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.

• 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

PURPOSE: STereotactic Arrhythmia Radioablation (STAR) showed promising results in patients with refractory ventricular tachycardia. However, clinical data are scarce and heterogeneous. The STOPSTORM.eu consortium was established to investigate and harmonize STAR in Europe. The primary goal of this benchmark study was to investigate current treatment planning practice within the STOPSTORM project as a baseline for future harmonization. METHODS AND MATERIALS: Planning target volumes (PTVs) overlapping extracardiac organs-at-risk and/or cardiac substructures were generated for 3 STAR cases. Participating centers were asked to create single-fraction treatment plans with 25 Gy dose prescriptions based on in-house clinical practice. All treatment plans were reviewed by an expert panel and quantitative crowd knowledge-based analysis was performed with independent software using descriptive statistics for International Commission on Radiation Units and Measurements report 91 relevant parameters and crowd dose-volume histograms. Thereafter, treatment planning consensus statements were established using a dual-stage voting process. RESULTS: Twenty centers submitted 67 treatment plans for this study. In most plans (75%) intensity modulated arc therapy with 6 MV flattening filter free beams was used. Dose prescription was mainly based on PTV D95% (49%) or D96%-100% (19%). Many participants preferred to spare close extracardiac organs-at-risk (75%) and cardiac substructures (50%) by PTV coverage reduction. PTV D0.035cm3 ranged from 25.5 to 34.6 Gy, demonstrating a large variety of dose inhomogeneity. Estimated treatment times without motion compensation or setup ranged from 2 to 80 minutes. For the consensus statements, a strong agreement was reached for beam technique planning, dose calculation, prescription methods, and trade-offs between target and extracardiac critical structures. No agreement was reached on cardiac substructure dose limitations and on desired dose inhomogeneity in the target. CONCLUSIONS: This STOPSTORM multicenter treatment planning benchmark study not only showed strong agreement on several aspects of STAR treatment planning, but also revealed disagreement on others. To standardize and harmonize STAR in the future, consensus statements were established; however, clinical data are urgently needed for actionable guidelines for treatment planning.

• MeSH
• benchmarking * MeSH
• celková dávka radioterapie MeSH
• komorová tachykardie chirurgie   radioterapie   MeSH
• konsensus * MeSH
• kritické orgány * účinky záření   MeSH
• lidé MeSH
• plánování radioterapie pomocí počítače * normy   metody   MeSH
• radiochirurgie * normy   metody   MeSH
• radioterapie s modulovanou intenzitou metody   normy   MeSH
• srdce účinky záření   MeSH
• srdeční arytmie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• Geografické názvy
• Evropa MeSH

Nucleus pulposus cells (NPC) are important for the development of intervertebral disc degeneration (IVDD). miR-4478 can aggravate IVDD, but whether it can aggravate IVDD by regulating ferroptosis in NPC remains unclear. The optimal level of ferroptosis activator RSL3 for eliciting ferroptosis in NPC was screened by Western blot and CCK-8 assay. The targeting relationship between miR-4478 and its potential target solute carrier family 7 member 11 (SLC7A11) was explored based on dual luciferase assay. On this basis, IVDD models were constructed. After over-expression or knockdown of miR-4478 or SLC7A11, CCK-8 and calcein-AM/PI assays were employed to evaluate cell damage. Flow cytometry, Western blot and Prussian blue staining were employed to evaluate oxidation and ferroptosis levels, and histopathological staining was applied to evaluate the intervertebral disc tissue injury degree. The optimal concentration of RSL3 was 1 μM. Under these conditions, miR-4478 or SLC7A11 can be effectively over-expressed or knocked down after transfection. Knockdown of miR-4478 can improve the survival rate of NPC, the level of Fe2+ ions, improve the pathological damage of intervertebral disc structure, reduce iron deposition in tissues, and significantly reduce expression of reactive oxygen species (ROS) and ferroptosis-related protein. The levels of antioxidant enzymes were significantly increased. When miR-4478 was over-expressed, the above phenomenon was reversed. On this basis, after SLC7A11 was over-expressed, the effect of miR-4478 up-regulation was weakened, and NPC ferroptosis was improved. miR-4478 can target SLC7A11 to promote NPC damage, peroxide accumulation and iron metabolism disorders, leading to ferroptosis, thereby inducing IVDD.

