BACKGROUND: Marathon training and running have many beneficial effects on human health and physical fitness; however, they also pose risks. To date, no comprehensive review regarding both the benefits and risks of marathon running on different organ systems has been published. MAIN BODY: The aim of this review was to provide a comprehensive review of the benefits and risks of marathon training and racing on different organ systems. A predefined search strategy including keywords (e.g., marathon, cardiovascular system, etc.) and free text search was used. Articles covering running regardless of sex, age, performance level, and event type (e.g., road races, mountain marathons) were considered, whereas articles examining only cycling, triathlon, stress-tests or other sports were excluded. In total, we found 1021 articles in PubMed, Scopus, and Google Scholar, of which 329 studies were included in this review. Overall, marathon training offers several benefits for different organ systems and reduces all-cause mortality. As such, it improves cardiovascular risk factors, leads to favorable cardiac adaptations, enhances lung function, and improves quality of life in chronic kidney disease patients. It also enhances gastrointestinal mobility and reduces the risk of specific tumors such as colorectal cancer and hepatocellular carcinoma. Marathon training enhances bone health and skeletal muscle metabolism. It further positively affects hematopoiesis and cytotoxic abilities of natural killer cells, and may act neuroprotective on a long-term basis. After a marathon, changes in biomarkers suggesting pathological events in certain organ systems such as cardiovascular, renal, gastrointestinal, liver, hematological, immune, musculoskeletal, central nervous, and endocrine systems can often be observed. Mostly, these changes are limited to 1-3 days post-race and usually normalize within a week. Moreover, marathon running poses the risk of serious adverse events such as sudden cardiac death or acute liver failure. Concerning lung function, a decrease after a marathon race was observed. Acute kidney injury, as well as electrolyte imbalances, are relatively common amongst marathon finishers. Many runners complain of gastrointestinal symptoms during or after long-distance running. Many runners suffer from running-related musculoskeletal injuries often impairing performance. A marathon is often accompanied by an acute inflammatory response with transient immunosuppression, making runners susceptible to infections. Also, hormonal alterations such as increased cortisol levels or decreased testosterone levels immediately after a race are observed. Disturbances in sleep patterns are commonly found in marathon runners leading up to or directly after the race. CONCLUSION: All in all, marathon training is generally safe for human health and individual organ systems. Considering the high popularity of marathon running, these findings supply athletes, coaches, sports scientists, and sports medicine practitioners with practical applications. Further large-scale studies examining long-term effects on the cardiovascular, renal, and other system are needed.

• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Antiphospholipid syndrome (APS) is associated with recurrent pregnancy morbidity, yet the underlying mechanisms remain elusive. We performed multifaceted characterization of the biological and transcriptomic signatures of mouse placenta and uterine natural killer (uNK) cells in APS. Histological analysis of APS placentas unveiled placental abnormalities, including disturbed angiogenesis, occasional necrotic areas, fibrin deposition, and nucleated red blood cell enrichment. Analyses of APS placentas showed a reduced cell proliferation, lower protein content and thinning of endothelial cells. Disturbances in APS trophoblast cells were linked to a cell cycle shift in cytotrophoblast cells, and a reduced number of spiral artery-associated trophoblast giant cells (SpA-TGC). Transcriptomic profiling of placental tissue highlighted disruptions in cell cycle regulation with notable downregulation of genes involved in developmental or signaling processes. Cellular senescence, metabolic and p53-related pathways were also enriched, suggesting potential mechanisms underlying placental dysfunction in APS. Thrombotic events, though occasionally detected, appeared to have no significant impact on the overall pathological changes. The increased number of dysfunctional uNK cells was not associated with enhanced cytotoxic capabilities. Transcriptomic data corroborated these findings, showing prominent suppression of NK cell secretory capacity and cytokine signaling pathways. Our study highlights the multifactorial nature of APS-associated placental pathologies, which involve disrupted angiogenesis, cell cycle regulation, and NK cell functionality.

• MeSH
• antifosfolipidový syndrom * imunologie   patologie   MeSH
• buňky NK * imunologie   metabolismus   MeSH
• modely nemocí na zvířatech * MeSH
• myši MeSH
• placenta * metabolismus   patologie   MeSH
• proliferace buněk MeSH
• stanovení celkové genové exprese MeSH
• těhotenství MeSH
• transkriptom MeSH
• trofoblasty metabolismus   patologie   imunologie   MeSH
• uterus * patologie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Circular RNAs (circRNAs) have played an essential role in cancer development. This study aimed to illustrate the impact and potential mechanism of circRACGAP1 action in NSCLC development. The expression patterns of circRACGAP1, miR-1296, and CDK2 in NSCLC tissues and cell lines were analysed by RT-qPCR. The function of circRACGAP1 in NSCLC cell proliferation and apoptosis was investigated using the CCK-8 assay, flow cytometry, TUNEL staining, and Western blot. The interaction among circRACGAP1, miR-1296, and CDK2 was clarified by dual-luciferase reporter assay while the correlation was confirmed by the Pearson correlation coefficient. The expression of circRACGAP1 and CDK2 was up-regulated in NSCLC tissues, while the expression of miR-1296 was down-regulated. Cell function studies further revealed that circRACGAP1 could promote NSCLC cell proliferation, accelerate the cell cycle process, up-regulate B-cell lymphoma 2 (Bcl2) expression, and down-regulate Bcl2-associated X (Bax) expression. miR-1296 was identified as a downstream target to reverse circRACGAP1-mediated cell proliferation. miR-1296 directly targeted the 3'-UTR of CDK2 to regulate proliferation and apoptosis of NSCLC cells. Additionally, the dual-luciferase reporter assay and Pearson correlation coefficient analysis proved that circRACGAP1 acted in NSCLC cells by negatively regulating miR-1296 expression and positively regulating CDK2 expression. In summary, our study revealed that circRACGAP1 promoted NSCLC cell proliferation by regulating the miR-1296/CDK2 pathway, providing potential diagnostic and therapeutic targets for NSCLC.

• MeSH
• apoptóza * genetika   MeSH
• cyklin-dependentní kinasa 2 * metabolismus   genetika   MeSH
• kruhová RNA * genetika   metabolismus   MeSH
• lidé MeSH
• mikro RNA * genetika   metabolismus   MeSH
• nádorové buněčné linie MeSH
• nádory plic * genetika   patologie   metabolismus   MeSH
• nemalobuněčný karcinom plic * genetika   patologie   metabolismus   MeSH
• proliferace buněk * genetika   MeSH
• proteiny aktivující GTPasu genetika   metabolismus   MeSH
• regulace genové exprese u nádorů MeSH
• signální transdukce genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Current diabetic retinopathy (DR) treatment involves blood glucose regulation combined with laser photocoagulation or intravitreal injection of vascular endothelial growth factor (VEGF) antibodies. However, due to the complex pathogenesis and cross-interference of multiple biochemical pathways, these interventions cannot block disease progression. Recognizing the critical role of the retinal microenvironment (RME) in DR, it is hypothesized that reshaping the RME by simultaneously inhibiting primary and secondary blood-retinal barrier (BRB) injury can attenuate DR. For this, a glucose-responsive hydrogel named Cu-PEI/siMyD88@GEMA-Con A (CSGC) is developed that effectively delivers Cu-PEI/siMyD88 nanoparticles (NPs) to the retinal pigment epithelium (RPE). The Cu-PEI NPs act as antioxidant enzymes, scavenging ROS and inhibiting RPE pyroptosis, ultimately blocking primary BRB injury by reducing microglial activation and Th1 differentiation. Simultaneously, MyD88 expression silence in combination with the Cu-PEI NPs decreases IL-18 production, synergistically reduces VEGF levels, and enhances tight junction proteins expression, thus blocking secondary BRB injury. In summary, via remodeling the RME, the CSGC hydrogel has the potential to disrupt the detrimental cycle of cross-interference between primary and secondary BRB injury, providing a promising therapeutic strategy for DR.

• MeSH
• buněčné mikroprostředí účinky léků   MeSH
• diabetická retinopatie * farmakoterapie   metabolismus   MeSH
• glukosa * metabolismus   MeSH
• hematoretinální bariéra * metabolismus   účinky léků   MeSH
• hydrogely * farmakologie   MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• nanočástice MeSH
• retina účinky léků   metabolismus   MeSH
• retinální pigmentový epitel metabolismus   účinky léků   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Prostate cancer develops through malignant transformation of the prostate epithelium in a stepwise, mutation-driven process. Although activator protein-1 transcription factors such as JUN have been implicated as potential oncogenic drivers, the molecular programs contributing to prostate cancer progression are not fully understood. METHODS: We analyzed JUN expression in clinical prostate cancer samples across different stages and investigated its functional role in a Pten-deficient mouse model. We performed histopathological examinations, transcriptomic analyses and explored the senescence-associated secretory phenotype in the tumor microenvironment. RESULTS: Elevated JUN levels characterized early-stage prostate cancer and predicted improved survival in human and murine samples. Immune-phenotyping of Pten-deficient prostates revealed high accumulation of tumor-infiltrating leukocytes, particularly innate immune cells, neutrophils and macrophages as well as high levels of STAT3 activation and IL-1β production. Jun depletion in a Pten-deficient background prevented immune cell attraction which was accompanied by significant reduction of active STAT3 and IL-1β and accelerated prostate tumor growth. Comparative transcriptome profiling of prostate epithelial cells revealed a senescence-associated gene signature, upregulation of pro-inflammatory processes involved in immune cell attraction and of chemokines such as IL-1β, TNF-α, CCL3 and CCL8 in Pten-deficient prostates. Strikingly, JUN depletion reversed both the senescence-associated secretory phenotype and senescence-associated immune cell infiltration but had no impact on cell cycle arrest. As a result, JUN depletion in Pten-deficient prostates interfered with the senescence-associated immune clearance and accelerated tumor growth. CONCLUSIONS: Our results suggest that JUN acts as tumor-suppressor and decelerates the progression of prostate cancer by transcriptional regulation of senescence- and inflammation-associated genes. This study opens avenues for novel treatment strategies that could impede disease progression and improve patient outcomes.

• MeSH
• fosfohydroláza PTEN * genetika   metabolismus   MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádorové mikroprostředí * imunologie   MeSH
• nádory prostaty * patologie   genetika   metabolismus   MeSH
• progrese nemoci * MeSH
• protoonkogenní proteiny c-jun metabolismus   MeSH
• regulace genové exprese u nádorů MeSH
• sekreční fenotyp asociovaný se senescencí MeSH
• stanovení celkové genové exprese MeSH
• stárnutí buněk genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

The role of benzo[a]pyrene (BaP), a prominent genotoxic carcinogen and aryl hydrocarbon receptor (AhR) ligand, in tumor progression remains poorly characterized. We investigated the impact of BaP on the process of epithelial-mesenchymal transition (EMT) in normal human bronchial epithelial HBEC-12KT cells. Early morphological changes after 2-week exposure were accompanied with induction of SERPINB2, IL1, CDKN1A/p21 (linked with cell cycle delay) and chemokine CXCL5. After 8-week exposure, induction of cell migration and EMT-related pattern of markers/regulators led to induction of further pro-inflammatory cytokines or non-canonical Wnt pathway ligand WNT5A. This trend of up-regulation of pro-inflammatory genes and non-canonical Wnt pathway constituents was observed also in the BaP-transformed HBEC-12KT-B1 cells. In general, transcriptional effects of BaP differed from those of TGFβ1, a prototypical EMT inducer, or a model non-genotoxic AhR ligand, TCDD. Carcinogenic polycyclic aromatic hydrocarbons could thus induce a unique set of molecular changes linked with EMT and cancer progression.

• MeSH
• benzopyren * toxicita   MeSH
• epitelové buňky * metabolismus   MeSH
• lidé MeSH
• ligandy MeSH
• poškození DNA MeSH
• receptory aromatických uhlovodíků genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

The unicellular parasite Leishmania has a precisely defined cell architecture that is inherited by each subsequent generation, requiring a highly coordinated pattern of duplication and segregation of organelles and cytoskeletal structures. A framework of nuclear division and morphological changes is known from light microscopy, yet this has limited resolution and the intrinsic organisation of organelles within the cell body and their manner of duplication and inheritance is unknown. Using volume electron microscopy approaches, we have produced three-dimensional reconstructions of different promastigote cell cycle stages to give a spatial and quantitative overview of organelle positioning, division and inheritance. The first morphological indications seen in our dataset that a new cell cycle had begun were the assembly of a new flagellum, the duplication of the contractile vacuole and the increase in volume of the nucleus and kinetoplast. We showed that the progression of the cytokinesis furrow created a specific pattern of membrane indentations, while our analysis of sub-pellicular microtubule organisation indicated that there is likely a preferred site of new microtubule insertion. The daughter cells retained these indentations in their cell body for a period post-abscission. By comparing cultured and sand fly derived promastigotes, we found an increase in the number and overall volume of lipid droplets in the promastigotes from the sand fly, reflecting a change in their metabolism to ensure transmissibility to the mammalian host. Our insights into the cell cycle mechanics of Leishmania will support future molecular cell biology analyses of these parasites.

• MeSH
• buněčné dělení MeSH
• buněčný cyklus MeSH
• Leishmania mexicana * genetika   MeSH
• Leishmania * MeSH
• paraziti * MeSH
• Psychodidae * parazitologie   MeSH
• savci MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

The fertilizing spermatozoa induce a Ca2+ oscillatory pattern, the universal hallmark of oocyte activation, in all sexually reproducing animals. Assisted reproductive technologies (ARTs) like intracytoplasmic sperm injection (ICSI) bypass the physiological pathway; however, while a normal Ca2+ release pattern occurs in some species, particularly humans, artificial activation is compulsory for ICSI-fertilized oocytes to develop in most farm animals. Unlike the normal oscillatory pattern, most artificial activation protocols induce a single Ca2+ spike, undermining proper ICSI-derived embryo development in these species. Curiously, diploid parthenogenetic embryos activated by the same treatments develop normally at high frequencies and implant upon transfer in the uterus. We hypothesized that, at least in ruminant embryos, the oscillatory calcium waves late in the first cell cycle target preferentially the paternal pronucleus and are fundamentally important for paternal nuclear remodeling. We believe that Ca2+ signaling is central to full totipotency deployment of the paternal genome. Research in this area could highlight the asymmetry between the parental genome reprogramming timing/mechanisms in early development and impact ARTs like ICSI and cloning.

• MeSH
• cytoplazma metabolismus   MeSH
• fertilizace MeSH
• lidé MeSH
• oocyty metabolismus   MeSH
• sperma * metabolismus   MeSH
• spermie metabolismus   MeSH
• vápník * metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Disseminated pulmonary involvement in pediatric Hodgkin lymphoma (pHL) is indicative of Ann Arbor stage IV disease. During staging, it is necessary to assess for coexistence of non-malignant lung lesions due to infection representing background noise to avoid erroneously upstaging with therapy intensification. OBJECTIVE: This study attempts to describe new lung lesions detected on interim staging computed tomography (CT) scans after two cycles of vincristine, etoposide, prednisolone, doxorubicin in a prospective clinical trial. Based on the hypothesis that these new lung lesions are not part of the underlying malignancy but are epiphenomena, the aim is to analyze their size, number, and pattern to help distinguish true lung metastases from benign lung lesions on initial staging. MATERIALS AND METHODS: A retrospective analysis of the EuroNet-PHL-C1 trial re-evaluated the staging and interim lung CT scans of 1,300 pediatric patients with HL. Newly developed lung lesions during chemotherapy were classified according to the current Fleischner glossary of terms for thoracic imaging. Patients with new lung lesions found at early response assessment (ERA) were additionally assessed and compared to response seen in hilar and mediastinal lymph nodes. RESULTS: Of 1,300 patients at ERA, 119 (9.2%) had new pulmonary lesions not originally detectable at diagnosis. The phenomenon occurred regardless of initial lung involvement or whether a patient relapsed. In the latter group, new lung lesions on ERA regressed by the time of relapse staging. New lung lesions on ERA in patients without relapse were detected in 102 (7.8%) patients. Pulmonary nodules were recorded in 72 (5.5%) patients, the majority (97%) being<10 mm. Consolidations, ground-glass opacities, and parenchymal bands were less common. CONCLUSION: New nodules on interim staging are common, mostly measure less than 10 mm in diameter and usually require no further action because they are most likely non-malignant. Since it must be assumed that benign and malignant lung lesions coexist on initial staging, this benign background noise needs to be distinguished from lung metastases to avoid upstaging to stage IV disease. Raising the cut-off size for lung nodules to ≥ 10 mm might achieve the reduction of overtreatment but needs to be further evaluated with survival data. In contrast to the staging criteria of EuroNet-PHL-C1 and C2, our data suggest that the number of lesions present at initial staging may be less important.

• MeSH
• dítě MeSH
• doxorubicin terapeutické užití   MeSH
• etoposid terapeutické užití   aplikace a dávkování   MeSH
• Hodgkinova nemoc * diagnostické zobrazování   patologie   farmakoterapie   MeSH
• lidé MeSH
• mladiství MeSH
• nádory plic * diagnostické zobrazování   patologie   MeSH
• počítačová rentgenová tomografie * metody   MeSH
• předškolní dítě MeSH
• prevalence MeSH
• prospektivní studie MeSH
• protokoly protinádorové kombinované chemoterapie terapeutické užití   MeSH
• retrospektivní studie MeSH
• staging nádorů * MeSH
• vinkristin terapeutické užití   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Patients with myelodysplastic neoplasms (MDS) are classified according to the risk of acute myeloid leukemia transformation. Some lower-risk MDS patients (LR-MDS) progress rapidly despite expected good prognosis. Using diagnostic samples, we aimed to uncover the mechanisms of this accelerated progression at the transcriptome level. RNAseq was performed on CD34+ ribodepleted RNA samples from 53 LR-MDS patients without accelerated progression (stMDS) and 8 who progressed within 20 months (prMDS); 845 genes were differentially expressed (ІlogFCІ > 1, FDR < 0.01) between these groups. stMDS CD34+ cells exhibited transcriptional signatures of actively cycling, megakaryocyte/erythrocyte lineage-primed progenitors, with upregulation of cell cycle checkpoints and stress pathways, which presumably form a tumor-suppressing barrier. Conversely, cell cycle, DNA damage response (DDR) and energy metabolism-related pathways were downregulated in prMDS samples, whereas cell adhesion processes were upregulated. Also, prMDS samples showed high levels of aberrant splicing and global lncRNA expression that may contribute to the attenuation of DDR pathways. We observed overexpression of multiple oncogenes and diminished differentiation in prMDS; the expression of ZEB1 and NEK3, genes not previously associated with MDS prognosis, might serve as potential biomarkers for LR-MDS progression. Our 19-gene DDR signature showed a significant predictive power for LR-MDS progression. In validation samples (stMDS = 3, prMDS = 4), the key markers and signatures retained their significance. Collectively, accelerated progression of LR-MDS appears to be associated with transcriptome patterns of a quiescent-like cell state, reduced lineage differentiation and suppressed DDR, inherent to CD34+ cells. The attenuation of DDR-related gene-expression signature may refine risk assessment in LR-MDS patients.

• MeSH
• buněčná adheze MeSH
• buněčný cyklus MeSH
• kinasy NEK genetika   metabolismus   MeSH
• lidé MeSH
• myelodysplastické syndromy * genetika   MeSH
• nádory * MeSH
• oprava DNA MeSH
• transkriptom MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH