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.

Osteosarcoma (OS) is an aggressive primary bone tumour with high metastatic potential. Current treatments including surgery and chemotherapy are limited by side effects and chemoresistance, underscoring the need for novel therapies. This study aimed to investigate the antitumor potential of resveratrol (RSV), a natural polyphenol, as a novel treatment for OS. The effects of RSV were evaluated in two osteosarcoma cell lines (SAOS-2 and U2-OS). A viability assay established 100 μM as the effective concentration, and hyperspectral imaging confirmed cellular uptake. Apoptosis was measured via caspase-3/7 activity and Annexin V/PI staining, while qRT-PCR assessed pro-apoptotic gene expression. Flow cytometry evaluated cell-cycle progression, and a wound-healing assay measured migration. Gene expression analyses (qRT-PCR) examined markers of cell adhesion, tumour progression and epithelial-mesenchymal transition. Finally, RSV's impact on the Wnt/β-catenin pathway was determined by quantifying nuclear β-catenin accumulation and the expression of its downstream oncogenic targets. RSV inhibited cell proliferation and induced apoptosis, increasing caspase-3/7 activity and modulating apoptotic gene expression. RSV also caused cell cycle arrest in S-phase. It reduced the cells' migration and altered the expression of cell adhesion and tumour progression genes, promoting a less invasive phenotype. Notably, RSV decreased nuclear β-catenin accumulation, downregulated oncogenic targets like c-Myc and MMPs, and upregulated E-cadherin while reducing vimentin levels, suggesting a reversal of epithelial-mesenchymal transition. These results suggest that RSV may offer a promising therapeutic approach for osteosarcoma, modulating key pathways involved in tumour progression, metastasis and chemoresistance. Further studies are required to assess its clinical applicability.

Arsenite is a highly toxic metalloid for living organisms; however, numerous microorganisms have evolved effective mechanisms to adapt to arsenic stress. The facultative anaerobic betaproteobacterium Aromatoleum sp. CIB exhibits a good level of arsenite tolerance, mediated by the coordinated action of multiple molecular systems involved in detoxification and cellular homeostasis. Here, we identified the arsSM genes, encoding enzymes responsible for the production of methylated arsenic species and putative precursors of arsenosugar biosynthesis. The organization of these genes within the arsSM operon suggests a role in arsenic homeostasis, potentially supported by their constitutive expression. This finding extends the known taxonomic distribution of arsSM-mediated arsenic transformation mechanisms beyond cyanobacteria and supports horizontal gene transfer as a likely route for arsSM operon acquisition. Moreover, we present the first comparative analysis of arsenite responses under aerobic and anaerobic conditions within a single bacterial species, revealing distinct physiological constraints and adaptive strategies. Transcriptomic profiling of Aromatoleum sp. CIB exposed to arsenite revealed a stronger global transcriptional response under aerobic conditions. Although canonical arsenic resistance genes (the ars cluster) were induced under both conditions, oxygen availability markedly intensified the global stress response, particularly oxidative stress-related pathways. In contrast, genes encoding protein-folding chaperones were preferentially upregulated under anaerobic conditions. These results indicate a context-dependent reorganization of cellular functions in response to arsenite stress, favoring survival over growth. Overall, this study highlights the complexity and flexibility of bacterial arsenic resistance and provides insights relevant to microbial ecology and arsenic biogeochemical cycling.

Triokinase/FMN cyclase (TKFC) is a bifunctional homodimeric enzyme in which the triokinase activity-requiring both the K and L domains from opposing subunits-catalyzes the ATP-dependent phosphorylation of triose sugars, while the L domain alone catalyzes the Mn2 + -dependent cleavage of FAD into cyclic FMN and AMP. Despite its metabolic importance, the role of TKFC in hepatocellular carcinoma (HCC) and regulated cell death remains unclear.

