Drought, heat, and salinity severely constrain the yield and fiber quality of Gossypium hirsutum. Although abscisic acid (ABA) is a central regulator of plant abiotic stress responses, whether exogenous ABA elicits a core response shared with multiple abiotic stresses in G. hirsutum remains unclear. Here, we identified 200 μM ABA as an effective concentration for mitigating physiological damage under drought, heat, and salt stress, and integrated time-series RNA-seq, hormone profiling, and assay for transposase-accessible chromatin sequencing (ATAC-seq) to characterize ABA-induced responses. Comparative transcriptome analysis identified 3345 core differentially expressed genes (DEGs) shared among ABA, drought, heat, and salt treatments, which were enriched in circadian rhythm, photosynthesis, water homeostasis, and carbon metabolism. Hormone profiling showed rapid accumulation of ABA and ABA-glucose ester after ABA treatment, accompanied by enhanced jasmonate- and ethylene-related signals and reduced salicylic acid and gibberellin levels. ATAC-seq revealed increased promoter chromatin accessibility at 12h after ABA treatment, and accessibility changes were generally positively associated with the expression of nearby genes. Integration of shared DEGs, promoter-associated differentially accessible regions (DARs), and motif enrichment identified a candidate regulatory network consisting of 24 transcription factors (TFs) and 439 putative target genes. Functional analysis further supported Gh_MYB-D as a positive regulator associated with tolerance to multiple abiotic stresses. Together, these results provide a candidate regulatory framework for ABA-enhanced abiotic stress tolerance in G. hirsutum and nominate genes for future functional validation.

Salicylic acid treatment significantly enhances the production of bioactive Euphorbia diterpenoids in Euphorbia lathyris suspension cultures by activating defense and diterpenoid biosynthetic pathways, including upregulating the key acyltransferase gene ElBAHD1. The medicinal plant Euphorbia lathyris produces pharmacologically active diterpenoids, but the content of which is limited in Euphorbia plants. An efficient suspension culture system of E. lathyris was established to enhance the production of bioactive diterpenoids. Salicylic acid (SA) treatment (550 μM, 10 days) significantly enhanced the production of lathyrane-type diterpenoids jolkinol A' (1), jolkinol A (2), jolkinol B (5), and a new 16-hydroxylated jolkinol A derivative (7). In particular, the volumetric yield of jolkinol A (2) was achieved to 47.00 mg L-1, a 5.4-fold increase over unelicited controls. Intriguingly, SA also induced the production of polycyclic diterpenoids, including ent-atisane and ent-kaurane. Transcriptomic analysis revealed SA activated defense and diterpenoid biosynthetic pathways, upregulating a series of genes including the acyltransferase gene ElBAHD1. Overexpression of ElBAHD1 promoted the accumulation of jolkinol A' (1), jolkinol A (2), and jolkinol B (5) in transgenic hairy roots and influenced the expression of diterpenoid biosynthetic genes. Notably, jolkinol A (2) exhibited potent antifungal activity against Phytophthora capsici, comparable to that of the commercial fungicide metalaxyl (84.76%) at 200 μg mL-1. This work provides insights into SA-induced biosynthesis mechanism of bioactive Euphorbia diterpenoids, and lays a robust foundation for the future metabolic engineering of E. lathyris.

Androgen deprivation therapy (ADT) remains the standard treatment for advanced prostate cancer (PCa); however, most patients ultimately progress to lethal castration-resistant PCa (CRPC). Emerging evidence implicates RNA N⁶-methyladenosine (m⁶A) modification as a key regulator of cancer biology, yet its role in CRPC remains poorly understood. As a critical adaptor in the m⁶A methyltransferase complex, RNA-binding motif protein 15 (RBM15) directs m⁶A deposition to specific mRNA targets. Here, we identified RBM15 as the key methyltransferase member significantly upregulated in CRPC tissues and strongly correlated with poor patient survival. Functionally, RBM15 overexpression reduces PCa cell sensitivity to enzalutamide, whereas its knockdown suppresses tumor growth and invasion. Mechanistically, RBM15 is an androgen-responsive protein whose expression increases upon chronic androgen deprivation. It catalyzes m⁶A methylation at position A1384 of damaged DNA binding protein 1 (DDB1) mRNA, leading to YTHDF2-dependent transcript decay and reduced DDB1 protein levels. Lower DDB1 impairs K48-linked polyubiquitination of the androgen receptor (AR), thereby stabilizing AR and amplifying AR signaling. Importantly, AR transcriptionally activates RBM15, forming a feed-forward loop that drives CRPC progression. Collectively, our findings establish RBM15 as a central epitranscriptomic driver of CRPC and identify the RBM15-DDB1-AR axis as a promising therapeutic target. Dual inhibition of RBM15 and AR may offer a novel strategy to overcome treatment resistance in advanced PCa.

Ulcerative colitis (UC) remission is marked by gut microbiota restructuring, but how microbial metabolites influence immune-mediated tissue repair is unclear. Here, we demonstrate that oral vancomycin alleviates colitis symptoms in murine models, mirroring its clinical efficacy in inducing remission in patients with UC. Mechanistically, vancomycin's therapeutic effect is achieved by reducing deoxycholic acid (DCA). We reveal that DCA impairs mucosal repair driven by group 2 innate lymphoid cells (ILC2s) by inducing ER stress through direct binding to thioredoxin-related transmembrane protein 2 (TMX2). This interaction disrupts TMX2's role in protein folding, triggering unresolved unfolded protein response via hyperactivation of PERK/eIF2α signaling, which suppresses the production of pro-healing molecules by ILC2s. Pharmacological inhibition of PERK phosphorylation restores ILC2 function and accelerates colitis resolution. Our work uncovers a pathogenic microbiota/DCA/ILC2 axis that obstructs mucosal healing and positions vancomycin as a targeted strategy to eliminate DCA, thereby promoting UC remission.

Cadmium (Cd) is a toxic heavy metal that severely disrupts plant growth, induces oxidative stress and disruption of physiological processes in plants. In this study, we evaluated the potential of two biostimulants, 28-homobrassinolide (28-HBL), a brassinosteroid, and the root endophytic fungus Piriformospora indica, to alleviate Cd-induced stress in Brassica juncea. seedlings. Exposure to Cd significantly impaired seedling morphology and elevated reactive oxygen species (ROS) levels, while biopriming with 28-HBL and root inoculation with P. indica markedly improved morphology and stress resilience. Enzymatic antioxidants (SOD, CAT, APOX, DHAR, MDHAR) and non-enzymatic antioxidants (GSH, phenolics, flavonoids) effectively attenuated ROS levels, with the combined treatment showing the strongest impact. These biochemical enhancements were supported by transcriptional upregulation of antioxidant defense genes. In addition, osmolyte accumulation (proline, glycine betaine [GB]) supported cellular homeostasis under stress. Atomic absorption spectroscopy confirmed reduced Cd uptake in treated seedlings. Notably, P. indica colonization upregulated key brassinosteroid signaling genes (BRI1, BAK1, BES1, and BZR1), suggesting a hormone-mediated mechanism of stress mitigation. The findings highlight a promising synergy between 28-HBL and P. indica, offering an eco-friendly strategy to enhance plant tolerance to Cd stress.

Pharmacovigilance has revealed an alarming correlation between certain medications and a higher risk of cancer. In this narrative review, included research from 2020 to 2025, along with a few seminal older studies, so that it provides a clear picture of which drugs actually set off cancer and mechanisms involved at the molecular level. An extensive literature review of the subject was designed on PubMed, Embase, Scopus, and Web of Science using systematic search. Search words and phrases included: "Carcinogenic drugs," "drug-induced cancer," "medication-induced carcinogenesis," "immunosuppressant cancer risk," "hormone therapy and cancer," "chemotherapy-induced secondary malignancies," and names of relevant drugs.

Chemotherapy resistance remains a critical bottleneck limiting its clinical efficacy in small cell lung cancer (SCLC), with its core mechanisms and targeted intervention strategies urgently requiring breakthroughs. Our study revealed that the BMX (bone marrow tyrosine kinase on chromosome X)-E2F1 (E2F transcription factor 1) axis is a pivotal regulator of chemoresistance in SCLC. Synchronous upregulation of phosphorylated BMX (Tyr566) and E2F1 was observed in SCLC tissues and cells. Mechanistically, BMX stabilized E2F1 via the ERK1/2 (extracellular signal-regulated kinase 1/2)-Cyclin D1/CDK4/6 (cyclin-dependent kinase 4/6) signaling axis, phosphorylating E2F1 at Ser332/337 and inhibiting its degradation via the ubiquitin-proteasome pathway. Inhibition or knockdown of BMX reduced E2F1 stability, promoting its degradation and reversing chemoresistance. E2F1 knockdown decreased the expression of genes associated with cell cycle regulation, migration, invasion, and DNA repair, further sensitizing chemoresistant SCLC cells to cisplatin. We also discovered IHMT-15137, a potent and selective BMX inhibitor. In vitro studies using SCLC patient-derived cells (PDCs)/patient-derived organoids (PDOs) and chemoresistant cell lines revealed that IHMT-15137, combined with cisplatin, synergistically induced cell cycle arrest, apoptosis, and DNA damage while suppressing cell migration and invasion. In vivo xenograft models demonstrated that the combination significantly inhibited tumor growth without causing significant toxicity. Our findings reveal the molecular mechanisms of SCLC chemoresistance and suggest potential therapeutic strategies targeting the BMX-E2F1 axis to overcome this challenge.

Resistance to lenvatinib remains a major barrier in the treatment of advanced hepatocellular carcinoma (HCC), underscoring the urgent need to elucidate the underlying mechanisms and identify actionable therapeutic targets. In this study, we identified a neurosecretory factor derived from HCC cells, Nerve Growth Factor (NGF), as a critical mediator of lenvatinib resistance. Utilizing an innovative in vivo-in vitro cross-circulated strategy, we established a phenotypically stable lenvatinib-resistant HCC cell line (LenR-cells). Through proteomic screening of conditioned media and subsequent functional validation, we demonstrated that NGF secretion progressively increases with the acquisition of resistance. Mechanistically, we uncovered that the SRPK1-SRSF1 axis drives enhanced NGF production by regulating alternative splicing of its precursor transcript, specifically promoting the expression of a shorter, translationally efficient isoform (proNGF-B). Elevated NGF subsequently activates the non-canonical MAPK pathway (MEK5-ERK5) via its high-affinity receptor TrkA, thereby sustaining tumor cell viability and proliferation under sustained tyrosine kinase inhibitor pressure. Critically, pharmacological co-targeting of TrkA with the clinically approved inhibitor larotrectinib restored lenvatinib sensitivity in both patient-derived organoids and xenograft models, producing marked synergistic anti-tumor effects without evidence of exacerbated toxicity. Clinical analyses of two independent patient cohorts further confirmed that elevated NGF expression is significantly associated with poor response to lenvatinib, shorter recurrence-free survival, and worse overall survival. Our findings unveil a critical and previously underappreciated role for tumor-derived NGF in orchestrating adaptive signaling through a precise post-transcriptional regulatory circuit and propose a readily translatable, biomarker-guided combination strategy to overcome lenvatinib resistance in HCC.

One of the most prevalent oral cancers, oral squamous cell carcinoma (OSCC), is distinguished by its rapid growth, invasiveness, and high metastatic potential. Green AgNPs are important because they can reduce systemic toxicity by inducing oxidative stress, cytotoxicity, and apoptosis in cancer cells. The goal of this study was to use saponins as natural stabilizers to create AgNPs, and the detrimental apoptotic effects on cancer cells were examined using high-content screening (HCS) assays such as TNI, CMP, and VCC.

Cervical cancer is the second leading cause of mortality in women globally, with its incidence increasing due to multidrug resistance (MDR) and adverse side effects associated with chemotherapeutic agents. Hence, this study was carried out to investigate the selective cytotoxicity and apoptotic induction potential of Buddleja polystachya leaf diethyl ether (BPL-DE) extract on cervical cancer HeLa cell lines.

The aim of the study was to determine how the chemotherapeutic alkylating agent dacarbazine, together with the application of the miR-204-5p mimic in vivo, affects the presence of disseminated melanoma cells in distant organs - the lungs and liver.

To elucidate how ALX Homeobox 4 (ALX4) modulates cisplatin sensitivity via DNA damage regulation in breast cancer (BC), this study explored the established role of mRNA-mediated DNA repair in driving chemoresistance.

Anthropogenic activities have increased cadmium (Cd) accumulation in agricultural soils, severely affecting crop productivity. This study investigated the role of melatonin (Mlt) and a Pseudomonas consortium (PGPR) in modulating secondary metabolism in Brassica juncea L. seedlings under Cd stress. Combined Mlt-PGPR treatment significantly reduced Cd accumulation and regulated the expression of genes involved in Cd transport and detoxification. Enhanced levels of osmolytes and organic acids were observed, along with upregulation of genes associated with osmoprotection and metal chelation. Antioxidant defense was experimentally assessed through enzymatic and non-enzymatic analyses, confirming improved redox homeostasis. FTIR spectroscopy supported treatment-induced biochemical alterations. Transcriptomic profiling revealed activation of melatonin biosynthesis genes and secondary metabolism-related pathways. A structural model of BjCand2, a putative melatonin receptor, and docking analysis suggested its involvement in signaling regulation. Overall, Mlt-PGPR application mitigates Cd toxicity through coordinated receptor-mediated signaling and metabolic reprogramming.

Overuse of chemical pesticides motivates green disease control strategy. Levan-derived oligosaccharides (LOS) are immune elicitors, but its structure information and underlying regulatory mechanisms remain unclear. In this study, LOS produced from sucrose using LevB1SacB fusion enzyme, was purified by CSR-1Na resin, and characterized by HPLC, ATR-FTIR and 1D/2D NMR. Foliar LOS spraying (0.5‰) enhanced barley resistance to Rhizoctonia solani and Pyrenophora graminea, reducing necrotic area by 60.5% and 22.4%, but had little effect on the hemibiotrophic pathogen Bipolaris sorokiniana of spot blotch. LOS itself did not inhibit fungal growth in vitro. LOS priming strengthened infection-triggered antioxidant and defense responses. RNA-seq analysis indicated pathogens but not LOS enhanced transcriptional reprogramming, with differential genes enriched in amino acid metabolism. Among transcriptome-guided candidates, HvAS1, an asparagine synthetase, was verified to participate in LOS-enhanced resistance: HvAS1 overexpression in Arabidopsis accumulated more asparagine and jasmonate after infection and reduced R. solani lesions by >50%, whereas virus-induced silencing in barley compromised resistance. Besides, foliar asparagine spraying also increased barley resistance to R. solani. Together, LOS acts as an efficient elicitor and reveals the link between amino acid metabolism and plant immunity.

Temozolomide (TMZ) resistance in glioblastoma (GBM) remains a critical barrier to treatment success, driven by O6-methylguanine-DNA methyltransferase (MGMT) overexpression, glioma stem cell (GSC) persistence, and redox adaptation.

Brassica species are major oilseed crops valued for their high seed oil content; however, salinity severely limits their growth, productivity, and oil quality. Since membrane stability and oil composition are primarily governed by fatty acid metabolism, this study focused on two key lipid biosynthesis genes, FAE1 (Fatty Acid Elongase 1) and FAD2 (Fatty Acid Desaturase 2), to elucidate their role under NaCl-induced stress. Understanding the regulatory and functional behavior of these genes under salinity is essential for developing salt-resilient Brassica cultivars capable of maintaining oil quality on saline soils. To establish a mechanistic foundation, gene and protein sequences of FAE1 and FAD2 were retrieved from publicly available genomic databases. Various bioinformatics analyses were conducted to identify conserved domains, structural integrity, phylogenetic relationships, and regulatory features, thereby verifying their functional relevance in fatty acid biosynthesis. Promoter regions were also examined for stress-responsive cis-acting elements, including dehydration-responsive elements (DRE) and ABA-responsive elements (ABRE), providing predictive evidence of transcriptional regulation under salt stress. Based on these computational predictions, controlled salt stress was imposed to experimentally evaluate gene responsiveness and physiological adaptation. Tissue-specific expression analysis revealed significant differential regulation of FAE1 and FAD2 under salt stress, with pronounced transcriptional modulation observed in developing siliques and leaves compared to roots. Salt stress caused a dose-dependent reduction in growth attributes and yield-related traits in both species. Two-way ANOVA revealed significant NaCl effects on yield parameters (F = 6.6-20, P < 0.05), with seed yield declining by approximately 25-35% at 200 mM NaCl, with comparatively higher yield stability in B. juncea than in B. napus under salinity. Seed quality analysis showed species-specific responses in oil and protein content, whereas most fatty acids, including erucic acid, remained relatively stable. Despite transcriptional modulation of both genes, the overall fatty acid profile exhibited limited variation, suggesting metabolic buffering within the lipid biosynthetic network. Together, this integrative approach links in silico predictions with experimental validation, establishing a continuum from gene structure and regulation to phenotypic performance and seed quality. These findings enhance our understanding of lipid metabolism-mediated salt stress adaptation and provide a foundation for breeding and genome-editing strategies aimed at improving oilseed stability in Brassica under saline conditions.

