Search Results (215)

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

Platinum resistance represents an urgent medical need in the management of ovarian cancer. The activity of the combinations of onvansertib, an inhibitor of polo-like kinase 1, with gemcitabine or carboplatin was tested using patient-derived xenografts of high-grade serous ovarian carcinoma resistant to cisplatin (DDP). Two PDX models were selected from our xenobank: one with acquired resistance to DDP (#266R) and the other (#315) with intrinsic DDP resistance. Tumor-bearing mice were randomized to receive vehicle, single onvansertib, gemcitabine and carboplatin, and their combinations. Onvansertib/gemcitabine and onvansertib/carboplatin combinations were well tolerated. In the #266R model, single drug treatments were completely inactive, while the combinations of onvansertib/gemcitabine and onvansertib/carboplatin resulted in a significant increase in survival compared to controls and single drugs (p < 0.001 versus control, onvansertib, gemcitabine and carboplatin). Similar efficacy was observed in the s.c. #315 PDX model; indeed, onvansertib and carboplatin monotherapies were inactive, gemcitabine monotherapy was marginally active, while both combinations were highly active. The molecular mechanism underlying the efficacy of the combinations suggests a higher induction of DNA damage which seems plausible considering that, in both cases, gemcitabine and carboplatin, respectively, interfere with DNA metabolism and induce alkylation damage. The results suggest that the combinations of onvansertib/gemcitabine and onvansertib/carboplatin are safe and were shown to be of therapeutic value in the platinum-resistant setting of ovarian carcinoma, strongly supporting their clinical translatability. Full article

Biochanin A, a naturally occurring isoflavone derived from legumes, possesses anti-inflammatory, estrogenic, and anticancer activities. In this study, we investigated the cytotoxic effects and underlying molecular mechanisms of Biochanin A in acute myeloid leukemia (AML) cell lines, U937 and THP-1, using in vitro cytotoxicity assays, RNA sequencing, and bioinformatic analyses. Biochanin A induced dose-dependent apoptosis, as evidenced by caspase-7 activation and PARP1 cleavage. Over-representation analysis (ORA) revealed that differentially expressed genes (DEGs) were significantly enriched in pathways related to inflammatory responses, DNA replication, and cell cycle regulation. Gene set enrichment analysis (GSEA) further confirmed the upregulation of apoptosis- and inflammation-related pathways and the downregulation of MYC targets, cholesterol biosynthesis, and G2/M checkpoint gene sets. RT-qPCR analysis demonstrated that Biochanin A downregulated oncogenes such as RUNX1, BCL2, and MYC while upregulating CHOP (GADD153), CDKN1A (p21), and SQSTM1 (p62), contributing to apoptosis and cell cycle arrest across both cell lines. Notably, Biochanin A downregulated PLK1 and UHRF1 in THP-1 cells, indicating a disruption of mitotic progression and epigenetic regulation. In contrast, in U937 cells, Biochanin A upregulated TXNIP and downregulated CCND2, highlighting the involvement of oxidative stress and G1/S cell cycle arrest. These findings support the potential of Biochanin A as a promising therapeutic candidate for AML through both shared and distinct regulatory pathways. Full article

Alveolar rhabdomyosarcoma (ARMS) is a highly aggressive pediatric soft-tissue sarcoma driven by PAX3/7-FOXO1 fusion proteins. Despite intensive multimodal therapy, outcomes remain poor for patients with fusion-positive ARMS. This review integrates recent advances in the molecular pathogenesis of ARMS, highlighting key diagnostic and therapeutic targets. We discuss the central role of fusion proteins in transcriptional reprogramming, impaired myogenic differentiation, and super-enhancer activation. Emerging biomarkers (YAP, TFAP2B, P-cadherin) and oncogenic kinases (Aurora A, CDK4, PLK1) are evaluated alongside receptor tyrosine kinases (FGFR, MET) and transcription factors involved in metabolic rewiring (FOXF1, ETS1). Additionally, we examine immunotherapeutic strategies, epigenetic modifiers, and noncoding RNAs as potential therapeutic avenues. Together, these insights provide a comprehensive framework for developing biomarker-guided, multi-targeted therapies to improve outcomes in ARMS. Full article

