Search Results (34,640)

Background/Objectives: Metabolic alterations, including dyslipidemia, may influence tumor biology and treatment outcomes in neuroendocrine tumors. However, the clinical relevance of dyslipidemia and lipid-lowering therapy in bronchopulmonary neuroendocrine tumors (BP-NETs) treated with somatostatin analogues (SSAs) remains poorly defined. This translational proof-of-concept study evaluated progression-free survival (PFS) in patients with advanced BP-NETs receiving SSAs according to dyslipidemia and statin therapy and explored the effects of statin-SSA combination treatment in vitro. Methods: We retrospectively analyzed 24 patients with advanced well-differentiated BP-NETs treated with SSAs as first-line therapy. Fourteen patients (58.3%) had dyslipidemia, and 11 of them were receiving statins. In parallel, NCI-H727 cells were treated with atorvastatin (10 µM), lanreotide (5 or 10 µM), or their combination for 48–72 h. Cell viability, proliferation, cell death, apoptosis, DNA damage, and ATP production were assessed. Results: Median PFS was 22.5 months overall. A trend toward longer PFS was observed in non-dyslipidemic vs. dyslipidemic patients (70 vs. 36 months, p = 0.08). Among dyslipidemic patients, statin therapy was associated with a non-significant trend toward longer PFS compared with no statin therapy (36 vs. 18 months, p = 0.30). In vitro, combined atorvastatin–lanreotide treatment reduced cell viability and proliferation, increased cell death, enhanced cleaved caspase-3 and p-γH2AX expression, and reduced ATP production. Conclusions: These findings support the potential relevance of lipid metabolism modulation as an adjunct strategy in advanced BP-NETs while highlighting the need for larger prospective studies and dedicated biochemical investigation of the underlying lipid-related pathways. Full article

Background: Glioblastoma (GBM) is the most common and aggressive brain tumor in adults. Changes in the ubiquitination system in GBM cells can promote uncontrolled tumor growth and reduce the effectiveness of treatments. However, the exact targets and regulatory elements of the ubiquitin–proteasome system involved in GBM are still not well understood. Methods: All data were obtained by using in silico analysis, immunohistochemistry, Western blot, RT-qPCR, gene silencing and proliferation assay. Results: Computational and protein analyses show that aggressive gliomas have higher expression of the RING ligase RNF182, with significantly greater levels in glioblastoma (GBM) than in low-grade gliomas. Elevated RNF182 is strongly associated with GBM growth. Experiments using siRNA to inhibit RNF182 in the human glioblastoma cell line U87MG significantly reduced cell proliferation, suggesting that RNF182 promotes tumor growth and may be a potential therapeutic target. Conclusions: These findings create a connection between the ubiquitin–proteasome system and the unchecked growth observed in GBM, identifying RNF182 as a new marker associated with GBM proliferation and an additional target for GBM treatment. Full article

Inflammation is associated with metabolic alterations that can lead to the release of volatile organic compounds (VOCs) reflecting cellular biochemical activity. Profiling these volatile metabolites may provide insight into cellular responses to inflammatory stimuli, although their characterization in skin-derived cells remains limited. In this exploratory proof-of-concept study, we investigated the volatile metabolite profiles of human skin fibroblasts exposed to different inflammatory stimuli. Fibroblast cell lines were stimulated with polyinosinic:polycytidylic acid (Poly I:C), tumor necrosis factor-alpha (TNF-α), and lipopolysaccharide (LPS) to model viral-, cytokine-, and bacterial-associated stress conditions. Headspace solid-phase microextraction coupled with comprehensive two-dimensional gas chromatography and time-of-flight mass spectrometry (HS-SPME-GC×GC-TOFMS) was applied to analyze volatile metabolites released from the cell cultures, enabling exploratory profiling of the fibroblast volatilome. A data-processing workflow including pairwise comparisons between experimental groups and statistical filtering was implemented to identify volatile features associated with the different conditions. Several VOCs were tentatively identified, mainly belonging to alcohol, ester, and hydrocarbon classes, and showed differential abundance patterns between stimulated and control samples. Multivariate analysis indicated a separation between stimulated and non-stimulated groups, suggesting stimulus-associated differences in the volatile profiles of fibroblast cultures. While these observations may reflect metabolic responses occurring under inflammatory stimulation, the chemical identity and biochemical origins of several detected features remain to be confirmed. All in all, this study demonstrates the feasibility of applying HS-SPME-GC×GC-TOFMS-based volatilome profiling to investigate stimulus-associated changes in fibroblast cultures. The detected VOC patterns should therefore be considered preliminary observations requiring further chemical characterization and independent validation. Future studies including larger sample numbers, complementary biological verification of the inflammatory response, and more physiologically relevant experimental models will be necessary to further assess the robustness and potential relevance of these volatile signatures in the context of inflammatory processes. Full article

