Search Results (258)

Taxanes, such as paclitaxel and docetaxel, are microtubule-stabilizing agents widely used in oncology, either as monotherapy or in combination regimens. While highly effective, these first-generation taxanes face important limitations, including significant toxicity, reduced water solubility, and the emergence of multidrug resistance. To address these challenges, semi-synthetic taxoids have been developed, aiming to improve pharmacological profiles and overcome therapeutic barriers. Central to these efforts is the understanding of structure-activity relationships, which guides the rational design of taxane analogues with enhanced efficacy and safety. This review explores recent advances in taxoid development, highlights findings from clinical trials, and evaluates how these new agents compare with traditional taxanes in terms of therapeutic potential and tolerability. While novel delivery systems offer improved outcomes with existing drugs, the development of new taxane analogues remains a promising approach to address drug resistance, albeit with challenges related to toxicity, high costs, and historically low success rates in drug development. Furthermore, taxanes are already used in certain cardiovascular conditions and show emerging potential in neurodegenerative diseases, although current evidence remains largely limited to preclinical or early-phase clinical studies. These developments mark an important evolution in the field and offer new opportunities for future therapeutic strategies. Full article

Winter rapeseed (Brassica rapa L.) is an important crop for vegetable oil production in China. However, its productivity is frequently threatened by severe cold waves during winter. To investigate the role of the microtubule cytoskeleton in cold adaptation of winter rapeseed, a microtubule stabilizer paclitaxel (Tax) and a microtubule depolymerizer colchicine (Col) were sprayed on winter rapeseed and transgenic proBrAFP1 Arabidopsis, respectively. The mRNA levels of cold-induced genes, along with cell membrane stability, antioxidant enzyme activities, and hormone levels were assessed under cold stresses of 4 °C and −4 °C. The results showed that low temperature significantly activated the proBrAFP1 promoter activity and increased the mRNA levels of core cold signaling pathway genes, such as C-REPEAT BINDING FACTORS (CBFs), Cyclic Nucleotide-Gated Channel (CNGC), OPEN STOMATA 1 (OST1) and Inducer of CBF EXPRESSION 1 (ICE1). Notably, under low-temperature stress, exogenous application of the microtubule stabilizer Tax markedly suppressed proBrAFP1-driven reporter activity in transgenic Arabidopsis, with consistent inhibition observed across both stem and leaf tissues; meanwhile, the Tax application alleviated reactive oxygen species (ROS) accumulation and mitigated membrane damage. In contrast, under the same low-temperature stress, the Col treatment exacerbated oxidative stress, enhanced lipid peroxidation, and elevated membrane damage. Collectively, these findings establish that microtubule regulators play indispensable roles in the cold stress response of winter rapeseed. It provides new insights into the mechanism by which plant microtubule cytoskeleton regulators mediate the cold response. Full article

Fat deposition plays a crucial role in regulating the production performance and meat quality of broilers. Although the heterogeneity of mammalian adipocytes has been extensively studied, research on the molecular mechanisms underlying differences in lipid droplet accumulation in avian adipocytes remains limited. This study confirmed a significant positive correlation (R² > 0.81, p < 0.001) between the SSC signal and lipid droplet content via fluorescence staining of lipid droplets, Oil Red O staining, and triglyceride (TG) quantification. Based on this, a label-free sorting strategy using SSC signals was established to sort differentiated chicken preadipocytes, obtaining high lipid droplet (H) and low lipid droplet (L) subpopulations, which were subsequently subjected to transcriptome sequencing and differential gene expression (DEG) analysis, followed by GO and KEGG enrichment analysis. The results indicated no significant differences in the expression of adipogenesis marker genes (PPARG, LPL, CD36, PLIN1, PLIN2) between the high lipid droplet (H) and low lipid droplet (L) groups, suggesting that both groups are at similar stages of differentiation. KEGG analysis revealed that both the H vs. NC and L vs. NC comparisons were enriched in common pathways, including the PPAR signaling pathway, ECM–receptor interaction, focal adhesion, cytokine–receptor interaction, and calcium–Apelin signaling pathway, suggesting that both groups of cells had activated the adipogenesis program. GO analysis showed that, in both H vs. NC and L vs. NC comparisons, differentially expressed genes (DEGs) were enriched in biological processes (BPs) related to cell adhesion, nucleosome assembly, chromatin remodeling, and receptor activity, as well as cellular components (CCs) such as the extracellular matrix, cytoskeleton, and nucleosome organization, indicating extensive gene reprogramming and activation of signaling transduction during differentiation. In the H vs. L comparison, enriched pathways included ABC transporters, ECM–receptor interaction, focal adhesion, gap junctions, microtubule-related processes, and neuroactive ligand–receptor interactions, involving lipid transmembrane transport, cytoskeleton stabilization, and signal transduction regulation, suggesting that high lipid droplet cells are more mature in lipid droplet transport, storage, and homeostasis maintenance. GO enrichment results further supported this conclusion, as H vs. L specifically enriched processes related to microtubule-related processes, cell cycle, and redox reactions (BPs), as well as chromosome organization, cytoskeleton, and motor activity (CC/MF), indicating that high lipid droplet cells maintain lipid droplet fusion and metabolic homeostasis via enhanced microtubule transport and antioxidant regulation. Differential gene analysis revealed that the L group upregulated genes associated with fatty acid synthesis and elongation (ACACA, FASN, SCD, FADS2, ELOVL1), cholesterol and isoprenoid biosynthesis (HMGCR, SQLE, MSMO1, DHCR7, DHCR24, FDPS, LSS), and fatty acid oxidation (PPARA, PPARD, ACAD11, SIRT5), reflecting a metabolic characteristic of concurrent lipid synthesis and mobilization; the H group, conversely, upregulated genes associated with lipid droplet formation and storage (G0S2, MOGAT1, GPAT4, PLIN4, AUP1), lipid transport (ABCA1, ABCA2, ABCG1, OSBPL3, VLDLR), and antioxidant defense (GPX3, GPX4, HMOX1), exhibiting a storage and homeostasis-oriented metabolic state. In the NC, L, and H groups, the expression of five genes—GEM, SPP1, ABCA1, PDLIM3, and ITGA8—showed a gradual increase, suggesting that these genes were associated with preadipocyte differentiation and lipid droplet deposition. In summary, although the high and low lipid droplet subpopulations of chicken preadipocytes exhibit similar differentiation states, they form distinct metabolic orientations. The L group is characterized by active lipid synthesis, fatty acid oxidation, and membrane lipid remodeling, while the H group predominantly features lipid droplet storage, lipid transport, and antioxidant homeostasis. This study highlights the molecular mechanisms underlying the metabolic heterogeneity of avian adipocytes and provides a theoretical basis for poultry fat deposition regulation and genetic improvement. Full article

Background/Objectives: SETD2 is a dual-function methyltransferase important for methylation of histone H3 at lysine 36 and α-tubulin in spindle microtubules. Genetic inactivation of SETD2 during oncogenesis drives loss of H3K36me3, genomic instability, and cancer progression. This study asked if disruption of genomic stability was a canonical feature of SETD2 inactivation via different pathways. Methods: We evaluated the impact of EPZ-719, a pharmacologic SETD2 inhibitor, and an H3.3K36M mutant histone (“oncohistone”) that binds and sequesters SETD2, on methylation activity and genomic stability in human cell lines. SETD2 activity was measured using in vitro methylation assays, H3K36me3 loss confirmed by Western analysis, and mitotic defects, specifically micronuclei and chromatin bridges, quantified with cytogenetic analysis. Results: EPZ-719 caused a dose- and time-dependent reduction in SETD2 activity on both histone and tubulin substrates, accompanied by significant increases in chromatin bridges and micronuclei in retinal pigmented epithelial (RPE-1) and 786-O ccRCC cells. Similarly, oncohistone expression markedly decreased SETD2 function, as determined by H3K36me3 levels, and induced comparable mitotic defects in 786-O cells, and aneuploidy in two chondrocyte cell lines expressing the H3.3K36M oncohistone. Combining EPZ-719 with H3.3K36M expression did not exacerbate mitotic defects beyond either oncohistone or pharmacologic inhibition alone, consistent with inhibition of SETD2 as their shared underlying mechanism of action. Conclusions: Pharmacologic inhibition and oncohistone-mediated sequestration of SETD2 converge on the induction of mitotic defects, underscoring SETD2’s essential role in maintaining genomic stability. Identification of loss of genomic stability as a canonical feature of SETD2 inactivation points to a potential therapeutic liability associated with targeting SETD2 in cancers where it is overexpressed and reveals a mechanism that could contribute to the progression of cancers expressing oncohistone mutations. Full article

Zebrafish epiboly is a critical morphogenetic event driven by the precise coordination of microtubule-mediated pulling forces and actomyosin-dependent constriction. While the phosphatase PRL-3 is known to regulate cytoskeletal remodeling in cancer metastasis, its physiological function during early vertebrate embryogenesis remains undefined. Here, we identify zfPRL-3 as an indispensable regulator of zebrafish epiboly. Morpholino-mediated depletion of zfPRL-3 resulted in severe developmental arrest, blastoderm destabilization, and mechanical rupture of the yolk cell. Time-lapse imaging revealed that zfPRL-3 morphants suffer from catastrophic structural failures, characterized by either blastoderm dispersion or excessive inward constriction. At the cellular level, we demonstrate that zfPRL-3 depletion disrupts the organization of the Yolk Syncytial Layer (YSL), evidenced by the irregular scattering of YSL nuclei—a hallmark of microtubule network collapse. Furthermore, zfPRL-3 morphants exhibit premature assembly of the contractile actomyosin ring at 60% epiboly, indicating a failure in the inhibitory mechanisms that normally restrain marginal constriction. We propose that zfPRL-3 functions as a molecular brake that couples YSL integrity with the timing of contractility. By maintaining microtubule stability and preventing premature actomyosin ring formation, zfPRL-3 ensures that the opposing physical forces driving epiboly are precisely balanced. Collectively, our findings define zfPRL-3 as a critical spatiotemporal regulator that orchestrates the successful progression of epiboly. Full article

Alzheimer’s disease (AD) is characterized by progressive cognitive decline, with amyloid beta oligomers (AβOs) emerging as the most neurotoxic species and acting as early triggers of cellular alterations. Before the appearance of other protein aggregates, AβOs disrupt the dynamics and stability of the neuronal cytoskeleton, a structure essential for maintaining neuronal morphology, axonal transport, and synaptic plasticity. Experimental evidence demonstrates that AβOs promote microtubule disassembly, Tau hyperphosphorylation, reduced kinesin levels, impaired axonal transport, and alterations in actin dynamics through the LIMK–cofilin signaling pathway. In addition, increased levels of neurofilament light chain have been identified as an early biomarker of axonal damage. Notably, these cytoskeletal disturbances arise in the absence of extensive neuronal death, underscoring the cytoskeleton as a critical early target in AD pathogenesis. In this review, we analyze cytoskeletal alterations induced by AβOs in neurons and discuss how these changes may contribute to disrupted neuronal communication, a defining early hallmark of AD pathology. Full article

Microtubule-associated proteins (MAPs) are multifunctional tubulin-binding proteins that contribute to essential aspects of mitotic spindle formation. In the present study, loss of the MAP CFDP1 in mice resulted in gastrulation defects and embryonic lethality at e8.5 due to chromosome segregation spindle defects and loss of K-fiber stability. CFDP1 decreased the association of the nuclear transport protein importin α with the essential spindle assembly factor TPX2, thereby promoting Aurora A kinase activation, microtubule nucleation and spindle assembly. Further defining the CFDP1 mode of action, we identified CFDP1 as a bipartite molecule with an acidic N-terminus that harbors a nuclear localization signal essential for importin α dissociation from TPX2 and a basic C-terminus that interacts with tubulin, co-localizes with the mitotic spindle, and promotes microtubule bundling and polymerization. Together, our studies have established CFDP1 as an essential bipartite MAP involved in chromosomal microtubule nucleation in conjunction with TPX2 and Aurora A while also facilitating nuclear TPX2 activation through importin α dissociation. Full article

In this paper, we study the time-space truncated M-fractional model of shallow water waves in a weakly nonlinear dispersive media that characterizes the nano-solitons of ionic wave propagation along microtubules in living cells. A fractional wave transformation is applied, reducing the model to a third-order differential equation formulated as a conservative Hamiltonian system. The stability of the equilibrium points is analyzed, and the corresponding phase portraits are constructed, providing valuable insights into the expected types of solutions. Utilizing the dynamical systems approach, a variety of predicted exact fractional solutions are successfully derived, including solitary, periodic and unbounded singular solutions. One of the most notable features of this approach is its ability to identify the real propagation regions of the desired waves from both physical and mathematical perspectives. The impacts of the fractional order and gravitational force variations on the solution profiles are systematically analyzed and graphically illustrated. Moreover, the quasi-periodic dynamics and chaotic behavior of the model are explored. Full article

Microtubule minus-end binding proteins (−TIPs) are critical regulators of microtubule dynamics and stability, whose dysfunctions are increasingly associated with tumorigenesis and cancer progression. This review systematically consolidates current research advances on the molecular characteristics, oncogenic mechanisms, and therapeutic potential of −TIPs in cancer. By integrating preclinical studies, multi-omics data, and clinical evidence, it was found that calmodulin-regulated spectrin-associated proteins (CAMSAPs) and abnormal spindle microtubule assembly (ASPM) primarily exhibit oncogenic properties, whereas CAMSAP3 acts as a tumor suppressor by negatively regulating tumor cell migration. Studies also demonstrate that pharmacological inhibition of the γ-tubulin ring complex (γ-TuRC) effectively attenuates the centrosomal hyper-clustering capacity of malignant cells, thereby suppressing invasive phenotypes. This result underscores the therapeutic value of targeting −TIPs. In summary, −TIPs play critical and complex roles in cancer progression and hold significant potential as prognostic biomarkers and therapeutic targets. Intervention strategies focusing on specific −TIPs, such as γ-TuRC, offer promising strategies for precision cancer therapy; however, the context-dependent functions of these proteins require further investigation to facilitate clinical translation. Full article

The epidermal cells of bracts, petals and sepals of Ornithogalum umbellatum L. (Star-of-Bethlehem, Asparagaceae) contain lipotubuloids, complex aggregates of lipid droplets (LDs) enmeshed by bundles of microtubules (MTs). We investigated lipotubuloid organization and stability through the transient expression of GFP fusion proteins targeted to different subcellular structures and with immunofluorescence and transmission electron microscopy (TEM). Live cell imaging confirmed that lipotubuloids contain LDs, organelles including endomembranes, mitochondria and peroxisomes, a tonoplast-defined vacuole, and that they move through actin microfilament-based streaming. Intriguingly, the different microscopy modes used showed different patterns of MT organization in the lipotubuloid. While MT sheets and bundles were visible by TEM, few MTs were seen with fusion proteins and immunofluorescence. Oryzalin-based MT depolymerization experiments suggest a possible resolution for this paradox: TEM showed that lipotubuloid MTs resisted depolymerization, even after 20 h in oryzalin, while MT polymerization was visible in lipotubuloids with fusion proteins during oryzalin wash-out. These results suggest that the Ornithogalum lipotubuloids contain hyperstable MTs, possibly formed with microtubule-associated proteins (MAPs) that normally occlude fusion protein and antibody binding sites. Full article

Best known as an organizer of the mitotic spindle, the protein product of the human assembly factor for spindle microtubules (ASPM) gene has recently been shown to function in the interphase nucleus during multiple DNA-associated processes, including BRCA1-mediated DNA DSB repair, ATR-CHK1 activation during replication stress, and transcription regulation alongside the transcription factor FOXM1. In this review, we provide an overview of these DNA-related roles of ASPM. Additionally, we suggest the facilitation of liquid–liquid phase separation (LLPS) as a potential unifying mechanism underlying ASPM function. We also consider the implications of LLPS and ASPM dysfunction in disease, and highlight the impact of cellular context including cell cycle phase-dependent post-translational protein modifications and ion concentrations. An increased understanding of LLPS in ASPM function relevant to genome stability may enable future drug discovery for diseases such as cancer. Full article

Ethylene glycol (EG) is a vital industrial raw material. However, it has the potential to be hazardous to the environment and human health. High operating temperatures and long response/recovery times limit the wide application of EG sensors. Thus, we need to develop high-performance room-temperature EG-sensing materials. This paper proposes the direct hydrothermal carbonization of magnolia hair to prepare porous microtubular carbon (CMH) for room-temperature EG sensing. SEM, TEM, and XPS characterization showed that the CMH exhibited a porous microtubular structure and contained Na, which enhanced the adsorption capacity of the CMH for ethylene glycol gas. The CMH sensor exhibits a high response (156.4) to 500 ppm ethylene glycol gas at room temperature with moderate response/recovery time (14.2/37.3 s). It exhibits good linearity in measuring EG gases in the 10–100 ppm range, with a 0.292 ppm theoretical detection limit. Additionally, CMH sensors provide excellent repeatability and long-term stability. The synergistic effect of microtubule porous structure and Na doping is the main reason for enhancing the response of the sensor to EG gas. On this basis, the gas-sensitive enhancement mechanism of CMH was analyzed. The results show that biomass carbon materials provide a new method to prepare high-performance EG gas sensors. Full article

Tau was initially identified as a microtubule-binding protein critical for microtubule stabilization. It is also a pathological hallmark of tauopathies, a group of neurodegenerative diseases that include Alzheimer’s disease. Under pathological conditions, Tau becomes hyperphosphorylated at numerous sites and aggregates into filamentous deposits, contributing to neuronal cell death and disease progression. While significant research has focused on Tau phosphorylation dynamics and their consequences in pathological contexts, comparatively few studies have investigated Tau phosphorylation during physiological processes, despite the potential relevance to the early onset of pathology. Previous findings have suggested similarities between mitotic Tau phosphorylation and hyperphosphorylation observed in tauopathies, particularly at sites such as AT8, PHF1, S214, and S422. In this study, we quantified the relative levels of phosphorylation at 12 Tau phospho-epitopes during interphase and mitosis in vitro to establish a preliminary mitotic phospho-Tau signature, which was subsequently validated in vivo. Our results demonstrated pronounced phosphorylation of Tau at AT8, p-T217, and p-S422 epitopes during mitosis, both in vitro and in vivo. These findings provide new insights into the physiological phosphorylation of Tau and its potential links to pathological processes. Full article

Kinesin spindle protein (KSP), also known as KIF11, is a member of the kinesin superfamily of motor proteins that plays a pivotal role in mitosis by regulating spindle assembly, chromosome alignment, and segregation. Its motor activity, which is essential for the proper organization of microtubules during mitosis, is crucial for maintaining genomic stability. KSP overexpression has been observed in several cancer types, where it promotes uncontrolled cell proliferation, making it a promising target for cancer therapy. This review provides a comprehensive analysis of the molecular mechanisms underlying KSP function, including its structural features, ATPase activity, and interactions with other mitotic proteins. Additionally, we review the regulation of KSP through post-translational modifications, such as phosphorylation, as well as the therapeutic strategies currently being explored to inhibit its activity in cancer treatment. Full article

Essential oils are increasingly recognized as promising agents for sustainable weed control due to their selectivity and complex modes of action. This study evaluated the effects of Acorus calamus essential oil (SEO) on mitosis in two Fabaceae species (Vicia faba, Lupinus luteus) and two Brassicaceae species (Brassica napus, Arabidopsis thaliana) treated with species-specific IC₅₀ concentrations (0.03%, 0.025%, 0.01%, and 0.005%, respectively). Previous research showed that SEO induces oxidative stress and S-phase delay via genome instability. Here, SEO consistently disrupted mitosis across all species, reducing mitotic index by 50–60%, decreasing Cdc2 (CDKA homolog) levels, and causing chromosomal aberrations, including uneven chromatin condensation, sticky chromosomes, bridges, and micronuclei. Cells accumulated in metaphase and exhibited abnormal karyokinetic and cytokinetic spindles. Immunolabeling revealed thick, tightly packed microtubules and actin filaments, indicating excessive stabilization and impaired reorganization. Epigenetic regulation was also affected: H3T3 phosphorylation was abnormally strong, widely distributed, and persistent into anaphase/telophase, while H3S10Ph intensity was weakened. These results suggest that SEO targets multiple components of mitotic machinery and epigenetic control, regardless of species. The observed selectivity depends on dosage, not mechanism. This multi-targeted action may limit the development of plant resistance, supporting the potential of SEO as a bioherbicide in sustainable agriculture. Full article