Twenty different amino acids are required for the human body for proper functioning as amino acids serve as building blocks for proteins. We screened different essential and non-essential amino acids for the ability to stimulate lysosomal biogenesis and, interestingly, found an essential amino acid L-leucine as the most potent one in stimulating lysosomal biogenesis in astrocytes. However, D-leucine remained weaker than L-leucine in terms of stimulation of lysosomal biogenesis. Accordingly, L-leucine increased autophagy in cultured brain cells and in vivo in the brain of 5XFAD mice, one of the animal models of Alzheimer's disease (AD). L-Leucine also stimulated the uptake and degradation of amyloid-β in astrocytes and reduced the plaque load and improved cognitive functions in 5XFAD mice. Although L-leucine was discovered about 200 years back, until now, no receptor has been identified for L-leucine. Here, we noticed that L-leucine binds to the ligand-binding domain of peroxisome proliferator-activated receptor α (PPARα) to activate this nuclear hormone receptor. Accordingly, L-leucine remained ineffective in increasing lysosomal biogenesis and autophagy in PPARα-/- brain cells. Lentiviral establishment of full-length PPARα, but not Y314D-PPARα, reinstated the autophagy-stimulating effect of L-leucine in PPARα-/- astrocytes, emphasizing the importance of leucine's interaction with the Y314 residue. Moreover, oral L-leucine decreased the plaque load and improved spatial learning and memory in 5XFAD mice, but not in 5XFADΔPPARα mice (5XFAD lacking PPARα), highlighting the involvement of PPARα in the neuroprotective effects of L-leucine. These results may be beneficial for AD patients.

This study investigated the effects of melatonin supplementation in the culture medium on the development, cellular dynamics and gene expression of bovine embryos produced in vitro under low (5%) or high (20%) oxygen tension. Zygotes were cultured without melatonin or with (10-9 M), and cleavage, blastocyst rates, blastomere number, apoptosis, mitochondrial activity, lipid accumulation, and expression of genes related to metabolism, oxidative stress and embryo quality were evaluated. Under high O₂ tension, melatonin increased blastocyst rate (39.8% vs. 34.0%), raised blastomere number, reduced apoptosis, and decreased lipid accumulation. It also upregulated SOD2, KRT8, IFN-τ, and PLAC8. Under low O₂ tension, melatonin increased cleavage rate and mitochondrial activity but did not affect blastocyst rate; only SOD2 was upregulated. Embryos cultured without melatonin under low O₂ showed higher IFN-τ and PLAC8 expression. In conclusion, melatonin improves embryo quality and viability mainly under high oxygen tension, acting as an antioxidant, gene modulator and apoptosis inhibitor. Its effects are more limited under low O2, likely because this environment is closer to physiological conditions and requires fewer responses to oxidative stress.

Cisplatin is a widely used chemotherapeutic agent; however, its therapeutic efficacy is often limited by severe cytotoxic side effects, particularly gastrointestinal toxicity, which manifests as intestinal mucositis. MicroRNAs (miRNAs) are small non-coding RNAs that play critical roles in both normal physiological and pathological processes by regulating gene expression. However, their role in cisplatin-induced gastrointestinal toxicity remains unclear. In this study, we investigated the regulatory effects of miRNAs on cisplatin-induced inflammation in intestinal epithelial cells (IEC-6). Our results demonstrate that cisplatin significantly decreases cell viability while inducing interleukin-6 (IL-6) expression in a dose-dependent manner. Moreover, we observed that cisplatin activates the phosphorylation of p38 and ERK but does not activate JNK in IEC-6 cells. Using specific inhibitors of p38 and ERK, we confirmed their roles in regulating IL-6 expression. Through analysis of the miRNA database, we identified several miRNAs that potentially target IL-6. Notably, rno-let-7f-5p and rno-let-7g-5p showed significant downregulation following cisplatin treatment. Transfection mimics and inhibitors of rno-let-7f-5p and rno-let-7g-5p further confirmed their regulatory role in IL-6 expression. Importantly, inhibition of the p38 and ERK pathways attenuated the cisplatin-induced reduction of rno-let-7f-5p and rno-let-7g-5p levels, suggesting a potential regulatory link between MAPK signaling and miRNA expression. In conclusion, our findings support a model in which cisplatin promotes inflammation in intestinal epithelial cells by activating the p38 and ERK pathways and is associated with the suppression of rno-let-7f-5p and rno-let-7g-5p. These findings provide mechanistic rationale that may inform future efforts to mitigate cisplatin-associated gastrointestinal toxicity.

Background/Aims: Globally, colorectal cancer ranks third in causing 900,000 deaths annually. Some patients undergoing chemotherapy develop resistance, leading to metastasis. We investigated CHGA and UCHL1 proteins correlate with lymph node metastasis (J Cell Mol Med. 2023;27:2004-2020). This study aimed to analyze the relationship of CHGA and UCHL1 with the epithelial-mesenchymal transition (EMT) and the Rho/ERK/NFκB signaling pathway in OXA-resistant CRC cells.