Cancer cell spheroids autonomously form in the ascites fluid and are considered a conduit for epithelial ovarian cancer metastasis within the peritoneal cavity. Spheroids are homotypic, avascular 3D structures that acquire resistance to anoikis to remain viable after cellular detachment. We used in vitro spheroid model systems to interrogate pathways critical for spheroid cell proliferation, distinct from those driving monolayer cancer cell proliferation. Using the 105C and KOC-7c human ovarian clear cell carcinoma (OCCC) cell lines, which have distinct proliferative phenotypes as spheroids but the same prototypical OCCC gene mutation profile of constitutively activated AKT signaling with the loss of ARID1A, we revealed therapeutic targets that efficiently kill cells in spheroids. RNA-seq analyses compared the transcriptome of 3-day monolayer and spheroid cells from these lines and identified the characteristics of dormant spheroid cell survival, which included the G2/M checkpoint, autophagy, and other stress pathways induced in 105C spheroids, in sharp contrast to the proliferating spheroid cells of the KOC-7c cell line. Next, we assessed levels of various G2/M checkpoint regulators and found a consistent reduction in steady-state levels of checkpoint regulators in dormant spheroid cells, but not proliferative spheroids. Our studies showed that proliferative spheroid cells were sensitive to Wee1 inhibition by AZD1775, but the dormant spheroid cells showed a degree of resistance to AZD1775, both in terms of EC50 values and spheroid reattachment abilities. Thus, we identified biomarkers of dormant spheroids, including the G2/M checkpoint regulators Wee1, Cdc25c, and PLK1, and showed that, when compared to proliferating spheroid cells, the transcriptome of dormant OCCC spheroids is a source of therapeutic targets. Full article

Genomic instability has been increasingly recognized over the past decade as a fundamental driver of cancer initiation and progression, largely owing to its association with specific genes and cellular mechanisms that offer therapeutic potential. However, a comprehensive molecular framework that captures the interconnected processes underlying this phenomenon remains elusive. In this study, we focused on polo-like kinase 1 (PLK1), a key cell cycle regulator frequently overexpressed in diverse human tumors, to reconstruct a regulatory network that consolidates pre-existing biological knowledge exclusively related to pathways involved in genome stability maintenance and cancer. The resulting model integrates nine biological processes, 1030 reactions, and 716 molecular species to form a literature-supported network in which PLK1 serves as a central regulatory node. However, rather than depicting an isolated PLK1-centric system, this network reflects a broader and more complex architecture of interrelated genomic instability mechanisms. As expected, the simulations reproduced known behaviors associated with PLK1 dysregulation, reinforcing the well-established role of the kinase in genome destabilization. Importantly, this model also enables the exploration of additional, less-characterized dynamics, including the potential involvement of genes such as kif2c, incenp, and other regulators of chromosomal segregation and DNA repair, which appear to contribute to instability events downstream of PLK1. While these findings are grounded in mechanistic simulations and require further experimental validation, gene expression and survival analyses across tumor types support their clinical relevance by linking them to poor prognosis in specific cancers. Overall, the model provides a systemic and adaptable foundation for studying PLK1-related genomic instability, enabling both the reinforcement of known mechanisms and discovery of candidate genes and circuits that may drive tumorigenesis through compromised genome integrity across distinct cancer contexts. Full article

Background/Objectives: Acute myeloid leukemia (AML) is an aggressive malignancy marked by high relapse rates and molecular heterogeneity, necessitating the identification of novel therapeutic targets. T-complex protein 1 (TCP1), a chaperonin implicated in protein folding, remains underexplored in AML pathogenesis. This study investigates the functional role of TCP1 in AML progression and evaluates its therapeutic potential. Methods: Using successive generations of xenografted tumor models, we systematically assessed the correlation between TCP1 expression and AML tumorigenicity. Functional consequences of TCP1 silence were evaluated through in vitro proliferation assays and in vivo tumor growth monitoring. Two distinct inhibitory strategies were employed: miR-340-5p-mediated transcriptional silencing and FTY720-induced disruption of TCP1 chaperone activity. Mechanistic insights were derived from ubiquitin–proteasome pathway analysis, cell cycle profiling, and apoptosis assays. Results: High TCP1 expression correlated strongly with enhanced AML tumorigenicity. Knockdown of TCP1 significantly inhibited AML cell growth and induced degradation of AML1-ETO and PLK1 proteins through the ubiquitin–proteasome pathway. miR-340-5p effectively silenced TCP1 expression, exhibiting an inverse correlation with TCP1 levels. FTY720 disrupted TCP1′s chaperone function, leading to cell cycle arrest, apoptosis, and reduced xenograft tumor growth in murine models. Conclusion: Our findings establish TCP1 as a promising therapeutic target for AML. Both miR-340-5p and FTY720 demonstrate potent anti-leukemic effects by suppressing TCP1 activity, highlighting their potential as novel strategies to inhibit AML proliferation and improve therapeutic outcomes. Full article

Lactation traits are critical economic attributes in domestic animals. This study investigates genetic markers and functional genes associated with lactation traits in Xinjiang donkeys. We analyzed 112 Xinjiang donkeys using 10× whole genome re-sequencing to obtain genome-wide single nucleotide polymorphisms (SNPs). Genome-wide association analyses were conducted using PLINK 2.0 and GEMMA 0.98.5 software, employing mixed linear models to assess several lactation traits: average monthly milk yield (AY), fat percentage (FP), protein percentage (PP), and lactose percentage (LP). A total of 236 SNPs were significantly associated with one or more milk production traits (p < 0.000001). While the two-software identified distinct SNP associations, they consistently detected the same 11, 95, 5, and 103 SNPs for AY, FP, PP, and LP, respectively. Several of these SNPs are located within potential candidate genes, including glycosylphosphatidylinositol anchored high density lipoprotein binding protein 1 (GPIHBP1), FLII actin remodeling protein (FLII), mitochondrial topoisomerase 1 (TOP1MT), thirty-eight-negative kinase 1 (TNK1), polo like kinase 1 (PLK1), notch homolog 1 (NOTCH1), developmentally regulated GTP-binding protein 2 (DRG2), mitochondrial elongation factor 2 (MIEF2), glutamine-fructose-6-phosphate transaminase 2 (GFPT2), and dual-specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2). Additionally, we validated the polymorphism of 16 SNPs (10 genes) using Kompetitive Allele Specific PCR, revealing that TOP1MT_g.9133371T > C, GPIHBP1_g.38365122C > T, DRG2_g.4912631C > A, FLII_g.5046888C > T, and PLK1_g.23585377T > C were significantly correlated with average daily milk yield and total milk yield in the studied donkeys. This study represents the first genome-wide association analysis of markers and milk components in Xinjiang donkeys, offering valuable insights into the genetic mechanisms underlying milk production traits. Further research with larger sample sizes is essential to confirm these findings and identify potential causal genetic variants. Full article

Background: Histiocytic sarcoma (HS) is a highly aggressive malignancy characterized by the excessive proliferation of histiocytes in dogs and humans. A subset of dog breeds, including the Bernese Mountain Dog (BMD), show a remarkably high prevalence of HS. Previous work by us and others has identified somatic driver mutations of HS in the PTPN11 and KRAS genes that activate the MAPK pathway in about 60% of canine HS. However, no somatic driver mutations have been identified in the remaining 40%. Objectives: Our goals are to study HS in BMDs to gain insight into the molecular pathogenesis of the disease, and identify rational approaches to therapy. Methods: Here, we report our whole transcriptome analysis of 18 well-characterized BMD HS tumor tissues, as well as three HS cell lines. Results: Our analysis reveals the significant upregulation of molecular pathways involving the FOXM1, AURKB, PLK1, and E2F genes, in HS as well as hemophagocytic HS, providing new information regarding pathways that may be targeted with inhibitors. In addition, we document the expression of multiple checkpoint genes, suggesting the option of treatment with small-molecule inhibitors together with checkpoint inhibitors. Further, we show that the transcriptomes of three canine HS cell lines mirror those of canine patient tumors, further highlighting their potential use in drug discovery and efficacy studies. Finally, we demonstrate, for the first time, that aurora kinase inhibitors are effective in curtailing the growth of HS cells in vitro and show synergism with MAPK inhibition. Conclusions: This study provides the most detailed analysis of the canine HS transcriptome to date, highlighting key pathways in its pathogenesis and suggesting new avenues for both single and combination treatment strategies, which may be pertinent to the treatment of human HS. Full article