Ovarian cancer (OC) remains one of the deadliest gynecological malignancies, largely due to late diagnosis and the emergence of resistance to platinum–based chemotherapy. Long non–coding RNAs (lncRNAs) have recently emerged as key regulators of tumor progression and therapeutic adaptation. In this study, we performed integrative transcriptomic profiling of patient–derived TCGA ovarian tumor samples and carboplatin–resistant A2780 (CBDCA–R–A2780) cells to identify lncRNAs whose dysregulation overlaps between a cell–line resistance model and patient tumors. Our analyses revealed extensive transcriptional remodeling across both datasets, with MNX1–AS1 consistently emerging as a strongly deregulated transcript. Differential expression analysis showed robust upregulation of MNX1–AS1 in resistant cells and tumor tissues, accompanied by correlations with epithelial–mesenchymal transition (EMT)–related transcription factors such as FOXA1 and SNAI2 and inverse associations with epithelial markers including CDH1. Computational predictions using RIblast identified specific MNX1–AS1 binding regions with candidate miRNAs and mRNAs, prioritizing EMT–related transcripts (e.g., SNAI2, FOXA1, ZEB1) with favorable hybridization energies for future validation. Additional prioritized interactors included genes linked to stress response (IER2, FOSB) and invasion (MMP11, MMP1). Because A2780 has been discussed as an endometrioid–like/non–serous ovarian cancer model, mechanistic inferences primarily apply to this in vitro context, while TCGA analyses provide associative support rather than mechanistic validation. Collectively, these findings highlight MNX1–AS1 as a candidate regulator associated with transcriptional reprogramming in OC and a promising prognostic biomarker warranting further functional testing. Full article

The cell membrane serves as the first line of defense against adverse environmental factors and is first to adapt to changing conditions. Cell membranes in both coral and its symbionts, which use different membrane adaptation strategies, have to acclimatize to various abiotic stressors. As our molecular-genetics analysis showed, colonies of Junceella fragilis were associated with dinoflagellates Cladocopium thermophilum, Gerakladium endoclionum and Breviolum minutum. We analyzed the phospholipid (PL) molecular species of the wild and cultivated Junceella fragilis and their dinoflagellates (phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidylinositol (PI), ceramideaminoethylphosphonate (CAEP)), as well as thylakoid membrane lipids of dinoflagellates (glycolipids and betaine lipids). When comparing wild and cultivated J. fragilis colonies, there were no significant differences in thylakoid lipids, but there were differences in host membrane phospholipids, namely in PC, PE and PS. Thus, the profile of PL molecular species of the membrane is very sensitive to environmental factors, which probably explains the observed differences in the profiles of molecular PL species in this study. Full article

Multicellular cancer cell aggregates, termed spheroids, are anoikis-resistant, avascular, heterogeneous structures responsible for transcoelomic metastasis of ovarian clear cell carcinoma (OCCC). OCCC is a rare subtype of ovarian cancer with high ARID1A gene mutation rates, resulting in genome-wide changes to H3K27Ac levels and histone deacetylase (HDAC) function. Our study investigated the utility of HDAC inhibitor (HDACi) treatment and H3K27Ac dynamics in OCCC spheroids. By comparing KOC-7c and 105C OCCC cell lines, which have opposing abilities to proliferate as spheroids, we revealed that KOC-7c and 105C spheroids differentially regulated H3K27Ac levels, which correlated with the sensitivity of KOC-7c and the resistance of 105C spheroids to H3K27Ac-altering HDACi treatment. RNA-seq of Entinostat-treated versus vehicle-treated spheroids resulted in a dramatic change in the 105C spheroid transcriptome such that it more closely resembled the proliferative KOC-7c transcriptome over the short term. Comparative pathway analysis identified preferential de-repression of a G2/M checkpoint gene program in 105C spheroids upon Entinostat treatment when compared directly to the KOC-7c spheroids. Our results suggest that the utility of HDACi in OCCC is highly context-dependent. Full article

