Search Results (223)

Objective: Identifying biomarkers that predict metastatic potential or guide treatment selection is critical for improving breast cancer (BC) management. Previously, we established the Mitotic Network Activity Index (MNAI) as a prognostic marker in BC. Here, we bioinformatically and experimentally evaluated MNAI as a biomarker for metastasis risk and therapeutic response. Methods: We used Kaplan–Meier and Cox proportional hazard regression analyses to assess the association between MNAI and distant metastasis-free survival (DMFS) across 14 published BC datasets. A total of 16 publicly available clinical trial datasets, including the I-SPY trials, were used to evaluate the predictive value of MNAI for treatment response. Additionally, wound-healing and transmembrane assays were conducted to determine the effects of PLK1, CHEK1, and BUB1 inhibition on BC cell migration and invasion. Results: High MNAI levels were strongly associated with shorter DMFS. Multivariate analysis further confirmed MNAI as an independent risk factor for DMFS, beyond estrogen receptor status and PAM50-based molecular subtypes. Functionally, pharmacologic disruption of the mitotic network using PLK1, CHEK1, or BUB1 inhibitors significantly reduced cell migration and invasion in MDA-MB-231 and BT-549 BC cell lines. Moreover, BC cells with high MNAI increased sensitivity to microtubule-targeting agents such as docetaxel, paclitaxel, and ixabepilone but increased resistance to tamoxifen, AKT1/2 inhibitors, and mTOR inhibitors. Consistent with these findings, analysis of 16 clinical trial cohorts revealed that patients with high MNAI achieved higher pathological complete response rates to taxane-containing and ixabepilone-based therapies. Conclusions: Our findings demonstrate the MNAI as a clinically actionable biomarker that can refine risk stratification and guide the selection of targeted or chemotherapy regimens, advancing precision medicine in BC management. Full article

Acute myeloid leukemia (AML) is one of the most aggressive types of leukemia, represented by the clonal proliferation of hematopoietic precursors, which mainly promotes quantitative and differentiation alterations, as well as normal hematopoiesis suppression. Throughout leukemogenesis, modifications may occur in several elements that make up cellular signaling pathways; among these, AURKA, AURKB, and PLK1 are key related regulators of mitotic progression and cellular proliferation. This study investigated the hematological profile and the expression of the AURKA, AURKB, and PLK1 genes in a cohort of individuals with AML, in order to understand their roles in the pathophysiology of the disease. The analyses revealed a significant hypoexpression of AURKA in the bone marrow of AML individuals compared to the control group (p = 0.0254) and AURKB showed no significant difference in bone marrow and peripheral blood samples. It was also observed a hyperexpression of PLK1 in bone marrow (p < 0.0001) and in peripheral blood (p = 0.0144). Our results also point to PLK1 as a potential biomarker for AML, since its hyperexpression did not differ with respect to gender, risk stratification, or age of the individuals. Finally, survival analyses indicate that AURKA expression in the bone marrow is associated with a protective factor and increased survival, and that those with higher expression of the three target genes had a lower mortality rate (p = 0.043). Full article

Colorectal cancer (CRC) therapy frequently relies on chemotherapeutic agents with high cytotoxicity, low selectivity, and suboptimal efficacy. Thus, the search for alternative therapeutic strategies for CRC continues. In the present work, the antitumor potential of a hybrid compound, which contains fragments derived from resveratrol and curcumin, was evaluated. These natural compounds are known by their antioxidant, chemopreventive, and chemotherapeutic properties. Different methodologic approaches were used to investigate cytotoxic, genotoxic, antiproliferative, and antioxidant effects of a hybrid compound, named PQM-162, on HCT-8 colorectal cancer cells. The results showed that PQM-162 displays radical scavenging capacity as demonstrated by DPPH assay. Furthermore, this substance reduced cell viability and inhibited cell cycle progression at G2/M in HCT-8 cells. Antiproliferative activity of PQM-162 was associated with its ability to modulate the expression of critical regulators of G2/M transition and mitosis progression such as PLK1, AURKB, and CDKN1A. Taken together, our data indicate that PQM-162 is a promising antitumor agent due to its disruption of the redox balance in cancer cells and its modulation of the expression of regulators of the cell cycle and mitotic apparatus. Full article

Polo-like kinase 1 (PLK1) is a serine/threonine kinase that orchestrates multiple critical events during mitosis, including centrosome maturation, spindle assembly, kinetochore–microtubule attachment, and cytokinesis. Dysregulation and overexpression of PLK1 are frequently observed in various cancers, correlating with increased proliferation, metastatic potential, and poor prognosis, which highlights its potential as a therapeutic target. Traditional small-molecule inhibitors have predominantly focused on the ATP-binding site of the N-terminal kinase domain, effectively inducing mitotic arrest and apoptosis in tumor cells; however, these compounds often suffer from limited selectivity and off-target toxicity. The C-terminal Polo-box domain (PBD), responsible for substrate recognition and subcellular localization, has emerged as an alternative and highly selective target for inhibitor design, enabling the disruption of protein–protein interactions critical for PLK1 function. Here, we present a comprehensive review demonstrating the potential inhibition of several compounds against PLK1. This work establishes a foundation for future preclinical development of small molecule-based therapeutics against PLK1-dependent malignancies. Full article