Systemic neoadjuvant chemotherapy, often combined with immunotherapy, is the standard of care for early-stage, non-breast cancer susceptibility gene (BRCA)-mutant triple negative breast cancer (TNBC). However, up to 70% of patients retain residual disease after treatment, which is linked to recurrence and mortality within 5 years. To define mechanisms of resistance, we performed single-cell RNA sequencing on orthotopic TNBC patient-derived xenografts during a cycle of treatment with doxorubicin and cyclophosphamide (AC). Clustering identified four tumor epithelial cell populations, with basal cells enriched in residual tumors. These basal cells up-regulated C15ORF48, a paralog of the mitochondrial cytochrome c oxidase associated subunit FA4 (NDUFA4), while exhibiting reciprocal down-regulation of NDUFA4. Functionally, C15ORF48 knockdown sensitized breast cancer cells to AC, increasing reactive oxygen species (ROS) and apoptosis. Thus, the up-regulation of C15ORF48 blunts ROS accumulation and induces resistance to chemotherapy in the basal cell subpopulations. Our findings identify C15ORF48 as a potential therapeutic target for overcoming AC resistance in TNBC.

Salt stress is a primary abiotic constraint that adversely affects the growth and development of tomato plants. Silicon, a beneficial element, has shown potential in mitigating various abiotic stresses. However, although numerous studies have been conducted in this field, the precise mechanism by which exogenous silicon mitigates salt stress in tomato seedlings remains to be fully elucidated. In this study, we analyzed the physiological responses and underlying molecular mechanisms in tomato seedlings under NaCl stress with or without silicon application. The results showed that salt stress severely inhibited seedling growth, as indicated by reductions in shoot and root fresh weight and plant height, while this damage was markedly alleviated by the application of exogenous silicon. Compared to the treatment with NaCl alone (Na), salt stress plus silicon treatment (Na + Si) improved plant growth, the leaf chlorophyll a content, the net photosynthetic rate (Pn), and the proline content and decreased the contents of reactive oxygen species (ROS) and malondialdehyde (MDA) in tomato seedlings. Transcriptomic analysis showed that there were 435 differentially expressed genes (DEGs) (397 upregulated and 38 downregulated) between Na + Si and Na treatments. Further enrichment analysis showed that the upregulated DEGs in Na + Si treatment were enriched in response to salt stress, ethylene and abscisic acid biosynthesis process, lignin catabolic process, cell wall biogenesis and the MAPK signaling pathway. Additionally, exogenous silicon application (Na + Si) upregulated the expression of key families of transcription factors, notably the AP2/ERF, WRKY and NAC families. Taken together, our study preliminarily revealed candidate genes and metabolic pathways affected by exogenous silicon treatment, which may provide a strategy for improving the adaptation of tomato to salt stress.

Progesterone (P4) is believed to inhibit breast cancer growth, but its role in counteracting estrogen (E2)-driven progression remains unclear. This study aimed to investigate the inhibitory effect of P4 on E2-induced cell proliferation, migration, and invasion in Estrogen receptor (ER)+/progesterone receptor (PR)+ breast cancer cells by examining its regulatory role in the epithelial-mesenchymal transition (EMT).

MicroRNAs (miRNAs) are small, non-coding RNAs that play a key role in the development of chemoresistance in various cancer types, including colorectal cancer (CRC). In this study, we aimed to study the underlying mechanisms of miRNA in chemotherapy-resistant CRC.

Androgen receptor (AR) signaling is a central driver of prostate cancer progression, yet the metabolic and transcriptional mechanisms regulating AR expression remain incompletely characterized. This study investigated whether the immunoproteasome inhibitor ONX-0914 suppresses hormone-sensitive prostate cancer (HSPC) through metabolic modulation of AR and aimed to identify the transcriptional mediator involved.

Pheochromocytomas and Paragangliomas (PPGL) are rare neuroendocrine tumors with favorable prognosis, although a significant subset (20-25%) progress to metastasis, worsening patient prognosis. For metastatic cases, pharmacological interventions become essential, yet most tumors show poor response to treatment. While clinical trials are ongoing, there is no established treatment for metastatic PPGL. Like other neuroendocrine tumors, PPGL exhibit high membrane expression of somatostatin receptors, and despite Peptide Receptor Radionuclide Therapy, PRRT, strategies have successfully been implemented, trials with cold somatostatin analogs were abandoned prematurely due to inconsistent results. To investigate this issue and identify potential therapeutic tools, we widely profiled somatostatin receptors expression in PPGL and conducted a comprehensive functional screening on wild-type and SDHB knockdown PPGL cell lines of native and synthetic somatostatin analogs. Results revealed that pheochromocytomas and paragangliomas similarly display a predominant SSTR2 and SSTR1 expression regardless of molecular cluster. Treatment with somatostatin, cortistatin, octreotide or pasireotide did not exert clear antitumoral effects on model cell lines. Notably, the selective SST2 agonist BIM-23120 significantly reduced cell proliferation and induced apoptosis in an SST2-dependent manner, but only in SDHB knocked-down PPGL cells. Indeed, only SDHB KD cells showed stronger membrane-enriched SST2 and clear receptor internalization upon BIM-23120 treatment. Molecular analysis revealed a generalized dephosphorylation affecting key proliferation, growth and cell survival pathways in response to BIM-23120 (unlike when treating with octreotide). Altogether, our results provide novel information on the status of the somatostatin system in PPGL and identify new potential therapeutic tools selectively targeting somatostatin receptors on this refractory tumor.

Proteasome inhibitors (PIs) are indispensable for the treatment of multiple myeloma (MM), the second most common hematologic malignancy. Although primary resistance to PIs is rare, most patients eventually relapse and develop acquired resistance, with underlying mechanisms that remain incompletely understood and appear to be drug-specific. In the case of bortezomib, resistance is often associated with PSMB5 mutations. In contrast, resistance to carfilzomib (CFZ) is mediated by overexpression of the drug efflux transporter ABCB1. However, the regulatory mechanisms driving ABCB1 upregulation in CFZ-resistant MM remain unclear.

Approximately 70% of clear cell renal cell carcinoma (ccRCC) patients harbor von Hippel‒Lindau (VHL) deficiency, which drives pseudohypoxia and metabolic reprogramming. Here, we report a histone H4 lysine 12 lactylation (H4K12la)-fueled phosphoglycerate kinase 1 (PGK1)-lactate positive feedback loop that sustains glycolytic flux in VHL-deficient ccRCC and is pharmacologically disruptable by glucocorticoids. H4K12la is markedly elevated in ccRCC tissues and is associated with advanced pathological stage and unfavorable patient outcome. Integrative transcriptomic and epigenomic profiling revealed that VHL deficiency amplifies H4K12la deposition at accessible promoters, coupled to transcriptional activation of glycolytic and tumor-promoting programs, exemplified by PGK1. Through high-content drug screening, we identify glucocorticoids as effective suppressors of H4K12la, which act via glucocorticoid receptor-mediated transcriptional repression of glycolytic genes and consequent attenuation of lactate production. Strikingly, VHL-deficient ccRCC exhibits greater on-target pathway sensitivity to dexamethasone at the H4K12la-glycolysis axis, and glucocorticoid dexamethasone potentiated the antitumor efficacy of the HIF-2α inhibitor belzutifan in both orthotopic cell line-derived and patient-derived xenograft models. Collectively, our findings establish H4K12la as a metabolic‒epigenetic amplifier in VHL-deficient ccRCC, reposition glucocorticoids as epigenetically active modulators that dampen lactate-driven chromatin activation and glycolytic output, and provide a mechanistically grounded combination strategy with HIF-2α blockade to target lactate-fueled transcriptional dependence in metabolically rigid tumors.

The persistence of latent HIV-1 reservoirs remains a major barrier to achieving a cure for HIV. While latency-reversing agents (LRAs) have been extensively studied, latency-promoting agents (LPAs) offer a complementary strategy to silence viral transcription and prevent immune activation. Here, we propose that modulation of IRF7-driven transcription may represent a novel approach to control HIV-1 latency, by characterizing the role of the Janus kinase 2 inhibitor (JAK2i) pacritinib as a novel latency-promoting agent (LPA).

Neurodegenerative diseases are complex disorders characterized by the progressive loss of neuronal structure and function, involving pathological mechanisms such as oxidative stress, chronic inflammation, protein misfolding, and impaired synaptic plasticity. Recent studies have revealed that epigenetic regulation plays a critical role in the onset and progression of these diseases, including mechanisms such as DNA methylation, histone modifications, and non-coding RNA regulation. Natural polyphenolic compounds, known for their safety and multi-target properties, have emerged as promising candidates for neuroprotection and therapeutic intervention.

In a randomised controlled trial (RCT), we compared the effects of treatment with furosemide + small volumes of hypertonic saline solution (HSS) with those of furosemide alone in patients with decompensated heart failure (HF), and their effects on inflammatory and remodelling markers and epigenetic signatures.