Hydralazine is widely used to treat hypertension during pregnancy and has epigenetic effects in cancer therapy. Cryoplatable human hepatocytes showed concentration-dependent increase in DNA damage response (linear trend p = 0.0069) following 24 h hydralazine treatment. DNA repair-deficient UV5 Chinese hamster ovary (CHO) cell lines expressing human CYP1A2 and either NAT2*4 (reference allele) or NAT2*5 (variant allele) were treated with hydralazine for 24 h. CHO cells expressing NAT2*4 showed a higher acetylation rate than those with NAT2*5 (p < 0.001), whereas CHO cell viability did not differ significantly following hydralazine treatment (p > 0.05). Hydralazine caused a concentration-dependent increase in DNA damage response in the un-transfected UV5 CHO cell line, as well as in each of the UV5 CHO cell lines transfected with human CYP1A2 and/or NAT2 alleles. CHO cells with CYP1A2 only showed higher DNA damage response from hydralazine compared to cells with CYP1A2/NAT2*4 or CYP1A2/NAT2*5 (p < 0.05 and p < 0.0001, respectively), and higher in CYP1A2/NAT2*4 versus CYP1A2/NAT2*5 cells (p = 0.0011). Apurinic/apyrimidinic (AP) sites in CHO cells expressing only CYP1A2 were significantly higher than in the un-transfected UV5 CHO cell line (p < 0.01) and higher in CHO cells expressing CYP1A2/NAT2*4 compared to CYP1A2/NAT2*5, but the difference was not significant (p > 0.05). In contrast, ROS levels were reduced following hydralazine treatment in CHO cells with CYP1A2/NAT2*4 and CYP1A2/NAT2*5 (p < 0.001 and p < 0.05, respectively). The results of the current study document DNA damage responses associated with hydralazine in human hepatocytes and CHO cells. The DNA damage response was increased following N-hydroxylation by CYP1A2, which competes with N-acetylation by NAT2. Full article

Extracellular vesicles (EVs) mediate intercellular communication by delivering proteins and RNAs, with their molecular cargo often reflecting the biological context of their source. Perinatal tissues are promising sources of EV-related biomaterials with potential dermatologic applications. In this study, we compared EV-related molecular cargo from two umbilical cord-associated sources, umbilical cord mesenchymal stem cell (UCMSC)-derived EVs and cord blood plasma (CBP), to investigate whether these materials exhibit distinct functional effects on melanogenesis. UCMSC-derived EVs were isolated from conditioned culture medium and characterized using nanoparticle tracking analysis (NTA), cryo-electron microscopy (cryo-EM), and canonical EV marker detection, while cord blood samples were processed to obtain plasma following centrifugation and filtration, containing EVs together with soluble plasma components. Functional assays in the murine melanocyte cell line B16F10 demonstrated that UCMSC-derived EVs suppressed melanin production, whereas CBP treatment enhanced melanogenesis. Integrative omics analyses combining microRNAs (miRNAs) microarray profiling and proteomic characterization revealed distinct molecular signatures between UCMSC-derived EVs and CBP samples. Functional validation using miRNA mimic assays showed that selected miRNAs, including miR-6862-5p, miR-3622b-5p, miR-7847-3p, miR-6774-5p, and miR-4685-5p, reduced melanin production, whereas others, including miR-203a-3p, miR-126-3p, miR-139-5p, and miR-15b-5p, increased melanin levels. Pathway analysis using Ingenuity Pathway Analysis (IPA) (QIAGEN Inc.) associated these miRNA subsets with signaling pathways involved in melanogenesis. Together, these findings indicate that UCMSC-derived EVs and CBP exhibit opposite functional effects on melanogenesis and possess distinct miRNA and protein cargo profiles, providing potential molecular targets for modulating pigmentation and supporting the development of EV-related therapeutic strategies for pigmentation disorders. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD), is the most common chronic liver disease in the world. The disease progresses from steatosis to metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis, and hepatocellular carcinoma. The modern concept of “multiple parallel hits” interprets disease progression as the result of the synergistic action of lipotoxicity, oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, proinflammatory signals, and gut–liver axis dysfunction. Against the background of the limited translation of preclinical data from animal models due to interspecies differences, the importance of human-oriented in vitro platforms compatible with controlled design and high-throughput screening is increasing. The current review analyzes MASLD models based on the HepG2 cell line, systematizing steatosis induction protocols, evaluating the metabolic characteristics and limitations of this cell, and comparing 2D monocultures, 3D systems, and co-cultures. HepG2 has been shown to demonstrate a predictable steatogenic response to free fatty acids (FFAs) and is convenient for reproducing early stages of pathogenesis and primary pharmacological selection of compounds. At the same time, key limitations of the model are highlighted, namely tumor origin, glycolytic shift (Warburg effect), reduced β-oxidation, impaired very-low-density lipoprotein (VLDL) assembly and secretion, and sharply reduced cytochrome P450 (CYP450) activity, as well as limited reproducibility of fructose-induced de novo lipogenesis (DNL). Comparative analysis demonstrates an increase in physiological relevance with the transition from 2D to 3D and multicomponent co-cultures, accompanied by increased complexity and cost, but allowing for the modeling of inflammation and fibrogenesis. The review justifies approaches to selecting the appropriate platform based on the specific research task. Full article

