells continue to mutate, often resulting in drug resistance. In addition, cancers such as triple-negative breast cancer (TNBC) lack the target proteins used in some of the most effective therapies. This necessitates the identification of novel target proteins and biomarkers for effective treatment strategies. Ubiquitin E3 ligases are often differentially expressed in cancer cells, and numerous anticancer agents have been developed to inhibit them. SMURF2 is an E3 ligase that is differentially expressed in multiple cancer types. Although inhibiting upregulated SMURF2 may be strategically straightforward, enhancing the downregulated gene is often difficult. In addition, because E3 ligases ubiquitinate a variety of substrate proteins, targeting SMURF2 requires detailed analysis to achieve anticancer effect. This review discusses the dual role of SMURF2 in carcinogenesis and addresses the complex context-dependent function of SMURF2 in the various cellular pathways. In addition, resistance to existing cancer therapy related to SMURF2 and sensitivity mechanisms is discussed. Lastly, theranostic strategies for anticancer agents and biomarker development are suggested.

Small molecules either derived from cell metabolic reactions or produced by gut bacterial flora have shown the potential of affecting gene expression, which suggests the possibility of interactions able to modulate cellular functions. In this context, the reported experiments were aimed at verifying a possible interplay between lactate and butyrate in modulating the efficacy of antineoplastic drugs. Butyrate is a product of gut bacterial flora, shown to be endowed with anticancer properties; conversely, increased lactate levels in cancer cells were found to be associated with higher proliferation and drug resistance. For the reported experiments, we adopted two cell lines from clinically relevant, but different cancer forms: pancreatic and triple-negative mammary adenocarcinomas. In spite of their different tissue origin, the two cell lines appeared to similarly respond to the effects of the two metabolites, which were found to modulate in opposite ways the expression of key genes involved in DNA repair by homologous recombination. As a consequence, changed efficacy of this repair pathway and modified response to PARP inhibitors were observed. Notably, our results also suggest that the counteracting effect between these two metabolites may be leveraged to address additional challenges limiting the success of anticancer therapies.

Resistance to 5-fluorouracil (5-FU), a cornerstone chemotherapy for gastric cancer (GC), is a major clinical obstacle, often driven by the upregulation of its target enzyme, thymidylate synthase (TS). In this study, we investigated the potential of the pan-histone deacetylase inhibitor (HDACi) panobinostat to synergize with 5-FU. In GC cell lines, panobinostat treatment alone suppressed cell viability, clonogenicity, and migration, and this was associated with the induction of G1-phase cell cycle arrest and mitochondria-mediated apoptosis. Crucially, Panobinostat acted synergistically with 5-FU, leading to enhanced cytotoxicity. Mechanistically, 5-FU treatment alone induced a compensatory upregulation of TS protein, a known resistance mechanism. Panobinostat not only suppressed basal TS expression but, more importantly, abrogated this 5-FU-induced upregulation. Furthermore, panobinostat downregulated a network of oncogenes and cell cycle regulators, including c-Myc and key cyclins. These findings indicate that panobinostat can enhance 5-FU cytotoxicity by targeting TS expression and reprogramming oncogenic transcriptional networks, supporting its potential as a complementary strategy for overcoming fluoropyrimidine resistance in GC therapy.

Osteosarcoma (OS), a highly aggressive bone malignancy, is hard to treat due to complex molecular mechanisms. This study aimed to identify key bioactive compounds from medicine-food homologous (MFH) substances for OS intervention. We analyzed GEO transcriptomic data to get 317 differentially expressed genes (DEGs), screened bioactive compounds from 106 MFH via dual databases, predicted compound-DEG protein interactions with GraphBAN, and filtered 11 core compounds through drug-likeness/toxicity evaluations. Regulatory networks identified 5 key target genes (SOST, ACACB, TACR1, GRIN2B, MPO), 10 key compounds (e.g., ellagic acid dihydrate) and 8 MFHs (e.g., Daidaihua). Molecular docking/MD confirmed stable complexes. GSEA/GSVA revealed pathway dysregulation (e.g., upregulated WNT signaling), and immune analysis showed altered infiltration of 5 cell subsets. 143B cell experiments and qRT-PCR validated findings. MFH-derived compounds, especially ellagic acid dihydrate, have multi-target anti-OS potential, laying a foundation for novel OS therapeutics.

