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BACKGROUND: The current requirement is to establish the preoperative diagnosis accurately as possible and to achieve an adequate extent of surgery. The aim of this study was to define the preoperative clinical and molecular genetic risks of malignancy in indeterminate thyroid nodules (Bethesda III and IV) and to determine their impact on the surgical strategy. METHODS: Prospectively retrospective analysis of 287 patients provided the basis of preoperative laboratory examination, sonographic stratification of malignancy risks and cytological findings. Molecular tests focused on pathogenic variants of genes associated with thyroid oncogenesis in cytologically indeterminate nodules (Bethesda III and IV). The evaluation included clinical risk factors: positive family history, radiation exposure and growth in size and/or number of nodules. RESULTS: Preoperative FNAB detected 52 cytologically indeterminate nodules (28.7%) out of 181 patients. Postoperative histopathological examination revealed malignancy in 12 cases (23.7%) and there was no significant difference between Bethesda III and IV categories (P=0.517). Clinical risk factors for malignancy were found in 32 patients (61.5%) and the presence of at least one of them resulted in a clearly higher incidence of malignancy than their absence (31.3% vs. 10.0%, respectively). Pathogenic variants of genes were detected in 12/49 patients in Bethesda III and IV, and in 4 cases (33.3%) thyroid carcinoma was revealed. The rate of malignancies was substantially higher in patients with pathogenic variants than in those without (33.3% vs. 16.2%, respectively). CONCLUSIONS: Our experience implies that molecular genetic testing is one of several decision factors. We will continue to monitor and enlarge our patient cohort to obtain long-term follow-up data.
- MeSH
- dospělí MeSH
- genetické testování MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádory štítné žlázy * genetika MeSH
- retrospektivní studie MeSH
- rizikové faktory MeSH
- senioři MeSH
- tenkojehlová biopsie MeSH
- uzly štítné žlázy * genetika patologie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
The glycoprotein clusterin (CLU) is involved in cell proliferation and DNA damage repair and is highly expressed in tumor cells. Here, we aimed to investigate the effects of CLU dysregulation on two human astrocytic cell lines: CCF-STTG1 astrocytoma cells and SV-40 immortalized normal human astrocytes. We observed that suppression of CLU expression by RNA interference inhibited cell proliferation, triggered the DNA damage response, and resulted in cellular senescence in both cell types tested. To further investigate the underlying mechanism behind these changes, we measured reactive oxygen species, assessed mitochondrial function, and determined selected markers of the senescence-associated secretory phenotype. Our results suggest that CLU deficiency triggers oxidative stress-mediated cellular senescence associated with pronounced alterations in mitochondrial membrane potential, mitochondrial mass, and expression levels of OXPHOS complex I, II, III and IV, indicating mitochondrial dysfunction. This report shows the important role of CLU in cell cycle maintenance in astrocytes. Based on these data, targeting CLU may serve as a potential therapeutic approach valuable for treating gliomas.
- MeSH
- astrocyty * metabolismus patologie MeSH
- klusterin * metabolismus genetika MeSH
- lidé MeSH
- membránový potenciál mitochondrií * fyziologie MeSH
- mitochondrie * metabolismus MeSH
- nádorové buněčné linie MeSH
- oxidační stres fyziologie MeSH
- oxidativní fosforylace MeSH
- poškození DNA MeSH
- proliferace buněk * MeSH
- reaktivní formy kyslíku metabolismus MeSH
- stárnutí buněk * fyziologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
High soil pH and excess CaCO3 are major contributors to calcareous soil limitations on crops' access to essential nutrients, especially phosphorus (P) and micronutrients, which in turn impact pulses yields and growth. The purpose of this study was to determine the effect of bio sulfur granules (BSG) on the growth of black gram and the availability of nutrients in calcareous vertisols deficient in sulfur. BSG was developed by using sulfur-oxidizing bacteria (SOB) and elemental sulfur (ES) through an incubation study. Developed BSG was tested in a pot and field conditions to evaluate their effectiveness on black gram growth and yield. In the incubation study, soil treated with Methylobacterium thiocyanatum VRI7-A4 and ES (40 kg S/ha) significantly decreased pH and increased available S (SO42-) in calcareous soils. After 40 days of incubation, the solubility of P, Fe, and Zn was greatly increased by the addition of ES @ 40 kg S/ ha in combination with M. thiocyanatum VRI7-A4 or Pandoraea thiooxydans ATSB16. Black gram in S-deficient calcareous soil was improved by the application of BSG (ES @ 40 kg S/ ha with M. thiocyanatum VRI7-A7) in terms of root and shoot lengths, nodule number, plant biomass, pod yield, and biological yield as compared to control. The same treatment greatly increased plant nutrient intake as well as the concentrations of P, Fe, and Zn in the soil. The results showed that the addition of BSG granules (ES @ 40 kg S/ha + M. thiocyanatum VRI7-A4) to calcareous vertisol deficient in S enhanced the nutrient solubility through S oxidation. The developed bio sulfur granules may be added to the fertilizer schedule of the pulses growers to get improved crop growth and yield of black gram in calcareous soil.