Background/Objectives: Non-small-cell lung cancer (NSCLC) involves oxidative stress and inflammation, driving chemoresistance. Paclitaxel (PTX), a first-line chemotherapy, is limited by these factors. Danggui Buxue Tang (DBT), a polyphenolic-rich traditional Chinese herbal formula, was investigated for its ability to potentiate PTX efficacy by inducing ferroptosis via the Nrf2/GPX4 axis. Methods: Effects of DBT + PTX on cell viability, lipid peroxidation, iron accumulation, and Nrf2/GPX4/SLC7A11 expression were evaluated in A549/HCC827 cells with/without ferrostatin-1 (Fer-1). Findings were validated in an A549 xenograft model. Results: DBT significantly enhanced PTX’s anti-tumor effects in vitro and in vivo, an effect reversed by Fer-1. Combination therapy increased ROS, MDA, and iron while suppressing GPX4/SLC7A11 and promoting Nrf2 nuclear translocation. DBT + PTX synergistically reduced tumor volume and proliferation markers (Ki67/PCNA). Crucially, DBT attenuated PTX-induced hepatotoxicity and nephrotoxicity. Conclusions: DBT potentiates PTX efficacy in NSCLC by disrupting the Nrf2/GPX4 axis to induce ferroptosis while mitigating chemotherapy-related toxicity, supporting its potential as an adjuvant strategy targeting oxidative stress pathways. Full article

Pyrrolo[2,3-d]pyrimidine is a privileged fused heterocyclic scaffold that has attracted considerable attention in medicinal chemistry due to its diverse biological activities. Herein, we report an efficient synthesis strategy for the preparation of the pyrrolo[2,3-d]pyrimidine-based natural toyocamycin aglycone and pyrrolo[2,3-d]pyrimidine derivatives. The synthesis of toyocamycin aglycone features a key benzylamine nucleophilic substitution followed by a palladium-catalyzed cyanation reaction. From a key intermediate derived from this route, nineteen new pyrrolo[2,3-d]pyrimidine derivatives were rapidly synthesized via key Suzuki–Miyaura coupling and amine nucleophilic substitution reactions. Their cytotoxic activities were evaluated against Huh-7 and HepG liver cancer cell lines. Most derivatives were inactive after 24 h. However, 28a–28c, 28e and 28f exhibited moderate cytotoxicity with IC₅₀ values ranging from 5.7 to 62.6 μM. Among them, compound 28e displayed the highest potency against HepG cells, with IC₅₀ values of 5.7 μM. Compared with normal HEK293 cells, it showed a selectivity index (SI) of 3.60 against HepG cells. Preliminary structure-activity relationship analysis suggested that incorporation of a cyclopropyl group further improves antitumor activity. Full article

Background/Objectives: EBV is an oncogenic virus linked to NPC and GC, driving cisplatin resistance. Resveratrol has anticancer activity, but its targets and mechanisms against EBV-positive cancers remain unclear. Methods: We assessed resveratrol’s cytotoxicity in EBV-positive cells via functional assays, identified targets by chemical similarity search and molecular docking, and validated PTPN1 via in vitro experiments and nude mouse xenograft models. Results: Resveratrol inhibited EBV-positive cell viability in a time- and concentration- dependent manner, with IC50 values ranging from 35.85 to 145.7 μM across different cell lines at 24–72 h. Apoptosis rates increased by approximately 2- to 4-fold after 80 μM resveratrol treatment for 24 h. Resveratrol directly targeted PTPN1 (docking score = −4.89) and promoted its degradation via the proteasome pathway, as MG132 reversed this effect. Notably, resveratrol synergized with cisplatin (combination index < 1) to reverse cisplatin resistance in both in vitro and in vivo models. Furthermore, resveratrol induced EBV lytic reactivation through ROS production, as evidenced by the increased expression of BZLF1, BMRF1, and BALF2, which was attenuated by the ROS scavenger NAC. Conclusions: Our findings identify PTPN1 as a direct anticancer target of resveratrol in EBV-positive cancers. Resveratrol enhances the therapeutic efficacy of cisplatin via PTPN1 proteasomal degradation and induces EBV lytic reactivation through ROS accumulation. These findings provide a mechanistic basis for the development of novel combination therapies targeting EBV-associated malignancies. Full article

