Objective. Endoplasmic reticulum stress and glucose supply are significant factors in glioblastoma growth. The present study aims to investigate the impact of glucose-dependent control of IGF2BP2, TOB1, HBEGF, TWIST1, CCNH, and E2F1 gene expression in U87MG glioblastoma cells in response to the inhibition of both enzymatic activities of signaling protein ERN1. Methods. The U87MG glioblastoma cells with inhibited both enzymatic activities of ERN1 (endoribonuclease and protein kinase; dnERN1) were used. Cells transfected with an empty vector served as a control. The expression level of the IGF2BP2 and other genes was studied by quantitative RT-PCR. Results. It was shown that the expression level of the IGF2BP2 gene is up-regulated, while that of TOB1 and E2F1 genes is down-regulated in control glioblastoma cells treated with glucose deprivation. Nevertheless, the ERN1 knockdown modified the sensitivity of IGF2BP2 and TOB1 genes to reduced glucose supply. At the same time, the expression of HBEGF, TWIST1, and CCNH genes in control glioblastoma cells was resistant to glucose deprivation conditions. However, inhibition of the enzymatic activities of ERN1 signaling protein strongly increased the impact of glucose deprivation on HBEGF gene expression, but down-regulated the expression of the TWIST1 gene. Conclusion. These results demonstrate that the enzymatic activity of signaling protein ERN1 controls the sensitivity of almost all studied genes to glucose deprivation in U87MG glioblastoma cells in a gene-specific manner. This is important for elucidating the endoplasmic reticulum stress-mediated sensitivity of key regulatory gene expression in glioblastoma cells to glucose supply, a significant factor in tumor growth.

Chlorpyrifos (CPF) is a pesticide commonly used for pest management. Regretfully, there is evidence that pesticides can cause pulmonary toxicity. The phytochemical umbelliferone (UMB) possesses anti-inflammatory and antioxidant bioactivities. This investigation aimed to determine whether UMB protects against pulmonary toxicity induced by CPF. Rats were divided into four groups: group I (control), group II (30 mg/kg of UMB), group III (10 mg/kg of untreated CPF), and group IV (30 mg/kg of CPF + UMB). Interestingly, UMB reduced pulmonary intoxication, as evidenced by the attenuation of CPF-induced histopathological alterations and the lowering of ALP, LDH, and CRP levels. Furthermore, UMB decreased CPF-induced pulmonary oxidative damage by reducing malondialdehyde (MDA) content and increasing GSH and SOD levels, which was mediated by the upregulation of Nrf2, HO-1, PPAR-γ, and cytoglobin expression. UMB decreased CPF-induced lung inflammation by lowering MPO, TNF-α, and IL-1β levels, as well as NF-κB expression. Additionally, UMB counteracted lung necroptosis by downregulating RIPK-1, RIPK3, mixed-lineage kinase domain-like pseudokinase (MLKL), and Caspase-8, as confirmed by in silico studies. Accordingly, UMB could be a sound therapeutic strategy for mitigating CPF-induced lung intoxication, as it balances antioxidants and oxidants, reduces cellular inflammation, and prevents lung tissue necroptosis.

Triterpenoids derived from Sanghuangporus baumii exhibit significant pharmacological activities. However, their production remains limited due to the naturally low yield of triterpenoids and insufficient knowledge of the biosynthetic pathway.

Breast cancer is the leading cause of cancer-related death in women. The Wnt pathway, essential for osteogenesis, may help counteract tumor-induced bone damage. Caffeic acid phenethyl ester (CAPE), a natural polyphenol, shows anti-tumor, anti-inflammatory, and bone anabolic effects. This study aimed to evaluate the in vitro effects of CAPE (10 nM) on osteoblastic cells (Saos-2) cocultured with breast adenocarcinoma cells (AU565).