The mechanisms underlying carfilzomib (CFZ)-induced cardiotoxicity remain incompletely elucidated. In this study, we used human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to characterize the transcriptional impact of CFZ and to evaluate whether atorvastatin could prevent these deleterious transcriptional changes. hiPSC-CMs were treated with 1 µM CFZ, CFZ + atorvastatin, atorvastatin, or vehicle control, followed by RNA sequencing, differential expression analyses, and pathway analyses. Transcriptomic profiling revealed a marked upregulation of genes in multiple proteasome subunits, including ATPase components (PSMC1, PSMC4, PSMC5, PSMC6) and non-ATPase regulatory subunits (PSMD1, PSMD2, PSMD12), suggesting a strong compensatory activation of proteostasis and protein quality-control pathways in response to CFZ exposure. In addition, several of the most significantly altered genes were those implicated in cardiomyopathy and heart failure, such as BAG3 and FLNC, and many heat-shock proteins, indicating the activation of cardiac stress-response pathways relevant to CFZ-associated cardiotoxicity. Atorvastatin co-treatment partially reversed a subset of CFZ-induced transcriptional changes, particularly within cholesterol biosynthesis and lipid-regulatory pathways (e.g., ACAT2 and ACTA1) but did not restore the CFZ-mediated downregulation of sarcomeric genes. Together, these findings define a multifactorial signature of deleterious CFZ-induced transcriptional changes and suggest that atorvastatin may provide partial metabolic, but not structural, cardio protection.

Iron (Fe) is an essential micronutrient for plant development and productivity. Nevertheless, the role of gibberellins (GAs) in the control of iron homeostasis is less studied compared to other growth regulators. We found that GAs modulate iron homeostasis in maize by inducing deficiency-like responses independent of rhizosphere iron availability. Plant phenotyping demonstrated that exogenous GA3 application under iron-sufficient conditions phenocopied iron deprivation, while inhibiting GA biosynthesis with mepiquat chloride prevented the development of typical symptoms of Fe deficiency (-Fe). Gibberellins positively control strategy II Fe uptake genes, albeit indirectly, as opposed to the direct negative transcriptional regulation of phytosiderophore biosynthesis. Additionally, gibberellins disrupt iron partitioning by suppressing root-to-shoot Fe translocation, causing iron overaccumulation in roots of GA3 treated plants. A functional ferrous iron uptake pathway was identified and was found to operate in conjunction with the strategy II uptake pathway via the differentially regulated Zea mays Iron-Regulated Transporter (IRT) paralogs ZmIRT1 and ZmIRT2. Root responses are spatially organized: gene expression in the lateral root sector reflects the shoot iron status, while transcriptional responses in the root apex correlate with local Fe demands. This study demonstrates that maize leverages a hybrid ferric/ferrous iron uptake strategy and establishes novel roles of GAs as pivotal regulators of iron homeostasis.

Salt stress is one of the main abiotic stresses that restrict crop production. Melatonin (MT), a signal molecule widely present in plants, plays an important role in regulating abiotic stress response. In this study, celery seedlings were used as experimental materials, and the control, salt stress, and exogenous MT treatment groups under salt stress were set up. Through phenotypic, physiological index determination, transcriptome sequencing, and expression analysis, the alleviation effects of MT on salt stress were comprehensively investigated. The results showed that exogenous MT treatment significantly reduced seedling growth inhibition caused by salt stress. Physiological measurements showed that MT significantly reduced malondialdehyde content, increased the activities of superoxide dismutase (SOD), peroxidase (POD) and catalase (CAT), promoted the accumulation of free proline and soluble protein, and increased photosynthetic parameters such as chlorophyll, ΦPSII, Fv/Fm, and ETR. Transcriptome analysis showed that MT regulates the expression of several genes associated with carbon metabolism, including β-amylase gene (AgBAM), sucrose-degrading enzyme genes (AgSUS, AgINV), and glucose synthesis-related genes (AgAG, AgEGLC, AgBGLU). The results of qRT-PCR verification were highly consistent with the transcriptome sequencing data, revealing that MT synergistically regulates starch and sucrose metabolic pathways, and effectively alleviates the damage of celery seedlings under salt stress at the molecular level. In summary, exogenous MT significantly improved the salt tolerance of celery by enhancing antioxidant capacity, maintaining photosynthetic function, promoting the accumulation of osmotic adjustment substances, and synergistically regulating carbon metabolism-related pathways. The concentration of 200 μM was identified as optimal, based on its most pronounced alleviating effects across the physiological parameters measured. This study provides an important theoretical basis for utilizing MT to enhance plant salt resistance.

Hericium erinaceus (H. erinaceus), a medicinal mushroom, is a source of bioactive compounds with demonstrated neuroprotective potential. This activity is primarily attributed to two distinct classes of compounds: erinacines from the mycelium, which potently induce the synthesis of neurotrophins, protein growth factors essential for neuronal survival and health, and hericenones from the fruiting body, which subsequently appear to enhance or potentiate neurotrophin-activated signaling pathways. Preclinical evidence substantiates their ability to enhance neurotrophin levels, particularly Nerve Growth Factor (NGF) and Brain-Derived Neurotrophic Factor (BDNF), and activate their cognate Trk receptors. Activation of these pathways, including PI3K/AKT/mTOR and MAPK/ERK, converges on transcription factors such as CREB, promoting neuronal survival, neurite outgrowth, and synaptic plasticity. However, the precise molecular mechanisms linking these small molecules to the complex orchestration of neurotrophic gene expression remain incompletely defined. This review synthesizes current knowledge of the neurotrophic pharmacology of H. erinaceus bioactives and proposes a novel framework suggesting that non-coding RNAs (ncRNAs) play a key regulatory role. We hypothesize that hericenones and erinacines modulate key transcriptional hubs, such as CREB, Nrf2, and NF-κB, which in turn regulate the expression of specific ncRNAs (e.g., miR-132, miR-146a) known to control neurogenesis, synaptogenesis, oxidative stress, and neuroinflammation. This ncRNA-mediated mechanism may represent an un-explored axis that explains the pleiotropic neuroprotective effects of these compounds. We critically appraise the existing preclinical evidence, identify significant methodological limitations and translational gaps, and propose a structured research roadmap to test these ncRNA-centric hypotheses, aiming to accelerate the rational development of H. erinaceus-derived compounds for neurodegenerative diseases.

This study aimed to elucidate the oncogenic role of FOXA1(forkhead box A1) in ovarian cancer and to evaluate its potential as both a therapeutic target and a diagnostic biomarker. We further investigated whether FOXA1 inhibition could enhance responsiveness to immune checkpoint blockade and overcome chemoresistance. A total of seventy-six ovarian tissue samples were analyzed, including nine normal, thirty-four benign, and thirty-three malignant specimens. IHC (immunohistochemistry) staining was performed to assess FOXA1 expression and its correlation with tumor stage. Functional studies were conducted using FOXA1 siRNA in SK-OV3 and HEYA8 cell lines. Changes in cell proliferation, migration, invasion, and wound-healing ability were evaluated following FOXA1 silencing. Quantitative RT-PCR was used to measure the expression of FOXA1 and EMT (epithelial-mesenchymal transition)-related genes. The effects of FOXA1 inhibition on sensitivity to carboplatin and the immune checkpoint inhibitor atezolizumab were also examined. IHC analysis revealed significant differences in FOXA1 expression among normal, benign, and malignant tissues, with levels correlating with tumor stage. FOXA1 silencing significantly reduced proliferation and decreased migration and invasion by 60-80%, accompanied by marked downregulation of EMT-related genes. Moreover, FOXA1 inhibition enhanced atezolizumab responsiveness and reduced carboplatin resistance in ovarian cancer cells. In summary, FOXA1 acts as an oncogenic driver in ovarian cancer, promoting proliferation, invasion, and EMT activation. Its overexpression correlates with disease progression, supporting its potential as a biomarker and therapeutic target. Targeting FOXA1 could enhance immunotherapy efficacy and help overcome chemoresistance in ovarian cancer.

Eutrema salsugineum is a model species for studying stress resistance, particularly extreme salinity, and is often compared with Arabidopsis thaliana. Previous research has shown that basal salicylic acid (SA) levels are significantly lower in E. salsugineum than in A. thaliana. In this study, subtractive hybridization revealed that SA-related genes were extensively induced in Arabidopsis but not in Eutrema. Using exogenous SA and the biosynthesis inhibitor paclobutrazol (PBZ), we further demonstrated that the low endogenous SA level in Eutrema significantly upregulates dehydroascorbate reductase (DHAR) and glutathione reductase (GR) gene expression, doubling the pools of total ascorbic acid and total glutathione. While SA treatment decreased the ratios of reduced ascorbic acid (ASA) to dehydroascorbate (DHA) and reduced glutathione (GSH) to oxidized glutathione (GSSG), PBZ treatment increased them, correspondingly modulating DHAR and GR activities and gene expression. The resulting enhancement of these key non-enzymatic antioxidants is a critical mechanism underpinning the superior salt tolerance of Eutrema.