Aryl hydrocarbon receptor (AhR) is a transcription factor that is primarily known as an intracellular sensor of environmental pollution. After five decades, the list of synthetic and toxic chemicals that activate AhR signaling has been extended to include a number of endogenous compounds produced by various types of cells via their metabolic activity. AhR signaling is active from the very beginning of embryonal development throughout the life cycle and participates in numerous biological processes such as control of cell proliferation and differentiation, metabolism of aromatic compounds of endogenous and exogenous origin, tissue regeneration and stratification, immune system development and polarization, control of stemness potential, and homeostasis maintenance. AhR signaling can be affected by various pharmaceuticals that may help modulate abnormal AhR signaling and drive pathological states. Given their role in immune system development and regulation, AhR antagonistic ligands are attractive candidates for immunotherapy of disease states such as advanced prostate cancer, where an aberrant immune microenvironment contributes to cancer progression and needs to be reeducated. Advanced stages of prostate cancer are therapeutically challenging and characterized by decreased overall survival (OS) due to the metastatic burden. Therefore, this review addresses the role of AhR signaling in the development and progression of prostate cancer and discusses the potential of AhR as a drug target for the treatment of advanced prostate cancer upon entering the phase of drug resistance and failure of first-line androgen deprivation therapy.Abbreviation: ADC: antibody-drug conjugate; ADT: androgen deprivation therapy; AhR: aryl hydrocarbon receptor; AR: androgen receptor; ARE: androgen response element; ARPI: androgen receptor pathway inhibitor; mCRPC: metastatic castration-resistant prostate cancer; DHT: 5a-dihydrotestosterone; FICZ: 6-formylindolo[3,2-b]carbazole; 3-MC: 3-methylcholanthrene; 6-MCDF: 6-methyl-1,3,8-trichlorodibenzofuran; MDSCs: myeloid-derived suppressor cells; PAHs: polycyclic aromatic hydrocarbons; PCa: prostate cancer; TAMs: tumor-associated macrophages; TF: transcription factor; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TME: tumor microenvironment; TRAMP: transgenic adenocarcinoma of the mouse prostate; TROP2: tumor associated calcium signal transducer 2.

• MeSH
• Molecular Targeted Therapy MeSH
• Humans MeSH
• Tumor Microenvironment drug effects   MeSH
• Prostatic Neoplasms * drug therapy   metabolism   pathology   MeSH
• Antineoplastic Agents * therapeutic use   pharmacology   MeSH
• Receptors, Aryl Hydrocarbon * metabolism   antagonists & inhibitors   MeSH
• Signal Transduction drug effects   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

An organism is considered "alive" if it can grow, reproduce, respond to external stimuli, metabolize nutrients, and maintain stability. By this definition, both mitochondria and viruses exhibit the key characteristics of independent life. In addition to their capacity for self-replication under specifically defined conditions, both mitochondria and viruses can communicate via shared biochemical elements, alter cellular energy metabolism, and adapt to their local environment. To explain this phenomenon, we hypothesize that early viral prototype species evolved from ubiquitous environmental DNA and gained the capacity for self-replication within coacervate-like liquid droplets. The high mutation rates experienced in this environment streamlined their acquisition of standard genetic codes and adaptation to a diverse set of host environments. Similarly, mitochondria, eukaryotic intracellular organelles that generate energy and resolve oxygen toxicity, originally evolved from an infectious bacterial species and maintain their capacity for active functionality within the extracellular space. Thus, while mitochondria contribute profoundly to eukaryotic cellular homeostasis, their capacity for freestanding existence may lead to functional disruptions over time, notably, the overproduction of reactive oxygen species, a phenomenon strongly linked to aging-related disorders. Overall, a more in-depth understanding of the full extent of the evolution of both viruses and mitochondria from primordial precursors may lead to novel insights and therapeutic strategies to address neurodegenerative processes and promote healthy aging.

• MeSH
• Energy Metabolism MeSH
• Humans MeSH
• Mitochondria * metabolism   MeSH
• Origin of Life * MeSH
• Viruses * metabolism   genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

• MeSH
• Biochemistry MeSH
• Metabolic Diseases MeSH
• Pathology MeSH

• Conspectus
• Patologie. Klinická medicína
• Učební osnovy. Vyučovací předměty. Učebnice
• NML Fields
• biochemie
• patologie
• NML Publication type
• učebnice vysokých škol

Fuchs endothelial corneal dystrophy (FECD) is an age-related cause of vision loss, and the most common repeat expansion-mediated disease in humans characterised to date. Up to 80% of European FECD cases have been attributed to expansion of a non-coding CTG repeat element (termed CTG18.1) located within the ubiquitously expressed transcription factor encoding gene, TCF4. The non-coding nature of the repeat and the transcriptomic complexity of TCF4 have made it extremely challenging to experimentally decipher the molecular mechanisms underlying this disease. Here we comprehensively describe CTG18.1 expansion-driven molecular components of disease within primary patient-derived corneal endothelial cells (CECs), generated from a large cohort of individuals with CTG18.1-expanded (Exp+) and CTG 18.1-independent (Exp-) FECD. We employ long-read, short-read, and spatial transcriptomic techniques to interrogate expansion-specific transcriptomic biomarkers. Interrogation of long-read sequencing and alternative splicing analysis of short-read transcriptomic data together reveals the global extent of altered splicing occurring within Exp+ FECD, and unique transcripts associated with CTG18.1-expansions. Similarly, differential gene expression analysis highlights the total transcriptomic consequences of Exp+ FECD within CECs. Furthermore, differential exon usage, pathway enrichment and spatial transcriptomics reveal TCF4 isoform ratio skewing solely in Exp+ FECD with potential downstream functional consequences. Lastly, exome data from 134 Exp- FECD cases identified rare (minor allele frequency <0.005) and potentially deleterious (CADD>15) TCF4 variants in 7/134 FECD Exp- cases, suggesting that TCF4 variants independent of CTG18.1 may increase FECD risk. In summary, our study supports the hypothesis that at least two distinct pathogenic mechanisms, RNA toxicity and TCF4 isoform-specific dysregulation, both underpin the pathophysiology of FECD. We anticipate these data will inform and guide the development of translational interventions for this common triplet-repeat mediated disease.

• MeSH
• Alternative Splicing genetics   MeSH
• Endothelial Cells metabolism   MeSH
• Trinucleotide Repeat Expansion * genetics   MeSH
• Fuchs' Endothelial Dystrophy * genetics   MeSH
• Humans MeSH
• Endothelium, Corneal metabolism   pathology   MeSH
• Transcription Factor 4 * genetics   metabolism   MeSH
• Transcriptome genetics   MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Hypoxia is a common feature of many solid tumors and causes radiotherapy and immunotherapy resistance. Pharmacological inhibition of oxidative phosphorylation (OXPHOS) has emerged as a therapeutic strategy to reduce hypoxia. However, the OXPHOS inhibitors tested in clinical trials caused only moderate responses in hypoxia alleviation or trials were terminated due to dose-limiting toxicities. To improve the therapeutic benefit, FDA approved OXPHOS inhibitors (e.g. atovaquone) were conjugated to triphenylphosphonium (TPP+) to preferentially target cancer cell's mitochondria. In this study, we evaluated the hypoxia reducing effects of several mitochondria-targeted OXPHOS inhibitors and compared them to non-mitochondria-targeted OXPHOS inhibitors using newly developed spheroid models for diffusion-limited hypoxia. METHODS: B16OVA murine melanoma cells and MC38 murine colon cancer cells expressing a HIF-Responsive Element (HRE)-induced Green Fluorescent Protein (GFP) with an oxygen-dependent degradation domain (HRE-eGFP-ODD) were generated to assess diffusion-limited hypoxia dynamics in spheroids. Spheroids were treated with IACS-010759, atovaquone, metformin, tamoxifen or with mitochondria-targeted atovaquone (Mito-ATO), PEGylated mitochondria-targeted atovaquone (Mito-PEG-ATO) or mitochondria-targeted tamoxifen (MitoTam). Hypoxia dynamics were followed and quantified over time using the IncuCyte Zoom Live Cell-Imaging system. RESULTS: Hypoxic cores developed in B16OVA.HRE and MC38.HRE spheroids within 24 h hours after seeding. Treatment with IACS-010759, metformin, atovaquone, Mito-PEG-ATO and MitoTam showed a dose-dependent reduction of hypoxia in both B16OVA.HRE and MC38.HRE spheroids. Mito-ATO only alleviated hypoxia in MC38.HRE spheroids while tamoxifen was not able to reduce hypoxia in any of the spheroid models. The mitochondria-targeted OXPHOS inhibitors demonstrated stronger anti-hypoxic effects compared to the non-mito-targeted OXPHOS inhibitors. CONCLUSIONS: We successfully developed a high-throughput spheroid model in which hypoxia dynamics can be quantified over time. Using this model, we showed that the mitochondria-targeted OXPHOS inhibitors Mito-ATO, Mito-PEG-ATO and MitoTam reduce hypoxia in tumor cells in a dose-dependent manner, potentially sensitizing hypoxic tumor cells for radiotherapy.

• Publication type
• Journal Article MeSH

The aim of this study was to evaluate the inorganic elemental composition (49 elements) of 29 botanical preparations obtained from fruits, leaves, peels, seeds, roots, fungi, and spirulina by using inductively coupled-mass spectrometry and a mercury analyzer. Simultaneously, the risk associated with the chronic dietary exposure to 12 toxic metals and metalloids among the European population was evaluated by using a probabilistic approach based on Monte Carlo simulations. The analysis revealed worrying intake levels of Al, As, and Ni, primarily stemming from the consumption of spirulina-, peel-, and leaf-based botanicals by younger age groups. The intake of As from all analyzed botanicals posed a significant risk for infants, yielding margins of exposure (MOEs) below 1, while those deriving from peel-based botanicals raised concerns across all age groups (MOEs = 0.04-2.3). The consumption of peel-based botanicals contributed substantially (13-130%) also to the tolerable daily intake of Ni for infants, toddlers, and children, while that of spirulina-based botanicals raised concerns related to Al intake also among adults, contributing to 11-176% of the tolerable weekly intake of this element. The findings achieved underscore the importance of implementing a monitoring framework to address chemical contamination of botanicals, thus ensuring their safety for regular consumers.

• MeSH
• Dietary Exposure * MeSH
• Child MeSH
• Adult MeSH
• Risk Assessment MeSH
• Infant MeSH
• Food Contamination * analysis   MeSH
• Metals analysis   toxicity   MeSH
• Humans MeSH
• Monte Carlo Method MeSH
• Adolescent MeSH
• Young Adult MeSH
• Metalloids * analysis   toxicity   MeSH
• Child, Preschool MeSH
• Plant Preparations chemistry   analysis   MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Child, Preschool MeSH
• Publication type
• Journal Article MeSH

Testing the hemocompatibility of medical devices after their interaction with blood entails the need to evaluate the activation of blood elements and the degree of their coagulation and adhesion to the device surface. One possible way to achieve this is to use scanning electron microscopy (SEM). The aim was to develop a novel SEM-based method to assess the thrombogenic potential of medical devices and their adhesiveness to blood cells. As a part of this task, also find a convenient procedure of efficient and non-destructive sample fixation for SEM while reducing the use of highly toxic substances and shortening the fixation time. A polymeric surgical mesh was exposed to blood so that blood elements adhered to its surface. Such prepared samples were then chemically fixed for a subsequent SEM measurement; a number of fixation procedures were tested to find the optimal one. The fixation results were evaluated from SEM images, and the degree of blood elements' adhesion was determined from the images using ImageJ software. The best fixation was achieved with the May-Grünwald solution, which is less toxic than chemicals traditionally used. Moreover, manipulation with highly toxic osmium tetroxide can be avoided in the proposed procedure. A convenient methodology for SEM image analysis has been developed too, enabling to quantitatively evaluate the interaction of blood with the surfaces of various medical devices. Our method replaces the subjective assessment of surface coverage with a better-defined procedure, thus offering more precise and reliable results.

• MeSH
• Histological Techniques * MeSH
• Microscopy, Electron, Scanning MeSH
• Osmium Tetroxide * MeSH
• Publication type
• Journal Article MeSH

The northern part of James Ross Island is the largest deglaciated area in the Antarctic Peninsula region with a unique ecosystem created during the Late Glacial. This research aims to evaluate the degree of contamination of the locality with toxic metals (As, Hg, Cd, and Pb) through bioindicators in the aquatic environment-colonies of cyanobacteria and algae. For this purpose, bottom lake sediments of Big Lachman Lake were studied for contents of Fe, As, Hg, Cd, Pb, Cr, Co, Ni, Cu, and Zn, as well as samples of cyanobacterial mat, in which Fe, As, Hg, Cd, and Pb were determined. Metal contents were determined by means of inductively coupled plasma optical emission spectrometry and atomic absorption spectrometry. The contents of metals in sediments did not differ from the usual values in the area of the Antarctic Peninsula. The bioaccumulation of metals in cyanobacterial mat was evaluated by calculating enrichment factors (the calculation to Fe as a reference element). According to this method, moderate pollution of Big Lachman Lake was confirmed for Hg and Cd.

• MeSH
• Water Pollutants, Chemical * analysis   MeSH
• Ecosystem MeSH
• Geologic Sediments chemistry   MeSH
• Risk Assessment MeSH
• Lakes chemistry   MeSH
• Cadmium analysis   MeSH
• Environmental Monitoring methods   MeSH
• Lead analysis   MeSH
• Mercury * analysis   MeSH
• Cyanobacteria * MeSH
• Metals, Heavy * analysis   MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Antarctic Regions MeSH

Thallium (Tl) is a highly toxic trace metal, included in the US EPA list of priority pollutants. Even though its toxicity is potentially higher or comparable to Cd or Hg, its environmental impact is largely unknown. Despite its toxicity, only a few recent studies are mapping the impact of recently introduced Tl on soil microbial communities, namely in agricultural systems but no studies focus on its long term effect. To complement the understanding of the impact of Tl on soil, this study aims to describe the influence of extremely high naturally occurring Tl concentration (50 mg/kg of potentially bioavailable Tl) on soil microbial communities. Our investigation concentrated on samples collected at Buus (Erzmatt, Swiss Jura, Switzerland), encompassing forest and meadow soil profiles of the local soil formed on hydrothermally mineralized dolomite rock, which is naturally rich in Tl. The soil profiles showed a significant proportion of potentially bioavailable Tl. Yet, even this high concentration of Tl has a limited impact on the richness of the soil bacterial community. Only the meadow soil samples show a reduced richness compared to control samples. Furthermore, our analysis of geogenic Tl contamination in the region unveiled a surprising finding: compared to other soils of Switzerland and in stark contrast to soils affected by recent mining activities, the structure of the bacterial community in Buus remained relatively unaffected. This observation highlights the unique ability of soil microbial communities to withstand extreme Tl contamination. Our study advances the understanding of Tl's environmental impact and underscores the resilience of soil microbes in the face of severe long-term contamination.

• MeSH
• Bacteria MeSH
• Soil Pollutants * analysis   MeSH
• Environmental Monitoring MeSH
• Soil chemistry   MeSH
• Mercury * analysis   MeSH
• Trace Elements * analysis   MeSH
• Thallium analysis   MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• China MeSH

Radioterapie je jedným ze základních složek léčby pacientů s intrakraniálními metastázami. Součástí nechirurgické léčby mozkových metastáz jsou celomozkové ozáření (whole brain radiotherapy – WBRT) a také stereotaktická radiochirurgie. V éře pokroku onkologické léčby s implikacemi pro dlouhodobé přežití pacientů je diskutovaným tématem toxicita těchto léčebných postupů, u které nemůžeme přehlédnout kognitivní poruchy. Mechanizmů, na jejichž základě kognitivní poruchy vznikají, je několik a jsou stále předmětem výzkumu. Zaměřujeme se na patofyziologické elementy, které se podílí na kognitivních poruchách, a na strategie, jakými jsou hipokampus šetřící (hippocampal avoidance; HA) WBRT pro kandidáty na cílenou léčbu s různými histologickými typy nádorů, která přechází hematoencefalickou bariéru. I když je léčba HA-WBRT plus memantinem jakožto standard stále předmětem diskuzí, v případech mnohočetných mozkových metastáz nebo metastáz, u kterých není vhodná cílená radioterapie, a u pacientů s očekávaným přežitím > 4 měsíce je nutné aplikovat strategii pro prevence poruch kognitivních funkcí. V budoucnu musí být do analýz a studií zařazeny nové studie, které zhodnotí kognitivní funkce u pacientů s dlouhodobým přežitím, ale také další faktory, jako je počet a objem mozkových metastáz, jejich intrakraniální a extrakraniální lokalizace a efekt moderních onkologických terapií.

Radiotherapy is one of the cornerstones for treatment of patients with intracranial metastases. Whole brain radiotherapy (WBRT) as well as stereotactic radiosurgery are part of the non-surgical treatment for brain metastases. The toxicities associated with the treatment, among which we cannot neglect cognitive impairment, represent a current topic in an era marked by advances in oncological treatments with implications for the long-term survival of these patients. The mechanisms that involve the onset of cognitive decline are multiple and are still the subject of research. We propose to highlight the pathophysiological elements involved in cognitive impairment as well as strategies including hippocampal avoidance (HA) WBRT for different histological cancer type candidates for target therapies that cross the blood-brain barrier. Even if the implementation of HA-WBRT plus memantine as standard is still a subject for debate, for cases with multiple brain metastases or metastases unsuitable for targeted radiotherapy and a life expectancy > 4 months, it is necessary to apply a preventive strategy for the impairment of cognitive function. New studies to evaluate cognitive function for long term survivals, but also an evaluation of other factors including the number and volume of brain metastases, their intracranial and extracranial localization and the effect of modern oncological therapies must be included in future analyzes and studies.

• MeSH
• Molecular Targeted Therapy methods   MeSH
• Radiation Dosage MeSH
• Cognition Disorders * chemically induced   physiopathology   prevention & control   MeSH
• Combined Modality Therapy methods   MeSH
• Humans MeSH
• Memantine pharmacology   therapeutic use   MeSH
• Brain Neoplasms drug therapy   complications   radiotherapy   MeSH
• Antineoplastic Agents classification   therapeutic use   MeSH
• Radiosurgery methods   MeSH
• Radiotherapy * methods   adverse effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Review MeSH