The extracellular matrix (ECM)-and its mechanobiology-regulates key cellular functions that drive tumor growth and development. Accordingly, mechanotherapy is emerging as an effective approach to treat fibrotic diseases such as cancer. Through restoring the ECM to healthy-like conditions, this treatment aims to improve tissue perfusion, facilitating the delivery of chemotherapies. In particular, the manipulation of ECM is gaining interest as a valuable strategy for developing innovative treatments based on nanoparticles (NPs). However, further progress is required; for instance, it is known that the presence of a dense ECM, which hampers the penetration of NPs, primarily impacts the efficacy of nanomedicines. Furthermore, most 2D in vitro studies fail to recapitulate the physiological deposition of matrix components. To address these issues, a comprehensive understanding of the interactions between the ECM and NPs is needed. This review focuses on the main features of the ECM and its complex interplay with NPs. Recent advances in mechanotherapy are discussed and insights are offered into how its combination with nanomedicine can help improve nanomaterials design and advance their clinical translation.

• MeSH
• extracelulární matrix * metabolismus   MeSH
• lidé MeSH
• nádory * terapie   MeSH
• nanočástice * chemie   MeSH
• nanomedicína * metody   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Neurons rely on the microtubule cytoskeleton to create and maintain their sophisticated cellular architectures. Advances in cryogenic electron microscopy, expansion microscopy, live imaging, and gene editing have enabled novel insights into mechanisms of centrosomal and acentrosomal microtubule nucleation, the key process generating new microtubules. This has paved the way for the functional dissection of distinct microtubule networks that regulate various processes during neuronal development, including neuronal delamination, polarization, migration, maturation, and synapse function. We review recent progress in understanding the molecular concepts of microtubule nucleation, how these concepts underlie neurodevelopmental processes, and pinpoint the open questions. Since microtubules play a pivotal role in axon regeneration within the adult central nervous system, understanding the processes of microtubule nucleation could inform strategies to enhance the regenerative capabilities of neurons in the future.

• MeSH
• centrozom * metabolismus   fyziologie   MeSH
• lidé MeSH
• mikrotubuly * metabolismus   fyziologie   MeSH
• neurogeneze * fyziologie   MeSH
• neurony * fyziologie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Anaplastic Large Cell Lymphoma (ALCL) is an aggressive T-cell lymphoma affecting children and young adults. About 30% of patients develop therapy resistance therefore new precision medicine drugs are highly warranted. Multiple rounds of structure-activity optimization of Caffeic Acid Phenethyl Ester have resulted in CM14. CM14 causes upregulation of genes involved in oxidative stress response and downregulation of DNA replication genes leading to G2/M arrest and subsequent apoptosis induction. In accordance with this, an unbiased proteomics approach, confocal microscopy and molecular modeling showed that TUBGCP2, member of the centrosomal γ-TuRC complex, is a direct interaction partner of CM14. CM14 overcomes ALK inhibitor resistance in ALCL and is also active in T-cell Acute Lymphoblastic Leukemia and Acute Myeloid Leukemia. Interestingly, CM14 also induced cell death in docetaxel-resistant prostate cancer cells thus suggesting an unexpected role in solid cancers. Thus, we synthesized and thoroughly characterized a novel TUBGCP2 targeting drug that is active in ALCL but has also potential for other malignancies.

• MeSH
• apoptóza * účinky léků   MeSH
• centrozom * účinky léků   metabolismus   MeSH
• fenethylalkohol * analogy a deriváty   farmakologie   chemie   MeSH
• kyseliny kávové * farmakologie   chemie   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky * farmakologie   chemie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

AIM: This work explores the synthesis of new bi-heterocyclic hybrid compounds based on quinoline ring and investigates their potential as anticancer agents. MATERIALS & METHODS: The novel fused quinoline-thiazolo[3,2-a] benzimidazole-3(2 h)one hybrids were prepared by regioselective nucleophilic ring opening of the corresponding quinolinyl-oxiranes. In vitro cytotoxic activity was evaluated against human lung (A549) and gastric (AGS) cancer cell lines. RESULTS: Global results showed that all tested compounds have promising inhibitory properties. Compounds 17 and 18 bearing two methoxy groups on the quinoline ring have exhibited remarkable and interesting activities. The investigation of the cell death process showed that these compounds activated a caspase-dependent apoptosis pathway. Results were further supported by molecular docking studies. CONCLUSION: Both compounds exhibited good drug-like characteristics, which make them promising drug candidates.

• MeSH
• apoptóza * účinky léků   MeSH
• benzimidazoly * farmakologie   chemie   chemická syntéza   MeSH
• chinoliny * chemie   farmakologie   chemická syntéza   MeSH
• kaspasy * metabolismus   MeSH
• lidé MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky * farmakologie   chemie   chemická syntéza   MeSH
• screeningové testy protinádorových léčiv MeSH
• simulace molekulového dockingu * MeSH
• thiazoly chemie   farmakologie   chemická syntéza   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Bio-nano interactions have been extensively explored in nanomedicine to develop selective delivery strategies and reduce systemic toxicity. To enhance the delivery of nanocarriers to cancer cells and improve the therapeutic efficiency, different nanomaterials have been developed. However, the limited clinical translation of nanoparticle-based therapies, largely due to issues associated with poor targeting, requires a deeper understanding of the biological phenomena underlying cell-nanoparticle interactions. In this context, we investigate the molecular and cellular mechanobiology parameters that control such interactions. We demonstrate that the pharmacological inhibition or the genetic ablation of the key mechanosensitive component of the Hippo pathway, i.e., yes-associated protein, enhances nanoparticle internalization by 1.5-fold. Importantly, this phenomenon occurs independently of nanoparticle properties, such as size, or cell properties such as surface area and stiffness. Our study reveals that the internalization of nanoparticles in target cells can be controlled by modulating cell mechanosensing pathways, potentially enhancing nanotherapy specificity.

• MeSH
• adaptorové proteiny signální transdukční metabolismus   MeSH
• buněčný převod mechanických signálů účinky léků   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nanočástice * chemie   MeSH
• nanomedicína MeSH
• signální dráha Hippo MeSH
• signální proteiny YAP MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Mitochondria represent pivotal cellular organelles endowed with multifaceted functionalities encompassing cellular respiration, metabolic processes, calcium turnover, and the regulation of apoptosis, primarily through the generation of reactive oxygen species (ROS). Perturbations in mitochondrial dynamics have been intricately linked to the etiology of numerous cardiovascular pathologies, such as heart failure, ischemic heart disease, and various cardiomyopathies. Notably, recent attention has been directed towards the detrimental impact of micro- and nanoplastic pollution on mitochondrial integrity, an area underscored by a paucity of comprehensive investigations. Given the escalating prevalence of plastic particle contamination and the concomitant burden of cardiovascular disease in aging populations, understanding the interplay between mitochondria within the cardiovascular system and micro- and nanoplastic pollution assumes paramount importance. This review endeavors to elucidate the current albeit limited comprehension surrounding this complex interplay. Key words Mitochondria, Nanoplastics, Microplastics, Cardiovascular system, Endothelial function, Oxidative phosphorylation.

• MeSH
• kardiovaskulární nemoci metabolismus   MeSH
• kardiovaskulární systém * metabolismus   účinky léků   MeSH
• lidé MeSH
• mikroplasty toxicita   MeSH
• mitochondrie * metabolismus   účinky léků   MeSH
• nanočástice MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Retroviral gene transfer is the preferred method for stable, long-term integration of genetic material into cellular genomes, commonly used to generate chimeric antigen receptor (CAR)-T cells designed to target tumor antigens. However, the efficiency of retroviral gene transfer is often limited by low transduction rates due to low vector titers and electrostatic repulsion between viral particles and cellular membranes. To overcome these limitations, peptide nanofibrils (PNFs) can be applied as transduction enhancers. Among these, PNFs derived from the 12-mer peptide EF-C are well-investigated and commercially available. EF-C PNFs enhance transduction by forming EF-C PNFs/virus complexes that overcome electrostatic repulsion through their polycationic surface and interaction with cellular protrusions. However, the safe application of PNFs as transduction enhancers in gene therapeutic applications requires a fundamental understanding of their transduction-enhancing mechanisms, uptake, and degradation. In this study, we demonstrate that EF-C PNFs induce plasma membrane invaginations, increasing the membrane surface for viral attachment and reducing the distance to the nuclear membrane, thereby facilitating viral entry and transport to the nucleus. Furthermore, we identified macropinocytosis as the main entry pathway for EF-C PNFs and their subsequent degradation by lysosomal peptidases. The lysosomal degradation of EF-C PNFs prevents their accumulation as amyloid deposits, mitigating potential side effects and supporting their safe use in clinical applications.

• MeSH
• endocytóza MeSH
• HEK293 buňky MeSH
• lidé MeSH
• myši MeSH
• nanovlákna * chemie   MeSH
• peptidy * chemie   metabolismus   MeSH
• pinocytóza * MeSH
• transdukce genetická metody   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

INTRODUCTION: The aging process is intricately linked to alterations in cellular and tissue structures, with the respiratory system being particularly susceptible to age-related changes. Therefore, this study aimed to profile the activity of proteases using activity-based probes in lung tissues of old and young rats, focusing on the expression levels of different, in particular cathepsins G and X and matrix Metalloproteinases (MMPs). Additionally, the impact on extracellular matrix (ECM) components, particularly fibronectin, in relation to age-related histological and ultrastructural changes in lung tissues was investigated. MATERIALS AND METHODS: Lung tissues from old and young rats were subjected to activity-based probe profiling to assess the activity of different proteases. Expression levels of cathepsins G and X were quantified, and zymography was performed to evaluate matrix metalloproteinases activity. Furthermore, ECM components, specifically fibronectin, were examined for signs of degradation in the old lung tissues compared to the young ones. Moreover, histological, immunohistochemical and ultrastructural assessments of old and young lung tissue were also conducted. RESULTS: Our results showed that the expression levels of cathepsins G and X were notably higher in old rat lung tissues in contrast to those in young rat lung tissues. Zymography analysis revealed elevated MMP activity in the old lung tissues compared to the young ones. Particularly, significant degradation of fibronectin, an essential ECM component, was observed in the old lung tissues. Numerous histological and ultrastructural alterations were observed in old lung tissues compared to young lung tissues. DISCUSSION AND CONCLUSION: The findings indicate an age-related upregulation of cathepsins G and X along with heightened MMP activity in old rat lung tissues, potentially contributing to the degradation of fibronectin within the ECM. These alterations highlight potential mechanisms underlying age-associated changes in lung tissue integrity and provide insights into protease-mediated ECM remodeling in the context of aging lungs.

• MeSH
• extracelulární matrix metabolismus   ultrastruktura   MeSH
• fibronektiny * metabolismus   MeSH
• kathepsin G metabolismus   MeSH
• krysa rodu rattus MeSH
• lyzozomy ultrastruktura   metabolismus   MeSH
• matrixové metaloproteinasy metabolismus   MeSH
• plíce * ultrastruktura   metabolismus   MeSH
• proteasy metabolismus   MeSH
• stárnutí * metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Using an active targeting approach of chemotherapeutics-loaded nanocarriers (NCs) with monoclonal antibodies is a potential strategy to improve the specificity of the delivery systems and reduce adverse reactions of chemotherapeutic drugs. Specific targeting of the human epidermal growth factor receptor-2 (HER-2), expressed excessively in HER-2-positive breast cancer cells, can be achieved by conjugating NCs with an anti-HER-2 monoclonal antibody. We constructed trastuzumab-conjugated chitosan iodoacetamide-coated NCs containing doxorubicin (Tras-Dox-CHI-IA-NCs) as a tumor-targeted drug delivery system, during the study. Chitosan-iodoacetamide (CHI-IA) was synthesized and utilized to prepare trastuzumab-conjugated NCs (Tras-NCs). The morphology, physicochemical properties, drug loading, drug release, and biological activities of the NCs were elucidated. The Tras-NCs were spherical, with a particle size of approximately 76 nm, and had a positive zeta potential; after incorporating the drug, the size of the Tras-NC increased. A prolonged, 24-h drug release from the NCs was achieved. The Tras-NCs exhibited high cellular accumulation and significantly higher antitumor activity against HER-2-positive breast cancer cells than the unconjugated NCs and the drug solution. Therefore, Tras-Dox-CHI-IA-NCs could be a promising nanocarrier for HER-2-positive breast cancer.

• MeSH
• chitosan * chemie   MeSH
• doxorubicin chemie   MeSH
• jodacetamid MeSH
• lékové transportní systémy MeSH
• lidé MeSH
• monoklonální protilátky chemie   MeSH
• nádory prsu * farmakoterapie   MeSH
• nanočástice * chemie   MeSH
• nosiče léků chemie   MeSH
• trastuzumab MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• DNA genetika   metabolismus   MeSH
• duševní procesy MeSH
• emoce fyziologie   MeSH
• endokrinní systém fyziologie   MeSH
• epigenetická paměť MeSH
• epigeneze genetická MeSH
• genetické jevy MeSH
• genom MeSH
• geny MeSH
• imunitní systém fyziologie   MeSH
• lidé MeSH
• mikrobiota MeSH
• nervový systém MeSH
• vědomí * fyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH