Propiconazole is a triazole fungicide previously shown to induce triglyceride accumulation in human liver HepaRG cells, potentially via activation of the Pregnane X Receptor (PXR). However, whether propiconazole can disrupt hepatic and whole-body metabolism in vivo is currently unknown. Therefore, we aimed to examine the metabolic effects of propiconazole in the context of metabolic dysfunction-associated steatotic liver disease (MASLD), obesity, and insulin resistance. To this end, male C57BL/6J mice were fed a high-fat diet for 20 weeks. During the last 10 weeks, mice additionally received vehicle, 0.04, 30, or 100 mg/kg body weight (bw)/day propiconazole via oral gavage. High-dose propiconazole, but not low or intermediate dose, reduced body weight gain and adipose tissue weight in obese mice. Mice receiving high-dose propiconazole displayed improved glucose tolerance and reduced levels of plasma triglycerides and cholesterol. Propiconazole dose-dependently increased liver weight and triglyceride levels and at high dose caused signs of hepatic inflammation. RNA sequencing on the liver revealed that propiconazole mainly induced PXR target genes. At intermediate and high dose, propiconazole induced pathways related to cell-cell interactions and inflammation, while oxidative phosphorylation was repressed by propiconazole. Comparison of gene regulation in wildtype and PXR knockout primary hepatocytes as well as gene reporter assays confirmed the activation of PXR by propiconazole. All in all, our data underscore the capacity of propiconazole to activate PXR in the liver and thereby promote the development of hepatic steatosis in vivo.

• Klíčová slova
• Lipid metabolism, Liver, MASLD, Metabolism disrupting chemicals (MDCs), Nuclear receptors/PXR, Propiconazole,
• MeSH
• dieta s vysokým obsahem tuků * MeSH
• fungicidy průmyslové * toxicita   MeSH
• inzulinová rezistence MeSH
• játra účinky léků   metabolismus   patologie   MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední C57BL * MeSH
• myši MeSH
• obezita * chemicky indukované   MeSH
• pregnanový X receptor * metabolismus   genetika   MeSH
• triazoly * toxicita   MeSH
• triglyceridy krev   metabolismus   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• ztučnělá játra * chemicky indukované   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• fungicidy průmyslové * MeSH
• pregnanový X receptor * MeSH
• propiconazole MeSH Prohlížeč
• triazoly * MeSH
• triglyceridy MeSH

BACKGROUND/AIM: New generation androgen receptor-targeting agents (ARTA) have been in the spotlight for their efficacy in metastatic castration-resistant prostate cancer (mCRPC). Prostate-specific antigen (PSA) represents one of the most commonly used serum cancer biomarkers worldwide. The present retrospective study focused on the prognostic role of serum PSA isoforms and their early dynamics in mCRPC patients treated with abiraterone acetate (ABI) or enzalutamide (ENZ). PATIENTS AND METHODS: The association between outcomes of 334 mCRPC patients treated with ABI or ENZ and the levels of serum total PSA (tPSA), free PSA (fPSA), [-2]proPSA and the Prostate Health Index (PHI) at baseline and one month after treatment initiation was analyzed retrospectively. RESULTS: In the multivariable Cox proportional hazards models, baseline tPSA>50 μg/l (p<0.001), and [-2]proPSA>300 ng/l (p=0.017) remained independent significant factors associated with inferior OS, while baseline fPSA>1.75 μg/l (p=0.050) and Δ [-2]proPSA >-50% approached statistical significance (p=0.062). The results of ROC analyses assessing the ability of baseline tPSA, fPSA, and [-2]proPSA to predict mortality within two years showed area under the curve (AUC) values of 0.709, 0.685, and 0.740, respectively. Among the subgroup with baseline tPSA≤20.0 μg/l, the results of ROC analyses for baseline tPSA, fPSA and [-2]proPSA showed AUC values of 0.441, 0.682, and 0.688, respectively. CONCLUSION: Our results suggest a significant correlation between pretreatment serum levels of tPSA and [-2]proPSA with OS in mCRPC patients receiving ARTA.

• Klíčová slova
• (−2)proPSA, ARTA, Castration-resistant prostate cancer, PSA, abiraterone acetate, enzalutamide, free PSA,
• MeSH
• abirateron terapeutické užití   aplikace a dávkování   MeSH
• androgenní receptory * krev   metabolismus   MeSH
• antagonisté androgenních receptorů terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• metastázy nádorů MeSH
• nádorové biomarkery krev   MeSH
• nádory prostaty rezistentní na kastraci * farmakoterapie   krev   patologie   mortalita   MeSH
• prognóza MeSH
• prostatický specifický antigen * krev   MeSH
• protein - isoformy * krev   MeSH
• retrospektivní studie MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• abirateron MeSH
• androgenní receptory * MeSH
• antagonisté androgenních receptorů MeSH
• nádorové biomarkery MeSH
• prostatický specifický antigen * MeSH
• protein - isoformy * MeSH

Indoor dust contains various endocrine-disrupting contaminants, yet the effect drivers of observed glucocorticoid activity are completely unknown. This study conducted an effect-directed analysis using orthogonal fractionation to identify effect drivers of glucocorticoid activity in indoor dust. After the detection of bioactivity using a human cell line stably transfected with a reporter gene, the sample underwent parallel HPLC fractionations with octadecyl, pentafluorophenyl, and aminopropyl columns to obtain orthogonal fractions. The bioassays were utilized to screen the fractions and guide efforts towards prioritization of the bioactive chemicals using targeted and non-targeted analysis with LC-HRMS. The glucocorticoid activity of the identified potential candidates was confirmed by their testing in the same bioassay. To assess their contribution to the detected mixture effects, we calculated their relative potencies. This approach led to the identification of two pharmaceuticals, clobetasol propionate and mometasone furoate, at concentrations ranging from ng to μg per gram of dust, which together accounted for up to 77% of the observed glucocorticoid activity. This is the first report documenting the effect drivers of glucocorticoid receptor agonism in indoor dust; however, together with previous studies of various environmental samples, it documents that in cases when glucocorticoid receptor-agonistic activity is detected, drugs should be considered as likely relevant contaminants. The discovery of potent drugs in household dust highlights concerns for individuals exposed within domestic environments and emphasizes the need to consider pharmaceuticals as relevant contributors to indoor contamination.

• Klíčová slova
• Effect-directed analysis, Endocrine disrupting compounds, Glucocorticoid activity, In vitro, Indoor dust, Orthogonal fractionation,
• MeSH
• chemická frakcionace MeSH
• endokrinní disruptory analýza   MeSH
• glukokortikoidy * analýza   MeSH
• klobetasol MeSH
• látky znečišťující vzduch analýza   MeSH
• lidé MeSH
• mometason furoát MeSH
• monitorování životního prostředí metody   MeSH
• prach * analýza   MeSH
• receptory glukokortikoidů metabolismus   MeSH
• znečištění vzduchu ve vnitřním prostředí * analýza   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• endokrinní disruptory MeSH
• glukokortikoidy * MeSH
• klobetasol MeSH
• látky znečišťující vzduch MeSH
• mometason furoát MeSH
• prach * MeSH
• receptory glukokortikoidů MeSH

Constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are closely related nuclear receptors with overlapping regulatory functions in xenobiotic clearance but distinct roles in endobiotic metabolism. Car activation has been demonstrated to ameliorate hypercholesterolemia by regulating cholesterol metabolism and bile acid elimination, whereas PXR activation is associated with hypercholesterolemia and liver steatosis. Here we show a human CAR agonist/PXR antagonist, MI-883, which effectively regulates genes related to xenobiotic metabolism and cholesterol/bile acid homeostasis by leveraging CAR and PXR interactions in gene regulation. Through comprehensive analyses utilizing lipidomics, bile acid metabolomics, and transcriptomics in humanized PXR-CAR-CYP3A4/3A7 mice fed high-fat and high-cholesterol diets, we demonstrate that MI-883 significantly reduces plasma cholesterol levels and enhances fecal bile acid excretion. This work paves the way for the development of ligands targeting multiple xenobiotic nuclear receptors. Such ligands hold the potential for precise modulation of liver metabolism, offering new therapeutic strategies for metabolic disorders.

• MeSH
• cholesterol * metabolismus   krev   MeSH
• cytochrom P-450 CYP3A metabolismus   genetika   MeSH
• dieta s vysokým obsahem tuků * škodlivé účinky   MeSH
• hypercholesterolemie * farmakoterapie   metabolismus   MeSH
• hypolipidemika farmakologie   terapeutické užití   MeSH
• játra metabolismus   účinky léků   MeSH
• konstitutivní androstanový receptor * MeSH
• lidé MeSH
• metabolismus lipidů účinky léků   MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• pregnanový X receptor * metabolismus   genetika   MeSH
• pyridiny MeSH
• receptory cytoplazmatické a nukleární * metabolismus   agonisté   genetika   MeSH
• regulace genové exprese účinky léků   MeSH
• žlučové kyseliny a soli * metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 1,4-bis(2-(3,5-dichloropyridyloxy))benzene MeSH Prohlížeč
• cholesterol * MeSH
• cytochrom P-450 CYP3A MeSH
• hypolipidemika MeSH
• konstitutivní androstanový receptor * MeSH
• pregnanový X receptor * MeSH
• pyridiny MeSH
• receptory cytoplazmatické a nukleární * MeSH
• žlučové kyseliny a soli * MeSH

The literature documenting the value of drug-like molecules found in natural products is vast. Although many dietary and herbal remedies have been found to be effective for treating intestinal inflammation, the identification of their active components has lagged behind. In this study, we find that a major ginger component, furanodienone (FDN), is a selective pregnane X receptor (PXR) ligand with agonistic transcriptional outcomes. We show that FDN binds within a sub-pocket of the PXR ligand binding domain (LBD), with subsequent alterations in LBD structure. Using male mice, we show that orally provided FDN has potent PXR-dependant anti-inflammatory outcomes that are colon-specific. Increased affinity and target gene activation in the presence of synergistically acting agonists indicates further opportunities for augmenting FDN activity, efficacy and safety. Collectively, these results support the translational potential of FDN as a therapeutic agent for the treatment and prevention of colonic diseases.

• MeSH
• antiflogistika farmakologie   chemie   MeSH
• furany farmakologie   MeSH
• kolitida farmakoterapie   chemicky indukované   metabolismus   patologie   MeSH
• kolon účinky léků   patologie   metabolismus   MeSH
• lidé MeSH
• ligandy MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• pregnanový X receptor * metabolismus   genetika   MeSH
• zánět farmakoterapie   metabolismus   MeSH
• zázvor lékařský * chemie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antiflogistika MeSH
• furany MeSH
• ligandy MeSH
• pregnanový X receptor * MeSH

In advanced prostate cancer (PC), in particular after acquisition of resistance to androgen receptor (AR) signaling inhibitors (ARSI), upregulation of AR splice variants compromises endocrine therapy efficiency. Androgen receptor splice variant-7 (ARV7) is clinically the most relevant and has a distinct 3' untranslated region (3'UTR) compared to the AR full-length variant, suggesting a unique post-transcriptional regulation. Here, we set out to evaluate the applicability of the ARV7 3'UTR as a therapy target. A common single nucleotide polymorphism, rs5918762, was found to affect the splicing rate and thus the expression of ARV7 in cellular models and patient specimens. Serine/arginine-rich splicing factor 9 (SRSF9) was found to bind to and increase the inclusion of the cryptic exon 3 of ARV7 during the splicing process in the alternative C allele of rs5918762. The dual specificity protein kinase CLK2 interferes with the activity of SRSF9 by regulating its expression. Inhibition of the Cdc2-like kinase (CLK) family by the small molecules cirtuvivint or lorecivivint results in the decreased expression of ARV7. Both inhibitors show potent anti-proliferative effects in enzalutamide-treated or -naive PC models. Thus, targeting aberrant alternative splicing at the 3'UTR of ARV7 by disturbing the CLK2/SRSF9 axis might be a valuable therapeutic approach in late stage, ARSI-resistant PC.

• Klíčová slova
• 3′ untranslated region, allele‐specific regulation, androgen receptor splice variant 7, dual specificity protein kinase CLK2, serine/arginine‐family of splicing factors, splicing inhibitors,
• MeSH
• 3' nepřekládaná oblast genetika   MeSH
• alternativní sestřih genetika   účinky léků   MeSH
• androgenní receptory * metabolismus   genetika   MeSH
• jednonukleotidový polymorfismus genetika   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádory prostaty * genetika   metabolismus   patologie   farmakoterapie   MeSH
• protein - isoformy genetika   metabolismus   MeSH
• protein-serin-threoninkinasy genetika   metabolismus   antagonisté a inhibitory   MeSH
• regulace genové exprese u nádorů * účinky léků   MeSH
• serin-arginin sestřihové faktory * metabolismus   genetika   MeSH
• sestřih RNA genetika   MeSH
• tyrosinkinasy * genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 3' nepřekládaná oblast MeSH
• androgenní receptory * MeSH
• Clk dual-specificity kinases MeSH Prohlížeč
• protein - isoformy MeSH
• protein-serin-threoninkinasy MeSH
• serin-arginin sestřihové faktory * MeSH
• tyrosinkinasy * MeSH

OBJECTIVE: The prognostic relevance of hormonal biomarkers in endometrial cancer (EC) has been well-established. A refined three-tiered risk model for estrogen receptor (ER)/progesterone receptor (PR) expression was shown to improve prognostication. This has not been evaluated in relation to the molecular subgroups. This study aimed to evaluate the ER/PR expression within the molecular subgroups in EC. METHODS: A retrospective multicenter cohort study was performed and data from the European Network for Individualized Treatment centers and Vancouver, Canada were used. ER/PR immunohistochemical expression was grouped as: ER/PR 0-10 %, 20-80 % or 90-100 %. Molecular subgroups were determined with full next-generation sequencing or combined with immunohistochemistry: POLEmut, mismatch repair deficient (MMRd), p53mut and no-specific molecular profile (NSMP). RESULTS: A total of 739 patients were included (median follow-up 5.0 years). Tumors were classified as POLEmut in 9.1 %(N = 67), MMRd in 27.6 %(N = 204), p53mut in 20.8 %(N = 154) and NSMP in 42.5 %(N = 314). Among all molecular subgroups, patients with ER/PR 90-100 % expression revealed the best disease-specific survival (DSS). Within p53mut, PR 90-100 % expression showed a 5-year DSS of 100.0 %. ER expression is prognostic more relevant in MMRd and NSMP tumors while PR expression in p53mut and NSMP tumors. Across all molecular subgroups, PR 0-10 %, p53mut, lympho-vascular space invasion and FIGO stage III-IV remained independently prognostic for reduced DSS Whereas PR 90-100 % and POLEmut remained independently prognostic for improved DSS. CONCLUSION: We demonstrated that ER/PR expression remain prognostically relevant within the molecular subgroups, and that a three-tiered cutoff refines prognostication. These data support incorporating routine evaluation of ER/PR expression in clinical practice.

• Klíčová slova
• Biomarkers, Endometrial carcinoma, Immunohistochemical, Molecular classification, Pathology, Prognosis,
• MeSH
• dospělí MeSH
• imunohistochemie MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádorové biomarkery * metabolismus   genetika   MeSH
• nádorový supresorový protein p53 metabolismus   genetika   MeSH
• nádory endometria * metabolismus   patologie   genetika   mortalita   MeSH
• prognóza MeSH
• receptory pro estrogeny * metabolismus   biosyntéza   MeSH
• receptory progesteronu * metabolismus   biosyntéza   MeSH
• retrospektivní studie MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• Názvy látek
• nádorové biomarkery * MeSH
• nádorový supresorový protein p53 MeSH
• receptory pro estrogeny * MeSH
• receptory progesteronu * MeSH

The conventional way steroid hormones work through receptors inside cells is widely acknowledged. There are unanswered questions about what happens to the hormone in the end and why there isn't always a strong connection between how much tissue takes up and its biological effects through receptor binding. Steroid hormones can also have non-traditional effects that happen quickly but don't involve entering the cell. Several possible mechanisms for these non-traditional actions include (a) changes in membrane fluidity, (b) steroid hormones acting on receptors on the outer surface of cells, (c) steroid hormones regulating GABAA receptors on cell membranes, and (d) activation of steroid receptors by factors like EGF, IGF-1, and dopamine. Data also suggests that steroid hormones may be inserted into DNA through receptors, acting as transcription factors. These proposed new mechanisms of action should not be seen as challenging the conventional mechanism. Instead, they contribute to a more comprehensive understanding of how hormones work, allowing for rapid, short-term, and prolonged effects to meet the body's physiological needs.

• Klíčová slova
• Cellular mechanism of steroid receptors, Estrogen receptor, Female sexual behavior, Progesterone receptor, Steroid action,
• MeSH
• centrální nervový systém metabolismus   fyziologie   účinky léků   MeSH
• lidé MeSH
• pohlavní steroidní hormony * metabolismus   MeSH
• steroidní receptory metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• pohlavní steroidní hormony * MeSH
• steroidní receptory MeSH

Homeostasis of cellular membranes is maintained by fine-tuning their lipid composition. Yeast lipid transporter Osh6, belonging to the oxysterol-binding protein-related proteins family, was found to participate in the transport of phosphatidylserine (PS). PS synthesized in the endoplasmic reticulum is delivered to the plasma membrane, where it is exchanged for phosphatidylinositol 4-phosphate (PI4P). PI4P provides the driving force for the directed PS transport against its concentration gradient. In this study, we employed an in vitro approach to reconstitute the transport process into the minimalistic system of large unilamellar vesicles to reveal its fundamental biophysical determinants. Our study draws a comprehensive portrait of the interplay between the structure and dynamics of Osh6, the carried cargo lipid, and the physical properties of the involved membranes, with particular attention to the presence of charged lipids and to membrane fluidity. Specifically, we address the role of the cargo lipid, which, by occupying the transporter, imposes changes in its dynamics and, consequently, predisposes the cargo to disembark in the correct target membrane.

• MeSH
• biologický transport MeSH
• buněčná membrána * metabolismus   MeSH
• fluidita membrány MeSH
• fosfatidylinositolfosfáty metabolismus   MeSH
• fosfatidylseriny metabolismus   MeSH
• Saccharomyces cerevisiae - proteiny * metabolismus   genetika   MeSH
• Saccharomyces cerevisiae metabolismus   MeSH
• steroidní receptory metabolismus   MeSH
• unilamelární lipozómy metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• fosfatidylinositolfosfáty MeSH
• fosfatidylseriny MeSH
• Oxysterol Binding Proteins MeSH
• phosphatidylinositol 4-phosphate MeSH Prohlížeč
• Saccharomyces cerevisiae - proteiny * MeSH
• steroidní receptory MeSH
• unilamelární lipozómy MeSH

G protein-coupled estrogen receptor 1 (GPER-1) has gained recognition for its role in conferring cardioprotection. However, the extent to which GPER-1 exerts equally important effects in both sexes remains unclear. The study found similar expressions of GPER-1 in rat heart apex in both sexes. In male rats, administering epinephrine (Epi) at a dose of 31.36 microg/100 g resulted in a rapid decline in cardiac function, accompanied by a sharp increase in bax/bcl-2 levels. In contrast, female rats did not display significant changes in cardiac function under the same conditions. Additionally, compared to the injection of Epi alone (at a dose of 15.68 microg/100 g), the administration of G15 (GPER-1 antagonist) further decreased cardiac function in both male and female rats. However, it only increased mortality and lung coefficient in male rats. Conversely, G1 (GPER-1 agonist) administration improved cardiac function in both sexes. Notably, the apex of the male heart exhibited lower levels of inhibitory G protein (Galphai). Furthermore, female and male rats treated with Epi displayed elevated phosphorylated protein kinase B (p-Akt). Compared to their respective Epi groups, the administration of G15 increased p-Akt levels in female rat hearts but decreased them in male rat hearts. Conversely, the administration of G1 decreased p-Akt levels in females but rapidly increased them in male rats. Our study uncovers the vital role of GPER-1 in protecting against stress-induced heart injuries in a sex-specific manner. These findings hold immense potential for advancing targeted cardiac therapies and enhancing outcomes for both females and males.

• MeSH
• adrenalin MeSH
• fyziologický stres fyziologie   MeSH
• krysa rodu Rattus MeSH
• pohlavní dimorfismus MeSH
• potkani Sprague-Dawley * MeSH
• protoonkogenní proteiny c-akt * metabolismus   MeSH
• receptory pro estrogeny metabolismus   MeSH
• receptory spřažené s G-proteiny * metabolismus   MeSH
• sexuální faktory MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• adrenalin MeSH
• Gper1 protein, rat MeSH Prohlížeč
• protoonkogenní proteiny c-akt * MeSH
• receptory pro estrogeny MeSH
• receptory spřažené s G-proteiny * MeSH