• MeSH
• degenerace meziobratlové ploténky * metabolismus   genetika   patologie   MeSH
• ferroptóza * genetika   MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• mikro RNA * metabolismus   genetika   MeSH
• nucleus pulposus * metabolismus   patologie   cytologie   MeSH
• potkani Sprague-Dawley MeSH
• transportní systém aminokyselin y+ * metabolismus   genetika   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Úvod: Shigelóza je vysoce nakažlivé průjmové onemocnění s potenciálně velmi závažným průběhem. I s ohledem na třetinový nárůst případů v roce 2023 ve srovnání s rokem předchozím jsme si stanovili za cíl podat přehled aktuálních informací o onemocnění a analyzovat data nahlášených případů shigelózy v České republice (ČR). Metody: Zpracovali jsme narativní rešerši odborné literatury v českém a anglickém jazyce, zejména cílenou na evropské studie od roku 2018. Dále jsme provedli analýzu dat hlášených pod kódem diagnózy A03 v národním systému pro hlášení infekčních nemocí (ISIN) v letech 2018–2023. Soustředili jsme se na hlavní epidemiologické ukazatele, zejména pohlaví, věk, geografickou distribuci, sezonnost a hospitalizace. Použity byly programy Excel (verze 2016), STATA (verze 17) a Datawrapper GmbH. Výsledky: Celkem bylo nahlášeno 681 případů onemocnění shigelózou s průměrnou roční incidencí 1/100 000 obyvatel: do roku 2021 byla incidence mírně vyšší u žen, od roku 2022 evidujeme trend opačný. V pandemických letech byl zaznamenán významný pokles případů. V letech 2022 a 2023 byl počet případů mírně vyšší než v období před pandemií. Nejvíce případů evidujeme v ČR každoročně v měsících srpen až prosinec. Ze všech sérotypů shigel byla nejčastěji detekována S. sonnei (80 %), následovaná S. flexneri (15 %). Incidence na 100 000 obyvatel byla nejvyšší u osob ve věku 5–9 let: 2,6 (chlapci 2,4 a dívky 2,8), dále 1–4 roky: 2,4 (chlapci 2,2, dívky 2,6) a osob ve věku 25–34 let: 1,8 (muži 1,8 a ženy 1,7). Podle krajů byla průměrná roční specifická incidence nejvyšší v krajích Moravskoslezském, Olomouckém a v hlavním městě Praze. Hospitalizováno bylo 27 % případů, nejvíce ve věkových skupinách 25–34 a 5–9 let (shodně 17,9 %). Proporce hospitalizovaných případů v rámci jednotlivých věkových skupin byla nejvyšší ve věkové skupině 75+ let (69 %), dále věkových skupinách 1–4 roky, 5–9 let a 65–74let (32–37 %). V souvislosti s onemocněním bylo vykázáno jedno úmrtí muže ve věku 52 let. V rámci epidemického výskytu bylo nahlášeno 11 % případů. Importováno bylo 39 % nahlášených případů. Závěr: V ČR je shigelóza spíše málo zastoupeným gastrointestinálním onemocněním, přičemž téměř 40 % případů tvoří importované nákazy. V současnosti je hrozbou pro veřejné zdraví především globální šíření multirezistentních kmenů podpořené narůstajícím cestovním ruchem a volnými sexuálními praktikami. Rizikovými skupinami zůstávají děti, imunokompromitované osoby (včetně seniorů) a muži mající sex s muži. Očkování není v Evropě dostupné. Stěžejním je nadále dodržování základních hygienických pravidel, zejména v kolektivech a při práci s potravinami. Důraz by měl být dále kladen na zdravotní edukaci osob, včetně poučení před vycestováním do zahraničí. Důkladná anamnéza, včasné trasování, dohled a racionální volba eventuální antibiotické terapie jsou zásadní. V ČR musí být všechny suspektní kmeny zaslány do NRL ke konfirmaci. Celogenomovou sekvenaci a testy citlivosti na antibiotika je vhodné provádět u všech izolátů.

Introduction: Shigellosis is a highly contagious diarrheal disease, which could potentially be very serious. Considering the onethird increase in cases in 2023 compared to the previous year, we aimed to provide an update on the disease and to analyse data on reported cases of shigellosis in the Czech Republic (CZ). Methods: We conducted a narrative search of the literature in Czech and English, particularly targeting European studies from 2018 onwards. We also analysed data reported under the diagnosis code A03 to the National Infectious Disease Reporting System (ISIN) in 2018–2023. We focused on the main epidemiological indicators, i.e. gender, age, geographical distribution, seasonality, and hospitalizations. Excel (version 2016), STATA (version 17), and Datawrapper GmbH were used. Results: A total of 681 shigellosis cases were reported with an average annual incidence of 1/100,000 population: until 2021, the incidence was slightly higher in women, while from 2022 onwards, the trend was reversed. A significant decrease in cases was recorded in the pandemic years. In 2022 and 2023, the number of cases was slightly higher than in the pre-pandemic period. Most cases were detected in CZ in August and December each year. Of all shigella serotypes, S. sonnei was the most frequently detected (80%), followed by S. flexneri (15%). The incidence per 100.000 population was highest among children aged 5–9 years: 2.6 (boys 2.4 and girls 2.8), followed by 1–4-year-olds: 2.4 (2.2 and 2.6, respectively) and persons aged 25–34 years: 1.8 (males 1.8 and females 1.7). Within individual age group, the average annual specific incidence rates were highest in the Moravian-Silesian and Olomouc regions and the capital city Prague. Hospitalizations accounted for 27% of cases, with the highest numbers in the 25–34 and 5–9 age groups (both 17.9%). The proportion of hospitalized cases was highest in the age groups 75+ (69%), 1–4, 5–9, and 65–74 (32–37%). A 52-year-old man was reported to have die in relation to the disease. Eleven percent of cases were reported in outbreak settings. Thirty-nine percent of reported cases were imported. Conclusions: In CZ, shigellosis is a relatively rare gastrointestinal disease, with nearly 40% of cases being imported. At present, the threat to public health is posed mainly by the global spread of multi-resistant strains linked to increasing tourism and free sexual practices. Children, immunocompromised persons (including the elderly), and men who have sex with men remain risk groups. Vaccination is not available in Europe. Compliance with basic hygiene rules, especially in collectives and when working with food, is still a key concern. Emphasis should also be placed on the health education, including instructions before traveling abroad. A thorough medical history, early tracing, surveillance, and rational choice of antibiotic therapy if appropriate are essential. In CZ, all suspected strains shall be sent to the NRL for confirmation. Whole genome sequencing and antibiotic susceptibility testing should be performed on all isolates.

• MeSH
• bacilární dyzentérie * epidemiologie   přenos   MeSH
• cestování MeSH
• hlášení nemocí statistika a číselné údaje   MeSH
• klinická studie jako téma metody   MeSH
• lidé MeSH
• sběr dat statistika a číselné údaje   MeSH
• sexuální chování MeSH
• Shigella patogenita   MeSH
• Check Tag
• lidé MeSH

BACKGROUND: The first-in-class hypoxia-inducible factor-2α (HIF-2α) inhibitor belzutifan is approved for patients with advanced renal cell carcinoma previously treated with immune checkpoint and anti-angiogenic therapy based on results of the phase 3 LITESPARK-005 trial. We present patient-reported outcomes (PROs) from LITESPARK-005. METHODS: LITESPARK-005 was an open-label, multicentre, randomised, active-controlled phase 3 trial conducted at 147 hospitals and cancer centres in six regions. Eligible participants were 18 years or older with advanced clear cell renal cell carcinoma, had a Karnofsky Performance Status score of 70% or higher, had measurable disease per Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1, had disease progression on or after treatment with anti-PD-1 or anti-PD-L1 immunotherapy and a VEGF tyrosine kinase inhibitor (in sequence or in combination), and had received no more than three previous systemic lines of therapy. Eligible participants were randomly assigned (1:1) centrally using interactive voice-response and web-response systems to receive either belzutifan 120 mg orally once daily or everolimus 10 mg orally once daily. Randomisation was stratified by International Metastatic Renal Cell Carcinoma Database Consortium prognostic score and number of previous VEGF-targeted or VEGF receptor-targeted therapies. The dual primary outcomes were progression-free survival and overall survival, results of which have been reported previously. In this study, prespecified secondary patient-reported outcomes (PROs) from LITESPARK-005 were assessed using the Functional Assessment of Cancer Therapy-Kidney Cancer Symptom Index: Disease Related Symptoms (FKSI-DRS) and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). The PRO analysis population included all participants who received at least one dose of study therapy and completed at least one PRO assessment. Least-squares mean change from baseline in PROs at week 17 was assessed using a constrained longitudinal data analysis model. Time to deterioration in physical functioning (prespecified) and role functioning (post hoc), as assessed by the EORTC QLQ-C30, were also evaluated in the PRO analysis population. This trial is ongoing, closed to recruitment, and registered with ClinicalTrials.gov, NCT04195750. FINDINGS: Between March 10, 2020, and Jan 19, 2022, 996 participants were screened for eligibility and 746 participants were randomly assigned to belzutifan (n=374) or everolimus (n=372). The PRO full analysis set population included 366 participants in the belzutifan group and 354 in the everolimus group. Median time from randomisation to the database cutoff date (June 13, 2023) was 25·7 months (IQR 21·7-30·4). Completion rates for FKSI-DRS and QLQ-C30 were higher than 94% at baseline and higher than 55% at week 17 in each group. Change from baseline to week 17 in FKSI-DRS score (difference in least-squares mean between groups 1·5 [95% CI 0·7 to 2·2]) and QLQ-C30 global health status-quality of life (QOL) score (6·4 [3·2 to 9·6]) suggested stability with belzutifan versus worsening with everolimus. Change from baseline to week 17 was similar between groups for QLQ-C30 physical functioning (difference in least-squares mean 2·5 [95% CI -0·6 to 5·5]) and QLQ-C30 role functioning (4·2 [0·1 to 8·4]) subscale scores. Time to deterioration was similar between the belzutifan and everolimus groups for EORTC physical functioning (median 19·3 months [95% CI 11·1 to not reached] in the belzutifan group vs 13·8 months [10·6 to not reached] in the everolimus group; hazard ratio 0·93 [95% CI 0·72 to 1·20]) and role functioning (median 12·0 months [9·2 to not reached] vs 10·2 months [4·7 to 14·4]; 0·88 [0·69 to 1·11]). INTERPRETATION: Belzutifan for advanced renal cell carcinoma was associated with improved disease-specific symptoms and QOL compared with everolimus. Taken together with the efficacy and safety data from LITESPARK-005, belzutifan could offer a clinical benefit without compromising the QOL of patients in this setting. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.

• MeSH
• doba přežití bez progrese choroby MeSH
• dospělí MeSH
• everolimus * terapeutické užití   škodlivé účinky   aplikace a dávkování   MeSH
• hodnocení výsledků péče pacientem * MeSH
• indeny MeSH
• karcinom z renálních buněk * farmakoterapie   patologie   mortalita   MeSH
• kvalita života * MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory ledvin * farmakoterapie   patologie   mortalita   MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• srovnávací studie MeSH

In the complex network of cellular physiology, the maintenance of cellular proteostasis emerges as a critical factor for cell survival, particularly under stress conditions. This homeostasis is largely governed by a sophisticated network of molecular chaperones and co-chaperones, among which Bcl-2-associated athanogene 3 (BAG3), able to interact with the ATPase domain of Heat Shock Protein 70 (HSP70), plays a pivotal role. The BAG3-HSP70 functional module is not only essential for cellular homeostasis but is also involved in the pathogenesis of various diseases, including cancer, neurodegenerative disorders, and cardiac dysfunction, making it an attractive target for therapeutic intervention. Inspired by our continuous interest in the development of new chemical platforms able to interfere with BAG3 protein, herein we report the discovery of compound 16, the first-in-class BAG3/HSP70 dual modulator, obtained by combining the multicomponent Ugi reaction with the alkyne-azide Huisgen procedure in a sequential tandem reaction approach. Through a combination of biophysical analysis, biochemical assays, and cell-based studies, we elucidated the mechanism of action of this inhibitor and assessed its potential as a therapeutic agent. Hence, this study can open new avenues for the development of novel anticancer strategies that leverage the simultaneous disruption of multiple chaperone pathways.

• MeSH
• adaptorové proteiny signální transdukční * metabolismus   antagonisté a inhibitory   MeSH
• lidé MeSH
• molekulární chaperony metabolismus   antagonisté a inhibitory   chemie   MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• proliferace buněk účinky léků   MeSH
• proteiny regulující apoptózu * metabolismus   antagonisté a inhibitory   MeSH
• proteiny tepelného šoku HSP70 * antagonisté a inhibitory   metabolismus   MeSH
• protinádorové látky * farmakologie   chemie   chemická syntéza   MeSH
• screeningové testy protinádorových léčiv MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Objectives: The relationship between the isokinetic maximal strength of internal or external shoulder rotation and serve speed in tennis is well established, yet the influence of segmental mass, height, and high-speed shoulder rotation strength on serve performance in junior players remains unclear. This study aimed to investigate the relationship between concentric or eccentric isokinetic shoulder strength, segmental mass, height, and first-serve speed aimed at the T-target zone. Methods: Fifteen male junior competitive tennis players (mean ± SD: age 15.9 ± 0.9 years; height: 180.1 ± 7.2 cm; body mass: 66.1 ± 5.7 kg) were assessed for maximal isokinetic strength during concentric and eccentric internal and external shoulder rotations. Segmental mass (arm, leg, and trunk) was measured using dual-energy X-ray absorptiometry, and serve speed was recorded using a radar gun. Results: Concentric shoulder rotations at 210°/s demonstrated significant positive correlations with serve speed for both external (ρ = 0.71, p ≤ 0.01) and internal rotation (ρ = 0.61, p ≤ 0.05). Although lean arm mass partially mediated the relationship between shoulder strength and serve speed (indirect effect = 0.502, 95% CI: -0.156 to 1.145), this mediation effect was not statistically significant. Height was moderately correlated with serve speed (ρ = 0.68, p ≤ 0.01) but did not moderate the relationship between shoulder strength and serve speed. Conclusions: Concentric shoulder strength at higher angular velocities and segmental mass contribute to serve speed in junior tennis players. While height provides structural advantages, strength and lean mass play important roles, emphasizing the need for targeted training programs.

• Publikační typ
• časopisecké články MeSH

Polymicrobial biofilms, the reason for most chronic wound infections, play a significant role in increasing antibiotic resistance. The in vivo effectiveness of the new anti-biofilm therapy is conditioned by the profound evaluation using appropriate in vitro biofilm models. Since nutrient availability is crucial for in vitro biofilm formation, this study is focused on the impact of four selected cultivation media on the properties of methicillin-resistant Staphylococcus aureus and Candida albicans dual-species biofilms. To reflect the wound environment, Tryptic soy broth, RPMI 1640 with and without glucose, and Lubbock medium were supplemented with different amounts of host effector molecules present in human plasma or sheep red blood cells. The study demonstrates that the Lubbock medium provided the most appropriate amount of nutrients regarding the biomass structure and the highest degree of tolerance to selected antimicrobials with the evident contribution of the biofilm matrix. Our results allow the rational employment of nutrition conditions within methicillin-resistant Staphylococcus aureus and Candida albicans dual-species biofilm formation in vitro for preclinical research. Additionally, one of the potential targets of a complex antibiofilm strategy, carbohydrates, was revealed since they are prevailing molecules in the matrices regardless of the cultivation media.

• MeSH
• antibakteriální látky farmakologie   MeSH
• biofilmy * účinky léků   růst a vývoj   MeSH
• Candida albicans * účinky léků   fyziologie   MeSH
• kultivační média * farmakologie   MeSH
• lidé MeSH
• methicilin rezistentní Staphylococcus aureus * účinky léků   fyziologie   MeSH
• mikrobiální testy citlivosti MeSH
• ovce MeSH
• živiny metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Nonalcoholic fatty liver disease (NAFLD) is characterized by elevated hepatic lipids caused by nonalcoholic factors, where histone lactylation is lately discovered as a modification driving disease progression. This research aimed to explore the role of histone 3 lysine 18 lactylation (H3K18lac) in NAFLD progression using a high-fat diet (HFD)-treated mouse model and free fatty acids (FFA)-treated L-02 cell lines. Lipids accumulation was screened via Oil Red O staining, real-time quantitative polymerase chain reaction (RT-qPCR), western blotting, and commercially available kits. Similarly, molecular mechanism was analyzed using immunoprecipitation (IP), dual-luciferase reporter assay, and RNA decay assay. Results indicated that FFA upregulated lactate dehydrogenase A (LDHA) and H3K18lac levels in L-02 cells. Besides, LDHA-mediated H3K18lac was enriched on the proximal promoter of methyltransferase 3 (METTL3), translating into an increased expression. Moreover, METTL3 or LDHA knockdown relieved lipid accumulation, decreased total cholesterol (TC) and triglyceride (TG) levels, and downregulated lipogenesis-related proteins in FFA-treated L-02 cell lines, in addition to enhancing the m6A and mRNA levels of stearoyl-coenzyme A desaturase 1 (SCD1). The m6A modification of SCD1 was recognized by YTH N6-methyladenosine RNA binding protein F1 (YTHDF1), resulting in enhanced mRNA stability. LDHA was found to be highly expressed in HFD-treated mice, where knocking down LDHA attenuated HFD-induced hepatic steatosis. These findings demonstrated that LDHA-induced H3K18lac promoted NAFLD progression, where LDHA-induced H3K18lac in METTL3 promoter elevated METTL3 expression, thereby promoting m6A methylation and stabilizing SCD1 via a YTHDF1-dependent manner. Keywords: Nonalcoholic fatty liver disease, LDHA, METTL3, YTHDF1, Histone lactylation.

• MeSH
• adenosin * metabolismus   analogy a deriváty   MeSH
• dieta s vysokým obsahem tuků škodlivé účinky   MeSH
• histony * metabolismus   MeSH
• L-laktátdehydrogenasa metabolismus   MeSH
• lidé MeSH
• methyltransferasy * metabolismus   genetika   MeSH
• myši inbrední C57BL * MeSH
• myši MeSH
• nealkoholová steatóza jater * metabolismus   patologie   MeSH
• progrese nemoci * MeSH
• proteiny vázající RNA * metabolismus   genetika   MeSH
• stearyl-CoA-desaturasa * metabolismus   genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Daunorubicin (DNR) is an anthracycline antibiotic originating from soil-dwelling actinobacteria extensively used to treat malignant tumors. Over the decades, extensive attempts were made to enhance the production of anthracyclines by introducing genetic modifications and mutations in combination with media optimization, but the target production levels remain comparatively low. Developing an appropriate culture medium to maximize the yield of DNR and preventing autotoxicity for the producing organism remains a challenge. Our prospective review sheds light on a method involving perturbation that enhances the precursors to regulate the type II PKS pathway, enhancing cells' capacity to increase secondary metabolite production. The suggested method also entails the preparation of culture media for the cultivation of Streptomyces sp. and enhanced yield of DNR, as well as making it inactive with iron or its reduced forms following efflux from the producer. The iron or iron-DNR complex is encapsulated by oleic acid or lipid micelle layers in the culture media, finally resulting in the generated inactive DNR and the DNR-iron-oil complex. This idea has the potential to protect the producer organism from autotoxicity and prevent the inhibition of metabolite production. The approach of substituting sugar with oil in culture media has a dual role wherein it promotes Streptomyces growth by utilizing lipids as an energy source and encapsulating the generated DNR-iron complex in the medium. In this review, we discussed aspects like anthracycline producers, biosynthesis pathways, and gene regulation; side effects of DNR; mechanisms for autotoxicity evasion; and culture media components for the enhancement of DNR production in Streptomyces sp. We anticipate that our work will help researchers working with secondary metabolites production and decipher a methodology that would enhance DNR yield and facilitate the extraction of the resulting DNR by lowering costs in large-scale fermentation.

• Publikační typ
• časopisecké články MeSH
• přehledy MeSH