Stenotrophomonas maltophilia, Achromobacter xylosoxidans, and Burkholderia cenocepacia are considered emerging pathogens classified as a public health problem due to extensive antimicrobial resistance. Therefore, the discovery of new therapeutic strategies has become crucial. This study aimed to evaluate the antimicrobial activity of gallic acid and methyl gallate against non-fermenting bacteria. The study included five clinical isolates of Stenotrophomonas maltophilia, Achromobacter xylosoxidans, and Burkholderia cenocepacia. The minimum inhibitory concentrations of gallic acid and methyl gallate were determined by the broth microdilution method. Growth curves, metabolic activity, and biofilm formation of each bacterial strain in the presence or absence of phenolic compounds were performed. Finally, the therapeutic efficacy of the compounds was evaluated using an in vivo model. Gallic acid and methyl gallate showed antibacterial activity against bacterial strains in a concentration range of 64 to 256 μg/mL, both compounds reduced bacterial growth and metabolic activity of the strains, even at subinhibitory concentrations. Only, methyl gallate exhibited activity to inhibit the formation of bacterial biofilms. Moreover, gallic acid and methyl gallate increased larval survival by up to 60% compared to 30% survival of untreated larvae in a bacterial infection model in Galleria mellonella. Our results highlight the potential of gallic acid and methyl gallate as therapeutic alternatives for infections by emerging non-fermentative bacteria.
Current antibiotics and chemotherapeutics are becoming ineffective because pathogenic bacteria and tumor cells have developed multiple drug resistance. Therefore, it is necessary to find new substances that can be used in treatment, either alone or as sensitizing molecules in combination with existing drugs. Peptaibols are bioactive, membrane-active peptides of non-ribosomal origin, mainly produced by filamentous fungi such as Trichoderma spp. This study focused on producing peptaibol-rich extracts from Trichoderma atroviride O1, cultivated on malt extract agar (MA) under circadian and constant darkness conditions for 13 days. Peptaibol production was detected by MALDI-TOF mass spectrometry after six days of cultivation. The extracts demonstrated antibacterial activity against Staphylococcus aureus strains, particularly the methicillin-resistant variant, but not against the Gram-negative Pseudomonas aeruginosa. Quorum sensing interference revealed that a peptaibol-rich extract suppressed Vibrio campbellii BAA-1119's AI-2 signaling system to a degree comparable with gentamycin. Beyond antibacterial properties, the extracts exhibited notable antiproliferative activity against human ovarian cancer cells and their adriamycin-resistant subline in both 2D and 3D models. Specifically, MA-derived extracts reduced ovarian cancer cell viability by 70% at 50 μg/mL, especially under light/dark regime of cultivation. Compared to previously published results for PDA-based extracts, MA cultivation shifted the biological effects of peptaibol-containing extracts toward anticancer potential. These findings support the idea that modifying fungal cultivation parameters, the bioactivity of secondary metabolite mixtures can be tailored for specific therapeutic applications.
- MeSH
- agar * chemie MeSH
- antibakteriální látky * farmakologie metabolismus MeSH
- Hypocreales MeSH
- kultivační média chemie MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- nádorové buněčné linie MeSH
- peptaiboly * farmakologie metabolismus biosyntéza chemie MeSH
- proliferace buněk účinky léků MeSH
- protinádorové látky * farmakologie metabolismus MeSH
- Pseudomonas aeruginosa účinky léků MeSH
- Staphylococcus aureus účinky léků MeSH
- Trichoderma * metabolismus růst a vývoj chemie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Tick-borne encephalitis virus (TBEV) is a significant threat to human health. The virus causes potentially fatal disease of the central nervous system (CNS), for which no treatments are available. TBEV infected individuals display a wide spectrum of neuronal disease, the determinants of which are undefined. Changes to host metabolism and virus-induced immunity have been postulated to contribute to the neuronal damage observed in infected individuals. In this study, we evaluated the cytokine, chemokine, and metabolic alterations in the cerebrospinal fluid (CSF) of symptomatic patients infected with TBEV presenting with meningitis or encephalitis. Our aim was to investigate the host immune and metabolic responses associated with specific TBEV infectious outcomes. METHODS: CSF samples of patients with meningitis (n = 27) or encephalitis (n = 25) were obtained upon consent from individuals hospitalised with confirmed TBEV infection in Brno. CSF from uninfected control patients was also collected for comparison (n = 12). A multiplex bead-based system was used to measure the levels of pro-inflammatory cytokines and chemokines. Untargeted metabolomics followed by bioinformatics and integrative omics were used to profile the levels of metabolites in the CSF. Human motor neurons (hMNs) were differentiated from induced pluripotent stem cells (iPSCs) and infected with the highly pathogenic TBEV-Hypr strain to profile the role(s) of identified metabolites during the virus lifecycle. Virus infection was quantified via plaque assay. RESULTS: Significant differences in proinflammatory cytokines (IFN-α2, TSLP, IL-1α, IL-1β, GM-CSF, IL-12p40, IL-15, and IL-18) and chemokines (IL-8, CCL20, and CXCL11) were detected between neurological-TBEV and control patients. A total of 32 CSF metabolites differed in TBE patients with meningitis and encephalitis. CSF S-Adenosylmethionine (SAM), Fructose 1,6-bisphosphate (FBP1) and Phosphoenolpyruvic acid (PEP) levels were 2.4-fold (range ≥ 2.3-≥3.2) higher in encephalitis patients compared to the meningitis group. CSF urocanic acid levels were significantly lower in patients with encephalitis compared to those with meningitis (p = 0.012209). Follow-up analyses showed fluctuations in the levels of O-phosphoethanolamine, succinic acid, and L-proline in the encephalitis group, and pyruvic acid in the meningitis group. TBEV-infection of hMNs increased the production of SAM, FBP1 and PEP in a time-dependent manner. Depletion of the metabolites with characterised pharmacological inhibitors led to a concentration-dependent attenuation of virus growth, validating the identified changes as key mediators of TBEV infection. CONCLUSIONS: Our findings reveal that the neurological disease outcome of TBEV infection is associated with specific and dynamic metabolic signatures in the cerebrospinal fluid. We describe a new in vitro model for in-depth studies of TBEV-induced neuropathogenesis, in which the depletion of identified metabolites limits virus infection. Collectively, this reveals new biomarkers that can differentiate and predict TBEV-associated neurological disease. Additionally, we have identified novel therapeutic targets with the potential to significantly improve patient outcomes and deepen our understanding of TBEV pathogenesis.
- MeSH
- cytokiny mozkomíšní mok MeSH
- dospělí MeSH
- klíšťová encefalitida * mozkomíšní mok metabolismus MeSH
- kultivované buňky MeSH
- lidé středního věku MeSH
- lidé MeSH
- metabolom * fyziologie MeSH
- metabolomika MeSH
- mladý dospělý MeSH
- neurony * metabolismus virologie MeSH
- senioři MeSH
- viry klíšťové encefalitidy * MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Aim: Complications associated with obesity may negatively affect the physiological growth and development of the fetus and the health of the child. The aim of the research was to determine the effect of pregnancy and the postpartum period on the body composition of first-time pregnant women using standardized anthropometric methods with the use of the Matiegka method for fractionation of body composition. Design: A longitudinal cohort study. Methods: The study was conducted in gynecological outpatient clinics on a population of 40 nulligravidas aged 18-40 years. The women were assessed in three stages corresponding to the trimesters of pregnancy and Stage IV, the postpartum period of six weeks. The parameters obtained were used to determine body composition according to the Matiegka method. The women were divided into two groups according to BMI, normal weight and overweight and obesity. Results: Significant changes in body composition were found during the measurements in Stages I-IV, with a decrease in skeletal muscle mass and an increase in fat component. There were significant changes in body composition between the categories of women with BMI normal weight and BMI overweight and obese in the ratio of skeletal muscle to body fat. Conclusion: The results indicate that monitoring body composition in pregnant women is important not only for preventing maternal obesity, but also for preventing fetal macrosomia and possible maternal and neonatal morbidity and mortality associated with childbirth and the postpartum period.
Drug resistance is a growing problem for many pathogens, including mycobacteria. Small heterocyclic molecules are among the leading scaffolds for developing potential antimycobacterial agents. Therefore, based on the molecular hybridization approach, we have prepared an extensive series of N-substituted 5-(3,5-dinitrophenyl)-1,3,4-oxadiazol-2-amine derivatives. We also investigated their isosteres and acyclic synthetic precursors. The compounds were evaluated for their in vitro activity against Mycobacterium tuberculosis (Mtb) H37Rv, a panel of multidrug- and extensively drug-resistant Mtb isolates and two nontuberculous mycobacterial strains (NTM; M. avium and M. kansasii). The ability to inhibit mycobacterial growth was quantified using minimum inhibitory concentration (MIC) values. Many compounds achieved MIC values ≤ 0.03 μM for NTM and Mtb, regardless of their resistance profile. The highest activity was associated with oxadiazole and thiadiazole scaffolds with benzylamino or C5-C9 alkylamino substitution. The experimentally confirmed mechanism of action of these compounds consists of disruption of mycobacterial cell wall biosynthesis via inhibition of decaprenylphosphoryl-β-D-ribose 2'-epimerase (DprE1). In vitro toxicity evaluation was performed in a hepatocyte model (HepG2), while in vivo toxicity was evaluated using Danio rerio embryos. These findings identify a promising new chemotype with potent, broad-spectrum and selective antimycobacterial activity, including efficacy against resistant strains, and support its further development as a potential therapeutic candidate.
- MeSH
- antituberkulotika * farmakologie chemická syntéza chemie toxicita MeSH
- dánio pruhované MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- Mycobacterium tuberculosis účinky léků MeSH
- oxadiazoly * farmakologie chemická syntéza chemie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Breast milk, as the optimal food for infants and young children, contains all the components necessary for proper growth and development. It is a rich source of both essential nutrients and biologically active factors, making breast milk a unique food with scientifically proven health-promoting properties. Among the entire range of biologically active factors, breast milk microorganisms and prebiotic factors, in the form of breast milk oligosaccharides, occupy an important place. The aim of our research was to determine the occurrence of bacteria with probiotic potential, belonging to the Lactobacillaceae family, in the environment of breast milk and breast milk oligosaccharides. The study included 63 human milk samples from breastfeeding women at various stages of lactation. Microorganism identification based on culture tests and MALDI TOF/MS, macronutrient analysis using the MIRIS human milk analyser, as well as analysis of human milk oligosaccharides using ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry were performed. The results have shown that breast milk from different breastfeeding women is characterized by great diversity in terms of the presence of Lacto-bacillaceae bacteria in its microbiological composition. These bacteria were present in 22.2 % of the tested breast milk samples. Analysis of the human milk oligosaccharide profile revealed a slightly higher content of prebiotic factors in breast milk samples containing Lactobacillaceae, including 2'-fucosyllactose, oligosaccharide occurring in the highest amount in breast milk.
The poor prognosis of colorectal cancer (CRC) contributes to a yearly increase in CRC mortality, while microRNAs (miRNAs) were found to play a regulatory function in diversiform cancers, including CRC. The objective of this research was to evaluate the clinical value and possible regulatory mechanisms of miR-767-5p in CRC. The expression level of miR-767-5p in CRC tissues and cells was examined. The Kaplan-Meier curve was utilized to analyse the function of miR-767-5p in CRC prognosis. The independent prognostic factors in CRC were assessed by a multivariate COX regression analysis. Additionally, the regulatory mechanism of miR-767-5p in CRC was determined through an in vitro cell experiment. The miR-767-5p expression was down-regulated in CRC tumour tissues and CRC cells. Indicators such as tumour differentiation, TNM, LNM and miR-767-5p were identified as independent prognostic factors for a poor CRC prognosis. The regulatory relationship between miR-767-5p and nuclear factor I A (NFIA) was verified by the dual-luciferase reporter assay, and the NFIA expression level was significantly suppressed by over-expressed miR-767-5p. The proliferation, migration and invasion of CRC cells were inhibited by over-expressing miR-767-5p, while the inhibition effect could be reversed by over-expressing NFIA. The over-expressed miR-767-5p could serve as a tumour suppressor to inhibit the progression of CRC by suppressing the expression level of NFIA.
- MeSH
- invazivní růst nádoru MeSH
- Kaplanův-Meierův odhad MeSH
- kolorektální nádory * genetika patologie metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- mikro RNA * genetika metabolismus MeSH
- nádorové buněčné linie MeSH
- pohyb buněk genetika MeSH
- prognóza MeSH
- proliferace buněk genetika MeSH
- regulace genové exprese u nádorů * MeSH
- senioři MeSH
- transkripční faktory NFI metabolismus genetika MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
