Search Results (224)

Cancer remains a major cause of mortality worldwide, driven by complex molecular mechanisms that promote metastasis and resistance to therapy. Receptor for hyaluronan-mediated motility (RHAMM) has emerged as a multifunctional regulator in cancer, contributing to cell motility, invasion, proliferation, and fibrosis. In addition to being regulated by non-coding RNAs (ncRNAs), including miRNAs, lncRNAs, and circRNAs, RHAMM serves as a promising therapeutic target. Recent developments in RHAMM-targeted strategies include function-blocking peptides (e.g., NPI-110, NPI-106, and P15-1), hyaluronan (HA) oligomers, and anti-RHAMM antibodies, all shown to modulate tumor stroma and suppress tumor invasiveness. Importantly, RHAMM-targeted peptide vaccines, such as the RHAMM-R3 epitope, have demonstrated immunogenicity and anti-leukemia efficacy in both pre-clinical and early clinical studies, suggesting their potential to elicit specific CD8⁺ T-cell responses and enhance graft-versus-leukemia effects. This review summarizes the intricate roles of RHAMM in cancer progression, its modulation by ncRNAs, and the translational promise of novel RHAMM-targeting approaches, providing insights into future directions for precision cancer therapy. Full article

Background/Objectives: Truncating mutations in PALB2, a critical component of the BRCA1-PALB2-BRCA2 homologous recombination repair complex, are associated with increased risk and aggressiveness of breast cancer. The consequences of PALB2 truncation on the expression, localization, and functional dynamics of the scaffold protein IQGAP1 were investigated in this study based on two cases of truncated PALB2 human breast invasive ductal carcinoma (IDC), specifically, c.1240C>T (p.Arg414*) and c.2257C>T (p.Arg753*). Methods: Using confocal microscopy, we examined co-expression patterns of IQGAP1 with PALB2, PCNA, CK7, and β-tubulin in tumor tissues from both control cancer and PALB2-mutated cases. Results: In PALB2-truncated tumors, IQGAP1 exhibited enhanced peripheral and plasma membrane localization with elevated co-localization levels compared to controls, suggesting altered cytoskeletal organization. PALB2 truncation increased nuclear and cytoplasmic N-terminal PALB2 immunoreactivity, indicating the presence of truncated isoforms disrupting the homologous recombination repair system. Co-expression analyses with PCNA revealed an inverse expression pattern between IQGAP1 and proliferation markers, suggesting S-phase cell cycle-dependent heterogeneity. Furthermore, the loss of IQGAP1 dominance over CK7 and β-tubulin in mutant tumors, along with persistent intercellular spacing, implied a loss of cell–cell cohesion and the acquisition of invasive traits. Conclusions: These data support a model where PALB2 truncation triggers a reorganization of IQGAP1 that disrupts its canonical structural functions and facilitates tumor progression via enhanced motility and impaired cell–cell interaction. IQGAP1 thus serves as both a functional effector and potential biomarker in PALB2-mutated IDC, opening novel paths for diagnosis and targeted therapeutic intervention. Full article

The discovery of bioactive natural compounds from microbes holds promise for regenerative medicine. In this study, we identified and characterized a steroid-like compound, 3,12-dioxochola-4,6-dien-24-oic acid (DOCDA), from a crude extract of Rhodococcus sp. DOCDA significantly promoted wound healing by enhancing HaCaT cell invasion and migration. It upregulated key growth factors (EGF, VEGF-A, IGF, TGF-β, and HGF), indicating the activation of regenerative signaling. Additionally, DOCDA increased the expression of genes related to focal adhesion and cytoskeletal regulation (ITGB1, ITGA4, FAK, SRC, RHOA, CDC42, RAC1, and paxillin), supporting enhanced cellular motility and remodeling. Notably, DOCDA promoted stem-like properties in HaCaT cells, as shown by increased spheroid formation and elevated levels of the stemness markers ALDH1 and CD44. Target prediction and molecular docking identified the glucocorticoid receptor (GR) as the primary target of DOCDA, with a docking score of −7.7 kcal/mol. Network and pathway enrichment analysis revealed that GR-linked pathways were significantly associated with wound healing, including steroid hormone signaling, inflammation, immune responses, and cell migration. In vivo, the topical application of DOCDA led to over 70% wound closure in mice by day 5. These findings suggest that DOCDA is a steroid-like compound that accelerates wound healing and may serve as a potential agent in regenerative therapy. Full article

Background/Objectives: The HOX genes encode a family of homeodomain-containing transcription factors that have important roles in defining cell and tissue identity in embryonic development, but which also show deregulated expression in many cancers and have been shown to have pro-oncogenic roles. Due to their functionally redundant nature, strategies to target HOX protein function in cancer have focused on their interaction with their PBX cofactor using competitive peptides such as HXR9. HOX/PBX inhibition triggers apoptosis through a sudden increase in target gene expression, including Fos, DUSP1, and ATF3, which are otherwise repressed by HOX/PBX binding. Methods: We analyzed publicly available transcriptomic data in the R2 platform. Results: We show that a specific subgroup of HOX genes is negatively correlated with Fos, DUSP1, and ATF3 expression in prostate cancer, and that this subgroup also shows a strong positive corelation with pathways that support tumour growth, most notably DNA repair and aminoacyl tRNA biosynthesis, and a negative correlation with genes that promote cell adhesion and prevent motility. In addition, this set of HOX genes strongly correlates with patient age, reflecting a previously identified progressive loss of regulation of HOX expression in normal peripheral blood cells. Conclusions: Our findings indicate these HOX genes may have pro-oncogenic functions in prostate cancer. Full article

Peptide vaccines possess several advantages over mRNA vaccines but are generally less effective at inducing antitumor immunity. The bottlenecks limiting peptide vaccine efficacy could be elucidated by tracking and comparing vaccine-induced T-lymphocytes in successful and unsuccessful cases. Here we have applied our recent database of neoantigen-specific T cell receptors (TCRs) to profile tumor-specific T cells following vaccination with a neoantigen peptide vaccine and to correlate this with the response. Mice were vaccinated prophylactically with p30 peptide encoding B16 melanoma neoantigen (K739N mutation in Kif18b gene). The B16F0 melanoma in the vaccinated mice was additionally treated by a CTLA-4 checkpoint blockade. T cells from the tumors, tumor-draining lymph nodes (tdLNs) and vaccine depots were isolated, phenotyped, sorted by subsets and sequenced for TCR repertoires. The vaccine induced the accumulation of tumor-specific CD4+ Th cells in the tdLNs, while in the tumors these cells were present and their frequencies were not changed by the vaccine. These cells also accumulated at the vaccine depots, where they were phenotypically skewed by the vaccine components; however, these effects were minor due to approximately 50-fold lower cell quantities compared to the tdLNs. Only some of the p30-specific Th cells showed tumoricidal activity, as revealed by the reverse correlation of their frequencies in the tdLNs with the tumor size. The CTLA-4 blockade did not affect the tumor growth or the frequencies of tumor-specific cells but did stimulate Th cell motility. Thus, we have shown that tumor-specific Th clones accumulate and/or expand in the tdLNs, which correlates with tumor suppression but only for some of these clones. Tumor infiltration by these clones is not correlated with the growth rate. Full article

Cuscutae Semen (CS), a traditional herb recognized as a nutraceutical food in China, has been widely utilized in managing aging-related diseases throughout history. However, whether this mechanism is associated with mitochondrial stress tolerance remains unclear. In the present study, Caenorhabditis elegans (C. elegans) was used to investigate the effects of CS on their longevity. The data demonstrated that CS prolonged the average lifespan of the nematodes by 15.26%, reducing lipofuscin accumulation by 61.46%, as well as improving spontaneous motility. CS treatment significantly enhanced the resistance of C. elegans to hydrogen peroxide-induced oxidative stress and 37 °C induced heat stress, reducing reactive oxygen species (ROS) production by 71.45%. Additionally, membrane potential (MMP) and adenosine triphosphate (ATP) were increased by 354.72% and 69.64%, respectively. However, mitochondrion-specific ROS and calcium flux were significantly reduced to 45.86% and 63.25%, respectively, in C. elegans treated with CS. Consistently, the polymerase chain reaction data revealed that CS significantly up-regulated the expressions of the antioxidant-related genes skn-1, ctl-1, sod-3, and gst-4; the heat shock gene hsp-16.2; and the autophagy-related genes lgg-1 and bec-1. Considering the crucial role of the silent information regulator sirtuin 1 (SIR-2.1/SIRT1) in aging-related mitochondrial oxidative stress, we examined its expression and transcriptional activity. As expected, treatment with CS induced SIRT1 expression, and isorhamnetin identified from CS extract significantly enhanced SIRT1 transcriptional activity in HEK293T cells. Collectively, our results provided evidence that CS prolonged the lifespan of C. elegans by ameliorating oxidative stress damage and mitochondrial dysfunction via SIRT1. Full article

Trypanosoma cruzi is a kinetoplastid parasite and etiological agent of Chagas disease. Given the significant morbidity and mortality rates of this parasitic disease, possible treatment alternatives need to be studied. 3-Bromopyruvate (3-BrPA) is a synthetic analog of pyruvate that was introduced in the early 21st century as an anticancer agent, affecting the proliferation and motility of certain microorganisms. Therefore, this work aims to evaluate the role of 3-BrPA in the energy metabolism, proliferation, and infectivity of T. cruzi, with a primary focus on the mitochondrial state, ATP production, and the key glycolytic pathway enzymes. It was observed that mitochondrial function in 3-BrPA cells was impaired compared to control cells. Accordingly, cells maintained in control conditions have a higher intracellular ATP content than cells maintained with 3-BrPA and higher ecto-phosphatase activity. However, the 3-BrPA reduced ecto-nuclease activity and was capable of hydrolyzing 5′-AMP, ADP, and ATP. When we evaluated two key glycolytic pathway enzymes, glucose kinase (GK) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), we observed that 3-BrPA induced higher GAPDH activity but did not alter GK activity. The compensatory energy mechanisms presented in T. cruzi may influence the process of cell metabolism and, consequently, the functional infectious process, suggesting the potential use of 3-BrPA in future clinical applications for Chagas disease. Full article

Self/non-self-discrimination is a fundamental aspect of adaptive immunity, which helps prevent harmful autoimmune responses. However, infectious agents can also act as environmental catalysts for autoimmune diseases. In this study, we investigated the role of molecular mimicry to self-antigens in epitope recognition in relation to infectious and autoimmune diseases. To this end, we performed BLAST searches against the human proteome, utilizing known virus-specific B and T cell peptide epitopes identified in association with autoimmune or infectious diseases in humans as our queries. Additionally, similar control analyses were carried out using non-B and non-T cell epitopes, consisting of random viral peptide sequences. Overall, our results endorsed a major role of molecular mimicry in instigating or sustaining autoimmunity associated with viral infections and challenged the prevailing view on self/non-self-discrimination for T cells. Additionally, we uncovered many virus-specific epitopes among those identified in association with infectious diseases with high similarity to self-antigens, which are primarily derived from human coronaviruses and various flaviviruses. Recognition of these epitopes could lead to autoimmunity against human proteins that are in cellular components concerning cell motility, cell membrane projections, and cellular synapses. Full article

Radiation therapy is a standard of care treatment for patients with glioblastoma. However, patients’ survival rate is dismal, with nearly all patients experiencing disease progression after treatment. Enriched iron content associated with increased transferrin receptor (TfR) expression is an indicator of poor glioblastoma patient outcomes; however, the underlying contributions to tumor progression remain elusive. The goal of this present study is to understand how iron metabolism in glioma contributes to radiation-induced glioblastoma cell motility. U251 and a doxycycline-inducible ferritin heavy chain overexpressing U251 (U251 FtH⁺) cell line were used. For in vitro studies, cells were irradiated with 2 Gy using a ³⁷Cs source, and after 72 h, atomic force microscopy (AFM) nanoindentation was employed to assess changes in cell stiffness following irradiation. Cell motility was studied using temporal confocal microscopy. For in vivo studies, U251 cells were grown in the rear flanks of female nude athymic mice, and the tumor was irradiated with five fractions of 2 Gy (10 Gy). The tumors were then imaged using a GE 7T small animal MRI to assess changes in T2* MRI, and colorimetric analysis of labile iron was performed using ferrozine. Following irradiation, a biomechanical shift characterized by decreased cell stiffness along with increased cell motility occurred in U251 cells, which corresponded to increased TfR expression. FtH overexpression completely reversed the enhanced cell motility following irradiation. Irradiation of U251 tumors induced the same iron metabolic shift. Interestingly, the change in labile iron in U251 tumors corresponded with an increase in T2* relaxation times, suggesting that T2* mapping may serve as a surrogate marker for assessing radiation-induced changes in iron metabolism. Full article

Type 1 diabetes (T1D) is a chronic metabolic disease defined by sustained hyperglycemia, leading to oxidative stress (OS) and systemic complications, including male subfertility. This study investigates the potential impact of T1D-induced OS on microtubule (MTs) dynamics and microtubule-associated proteins (MAPs) in the testis and spermatozoa (SPZ). Using a streptozotocin-induced T1D rat model, we examined the expression and localization of key MAPs, including Microtubule Affinity-Regulating Kinase 4 (MARK4), Microtubule-Associated Protein 1A (MAP1A), Dynein Light Chain LC8-Type 1 (DYNLL1), Prolyl Endopeptidase (PREP), and Radial Spoke Head 6 Homolog A (RSPH6A), alongside sperm functional parameters. Our findings showed that T1D significantly impaired the expression and distribution of these proteins, which may affect MTs organization and be associated with cytoskeletal disorganization, and impaired germ cell differentiation. Moreover, T1D rats exhibited reduced sperm count, viability, and motility, accompanied by increased DNA fragmentation and chromatin defects. Elevated levels of 4-hydroxy-2-nonenal (4-HNE), a marker of OS, were detected in SPZ, particularly in the acrosome and flagellum, correlating with mitochondrial dysfunction and ATP depletion. Additionally, decreased intracellular Ca²⁺ levels, downregulation of Cation Channel of Sperm (CATSPER) and Voltage-Dependent Anion Channel 3 (VDAC3), and altered tubulin acetylation, possibly due to imbalanced Alpha-Tubulin N-Acetyltransferase 1 (ATAT1) and Histone Deacetylase 6 (HDAC6) expression, were also associated with impaired sperm motility. The combined data suggest that T1D-induced OS is linked to disrupted MTs dynamics, which may contribute to testicular dysfunction and reduced sperm quality, potentially affecting male fertility. A better understanding of these associations may support the development of therapeutic strategies to mitigate the reproductive consequences of T1D and improve male fertility outcomes. Full article

Sex-related differences in the structure and function of the adrenal cortex in mature rats are well recognized, largely driven by the action of sex hormones on the hypothalamic–pituitary–adrenal axis (HPA). By replacing testosterone or estradiol in gonadectomized rats, we aimed to elucidate the regulation of micro RNA (miRNA) profiles by sex hormones and their role in physiological adrenal function, providing new insights into gene expression modulation in the adrenal gland. This paper focuses on the description of miRNA profiles using the microarray technique. In our study, we observed significant sex differences in miRNA and mRNA expression levels. These differences are as follows: miRNA expression profiles Male C vs. Female C-0 down, 25 up-regulated, while mRNA profiles were 43 down and 27 up-regulated. Moreover, we observed the most significant differences in miRNA profiles between orchiectomized male rats supplemented with testosterone (ORX + T) and ovariectomized female rats treated with estradiol (OVX + E). Furthermore, we described changes in target gene expression and biological processes regulated by miRNAs. The processes most differentially expressed between the ORX + T and OVX + E groups are those related to the metabolism and synthesis of sterol compounds, the positive and negative regulation of metabolic processes in cells, e.g., cholesterol metabolism, response to various external factors, e.g., hormones, regulation of processes related to cell motility. We also identified several miRNAs, such as miR-370, miR-377, and miR-503, that exhibited interesting changes in their expression after testosterone or estradiol replacement. These results contribute to a deeper understanding of adrenal physiology. Full article

Dysregulated cell movement is a hallmark of cancer progression and metastasis, the leading cause of cancer-related mortality. The metastatic cascade involves tumour cell migration, invasion, intravasation, dissemination, and colonisation of distant organs. These processes are influenced by reciprocal interactions between cancer cells and the tumour microenvironment (TME), including immune cells, stromal components, and extracellular matrix proteins. The epithelial–mesenchymal transition (EMT) plays a crucial role in providing cancer cells with invasive and stem-like properties, promoting dissemination and resistance to apoptosis. Conversely, the mesenchymal–epithelial transition (MET) facilitates metastatic colonisation and tumour re-initiation. Immune cells within the TME contribute to either anti-tumour response or immune evasion. These cells secrete cytokines, chemokines, and growth factors that shape the immune landscape and influence responses to immunotherapy. Notably, immune checkpoint blockade (ICB) has transformed cancer treatment, yet its efficacy is often dictated by the immune composition of the tumour site. Elucidating the molecular cross-talk between immune and cancer cells, identifying predictive biomarkers for ICB response, and developing strategies to convert cold tumours into immune-active environments is critical to overcoming resistance to immunotherapy and improving patient survival. Full article

Visceral fat mass is associated with a condition of chronic inflammation and can predispose the overweight to an increased cancer risk. Although it is known that adipocytes are active producers of the pro-inflammatory transforming growth factor β (TGFβ), the causes of their excessive synthesis are not clear. In this study, we reproduced two metabolic stress conditions frequently occurring in vivo, namely hypoxia and the fatty acid-driven metabolic uncoupling, and we characterized the response of an in vitro model of 3T3-L1 mouse adipocytes. For the first time, we demonstrated that the mitochondrial dysmetabolism of differentiated adipocytes induced the secretion of TGFβ. The paracrine activity of the secreted cytokine was then tested on two human pancreatic cancer cell lines. Cancer cells responded to the stimulation by increasing mitochondrial respiration, switching on the epithelial–mesenchymal transition (EMT) program and enhancing their motility. The data obtained in this proof-of-concept research show that TGFβ can be produced by dysmetabolic adipocytes, linking the altered metabolism with pro-tumorigenic inflammation. The novel observations of this study identify in metabolic stress a still unexplored cause of inflammation and cancer progression and pave the way to more detailed in vitro and clinical studies on pancreatic cancer. Full article

Penaeus monodon (black tiger shrimp) is one of the important shrimp species in aquaculture. Cryopreserving its sperm not only provides technical support for breeding but also effectively prevents the decline of genetic resources, promoting the sustainable development of its aquaculture industry. This study screened different types of diluents, cryoprotectants, and concentrations and explored equilibration time, cooling protocols, and thawing conditions, ultimately determining the optimal cryopreservation protocol for P. monodon sperm. The results showed that the optimal cryopreservation protocol involved using natural seawater as the diluent with 10% dimethyl sulfoxide (DMSO) as the cryoprotectant, in which the sperm suspension and cryoprotectant were mixed at a 1:1 (v/v) ratio and equilibrated at 4 °C for 30 min. Subsequently, cooling was performed using a programmable controlled-rate freezer: the temperature was reduced to −20 °C at −5 °C/min and held for 5 min; then cooled to −80 °C at −10 °C/min and held for 5 min; finally, the temperature was reduced to −180 °C at −20 °C/min. After cooling, the sperm samples were transferred to liquid nitrogen for long-term storage. The results demonstrated that thawing in a 37 °C water bath achieved the highest sperm motility compared to conditions at 27 °C, 32 °C, 42 °C, and 60 °C. After 15 days of liquid nitrogen storage, the sperm survival rate was 53.33 ± 9.18%. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) observations revealed that the sperm structure was intact before freezing, with a rounded head, a distinct acrosomal spike anterior to the head, a concentrated nucleus in the head, dense chromatin, and a smooth cell membrane surface. However, after freezing and thawing, the acrosomal spikes of some sperm were fractured, and the membrane structure was damaged. Enzyme activity analysis showed that during liquid nitrogen storage from 0 to 15 days, the enzyme activity of alkaline phosphatase (AKP) and acid phosphatase (ACP) in sperm gradually increased with significant differences observed compared to day 0 (p < 0.05). The activity of malondialdehyde (MDA) showed a gradual increase at 0, 5, and 10 days, but then decreased at day 15. The enzyme activity of catalase (CAT) showed no significant changes from 0 to 10 days (p > 0.05) but significantly increased on day 15 (p < 0.05). The activity of total superoxide dismutase (T-SOD) showed no significant changes from 0 to 5 days (p > 0.05) but significantly increased from days 10 to 15 (p < 0.05). These findings provide valuable insights into the cryopreservation of P. monodon sperm and will guide the optimization of cryoprotectant combinations and freezing protocols aimed at improving sperm survival rates. Full article

The survival of patients with locally advanced and metastatic bladder cancer (BCa) is persistently low. Hence, new treatment options are urgently needed. Artesunate (ART) a derivative of artemisinin, used in Traditional Chinese Medicine, shows anti-tumor activity extending over a broad spectrum of human cancers. As we have previously shown, ART inhibits growth in cisplatin-sensitive (parental) and cisplatin-resistant BCa cells. However, how ART acts on the metastatic potential of BCa remained unclear. To clarify, we applied ART to parental and cisplatin-resistant RT4, RT112, T24, and TCCSup BCa cell lines. We examined tumor cell adhesion to vascular endothelium and immobilized collagen and evaluated chemotactic activity, migration, and invasive activity of the BCa cells. Adhesion receptors, integrin α and β subtypes, integrin-linked kinase (ILK), and focal adhesion kinase (FAK) were investigated. The functional relevance of integrin expression altered by ART was determined by blocking studies. ART significantly reduced tumor cell adhesion to vascular endothelium and immobilized collagen in parental as well as in cisplatin-resistant BCa cells. Depending on cell type, ART suppressed tumor cell motility and diminished integrin expression (surface and total). Functional blocking of integrins altered by ART reduced cell adhesion and invasion of the BCa cells. Thus, the metastatic potential of parental and cisplatin-resistant BCa cells was significantly inhibited by ART, making it a promising treatment option for patients with advanced or therapy-resistant BCa. Full article