Background: Konjac (Amorphophallus spp.) is an economically important crop valued for the glucomannan content in its corms. Currently, the konjac industry faces germplasm degeneration due to long-term asexual propagation. Developing tissue culture and genetic transformation techniques is essential for its genetic improvement. The WUSCHEL-related homeobox (WOX) transcription factors are critical regulators of somatic embryogenesis and stem cell maintenance in plants. Methods: In this study, we performed genome-wide identification and characterization of WOX genes in the A. konjac reference genome. Furthermore, comparative transcriptomic analyses and functional verification were conducted in A. bulbifer. Results: A total of 12 AkWOX genes were identified in A. konjac, and their structural features were documented. Comparative transcriptomic analysis of A. bulbifer revealed that AbWOX genes were differentially expressed between embryogenic calli (EC) and non-embryogenic calli (nEC). Notably, AbWOX2 was significantly upregulated in EC. Overexpression of AbWOX2 significantly promoted callus proliferation and shoot regeneration in A. bulbifer. Furthermore, AbWOX2-overexpressing lines exhibited a 5.3-fold increase in genetic transformation efficiency (from 5.12% to 27.31%) compared to the control. Conclusions: We characterized the diverse expression patterns of the WOX gene family in Amorphophallus. Crucially, we identified specific individual members—most notably the markedly upregulated AbWOX2—that function as pivotal drivers of somatic embryogenesis and serve as promising candidates for enhancing regeneration and genetic engineering efficiency in Amorphophallus species. Full article

Surface-enhanced Raman spectroscopy (SERS) amplifies Raman scattering by placing molecules in the near-field of plasmonic nanostructures, enabling label-free molecular fingerprinting. While attractive for living cell phenotyping, many cellular SERS works rely on internalized colloidal nanoparticles, leading to variable uptake/localization, aggregation-driven hotspot fluctuations, and potential cellular perturbation. Here, we report a chip-like Au/SiO₂ nanolaminate SERS substrate that supports direct culture and label-free measurements of living cells on spatially defined hotspots without nanoparticle uptake. The periodic nanolaminate forms dense nanogaps and is engineered for 785 nm excitation, providing uniform enhancement over a large, culture-compatible area with high hotspot uniformity. By engineering the cell–substrate nano–bio interface, the platform enables reproducible acquisition of intrinsic cellular vibrational fingerprints under physiological conditions without Raman tags. Using MCF-7 and MDA-MB-231 breast cancer cells, we collected hundreds of spectra per line, and MDA-MB-231 exhibited broader spectral variations, indicating greater heterogeneity. Principal component analysis and linear discriminant analysis achieved 99% classification accuracy for MCF-7 and MDA-MB-231, and bright-field imaging confirmed preserved adhesion and canonical morphologies. This chip-based, label-free living cell SERS platform enables scalable, nonperturbative phenotyping and may support rapid malignancy classification and treatment response screening across subtle cancer states. Full article

Chandipura virus (CHPV) is a neurotropic rhabdovirus associated with recurrent outbreaks of acute encephalitis in children and a high case fatality rate, particularly in India. Despite its public health relevance, the host molecular processes governing CHPV infection and disease progression remain poorly defined. To address this gap, we conducted a time-resolved transcriptomic analysis to characterize host responses to CHPV infection and to explore host-directed therapeutic opportunities. Human HEK293T cells were infected with CHPV, followed by RNA sequencing (RNA-seq) at 6, 12, 18, and 24 h post infection (hpi). Transcriptome profiling revealed a temporally ordered host response. At 6 hpi, CHPV infection was dominated by strong activation of innate immune and inflammatory pathways, including interferon-stimulated genes and cytokine signaling. Antiviral responses persisted at 12 hpi, accompanied by suppression of metabolic and translational processes, indicating a shift in host cellular priorities. By 18 hpi, metabolic reprogramming—particularly involving lipid and sphingolipid metabolism—was observed alongside altered immune signaling, consistent with viral exploitation of host cellular machinery. At 24 hpi, repression of genes involved in chromatin organization, RNA processing, spliceosome assembly, and ribosome biogenesis reflected a global transcriptional shutdown associated with cytopathic effects. Integration of temporal transcriptomic signatures enabled identification of host pathways amenable to pharmacological targeting. Selected host-directed compounds were evaluated in vitro and exhibited antiviral activity against CHPV in a neuronal cell line. Collectively, this study provides the first time-resolved transcriptomic landscape of CHPV infection in human cells and identifies host-targeted strategies relevant for antiviral development. Full article