In this work, we report an efficient synthetic strategy for accessing novel 1,4-disubstituted-1,2,3-triazole-1,3-oxazole hybrids. The synthesis involves a two-step, three-sequence approach: a multicomponent reaction, subsequent oxidation, and the Van Leusen reaction. This operationally simple protocol proceeds under mild reaction conditions and allows the rapid assembly of structurally diverse heterocyclic systems. Three new hybrid molecules were synthesized and structurally characterized. To investigate their biological potential, we performed bioactivity prediction studies using cheminformatics tools. Polo-like kinase 3 (PLK3), a serine/threonine-protein kinase involved in cell cycle regulation and apoptosis, was identified as a potential molecular target, for which docking studies were performed, obtaining good ligand efficiency. Full article

Polo-like kinase 1 (PLK1) is a serine/threonine protein kinase expressed in smooth muscle cells (SMCs), with emerging roles in regulating contraction. We hypothesize that PLK1 contributes to smooth muscle contractility in pudendal arteries (PA), small mesenteric arteries (SMA), and the corpus cavernosum (CC). Using male C57BL/6J mice, we assessed mRNA and protein expression of PLK1 in these tissues. In addition, the arteries and CC were mounted in myographs for isometric force measurement. We then investigated whether PLK1 regulates SMC contractility induced by phenylephrine (PE), U46619, and angiotensin II (Ang II) in arteries, and by PE, serotonin (5-HT), and electrical field stimulation (EFS; 1–16 Hz) in the CC, both in the presence and absence of the PLK1 inhibitor volasertib. PLK1 expression was confirmed in the SMA, PA, and CC by RT-qPCR or Western blotting. Notably, PLK1 inhibition significantly reduced Ang II-induced contraction in the PA and SMA and attenuated EFS-induced contraction at 2 and 4 Hz in the CC. In contrast, responses to PE, U46619, and 5-HT were unaffected by PLK1 inhibition. These results suggest that PLK1 selectively mediates contraction in response to Ang II and neurogenic stimuli. PLK1 may therefore represent a novel, stimulus-specific regulator of vascular and erectile smooth muscle contractility. Full article

Lung adenocarcinoma (LUAD) remains the most common subtype of non-small-cell lung cancer and a major cause of cancer mortality, with many patients lacking actionable mutations or durable responses to targeted or immune therapies. Here, we report an integrative analysis of TCGA LUAD transcriptomes (n = 598) seeded from a curated ferroptosis gene catalogue, yielding a compact six-gene signature (AQP4, CDCA3, HJURP, KIF20A, PLK1, UHRF1) with diagnostic, prognostic, and therapeutic relevance. The signature was consistently dysregulated in tumours versus normal lung and stratified patients into high- and low-risk groups with distinct survival outcomes (log-rank p < 0.0001), outperforming conventional staging when incorporated into multivariable models. Across ten machine learning algorithms, the panel achieved near-perfect tumour-normal classification (AUC 0.99–1.00), highlighting its translational potential for early detection. Functional analyses linked the signature to cell-cycle, angiogenic, and immune modulation, while exploratory drug-gene correlations identified PLK1 and other candidates as potential therapeutic targets. Together, these findings establish a biologically anchored six-gene panel that complements existing mutation-based classifiers and provides a framework for advancing diagnostic precision, prognostic refinement, and biomarker-guided therapeutic strategies in LUAD. Full article

Skin cancer remains a significant global health challenge, with rising incidence and associated mortality in late-stage and drug-resistant cases. This underscores a continuing need for more effective novel therapeutic options that can be utilized for efficient management of skin cancers. A promising approach involves exploiting novel targets, which are dysregulated in skin cancer, either alone or in combination with existing therapeutics. Among these, polo-like kinases (PLKs), a family of serine/threonine kinases, has emerged as promising candidates due to their essential role in cell cycle and maintaining genomic stability, key hallmarks of cancer. Within this family, polo-like kinase 4 (PLK4) stands out as a structurally distinct member and the master regulator of centriole duplication, ensuring this process occurs only once per cell division. Dysregulation of PLK4 can disrupt genomic integrity, contributing to tumorigenesis, thus making it a promising target for cancer management. Notably, PLK4 is frequently overexpressed in several cancers, including skin cancer, and its precise role in skin cancer is an area of current investigation. Further, several small-molecule PLK4 inhibitors such as centrinone, YLZ-F5, CFI-400945, and RP-1664 have demonstrated efficacy in targeting PLK4. Among these, CFI-400945 has advanced to clinical trials, where it has shown modest anti-cancer activity. In this review, we provide a comprehensive overview of the known functions of PLK4 in skin cancer. Additionally, we discuss potential mechanistic insights into PLK4′s involvement in skin cancer progression by extrapolating evidence from studies in other cancer types including colorectal cancer, thyroid cancer, lymphomas, leukemia, etc., while identifying gaps for future research. Full article

This review provides an overview of the most significant developments in gout pathophysiology research published in 2024. Thirteen studies were selected based on originality, scientific rigor, and potential clinical impact and grouped into four major categories: inflammation and pain mechanisms (LRRC8 anion channels, CXCL5-CXCR2 axis, CD38 and NAD⁺ metabolism, PLK1 and NLRP3 inflammasome localization, and IFN1 suppression), biomarkers and proteomics (scRNA-seq reveals monocyte and T-cell flare signatures, and Olink serum profiling reveals a proinflammatory signature in hyperuricemia and also identifies TNFSF14 as a novel flare biomarker, while a multi-omics integrative study implicates TRIM46 as a key causal gene), gut virome, and novel therapies (vagus nerve stimulation, biomimetic nanosystem, and restoration of Urate Oxidase (Uox) function). The studies selected focused primarily on work on subjects other than on hyperuricemia. The findings collectively expand our understanding of gout’s complex pathophysiology and highlight potential strategies for diagnosis, management, and innovative treatments. Full article

Background: Cervical cancer remains a major global health concern, with existing chemotherapy facing limited effectiveness owing to resistance. Polo-like kinase 1 (PLK1) overexpression in cervical cancer cells is a promising target for developing novel therapies to overcome chemoresistance and improve treatment efficacy. Methods: In this study, we developed a novel PROTAC, NC1, targeting PLK1 PBD via the N-end rule pathway. Results: This PROTAC effectively depleted the PLK1 protein in HeLa cells by inducing protein degradation. The crystal structure of the PBD-NC1 complex identified key PLK1 PBD binding interactions and isothermal titration calorimetry (ITC) confirmed a binding affinity of 6.06 µM between NC1 and PLK1 PBD. NC1 significantly decreased cell viability with an IC₅₀ of 5.23 µM, induced G2/M phase arrest, and triggered apoptosis in HeLa cells. In vivo, NC1 suppressed tumor growth in a HeLa xenograft mouse model. Conclusions: This research highlights the potential of N-degron-based PROTACs targeting the PLK1 protein in cancer therapies, highlighting their potential in future cervical anticancer treatment strategies. Full article

Centriole duplication is a vital process for cellular organisation and function, underpinning essential activities such as cell division, microtubule organisation and ciliogenesis. This review summarises the latest research on the mechanisms and regulatory pathways that control this process, focusing on important proteins such as polo-like kinase 4 (PLK4), SCL/TAL1 interrupting locus (STIL) and spindle assembly abnormal protein 6 (SAS-6). This study examines the complex steps involved in semi-conservative duplication, from initiation in the G1–S phase to the maturation of centrioles during the cell cycle. Additionally, we will explore the consequences of dysregulated centriole duplication. Dysregulation of this process can lead to centrosome amplification and subsequent chromosomal instability. These factors are implicated in several cancers and developmental disorders. By integrating recent study findings, this review emphasises the importance of centriole duplication in maintaining cellular homeostasis and its potential as a therapeutic target in disease contexts. The presented findings aim to provide a fundamental understanding that may inform future research directions and clinical interventions related to centriole biology. Full article

The yak (Bos grunniens) has exceptional hypoxia resilience, making it an ideal model for studying high-altitude adaptation. Here, we investigated the effects of oxygen concentration on yak cardiac fibroblast proliferation and the underlying molecular regulatory pathways using RNA sequencing (RNA-seq) and metabolic analyses. Decreased oxygen levels significantly inhibited cardiac fibroblast proliferation and activity. Intriguingly, while the mitochondrial DNA (mtDNA) content remained stable, we observed coordinated upregulation of mtDNA-encoded oxidative phosphorylation components. Live-cell metabolic assessment further demonstrated that hypoxia led to mitochondrial respiratory inhibition and enhanced glycolysis. RNA-seq analysis identified key hypoxia adaptation genes, including glycolysis regulators (e.g., HK2, TPI1), and hypoxia-inducible factor 1-alpha (HIF-1α), with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses highlighting their involvement in metabolic regulation. The protein–protein interaction network identified three consensus hub genes across five topological algorithms (CCNA2, PLK1, and TP53) that may be involved in hypoxia adaptation. These findings highlight the importance of metabolic reprogramming underlying yak adaptation to hypoxia, providing valuable molecular insights into the mechanisms underlying high-altitude survival. Full article

Background: TNBC patients respond poorly to chemotherapy, leading to high mortality rates and a worsening prognosis. Here, we investigated the effect of M-I on TNBC tumor growth suppression and its potential mechanisms. Methods: Signaling pathways were analyzed to study the effect of M-I on TNBC cells (human MDA-MB-231 and mouse 4T1). We used orthotopic mouse models to examine the anti-tumor efficacy of M-I. Tumor volume and the status of tumor-associated macrophages (TAMs) were assessed by qRT-PCR or FACS analysis. Results: We found a significant dose- and time-dependent inhibition of TNBC cell proliferation following treatment with M-I. Cell cycle analysis revealed a shortened S phase in M-I-treated cells and downregulation of AURKA, PLK1, CDC25c, CDK1, and cyclinB1. Furthermore, M-I treatment reduced the expression of pSTAT3, cyclinD1, and c-Myc in TNBC cells. To evaluate the anti-tumor efficacy of M-I, we employed orthotopic TNBC mouse models and observed a significant reduction in tumor growth without measurable toxicity. Next, we analyzed RNA from control and M-I-treated tumors to further assess the status of TAMs and observed a significant decrease in M2-like macrophages in the M-I-treated group. Immortalized bone marrow-derived mouse macrophages (iMacs) exposed to conditioned media (CM) of TNBC cells with or without M-I treatment indicated that the M-I treated CM of TNBC cells significantly reduce the M2phenotype in iMacs. Mechanistically, we found that M-I specifically targets the IL-4/MAPK signaling axis to reduce immunosuppressive M2 macrophage polarization. Conclusions: Our study reveals a novel mechanism by which M-I inhibits TNBC cell proliferation by regulating intracellular signaling and altering TAMs in the tumor microenvironment and highlights its potential as a promising candidate for TNBC therapy. Full article

This study examined genetic diversity in the endangered medicinal plant Celastrus paniculatus using 62 individual samples from seven natural populations in northern and northeastern Thailand to inform conservation strategies. The analysis of the nuclear internal transcribed spacer (ITS) and ribulose-1,5-bisphosphate carboxylase/oxygenase large subunit (rbcL) markers revealed 17 haplotypes (CpI1–CpI17) across these populations, with 15 being population-specific. The genetic diversity varied significantly among populations: CMI showed the highest diversity (Hd = 0.944 ± 0.070), while LEI and LPN displayed complete homogeneity. The haplotype network identified a central shared haplotype (CpI4), suggesting a common ancestry, with the PLK population showing a distinct genetic divergence through unique haplotypes separated by multiple mutation steps. Genetic distance calculations revealed close relationships between LEI and NPM populations (distance = 0.0004), with greater differentiation between PLK and other populations (distances > 0.005). Phylogenetic analyses confirmed the species integrity while highlighting population clusters, especially PLK in ITS analyses and LPN in rbcL analyses. This genetic structure information provides a foundation for targeted conservation planning. Results suggest that conservation efforts should prioritize both genetically diverse populations (like CMI and MKM) and genetically distinct ones (like PLK) to preserve the maximum evolutionary potential. This study delivers crucial molecular data for developing evidence-based conservation strategies to protect this valuable medicinal species from further decline. Full article

Given the escalating global temperatures and the consequent exacerbation of heat stress, dietary interventions have emerged as a promising therapeutic strategy. The gastrointestinal tract, being exquisitely sensitive to thermal challenges, revealing the underlying mechanisms of intestinal cell injury under high temperature, is essential for developing strategies to prevent heat stress. Here, we integrated metabolomic and transcriptomic analyses to investigate the metabolic and genetic changes in murine intestinal cells in response to different levels of heat stress. The results identified the PI3k-Akt-FoxO pathway as the major heat stress regulatory pathway Kin MODE-K cells. The possible regulatory mechanism is to reduce the expression of the FoxO gene through the downstream phosphorylation of PI3K under the stimulation of growth factors such as INS, IGF1 and TGF-β. Then, through acetylation modification, it regulates the expression of the Gadd45 gene, promotes the expression of p19 and BNIP3 genes, and inhibits the expression of the ATG8 gene, thus inducing apoptosis to remove cells that cannot be repaired. It also promotes cyclinB, PLK, and Bcl-6 gene expression in cells surrounding apoptotic cells to inhibit apoptosis. It promotes the expression of RAG1/2 to enhance cellular immunity and regulates the G6pc gene to maintain the homeostasis of glycogen metabolism and glucose under heat stress. Our findings provide a basis for the regulation of intestinal cell damage due to heat stress through dietary interventions. Full article