Search Results (1,307)

Background: Ideal plant architecture is central to high-yield maize breeding. The proportional length of internodes above the ear plays a crucial role in determining plant architecture. Methods: In this study, we used an association panel comprising 288 maize inbred lines and performed genome-wide association studies (GWASs) with 1.25 M high-density single nucleotide polymorphism (SNP) markers under a Q + K mixed linear model. Results: A total of 821 significant SNPs associated with plant height (PH), height above ear (HAE), and internode-related traits were detected, which were further classified into 417 quantitative trait loci (QTL). Among these, 128 significant SNPs and 44 QTL were identified for the U1/HAE trait, and 37 significant SNPs and 27 QTL for the U1/PH trait. Four stable QTL (qU1–qU4) were identified through colocalization analysis. Two candidate genes, Zm00001d013222 (involved in gibberellin signaling) and Zm00001d021304 (involved in cell wall metabolism), were further supported by haplotype analysis. For the former gene, U1/PH values in Hap1 and Hap3 were significantly lower than those in Hap2 (p < 0.01). For the latter gene, Hap2 exhibited a significantly higher U1/HAE value compared to Hap1 (p < 0.001). Conclusions: These findings provide new genetic insights into the regulation of maize internode proportion and plant architecture, offering potential targets for molecular breeding. Full article

Background/Objectives: Although 90% of prostate cancer (PCa) metastasis occurs in the bone, there are limited studies and rarely available genome-wide profiles at individual sample level for genomic copy number changes in the literature. Methods: We performed Affymetrix SNP 6.0 high-density microarray analysis to generate the genome-wide copy number change profiles for six cases of PCa bone metastases. A common genomic loss was confirmed by fluorescence in situ hybridization (FISH) in paraffin-embedded PCa bone metastasis samples together with primary PCa and benign prostate hyperplasia samples. We overexpressed the candidate miRNA in PCa cell lines and knocked down its target genes by siRNA transfection and investigated the effect on protein expression and cell viability, migration, and invasion abilities, respectively. Protein expression in PCa tissues was analyzed by immunohistochemical staining. Results: We provided high-resolution PCa bone metastasis profiles of six cases and identified potential bone metastasis-specific common genomic alterations, including a 1.6 mb region on 17q11.2, as well as those shared by non-bone metastatic PCa. The common 17q11.2 loss was confirmed by FISH in further 14/21 PCa bone metastasis samples but was only found in 9/151 primary PCa samples. The well-established tumor-suppressing miRNA located within this small genomic region, miR-193a-3p, was downregulated in both bone metastasis and primary PCa cases, leading to overexpression of cyclin D1 and uPA to promote cancer cell migration and invasion. Cyclin D1 was highly expressed in both localized PCa and bone metastasis samples, and the expression was significantly higher in the latter group (p = 0.013). Conclusions: We generated high-resolution copy number change profiles for bone metastasis samples. This led to the identification of a common, small genomic loss and downregulation of miR-193a-3p, which suppresses PCa bone metastasis through inhibition of its target proteins, providing new insight into bone metastasis development. Full article

HIV-1 entry into host cells culminates in integration of the reverse transcribed double-stranded viral DNA into host genes. Several lines of evidence suggest that intact, or nearly intact, HIV-1 cores—large, ~60 nm-wide structures—pass through the nuclear pore complex (NPC), and that this passage is associated with pore remodeling. Cryo-electron tomography studies support the dynamic nature of NPCs and their regulation by cytoskeleton and ATP-dependent processes. To explore NPC remodeling, we used super-resolution Stochastic Optical Reconstruction Microscopy (STORM) of U2OS cells endogenously expressing nucleoporin 96 tagged with SNAP. Single-molecule localization imaging and computational averaging resolved 8-fold symmetric nuclear pores with an average radius of ~51 nm. Depletion of cellular ATP using sodium azide or antimycin A, previously reported to reduce the size of yeast NPCs, did not significantly alter the nuclear pore radius in U2OS cells. Similarly, stressing the nuclear envelope by hypotonic or hypertonic conditions failed to induce detectable expansion or contraction of NPCs. These results indicate that the NPCs in U2OS cells do not respond to ATP depletion nor mechanical stresses on changes in pore morphology that can be resolved by STORM. Since these cells are infectable by HIV-1, we surmise that direct multivalent interactions between HIV-1 capsid and phenylalanine-glycine nucleoporins lining the pore’s interior drive the core penetration into the nucleus and the associated changes in the pore structure. Full article

Citrus reticulata Blanco peel is a dominant industrial waste that was recently revalued as a source of bioactive molecules. This study explored its phytochemical and antileukemic potentials. The bioassay-guided fractionation of the dichloromethane extract yielded nobiletin, scoparone, and tangeretin, which were identified spectroscopically. The extract, fractions, and compounds showed antiproliferative effects in both THP-1 and U937 cells, which were employed as in vitro models of acute myeloid leukemia (AML). According to cytofluorimetric analysis, the extract and fractions inhibited cell growth by both apoptosis and necrosis, whereas the single molecules induced apoptosis. This mechanism was mediated by the modulation of BAX and BCL-2 genes in both AML cell lines. Notably, each treatment drove THP-1 and U937 cells into the sub-G0 phase, together with an increase in the cell population in the G1 phase of the cell cycle, both of which were detected cytofluorimetrically. In line with these findings, the extract, fractions, and single molecules counteracted the overexpression of CYCLIN A1 in THP-1 cells while reducing the expression of CYCLIN D2 in U937 cells. Moreover, cell treatments attenuated the invasiveness of AML cells through the upregulation of TIMP-2 at the transcriptional level. Therefore, this study supports pharmaceutical interest in citrus waste for cancer management, providing evidence on its antileukemic potential in vitro. Full article

Glioblastoma (GBM) is the most aggressive primary brain tumor, marked by molecular heterogeneity and poor clinical prognosis. Lysyl oxidase-like 3 (LOXL3) is frequently upregulated in GBM, but its mechanistic contribution remains insufficiently defined. Here, we investigated the functional role of LOXL3 in GBM using CRISPR-Cas9-mediated LOXL3 knockdown in two genetically distinct GBM cell lines: U87MG (wild-type TP53) and U251 (mutant TP53). Reduced LOXL3 expression markedly reduced α-tubulin acetylation, particularly in U87MG cells, and downregulated genes involved in cell cycle progression and proliferation. Both cell lines exhibited mitotic defects, including delayed cell cycle progression and spindle abnormalities; however, cell fate diverged according to TP53 status. U87MG cells, sustained spindle checkpoint activation triggered a p53-dependent spindle checkpoint response culminating in apoptosis, while U251 cells underwent mitotic slippage and senescence. Transcriptomic analyses confirmed differential regulation of apoptosis versus senescence pathways in accordance with TP53 functionality. Additionally, reduced LOXL3 expression markedly impaired adhesion and migration in U87MG cells, whereas U251 cells were minimally affected, consistent with more pronounced microtubule destabilization. Collectively, these findings identify that LOXL3 is a key regulator of microtubule homeostasis, mitotic fidelity, adhesion, and invasive behavior in GBM. Targeting LOXL3 may therefore provide a therapeutic opportunity for genotype-informed intervention in GBM. Full article

Extracellular vesicles (EVs) are emerging as key factors in maintaining cellular homeostasis, critical mediators of intercellular communication, potential biomarkers, and therapeutic tools. While small EVs have been extensively characterized, the molecular signatures of large EVs (including those generated during regulated cell death pathways) remain poorly defined. Here, we investigated the characteristics of large EVs released during apoptosis and pyroptosis by human monocytic cell lines (THP-1 and U937). Apoptosis was induced by staurosporine and blocked using the pan-caspase inhibitor Q-VD-OPh, whereas pyroptosis was triggered by LPS/nigericin and inhibited with a selective NLRP3 inhibitor. We found that both forms of regulated cell death markedly enhanced the release of large EVs. Both apoptotic and pyroptotic large EVs showed increased Annexin V binding and decreased CD9 expression compared with those released by healthy cells. Large EVs derived from apoptotic and pyroptotic cells exhibited distinct proteomic profiles. Pyroptotic large EVs carried interacting protein networks of RNA-binding proteins and chromatin-associated proteins many of which are known damage-associated molecular patterns or alarmins. In contrast, we found that a subpopulation of apoptotic large EVs was characterized by the presence of dsDNA, and active caspase-3/7. Together, our data shed light on the specific protein cargo of large EVs released by cells during apoptosis and pyroptosis. This study identifies candidate markers of large EVs released by dying cells and may enhance our understanding of the role of EVs in regulated cell death. Full article

Background: Recombinant human arginase (rhArg) has been proven to exhibit an anticancer effect via arginine starvation. To further improve the efficacy of rhArg, we examined the feasibility of a combination strategy with Bcl-2 inhibitors (ABT263 and ABT199) or an antidiabetic drug (metformin) and investigated the mechanistic basis for these strategies. Methods: The combination effects were evaluated in a panel of human cancer cell lines modeling pancreatic ductal carcinoma (PDAC), triple-negative breast cancer (TNBC), colorectal cancer (CRC) and glioblastoma (GBM). Western blot analysis was used to evaluate the expression of apoptotic and cell cycle markers. MTT assay was used to evaluate the combination efficacy. Flow cytometric assays were used to investigate the apoptotic and cell cycle effects. Results: The combination of rhArg with sublethal doses of ABT263 significantly induced dose-dependent apoptosis, with elevated expression of apoptotic markers and a CI of 0.47 in U251. The combination inhibited CDK2 and cyclin A expression, indicating that the observed synergy also resulted from cell cycle arrest. We also found that rhArg + metformin was synergistic in a time-dependent manner. Compared to other amino acid depletion agents, rhArg + ABT263 was the most favorable combination pair. Conclusions: The combination of rhArg and ABT263 enhanced apoptosis and cell cycle arrest, demonstrating a potential broad-spectrum antitumor strategy. Full article

Chromatin architecture is highly dynamic, undergoing nanoscale rearrangements throughout the cell cycle and in response to environmental cues. In this study, we employed high-resolution stochastic optical reconstruction microscopy (STORM) to visualize chromatin organization and cellular plasticity at the nanoscale in two osteosarcoma cell lines, U2OS and MG63. To promote a tumor-suppressive bone microenvironment, we applied three biophysical modalities, namely mechanical vibration, electrical stimulation, and optical pulses, each previously linked to altered tumor behavior by reprogramming cells and generating induced tumor-suppressing (iTS) cells. These stimuli enlarged nuclear size and disrupted nuclear envelope integrity, as revealed by increased surface roughness. Critically, all three modalities transiently scattered nucleosome clusters, indicating chromatin decondensation as a hallmark of iTS cell generation. iTS cells exhibited elevated expression of histone demethylases lysine demethylase 3A (KDM3A) and lysine demethylase 4 (KDM4), accompanied by reduced levels of trimethylated histone H3 lysine 9 (H3K9me3). Consistently, pharmacological agents—Trichostatin A as a histone deacetylase inhibitor and chaetocin as a histone methyltransferase inhibitor—induced nucleosome scattering and converted U2OS cells into iTS cells, whose conditioned media exerted tumor-suppressive effects. Our findings highlight nucleosome clustering as a key epigenetic feature responsive to both biophysical and chemical cues, underscoring its role in microscale chromatin remodeling and reprogramming of the tumor microenvironment. Full article

Background: Non-small-cell lung cancer (NSCLC) remains a major therapeutic challenge due to its high incidence and mortality. Herba Patriniae (HP), a traditional Chinese medicine, has long been used for respiratory disorders and exhibits anti-cancer potential. However, the therapeutic effects of HP on NSCLC and the underlying mechanisms have not been fully elucidated. Methods: Network pharmacology was applied to identify the core active components of HP and their potential targets in NSCLC. The anti-cancer effects of the core HP component Linarin on the malignant phenotypes of NSCLC cells were characterized using Tumor Protein P53 (p53) wild-type A549 and p53-null H1299 cell lines with Cell Counting Kit-8 (CCK-8), EdU fluorescence staining, colony formation, apoptosis analysis, cell cycle analysis, and senescence-associated β-galactosidase (SA-β-gal) staining, together with molecular docking and Western blotting analyses. Results: Network pharmacology analysis identified Linarin as the core active component of HP and screened out six hub targets, including Cyclin Dependent Kinase 1/4 (CDK1/4), Cyclin A2/B1 (CCNA2/B1), and Checkpoint Kinase 1/2 (CHEK1/2), which were found to be mainly enriched in cell cycle and senescence pathways. In vitro assays showed that Linarin dose-dependently (0–200 μM) inhibited NSCLC cell proliferation, induced G0/G1 phase arrest, and promoted cellular senescence and apoptosis in both cell lines, irrespective of p53 status. Molecular docking confirmed strong binding affinities between Linarin and the hub targets, and Western blotting confirmed that Linarin downregulated CCNA2/B1 and CHEK1. Conclusions: This study demonstrates that Linarin, the core active component of HP, exerts potent anti-NSCLC effects by inducing G0/G1 arrest, senescence, and apoptosis. These effects are associated with the downregulation of key cell cycle regulators, including CCNA2/B1 and CHEK1. Together, these findings highlight the potential of Linarin as a promising therapeutic option for NSCLC. Full article

Necrosis is a characteristic feature of glioblastoma multiforme (GBM) and is closely associated with tumor-associated inflammation and poor clinical outcomes. However, the molecular consequences of necrotic cell death on endoplasmic reticulum (ER) stress signaling in GBM cells remain unclear. In this study, we examined the effects of necrotic cells on the ER stress signaling and unfolded protein response (UPR) in human glioblastoma cell lines. Exposure to necrotic cells reduced IRE1α phosphorylation and increased unspliced XBP1 (XBP1u) accumulation, without affecting PERK or ATF6 pathways. These changes were accompanied by enhanced IκBα phosphorylation and impaired autophagic degradation. Treatment with ER stress inducers failed to reverse XBP1u accumulation, and reduced phosphorylation of PKAc was observed together with decreased IRE1α activation. Transcriptomic analysis and quantitative reverse transcription PCR (qRT-PCR) revealed that necrotic cell-induced XBP1u was associated with altered expression of XBP1-related genes, while XBP1 knockdown produced similar transcriptional changes and enhanced the effects of necrotic cell treatment. These findings suggest that necrotic cells impair canonical IRE1α-XBP1 signaling and induce transcriptional reprogramming in glioblastoma cells, which may contribute to tumor progression. Full article

A collection of 40 derivatives of 1,2-diphenyl-2-[1,2,3]triazol-1-yl-ethanol was obtained through a sequence of reactions, starting with benzoin as the initial raw material and using the CuAAC reaction as the key step in this process. The structure of a pair of these compounds was ultimately corroborated by single-crystal X-ray diffraction studies, which also reveals important O-H···N interactions. The antimicrobial activity of synthesized 1,2,3-triazoles was assessed against strains that include Candida albicans and Staphylococcus aureus. The antiproliferative properties of some of these novel compounds were also tested using a variety of tumor cell lines, including U251 (human glioblastoma), PC-3 (human prostate cancer cell line), K562 (human leukemia), HCT-15 (human colorectal adenocarcinoma), MCF-7 (human breast adenocarcinoma), and SKLU (human lung adenocarcinoma). Full article

Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. Since numerous studies highlight the significance of cholinergic system components in tumor development, acetylcholine (ACh) and the differential activation of its receptors could play a crucial role in GBM progression. The aim of this study was to test this hypothesis by assessing the relevance of the cholinergic system in GBM cells and their microenvironment. We analyzed bulk RNA-seq expression data using the TIMER2.0 web server, focusing on the impact of patient survival in relation to muscarinic receptors (CHRM) and neutrophil infiltration in low-grade glioma (LGG) and GBM. Our analysis revealed a marked decrease in survival associated with all CHRMs, particularly in LGG. Moreover, GBM showed higher neutrophil infiltration and reduced survival, especially in relation to CHRM3. These findings were validated in the U251 cell line and in human GBM tumor biopsies (GBM-b), which also displayed CHRM3 expression. Additionally, we show that GBM cells exposed to cholinergic stimulation exhibited increased vascular endothelial growth factor (VEGF), IL-8 production, and PD-L1 expression, while the VEGF increase was blocked by tiotropium (Tio), a CHRM3 antagonist. Similarly, polymorphonuclear cells from GBM patients (PMN-p) displayed increased PD-L1 expression and IL-8 production upon cholinergic stimulation. Finally, as we previously reported on the relevance of thymic stromal lymphopoietin (TSLP) in GBM pathophysiology, here, we found that TSLP upregulated CHRM3 expression. Our findings highlight the importance of the cholinergic system in the tumor microenvironment, where it may act directly on tumor cells or influence neutrophil physiology, thereby modulating tumor progression. Full article

Background: The survival of newly diagnosed multiple myeloma (NDMM) has improved markedly worldwide with the introduction of proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and anti-CD38 monoclonal antibodies. However, real-world progress among Chinese patients remains underexplored. This study evaluated 20-year survival trends in patients with NDMM treated in our institute and benchmarked them against outcomes from the Flatiron Health database in the United States. Patients and methods: Consecutive adults diagnosed with NDMM in our institute between 2003 and 2023 were retrospectively analyzed. U.S. patients were identified from the Flatiron Health database using similar inclusion criteria. Clinical characteristics, first-line regimens, and autologous stem cell transplantation (ASCT) rates were summarized. Overall survival (OS) and progression-free survival (PFS) were estimated by Kaplan–Meier methods. Results: Among 1622 Chinese and 12,582 US patients, median age was 57 vs. 68 years. The median PFS and OS of NDMM patients in our institute was 40.1 months and 99.6 months, respectively. Induction therapy in the NICHE cohort changed markedly from primarily chemo-based therapy to combined PIs + IMIDs-based treatment, whereas these treatments were used much earlier in Flatiron. Uptake of new therapies in China increased rapidly after their inclusion in national health insurance. ASCT utilization was higher overall in China (34.9% vs. 22.1%) but remained lower among patients >65 years (6.7% vs. 12.1%). Conclusions: Two decades of real-world data from a major Chinese myeloma center demonstrate substantial improvements in survival and modernization of NDMM treatment, while highlighting persistent disparities amongst older adults. Full article

Glioblastoma (GBM) represents a highly invasive primary malignant tumor within the central nervous system (CNS). Temozolomide (TMZ), a first-line chemotherapy agent for GBM treatment, has significant limitations, including drug resistance, poor water solubility, a short half-life, and notable toxic side effects. The innovation of the TMZ dosage form is pivotal for enhancing its therapeutic efficacy. In this study, solid lipid nanoparticles (SLN) loaded with Angiopep-2 (A2) and TMZ (TMZ-A2SLN), a nanopolymer featuring a solid spherical morphology and a particle size of approximately 100 nm, were constructed. The combined effect of TMZ-A2SLN and small-interfering RNA (siRNA) that can knock down the expression of the HOXB9 gene (siHOXB9) augmented the sensitivity of the glioma cell line U251 to TMZ. Under the combined effect, the viability of U251 cells was reduced by 77%. Meanwhile, the mortality rate increased by approximately 45%, and the cell apoptosis rate rose by around 36%. The number of cells arrested in the G2/M and S phases rose. Proteomic analysis indicates that TMZ-A2SLN might be implicated in the pro-inflammatory signaling cascade, tumor migration, invasion, and angiogenesis during the treatment of glioma cells. Moreover, HOXB9 may play a crucial regulatory role in the PPAR signaling pathway, the neural signaling pathway, the phospholipase D signaling pathway, the IL-17 signaling pathway, mineral absorption, and other pathways during glioma cell treatment. Full article

Zn-based ternary deep eutectic solvents (TDESs) have attracted significant attention due to their good biodegradability, stability, and sustainability. In this work, TDESs composed of choline chloride:urea (ChCl:U) and zinc salts, ZnCl₂, Zn(CH₃COO)₂, and ZnSO₄ were synthesized and characterized by Fourier transform infrared (FTIR) spectroscopy and laser desorption ionization mass spectrometry (LDI MS). Their antibacterial activity against cariogenic Streptococcus species isolates was determined by microdilution assay, while their cytotoxic potential and effect on the intracellular reactive oxygen species (ROS) induction were analyzed on the MRC-5 fibroblast cell line by XTT, trypan blue, and DCF assays, respectively. FTIR confirmed that hydrogen bonds prevail in the molecular structure of ChCl:U:Zn salts, while LDI MS revealed the interactions between zinc salts and ChCl:U. The antibacterial TDES potential was high, especially against Streptococcus sanguinis, with ChCl:U:ZnCl₂ displaying the most promising effects (MICs 1.13–18.12 µg/mL). Cytotoxicity assessment showed that concentrations up to 100 µg/mL of all TDESs did not display significant cytotoxicity, while higher concentrations significantly reduced cell viability by increasing ROS production and cell membrane damage, outlining the safety window of up to 100 µg/mL. Strong antibacterial activity of low TDESs concentrations combined with their good biocompatibility highlights their potential as innovative candidates for biomedical application. Full article