Gastric cancer is the fourth most common cancer globally and the leading cause of cancer-related deaths in Peru. Current synthetic treatments often fail to distinguish cancerous cells from healthy cells, resulting in severe side effects and drug resistance. This study aimed to evaluate the effects of the chloroform fraction of Dracontium spruceanum bulb (DSBCl) on cancer stem cells (CSCs) from AGS and KATO III gastric cancer cell lines, which represent primary and metastatic cancers. The methanolic extract was prepared and characterized via thin-layer chromatography to isolate the chloroform fraction. CSCs were identified via the CD44 marker and isolated via magnetic assisted cell sorting. The cytotoxic effect of DSBCl was evaluated to determine the IC50, revealing its ability to modulate CSC markers and genes associated with tumorigenesis, chemoresistance, and metastasis. In AGS CSCs, DSBCl reduced CD24 expression and downregulated the expression of genes, including ID1, BCL2L2, ABCC2, NANOG, and OCT4, while it upregulated KLF17, BAX, and KLF4. In KATO III CSCs, DSBCl increased ID1 and MYC but decreased BCL2L1 and BAX. These findings suggest that DSBCl modulates critical markers and genes in gastric CSCs, highlighting its potential for gastric cancer treatment.

2-Amino-14,16-dimethyloctadecan-3-ol (AOD) is commonly found in foods contaminated with Fusarium avenaceum, particularly cereals or fruits, and is structurally related to Fusarium mycotoxins (fumonisins) and mammalian sphingoid bases, especially 1-deoxysphinganine (m18:0); therefore, it might enter systemic circulation and tissues upon dietary intake. Knowledge about what happens when cells are exposed to AOD is limited, but it has been reported to be cytotoxic and to induce vacuolization in HepG2 cells. We also found that AOD is cytotoxic for HepG2 cells, but even at a concentration where cell viability remained above 85% (5 μM), it altered 24 differentially expressed genes based on RNA sequencing-based transcriptomic profiling. Among these genes, 13 were shared with cells treated with m18:0. These overlapping differentially expressed genes were primarily enriched in activated stress response pathways of cells, including the upregulation of specific genes in the hypoxia-inducible factor 1α (HIF-1α) signaling pathway, such as hexokinase 1 (HK1) and egl-9 family hypoxia-inducible factor 3 (EGLN3), the activation of key components in the p53 signaling pathway, and the induction of cellular senescence-associated transcriptional programs involving serpin family E member 1 (SERPINE1). Transcriptional analysis of genes related to sphingolipid metabolism showed that treatment with AOD increased the mRNA expression of ceramide synthase 4 (CerS4), sphingosine-1-phosphate phosphatase 1 (SGPP1), and UDP-glucosylceramide glucosyltransferase (UGCG), while decreasing the expression of dihydroceramide desaturase 1 (DEGS1) and fatty acid desaturase 3 (FADS3), a pattern of gene expression changes that mirrored the alterations observed with m18:0 treatment. Lipidomic analyses revealed that AOD significantly perturbed the sphingolipid composition of HepG2 cells, specifically increasing hexosylceramide content while decreasing ceramide and sphingomyelin levels. Moreover, AOD was found to undergo intracellular metabolism to N-acyl-AODs, perhaps by ceramide synthase(s), since this acylation was inhibited by fumonisin B1 (FB1). These findings demonstrate that AOD or possibly its N-acyl metabolites can alter cellular sphingolipid metabolism and affect the expression of genes involved in cell stress. These new insights call for more studies of the impact of this food contaminant on cells and the implications for human health.

Colchicine is commonly prescribed for inflammation and gout, but its nephrotoxicity and underlying mechanisms remain incompletely understood. The objective of this research was to clarify the association between m6A methylation modifications and nephrotoxicity caused by colchicine. A significant decrease in HK2 cell viability was observed following colchicine treatment, and mRNA sequencing (mRNA-seq) revealed the differential expression of genes associated with DNA damage and autophagy. Further methylated RNA immunoprecipitation sequencing (MeRIP-seq) analysis revealed an association between N6-methyladenosine (m6A) modifications and the expression of genes involved in DNA damage and autophagy after colchicine exposure. Molecular docking and a molecular dynamics (MD) analysis identified ZC3H13 as a potential regulator of colchicine-induced cytotoxicity in HK2. Experimental validation confirmed that colchicine induces DNA damage and autophagy in HK2 cells, with ZC3H13 playing a significant role in these processes. In conclusion, the findings suggested that colchicine-induced damage in HK2 cells is associated with changes in m6A methylation levels in target genes and the altered expression of m6A regulator.

Pancreatic cancer is one of the most aggressive malignant tumors in humans, with poor prognosis. The acetylase tumor inhibitor (Pracinostat) has been shown to suppress the growth of various tumors. This study aimed to investigate the effects of Pracinostat on the pancreatic cancer cell line BxPC3 and to explore the underlying molecular mechanisms through both in vivo and in vitro experiments.

Colorectal cancer (CRC) is the second leading cause of cancer-related mortality worldwide. The limitations of conventional therapies, namely severe side effects and the emergence of drug resistance, underscore the urgent need for novel and more effective treatment strategies. Natural products, including bioactive compounds derived from scorpion venom (SV), have demonstrated promising anticancer properties in various studies. This study aimed to investigate the potential chemopreventive and therapeutic effects of Leiurus quinquestriatus venom (LQV) and Androctonus bicolor venom (ABV) against chemically induced CRC in a rat model. Male rats were randomly assigned to four groups: Group 1 (Gp1) (control), Gp2 (CRC induced using 40 mg/kg 1,2-dimethylhydrazine (DMH), administered subcutaneously for 4 weeks), and Gp3 and 4 (DMH-induced CRC treated intraperitoneally with 0.025 mg/kg LQV and 0.05 mg/kg ABV, respectively, for 11 weeks). At the end of the experimental period, colon tissues were collected for histopathological examination, tumor biomarker analysis, gene expression profiling, cell cycle distribution, and apoptotic assays. Both LQV and ABV significantly reduced the number of aberrant crypt foci (ACF) and mucin-depleted foci (MDF) while enhancing the number of goblet cells in colonic mucosa. Treatment also resulted in a marked downregulation of proliferating cell nuclear antigen (PCNA) and cyclin D1 and upregulation of the tumor suppressor gene PTEN. Moreover, flow cytometry analysis revealed an increase in late apoptotic cells and cell cycle arrest at sub-G1 and G0 phases in venom-treated groups. These findings suggest that LQV and ABV possess notable anti-CRC activity through modulation of proliferation, apoptosis, and gene regulation, highlighting their potential as candidates for alternative CRC therapies.

Calcium chloride and sodium nitroprusside mitigate PEG-induced drought in saffron by enhancing antioxidant defense, osmolyte levels, and stress-responsive genes expression, promoting resilience and adaptive growth. While calcium ions (Ca2+) and nitric oxide (NO), are key signalling mediators, which enhance plant's ability to survive abiotic stress, their definitive role in enhancement of drought tolerance in saffron is not fully studied yet. We aim to examine the effect of different concentration of calcium chloride (CaCl₂) (25, 50, 75 mM) and sodium nitroprusside (SNP) (25, 50, 100 µM) on saffron cultured on MS media containing 10% polyethylene glycol (PEG) for 30 days. Results showed plants exposed to drought produced ROS (H2O2) that caused oxidative damage to the cells such as membrane damage. Moreover, drought has reduced biomass accumulation, relative water content, and photosynthetic pigment. Elicitor treatment significantly alleviated these effects, with 50 mM CaCl₂ improving relative water content by 84% and 25 µM SNP enhancing biomass by 72% over drought-stressed plants. Both elicitors restored chlorophyll and carotenoid levels, reduced electrolyte leakage, enhanced antioxidant enzyme activities (SOD, POD), increased proline and phenolic contents, and improved total antioxidant capacity. Furthermore, expression of drought-responsive genes (DREB1,2, AREB1, SnRK2, NAC1, MYB37, bZIP23, DHN1) was upregulated under elicitor treatment. These findings highlight that CaCl₂ and SNP have potential to support plant growth and development and to minimize the detrimental effect of drought stress on saffron.

Glioblastoma (GBM) is a highly vascularized, heterogeneous tumor, yet antiangiogenic therapies have yielded limited survival benefits. The lack of validated predictive biomarkers for treatment response stratification remains a major challenge. Aminoacyl tRNA synthetase complex-interacting multicomplex proteins (AIMP) 1/2/3 have been implicated in central nervous system diseases, but their roles in gliomas remain unexplored. We investigated their association with angiogenesis and their significance as predictive biomarkers for antiangiogenic treatment response. In this multi-cohort retrospective study, we analyzed glioma samples from The Cancer Genome Atlas, Chinese Glioma Genome Atlas, REMBRANDT, Gravendeel, BELOB, and REGOMA trials, and four single-cell transcriptomic datasets. Multiomic analyses incorporated transcriptomic, epigenetic, and proteomic data. Kaplan-Meier and Cox proportional hazards models were used to assess the potential prognostic value of AIMPs in heterogeneous and homogeneous treatment groups. Using single-cell transcriptomics, we explored spatial and cell type-specific AIMP2 expression in GBM. AIMP1/2/3 expressions correlated significantly with angiogenesis across The Cancer Genome Atlas cancers. In gliomas, AIMPs were upregulated in tumor versus normal tissues, higher- versus lower-grade gliomas, and recurrent versus primary tumors (P < 0.05). Upon retrospective analysis of two clinical trials assessing different antiangiogenic drugs, we found that high-AIMP2 subgroups had improved response to therapies in GBM [REGOMA: HR, 4.75 (1.96-11.5), P < 0.001; BELOB: HR, 2.3 (1.17-4.49), P = 0.015]. AIMP2-cg04317940methylation emerged as a clinically applicable stratification marker. Single-cell analysis revealed homogeneous AIMP2 expression in tumor tissues, particularly in astrocyte-like cells, suggesting a mechanistic link to tumor angiogenesis. These findings provide novel insights into the role of AIMPs in angiogenesis, offering improved patient stratification and therapeutic outcomes in recurrent GBM.

Tumor drug resistance, a major cause of treatment failure, involves complex multi-gene networks, remodeling of signaling pathways, and interactions with the tumor microenvironment. Yin Yang 1 (YY1) is a critical oncogene overexpressed in many tumors and mediates multiple tumor-related processes, such as cell proliferation, metabolic reprogramming, immune evasion, and drug resistance. Notably, YY1 drives resistance through multiple mechanisms, such as upregulation of drug efflux, maintenance of cancer stemness, enhancement of DNA repair capacity, modulation of the tumor microenvironment, and epithelial-mesenchymal transition, thereby positioning it as a pivotal regulator of drug resistance. This review examines the pivotal role of YY1 in resistance, elucidating its molecular mechanisms and clinical relevance. We demonstrate that YY1 inhibition could effectively reverse drug resistance and restore therapeutic sensitivity across various treatment modalities. Importantly, we highlight the promising potential of YY1-targeted strategies, particularly combined with anti-tumor agents, to overcome resistance barriers. Furthermore, we discuss critical translational considerations for advancing these combinatorial approaches into clinical practice.

Immunological correction of cognitive processes impaired due to the action of neurotoxic amyloidogenic forms of proinflammatory protein S100A9, a promoter of the inflammatory-amyloid cascade occurring in Alzheimer's disease, is poorly understood. Chronic intranasal administration of S100A9 fibrils leads to suppression of spatial memory formation in the Morris water maze in 12-month-old C57BL/6J mice and to an increase in activity of the ASCL1 gene involved in neurogenesis at the stage of cell differentiation, in the hippocampus and prefrontal cortex. In the case of combined administration of S100A9 fibrillar structures and antibodies to glutamate, the duration of the latency of reaching the platform in the water maze as well as ASCL1 gene expression in the hippocampus and prefrontal cortex returned to normal, but not in the cerebellum where a decrease in ASCL1 gene activity was observed.

Triple-negative breast cancers (TNBC) are defined as tumors that lack the expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). It exhibits unique clinical and pathological features, demonstrates high aggressiveness, and has a relatively poor prognosis and clinical outcome.

Preliminary research has found that MENK can upregulate the antiviral state of macrophages to inhibit influenza virus infection. To further study the immunomodulatory mechanism of MENK in macrophages against reovirus, we used RNA-Seq technology to analyze the genomic changes between macrophages infected with Nelson Bay orthoreoviruses (Miyazaki) after MENK pretreatment and those infected with Miyazaki alone. A total of 3,624 genes were screened, with 1,817 genes upregulated and 1,447 genes downregulated. Differentially expressed genes were mainly enriched in the cell cycle (ko04110), FoxO signaling pathway (ko04068), cell adhesion molecules (ko04514), Fc receptor-mediated endocytosis (ko04666), and antigen processing and presentation pathways (ko04612). Key genes such as IL6ST, TNFR2, CCL24, MHC I, MHC II, CD28, FOXO-1, SYK, and CYCD1 were successfully docked with the MENK molecule. Genomic analysis showed that MENK enhanced the immune function of macrophages by upregulating cytokine-related molecules such as CCL24, IL6ST, and TNFR2 to recruit and induce inflammatory responses. Moreover, MENK upregulated the expression of MHC I, MHC II, and CD28 to promote antigen presentation and initiate adaptive immune responses and regulated the FOXO-CYCD1 pathway to inhibit the cell cycle, thereby exerting antiviral effects during reovirus infection.

Esophageal cancer (ESCA) is a significant malignancy with rising global incidence rates and considerable impacts on patient survival and quality of life. Current diagnostic and therapeutic strategies face limitations, necessitating research into its underlying mechanisms and potential biomarkers for early diagnosis. This study aims to investigate the role of perfluorooctane sulfonate (PFOS), an environmental toxicant, in the development of ESCA through a comprehensive bioinformatics approach. Using the TCGA-ESCA dataset, we identified differentially expressed genes (DEGs) and intersected them with PFOS-related toxicity targets predicted via Comparative Toxicogenomics Database (CTD) and SuperPred. Machine learning (Random Forest, XGBoost, LASSO, SVM) were applied to prioritize core targets. Survival analysis, in vitro qPCR (ESO-26/FLO-1 cells), and molecular docking were performed. Immune infiltration and pathway activity (GSVA) were assessed. We identified 98 PFOS-related DEGs in ESCA, enriched in hypoxia response, epithelial migration, and cancer-associated pathways (e.g., AGE-RAGE, PI3K-Akt). Machine learning highlighted three core targets: PLAU, TOP2A, and BAX. High expression of these genes correlated with poor survival (PLAU, p = 0.047) and was upregulated in ESCA tissues. PFOS exposure significantly elevated their expression in esophageal cancer cells. Molecular docking revealed strong binding affinities between PFOS and core targets. GSVA linked PLAU/TOP2A/BAX to oncogenic pathways (angiogenesis, DNA repair), while immune analysis showed PLAU's association with stromal infiltration and TOP2A's negative correlation with CD8 + T cells. PFOS exacerbates ESCA by dysregulating PLAU, TOP2A, and BAX, which drive tumor progression via immune modulation, genomic instability, and oncogenic signaling. These targets may serve as biomarkers and therapeutic vulnerabilities for PFOS-associated ESCA, underscoring the need for environmental regulation and targeted therapies.

Candida onychomycosis is a common fungal nail infection where treatment efficacy can be compromised by antifungal resistance. This study investigates the role of efflux pump genes (CDR1, CDR2, and MDR1) and biofilm-associated genes (ALS1, ALS3) in Candida albicans isolates classified as resistant to itraconazole from patients with onychomycosis. Ten itraconazole-resistant and 10 sensitive isolates were collected for efflux pump and biofilm-associated gene expression analysis by Real-Time PCR methods. Itraconazole resistance was induced in sensitive isolates through pulse exposure. Biofilm formation was quantified both with and without itraconazole. Biofilm structures were visualized by scanning electron microscopy. Our findings indicate a statistically significant upregulation of CDR1 (P-value = 0.049), CDR2 (P-value = 0.023), and ALS3 (P-value = 0.010) in resistant isolates when compared to sensitive isolates. While MDR1 and ALS1 showed some variation, the differences were not statistically significant. Rhodamine 6G efflux assays demonstrated significantly higher efflux activity in resistant isolates (P-value = 0.001 at 60 min). Biofilm formation assays showed itraconazole's impact: pre-treatment reduced biofilm formation, while it had a limited effect on pre-formed biofilms. Scanning electron microscopy indicated less dense biofilms when the formation began in the presence of itraconazole. A pulse exposure to itraconazole also further upregulated CDR1, CDR2, and MDR1 in resistant isolates. Our results implicated CDR1, CDR2, and ALS3 in itraconazole resistance, suggesting their potential as therapeutic targets for future investigation. These findings emphasize the primary role of efflux pumps and biofilm-associated genes in the resistance of clinical C. albicans onychomycosis isolates, although specific mutations (e.g., ERG11, TAC1) were not examined.

Background: Prostate cancer (PCa) poses a significant health burden for men, with docetaxel constituting the primary therapeutic option for patients with metastatic PCa. However, the mechanisms governing docetaxel resistance remain incompletely understood. Several studies have implicated the role of the extracellular matrix (ECM) stiffness in cancer drug resistance, yet the precise role of ECM stiffness in docetaxel resistance in PCa remains elusive. The aim of this study was to explore the influence of ECM stiffness on docetaxel resistance in PCa and elucidate the underlying molecular mechanisms, thereby providing novel insights into PCa treatment. Methods: Polyacrylamide gels of varying stiffness were utilized to mimic different ECM stiffness conditions. The sensitivity of PCa cells to docetaxel was evaluated using CCK-8, TUNEL staining, flow cytometry, and western blotting. RNA-seq was employed to analyze the transcriptomic effects of different ECM stiffness on PC-3 cells. Western blotting, qPCR, and siRNA were utilized to validate the regulatory role of the key gene in the sensitivity of PCa cells to docetaxel under varying stiffness conditions. Results: Our findings indicate that high ECM stiffness enhances docetaxel resistance in PCa cells by inhibiting docetaxel-induced apoptosis. This process is mediated through the integrin-related mechanotransduction pathway. Specifically, high ECM stiffness upregulates the expression of PRRX1, thereby promoting docetaxel resistance in PCa cells. Conclusions: High ECM stiffness promotes docetaxel resistance in PCa, with PRRX1 identified as a pivotal gene in this process. These findings contribute to a deeper understanding of the mechanisms underlying docetaxel resistance in PCa and may inform the development of novel therapeutic strategies.

Platinum-based chemotherapy is the standard treatment for advanced non-small cell lung cancer (NSCLC); however, innate and acquired resistance is a major obstacle. To determine the transcriptional regulators of resistance, we first classified three-dimensional tumor spheroids derived from 11 NSCLC cell lines into cisplatin-sensitive or -resistant groups based on their cisplatin sensitivity and selected signature genes that were differentially altered between the groups. Using reverse engineering methods and functional validation, cAMP response element-binding protein 1 (CREB) was identified as a major regulator of cisplatin resistance. Among the putative target genes of CREB responsible for cisplatin resistance, cisplatin treatment significantly decreased the occupancy of CREB in the regulatory regions of TNKS and KDM6A in cisplatin-sensitive cells, but not in resistant cells, resulting in decreased expression of these protein in the sensitive group. Furthermore, CREB knockdown led to increased sensitivity to cisplatin with reduced levels of TNKS and KDM6A in both cisplatin-resistant tumor spheroids and tumors in a xenograft mouse model. In conclusion, our study delineates the role of CREB in cisplatin resistance and suggests that CREB inhibition is a potential therapeutic strategy for cisplatin-resistant NSCLCs.

Lenvatinib resistance significantly limits its clinical efficacy and application in the treatment of hepatocellular carcinoma (HCC). Mitofusin 2 (MFN2) is an important GTPase involved in mitochondrial fusion, energy balance and mitophagy. The role and regulatory mechanism of MFN2 in HCC progression and lenvatinib resistance remain unclear. Herein, we demonstrated that the family with sequence similarity 111 member B (FAM111B) regulated the stability of MFN2 and the sensitivity to lenvatinib in HCC. Mechanistically, FAM111B promoted MFN2 ubiquitination by recruiting RAN-binding protein 9 (RANBP9), a core subunit of the C-terminal to LisH (CTLH) E3 ligase complex. Targeting FAM111B generated hyperfused mitochondria, driving a metabolic shift from glycolysis to oxidative phosphorylation (OXPHOS) and antagonising cytoprotective mitophagy. Clinically, FAM111B protein levels were inversely correlated with MFN2 expression in HCC samples, with patients who exhibited high FAM111B levels having a worse prognosis and reduced sensitivity to lenvatinib treatment. More importantly, we developed glypican-3 (GPC3)-targeted lipid nanoparticles for efficient delivery of siFAM111B, which demonstrated strong efficacy in combination with lenvatinib. Together, our findings uncover a novel regulatory mechanism for MFN2 posttranscriptional regulation and highlight the therapeutic potential of targeting FAM111B in HCC treatment.