Microplastics role in cell migration and distribution during cancer cell division.

Amidst the global plastic pollution crisis, the gastrointestinal tract serves as the primary entry point for daily exposure to micro- and nanoplastics. We investigated the complex dynamics between polystyrene micro- and nanoplastics (PS-MNPs) and four distinct human colorectal cancer cell lines (HT29, HCT116, SW480, and SW620). Our findings revealed a significant size- and concentration dependent uptake of 0.25, 1, and 10 µm PS-MNPs across all cell lines, with HCT116 cells exhibiting the highest uptake rates. During cell division, particles were distributed between mother and daughter cells. Interestingly, we observed no signs of elimination from the cells. Short-term exposure to 0.25 µm particles significantly amplified cell migration, potentially leading to pro-metastatic effects. Particles demonstrated high persistence in 2D and 3D cultures, and accumulation in non-proliferating parts of spheroids, without interfering with cell proliferation or division. Our study unveils the disturbing fact of the persistence and bioaccumulation of MNPs in colorectal cancer cell lines, key toxicological traits under REACH (Regulation concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals). Our observations underscore the potential of MNPs as hidden catalysts for tumor progression, particularly through enhancing cell migration and possibly fueling metastasis - a finding that sheds light on a significant and previously underexplored area of concern.

Targeting YB-1 via entinostat enhances cisplatin sensitivity of pleural mesothelioma in vitro and in vivo.

Pleural mesothelioma (PM) is characterized by poor prognosis and limited therapeutic options. Y-box-binding protein 1 (YB-1) was shown to drive growth and migration of PM cells. Here, we evaluated the effect of genetic and pharmacological targeting of YB-1 on PM growth and response to cisplatin and radiation treatment. YB-1 knockdown via siRNA resulted in reduced PM cell growth, which significantly correlated with wt BAP1 and mutant NF2 and P53 status. Entinostat inhibited YB-1 deacetylation and its efficacy correlated with YB-1 knockdown-induced growth inhibition in 20 PM cell lines. Tumor growth inhibition by siRNA as well as entinostat was confirmed in mouse xenotransplant models. Furthermore, both YBX1-targeting siRNA and entinostat enhanced sensitivity to cisplatin and radiation. In particular, entinostat showed strong synergistic interactions with cisplatin which was linked to significantly increased cellular platinum uptake in all investigated cell models. Importantly, in a mouse model, the combination of cisplatin and entinostat also resulted in stronger growth inhibition than each treatment alone. Our study highlights YB-1 as an attractive target in PM and demonstrates that targeting YB-1 via entinostat is a promising approach to enhance cisplatin and radiation sensitivity.

Micro- and Nanoplastics Breach the Blood-Brain Barrier (BBB): Biomolecular Corona's Role Revealed.

Humans are continuously exposed to polymeric materials such as in textiles, car tires and packaging. Unfortunately, their break down products pollute our environment, leading to widespread contamination with micro- and nanoplastics (MNPs). The blood-brain barrier (BBB) is an important biological barrier that protects the brain from harmful substances. In our study we performed short term uptake studies in mice with orally administered polystyrene micro-/nanoparticles (9.55 µm, 1.14 µm, 0.293 µm). We show that nanometer sized particles-but not bigger particles-reach the brain within only 2 h after gavage. To understand the transport mechanism, we performed coarse-grained molecular dynamics simulations on the interaction of DOPC bilayers with a polystyrene nanoparticle in the presence and absence of various coronae. We found that the composition of the biomolecular corona surrounding the plastic particles was critical for passage through the BBB. Cholesterol molecules enhanced the uptake of these contaminants into the membrane of the BBB, whereas the protein model inhibited it. These opposing effects could explain the passive transport of the particles into the brain.

Nanoparticle-Mediated Drug Delivery of Doxorubicin Induces a Differentiated Clonogenic Inactivation in 3D Tumor Spheroids In Vitro.

Involvement of 3D tumor cell models in the in vitro biological testing of novel nanotechnology-based strategies for cancer management can provide in-depth information on the real behavior of tumor cells in complex biomimetic architectures. Here, we used polyethylene glycol-encapsulated iron oxide nanoparticles for the controlled delivery of a doxorubicin chemotherapeutic substance (IONPDOX), and to enhance cytotoxicity of photon radiation therapy. The biological effects of nanoparticles and 150 kV X-rays were evaluated on both 2D and 3D cell models of normal human keratinocytes (HaCaT) and tumor cells-human cervical adenocarcinoma (HeLa) and human squamous carcinoma (FaDu)-through cell survival. In all 2D cell models, nanoparticles were similarly internalized in a peri-nuclear pattern, but resulted in different survival capabilities following radiation treatment. IONP on normal keratinocytes showed a protective effect, but a cytotoxic effect for cancer cells. In 3D tumor cell models, IONPDOX were able to penetrate the cell spheroids towards the hypoxic areas. However, IONPDOX and 150 kV X-rays led to a dose-modifying factor DMFSF=0.1 = 1.09 ± 0.1 (200 µg/mL IONPDOX) in HeLa spheroids, but to a radioprotective effect in FaDu spheroids. Results show that the proposed treatment is promising in the management of cervical adenocarcinoma.

Localised multiple sclerosis-like disease after irradiation of the cervicothoracic spinal cord.

BACKGROUND: Radiation has been discussed as a potential causative factor for Multiple Sclerosis (MS). However, it is unresolved whether radiation increases the aggressiveness of the immune system or whether it alters the nervous tissue to become vulnerable to a pre-existing autoimmune attackdisposition. We report a patient with an MS-like disease confined to the irradiated part of his central nervous system (CNS). CASE REPORT: within the course of a year, a 29 year-old man developed three relapses that were distinguishable regarding their neurological signs and symptoms. Clinically and on MRI, all relapses were localised to the cervico-thoracic spinal cord (sensory level Th6, monoparesis right leg, sign of Lhermitte). Four years before, he had been diagnosed with supradiaphragmatic Hodgkin´s lymphoma stage IIa. Four courses of chemotherapy with the ABVD-protocol and irradiation with 29,5 Gray led to complete tumour remission. Consecutive MR-imaging of the brain and spinal cord revealed fluctuating and partially contrast-enhancing lesions exclusively in those sections of the spinal cord that were localised in the field irradiated four years before. Treatment with pulsed i.v. steroids led to improvement. CSF analysis showed mild pleocytosis and isolated oligoclonal bands. Extensive work-up for differential diagnoses was negative. Genetic sequencing for DNA repair enzymes and in-vitro assays of the patients peripheral blood mononuclear cells for increased sensitivity to irradiation was unrevealing. CONCLUSION: The fact that this patients MS-like disease was strictly confined to the irradiated parts of the body suggests that the co-occurrence of Hodgkins and MS-like disease was not simple coincidence but that they are pathogenetically linked. An increased aggressiveness of the immune system caused by the radiation is an unlikely explanation as the autoimmune attack would not be expected to spare the non-radiated parts of the CNS. We propose that in our patient the nervous tissue in the radiation clinical target volume was altered by radiation. This alteration of antigenic make-up, in turn, may have enabled an MS-specific autoimmune attack by a pre-existent immunological mechanism. This hypothesis is supported by experimental studies of induction of experimental autoimmune encephalitis (EAE) in irradiated rats.

Quantitative and qualitative analysis of integrin subtype expression in melanocytes and melanoma cells.

Objectives: Changes in the integrin expression pattern have been associated with the malignant transformation of melanocytes suggesting that integrins may be potential biomarkers as well as molecular targets for individualized therapy. Since there is a lack of comprehensive qualitative and quantitative expression data, we characterized the integrin expression profile in normal and malignant human cells of the melanocytic lineage.Methods: Seven melanoma cell lines as well as normal human melanocytes were investigated in western blots including recombinant integrin subunits for quantification.Results: Expression patterns were heterogeneous. In melanoma, overexpression of α4, α6, αL, ß5, and ß6 was found. Integrins α7, α9, and ß4 were overexpressed in a subset of the melanoma cell lines. Overexpression was defined as a lack of expression in melanocytes but expression in more than half (4) of the melanoma lines. 1.9 to 6.7 × 106 integrin molecules (about 0.3% of total cellular protein) were estimated to be expressed per cell. Expression of integrin αE at the protein level was found in melanoma and melanocytes, to the best of our knowledge, for the first time. Integrins αM and ß2 were not detected.Conclusion: Integrins α4, α6, αL, ß5, and ß6 appear to be overexpressed in melanoma cells. These subunits may serve as biomarkers and/or therapeutic targets.