In this study, we used Mendelian randomization analysis to explore the causal relationships between drug targets and cutaneous melanoma (CM) and subsequently screened for new drug targets for CM. In addition, we verified whether targeted drugs could inhibit the development of CM in CM cells by suppressing the expression of target genes.

Metformin is a biguanide and first line drug for type 2 diabetes (T2D) mellitus that is being recognized as a geroprotective agent capable of influencing important hallmarks of aging. Apart from its primary role in lowering blood glucose levels, metformin has been shown to have several effects at the molecular level. It acts by activating the AMPK, which leads to a cascade of downstream events such as the inhibition of mTOR, increased mitochondrial biogenesis, and autophagy, as well as epigenetic modifications. Current findings also showed its capacity to alter the gut microbiota by increasing short-chain fatty acid producing bacteria, indicating the involvement of other systemic pathways that aid in lowering inflammation, increasing metabolic fitness, and keeping epigenetic stability. The Targeting Ageing with Metformin (TAME), a landmark trial which seeks to evaluate metformin's ability to slow down several age-associated diseases, could lead to a paradigm shift in the clinical approach to aging. This article looks at metformin's various effects on aging and longevity by consolidating findings from cellular, molecular, and organismal levels. It also calls for more studies and trials on metformin and aging.

We investigated the potential of miR-640 to downregulate CDK4/6 inhibitor resistance-associated genes and evaluated its apoptotic, anti-metastatic and anti-proliferative effects, both alone and in combination with abemaciclib in breast cancer cells. miR-640 was identified via GSE126125 dataset analysis. Targets were predicted using miRDB, TargetScan and TargetMiner, filtering for resistance-associated genes. MTT assays determined IC50 values for abemaciclib and combinations. Functional effects were evaluated in MCF7 and MDA-MB-231 cells through Annexin V, cell cycle and wound healing assays. Target gene expression was quantified by RT-qPCR. Successful transfection significantly upregulated miR-640 (~50-fold). The miR-640/abemaciclib combination strongly inhibited migration, induced apoptosis and triggered cell line-specific phase arrests (S and G2/M in MCF7; G0/G1 in MDA-MB-231). Gene expression analysis showed significant downregulation of a comprehensive resistance network (including CDK4/6, CDKN2B, WNT7B, MAP3K1 and AURKA) in MCF7 cells. In MDA-MB-231 cells, PDK1, CDK6, CDKN2B, SMAD2, ZFP91, MAP3K1 and AURKA were significantly suppressed. This study identifies miR-640 as a potent tumour suppressor that resensitises breast cancer cells to CDK4/6 inhibition. By post-transcriptionally downregulating key resistance genes, miR-640-alone or additively with abemaciclib-suppresses proliferation and migration while inducing apoptosis, emerging as a promising combinatorial therapeutic strategy.

miRNAs are short RNA transcripts that modulate gene expression after transcription and have emerged as pivotal regulators of cancer biology. A subset, termed oncomiRNAs, functions as oncogenes or tumor suppressors, influencing key cellular events such as cell growth, programmed cell death, neovascularization, tissue invasion, and metastatic spread. Dysregulation of these miRNAs drives tumor initiation and progression, underscoring their role in cancer evolution. Traditionally, studies have relied on bulk tissue analyses, overlooking the profound spatiotemporal heterogeneity of oncomiRNA expression, including variations across tumor regions, metastatic sites, disease stages, and during treatment.

Abscisic acid (ABA) acts as a key signalling molecule that mediates plant responses to environmental cues as well as plant growth and development. Stress-induced and developmental changes in ABA content trigger a myriad of post-transcriptional and transcriptional events. Yet, ABA-dependent transcriptional responses are context dependent, and their temporal dynamics in roots under non-stress conditions remain poorly resolved. In this study, we characterised the hallmarks of ABA signalling and responses in the poplar root transcriptome (Populus nigra L.). We disturbed ABA homeostasis by exogenous ABA treatments, and we combined time-resolved transcriptomics with unsupervised gene network analysis to identify ABA-activated and ABA-inactivated gene co-expression modules. Considering the temporal dynamics of transcriptional events, we predicted the primary targets of the ABA signal, characterised early responding ABA-dependent processes, identified hub genes and revealed their putative functional links. We demonstrated that the properties of a master ABA-activated module induced by exogenous treatments were preserved in the transcriptome response to osmotic stress, revealing a core gene set of ABA-dependent stress responses. Our work sheds light on ABA repression of gene expression, the reprogramming of metabolism and the leaf-senescence pathway. Based on current functional knowledge and phylogenetic information, including poplar-specific features, we proposed a working model of ABA action on root transcriptome in poplar that integrates master genes, key responsive processes, and their putative regulatory architecture.

The rapid emergence of antibiotic resistance represents a critical global health challenge, particularly in biofilm-associated infections caused by Pseudomonas aeruginosa (P. aeruginosa). Quorum sensing plays a pivotal role in regulating bacterial virulence and biofilm formation. Consequently, targeting quorum sensing-regulated virulence factors represents a promising anti-virulence strategy to combat antibiotic resistance. In this study, the FDA-approved drugs vardenafil, valsartan, and olmesartan did not significantly affect the growth of ten clinical P. aeruginosa isolates. At sub-inhibitory concentrations, these drugs significantly reduced the production of key virulence factors, including hemolysin, proteases, pyocyanin, lipases, as well as impairing swarming motility, and biofilm formation. Gene expression analysis confirmed marked downregulation of quorum sensing-associated genes in five selected isolates. In vivo experiments revealed a substantial reduction in bacterial pathogenicity following treatment. Molecular docking analyses further supported these findings, revealing favorable interactions of the tested drugs with key quorum sensing regulatory proteins. Collectively, these results highlight the anti-quorum sensing, anti-virulence, and antibiofilm potential of these repurposed drugs and suggest their possible application in topical formulations as adjunctive therapies to conventional antibiotics for managing severe pseudomonal infections.

mRNA splicing represents a fundamental level of gene regulation that alters proteomic diversity and cellular state. Its dysfunction can profoundly rewire metabolism, yet underlying mechanisms remain elusive. Here, we investigate Verheij syndrome, caused by mutations in core splicing factor PUF60, using a Caenorhabditis elegans model, human cell lines, and patient-derived samples. We demonstrate that RNP-6/PUF60 deficiency disrupts splicing of genes governing one-carbon metabolism and phospholipid remodeling, impairing S-adenosylmethionine/S-adenosylhomocysteine cycling and phosphatidylcholine synthesis. These perturbations trigger the integrated stress response and compromise mTORC1 signaling, causing developmental growth defects. Vitamin B12 supplementation restores metabolic balance by reactivating S-adenosylmethionine-dependent phospholipid remodeling and mTORC1 activity, effectively rescuing Verheij-like phenotypes. Similar responses arise from perturbing another splicing factor, PRP-19. Mechanistically, intron retention of nhr-114/HNF4 transcription factor drives these phenotypes, while restoring its splicing rescues them. Our findings implicate vitamin B12-dependent one-carbon metabolism as a metabolic modulator with therapeutic potential to mitigate Verheij syndrome and other spliceosomopathies.

Cells adapt to fluctuating nutrient conditions by dynamically regulating gene expression, ensuring survival under stress. Ygp1, a secretory yeast glycoprotein, is one such gene that is induced by nutrition deprivation, particularly glucose starvation. In this study, we investigated the regulatory mechanisms underlying nutrition-deprivation-responsive changes in gene expression, focusing on YGP1 expression. Under glucose-rich conditions, YGP1 expression was positively regulated by the RNA-binding protein Puf5, a member of the Puf family. This regulation ensured rhythmic YGP1 expression during M phase of the cell cycle. The Puf5-mediated control targeted a specific 60-nucleotide region in the YGP1 promoter (-600 to -540 from the start codon), and this regulation was partly mediated by the acid stress-responsive transcriptional activator Haa1. In addition, upon glucose exhaustion (diauxic shift), YGP1 expression was strongly induced by the stress-responsive transcription factors Msn2 and Msn4 through the stress-response elements in the YGP1 promoter. Further analysis of the physiological significance of YGP1 expression revealed that the Puf5-mediated regulation contributes to the acid stress responses, and YGP1 expression supports cell survival in the puf5Δ background. In summary, YGP1 expression is regulated by two distinct factors in a glucose availability-dependent manner: Puf5 under glucose-rich conditions and the Msn2/Msn4 during glucose starvation. Especially, Puf5-mediated regulation contributes to the acid stress responses and subsequently supports long-term cell survival.

Drought stress is one of the important factors limiting the growth of the apple industry. Although 5-hydroxytryptamine (5-HT), an ancient indole amine, is widely present in plants, the role of 5-HT in drought stress in apples is unknown. We tested the impact of 5-HT on long-term drought stress in apple seedlings. Our findings revealed that 1 μM of exogenous 5-HT could improve the resistance of apple seedlings to short- and long-term drought stress. These plants experienced better root growth, more efficient water use, and less reactive oxygen species (ROS). The higher ABA levels mediated by 5-HT in leaves increased stomatal density and improved the photosynthetic capacity of leaves. Furthermore, exogenous 5-HT boosted the expression of drought stress-related genes, enabling apple plants to adapt to drought stress.

Selenium (Se), a beneficial element, plays a pivotal role in mitigating plant stress, yet its potential in alleviating manganese (Mn) toxicity in apple trees remains poorly understood. This study explores the potential of Se in alleviating Mn-induced stress in Malus domestica Borkh. cv. Red Fuji, a cultivar known for its sensitivity to Mn. Through a combination of physiological analysis and transcriptomic profiling, we provide comprehensive insights into the mechanisms by which Se enhances Mn tolerance. The results demonstrated that selenite application balanced nutrient elements, stabilized the photosynthetic system, and reduced oxidative stress. Additionally, selenite promoted cell wall remodeling and modulated hormone levels. Transcriptome analysis further revealed that selenite regulated genes associated with polyunsaturated fatty acid hydrolase, sucrose hydrolase, and photosynthesis, indicating its role in alleviating Mn stress. GO and KEGG enrichment analyses highlighted that differentially expressed genes were enriched in pathways related to phenylpropanoid biosynthesis, alpha-linolenic acid metabolism, and galactose metabolism, suggesting key metabolic pathways involved in Mn stress responses. Weighted gene co-expression network analysis (WGCNA) identified core module genes strongly correlated with antioxidant enzymes and substances, chlorophyll content, and mineral element concentrations. In conclusion, Se effectively mitigates Mn stress in 'Fuji' apples through multi-level regulatory mechanisms, providing a theoretical foundation for the application of Se-enriched agriculture in apple cultivation.

Given the limited knowledge of probiotic effects on clock genes, this study investigated whether probiotics that regulate gut integrity and microbiota balance influence central circadian clock gene expression. In this study conducted on three groups [control group (CG), shifted group (SG), and shifted and probiotic supplement group (SPG)] of eight BALB/c mice each, Clock, Bmal1, and Per2 gene expressions and weight gain were evaluated. Although body weights at baseline, week 8, and week 16 were similar among groups, weight gain over time was significantly higher in the SG and SPG groups (p<0.05). Significant differences were observed between CG and SG at week 8 and between SG and SPG at week 16. Gene expression analyses revealed no significant differences in Clock expression. However, Bmal1 expression at ZT18 was significantly different between the CG and SPG groups (p = 0.045). These findings demonstrate the regulatory effect of probiotic supplementation on circadian disruption and weight gain, suggesting a potential role in circadian rhythm management. Nevertheless, the results should be interpreted cautiously because they are based on limited gene expression changes and require confirmation in larger studies.

Transient receptor potential ankyrin 1 (TRPA1) is a cation channel originally identified in lung fibroblasts and extensively studied in sensory neurons, where it is associated with pain and neurogenic inflammation. We and others have recently shown that TRPA1 is also expressed in lung epithelial cells and that its expression is regulated by the cytokine environment. In the present study, we used next-generation sequencing to analyse the role of TRPA1 and the effects of its inhibition on human A549 lung epithelial cell phenotype under inflammatory conditions. Two different TRPA1 inhibitors (HC-030031 and A-967079) were used and found to alter the expression of 968 genes: 576 genes were downregulated, and 392 upregulated. Ingenuity Pathway Analysis (IPA) predicted that TRPA1 inhibitors significantly suppress the activity of pulmonary fibrosis idiopathic signalling and wound healing pathways. In these pathways, altered genes included matrix metalloproteinases (MMPs), growth factors, collagens and transcription factors. The major profibrotic mediators MMP-12 and MMP-7 were among the most strongly inhibited genes by TRPA1 inhibitors. STRING network analysis suggests that TRPA1 regulates fibrosis-related genes through FOS gene and AP-1 transcription factor. These findings together with previous data propose TRPA1 as a factor and therapeutic target in fibrotic lung diseases, which are associated with poor survival and critical need for novel disease-modifying therapies.

POLG (DNA polymerase γ catalytic subunit)-related mitochondrial diseases are among the most severe primary mitochondrial disorders and are characterized by progressive neurodegeneration with prominent dopaminergic involvement. However, the cell type-specific mechanisms linking mitochondrial DNA instability to neuronal vulnerability remain incompletely defined.

Ischemic stroke (IS) is a cerebrovascular disease with high mortality and disability rates, currently lacking effective therapeutic targets. The STING inhibitor SN-011 shows potential in IS treatment, but its mechanism of action remains unclear. This study aims to explore the key molecular mechanisms of SN-011 in treating IS through bioinformatics approaches. IS transcriptome datasets were analyzed to identify differentially expressed genes. Mendelian randomization using brain eQTL and IS-GWAS data identified genes with causal relationships to IS. Single-cell transcriptome, pseudo-time trajectory, intercellular communication, and transcription factor regulatory network analyzes were performed. Molecular docking and DARTS-WB assay validated SN-011 binding to transcription factors. Transcriptomic analysis identified 77 intersecting genes. Mendelian randomization revealed ADGRE5 as a protective gene for IS (OR < 1), significantly downregulated in venous endothelial cells (vECs) during disease progression. Cell communication analysis showed ADGRE5-high vECs interact with immune, glial, and stromal cells via LAMININ (Lamb2-CD44, Lamb2-Itga6+Itgb1, Lamb2-Dag1 pair) and JAM signaling pathways. Transcription factor analysis identified JUNB as a negative regulator of ADGRE5. Molecular docking (-6.8 kcal/mol) combined with an in vitro DARTS-WB assay confirmed the interaction between SN-011 and JUNB. In OGD-induced endothelial cell injury models, SN-011 suppressed JUNB expression, restored ADGRE5 expression inhibited by JUNB overexpression, reversed the downregulation of LAMB2 and CD44, and reduced the expression of the pro-inflammatory cytokines IL-6 and IL-1β. Notably, blockade of LAMB2 largely abolished these protective effects, indicating that the anti-inflammatory and endothelial-protective activities of SN-011 are mediated, at least in part, through restoration of the LAMB2-CD44 signaling axis. ADGRE5 downregulation in vECs may impair vascular repair by disrupting LAMININ-mediated intercellular communication. SN-011 may exert neuroprotective effects by targeting JUNB to upregulate ADGRE5 expression and restore the vEC-centered cellular communication network, providing a theoretical basis for SN-011 as a potential IS therapeutic.

Monocytes play a critical role in regulating immune response to exogenous and endogenous challenge. Recent studies have shown exogenous stimuli can induce metabolic, epigenetic and phenotypic changes in monocytes that reprogramme or 'prime' them to react with an altered response to subsequent stimuli. Obesity is associated with immune dysfunction. However, the ability of endogenous compounds associated with obesity to prime human monocytes and thereby modulate subsequent response remains to be investigated.

Recent studies have shown that while chemotherapy kills tumor cells, it may also induce adaptive changes in cells within the tumor microenvironment, particularly cancer-associated fibroblasts (CAFs), which could paradoxically promote tumor progression. This study aimed to investigate the role of CAFs exposed to paclitaxel (PTX) or doxorubicin (DOX) in tumor progression and explore the underlying mechanisms.

Lung cancer remains a major global health challenge, and the oncogenic function of KDM1B (Lysine-specific Demethylase 1B) is still poorly characterized. This study employed integrated bioinformatics and experimental approaches to investigate KDM1B's function in lung cancer. Pan-cancer analysis using databases such as TIMER revealed notably elevated KDM1B mRNA expression in LUAD datasets, suggesting its potential as a diagnostic biomarker. A strong association was also found between increased KDM1B levels and immune cell infiltration in LUAD datasets. Protein interaction networks constructed using STRING and Cytoscape revealed close associations between KDM1B and key regulatory genes in NSCLC. KEGG enrichment analysis linked KDM1B to the mTOR signaling, which is critical for cell proliferation and survival. RT-PCR and western blotting for experimental validation showed KDM1B expression was significantly increased in A549 and NCI-H460 lung cancer cells. The deletion of KDM1B inhibits cell growth, induces G0/G1 phase cell cycle arrest, and promotes apoptosis in A54 cells. Moreover, cell proliferation was significantly inhibited by the KDM1B inhibitor, tranylcypromine, and induced G0/G1 phase cell cycle arrest, increased apoptosis, ROS, and glycolytic activity in A549 cells. Collectively, these findings highlight KDM1B as a valuable therapeutic target in lung adenocarcinoma and emphasize its key role in lung cancer development.

To investigate the role of histone deacetylase 2 (HDAC2) in cisplatin resistance in ovarian cancer (OC). Cisplatin-resistant OC cell lines were employed to construct HDAC2 overexpression and knockdown models, and their effects on cell proliferation and apoptosis were examined. Chromatin immunoprecipitation, immunoprecipitation, and dual-luciferase reporter assays were performed to investigate the regulation of SMAD7 protein stability and promoter activity by HDAC2. Expression of DNA damage repair-related genes was detected by qRT-PCR. A xenograft mouse model was established for in vivo validation. HDAC2 was highly expressed in cisplatin-resistant OC cells. Overexpression of HDAC2 enhanced drug resistance and inhibited apoptosis and DNA damage, whereas knockdown of HDAC2 exhibited the opposite effects. Mechanistically, HDAC2 directly deacetylated the SMAD7 protein to prevent its degradation rather than suppressing its transcription via H3K27 deacetylation. The HDAC2/SMAD7 axis promoted drug resistance by activating the Wnt/β-catenin signalling pathway and modulating DNA damage repair-related genes. In vivo experiments confirmed that HDAC2 knockdown significantly inhibited tumour growth and enhanced the sensitivity. HDAC2 enhances cisplatin resistance in OC by deacetylating and stabilising SMAD7 protein, thereby activating the Wnt/β-catenin signalling pathway and promoting DNA damage repair.

Protein neddylation is an evolutionarily conserved posttranslational modification that conjugates NEDD8 to its substrate, catalyzed by an E1-activating enzyme, E2-conjugating enzyme, and E3 ligase. Neddylation is essential for cellular homeostasis, and its dysregulation has been implicated in diverse human diseases, including cancer, neurodegenerative diseases, and metabolic disorders, making the process a promising therapeutic target. In this Review, we systematically summarize the biochemical activity and biological functions of neddylation; its alterations in human diseases, particularly in cancers; and its validation as an attractive target for cancer therapy. We provide an overview on the discovery of neddylation inhibitors and the progress of MLN4924 (pevonedistat) and TAS4464 clinical trials and critically evaluate the core challenges and emerging opportunities for therapeutic strategies targeting neddylation.

Gene regulation plays a crucial role in coordinating developmental processes and behavioral responses in Drosophila melanogaster. This study investigates the impact of HU and Ecdysone induced modulation of gene expression on polytene chromosome puffing patterns, salivary gland glue protein synthesis, and pupation site preference. Larvae were exposed to Hydroxyurea and Ecdysone known to alter transcriptional activity, and subsequent changes in chromosomal puff sites were examined. Variations in glue protein expression were quantified, and alterations in pupation site preference were assessed. These findings suggest that chromosomal puffs (23B and 25C on 2L arm and 62E and 63E on 3L arm) and protein synthesis in Ecdysone treated larvae were increased whereas, in hydroxyurea treated larvae it is decreased. The above puffs are associated with glue protein synthesis and alteration in these puffs lead to variation in larval pupation site preference behavior.