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Cells Jun 2024Hepatitis C virus (HCV) is an oncogenic virus that causes chronic liver disease in more than 80% of patients. During the last decade, efficient direct-acting antivirals...
Hepatitis C virus (HCV) is an oncogenic virus that causes chronic liver disease in more than 80% of patients. During the last decade, efficient direct-acting antivirals were introduced into clinical practice. However, clearance of the virus does not reduce the risk of end-stage liver diseases to the level observed in patients who have never been infected. So, investigation of HCV pathogenesis is still warranted. Virus-induced changes in cell metabolism contribute to the development of HCV-associated liver pathologies. Here, we studied the impact of the virus on the metabolism of polyamines and proline as well as on the urea cycle, which plays a crucial role in liver function. It was found that HCV strongly suppresses the expression of arginase, a key enzyme of the urea cycle, leading to the accumulation of arginine, and up-regulates proline oxidase with a concomitant decrease in proline concentrations. The addition of exogenous proline moderately suppressed viral replication. HCV up-regulated transcription but suppressed protein levels of polyamine-metabolizing enzymes. This resulted in a decrease in polyamine content in infected cells. Finally, compounds targeting polyamine metabolism demonstrated pronounced antiviral activity, pointing to spermine and spermidine as compounds affecting HCV replication. These data expand our understanding of HCV's imprint on cell metabolism.
Topics: Proline; Humans; Hepacivirus; Polyamines; Urea; Virus Replication; Arginase; Antiviral Agents; Hepatitis C; Cell Line, Tumor; Proline Oxidase
PubMed: 38920664
DOI: 10.3390/cells13121036 -
HemaSphere Jun 2024Mitapivat is an investigational, oral, small-molecule allosteric activator of pyruvate kinase (PK). PK is a regulatory glycolytic enzyme that is key in providing the red...
Mitapivat is an investigational, oral, small-molecule allosteric activator of pyruvate kinase (PK). PK is a regulatory glycolytic enzyme that is key in providing the red blood cell (RBC) with sufficient amounts of adenosine triphosphate (ATP). In sickle cell disease (SCD), decreased 2,3-DPG levels increase the oxygen affinity of hemoglobin, thereby preventing deoxygenation and polymerization of sickle hemoglobin. The PK activator mitapivat has been shown to decrease levels of 2,3-DPG and increase levels of ATP in RBCs in patients with SCD. In this phase 2, investigator-initiated, open-label study (https://www.clinicaltrialsregister.eu/ NL8517; EudraCT 2019-003438-18), untargeted metabolomics was used to explore the overall metabolic effects of 8-week treatment with mitapivat in the dose-finding period. In total, 1773 unique metabolites were identified in dried blood spots of whole blood from ten patients with SCD and 42 healthy controls (HCs). The metabolic phenotype of patients with SCD revealed alterations in 139/1773 (7.8%) metabolites at baseline when compared to HCs (false discovery rate-adjusted < 0.05), including increases of (derivatives of) polyamines, purines, and acyl carnitines. Eight-week treatment with mitapivat in nine patients with SCD altered 85/1773 (4.8%) of the total metabolites and 18/139 (12.9%) of the previously identified altered metabolites in SCD (unadjusted < 0.05). Effects were observed on a broad spectrum of metabolites and were not limited to glycolytic intermediates. Our results show the relevance of metabolic profiling in SCD, not only to unravel potential pathophysiological pathways and biomarkers in multisystem diseases but also to determine the effect of treatment.
PubMed: 38919958
DOI: 10.1002/hem3.109 -
Current Medical Imaging 2024Accurately predicting the hepatocellular carcinoma (HCC) grade may facilitate the rational selection of treatment strategies. The diagnostic efficacy of the combination...
BACKGROUND
Accurately predicting the hepatocellular carcinoma (HCC) grade may facilitate the rational selection of treatment strategies. The diagnostic efficacy of the combination of Gadolinium ethoxybenzy diethylenetriamine pentaacetic (Gd-EOB-DTPA) enhancement T1 mapping and apparent diffusion coefficient (ADC) values in predicting HCC grade needs further validation.
OBJECTIVES
This study aimed to assess the capacity of Gd-EOB-DTPA-enhanced T1 mapping and ADC values, both individually and in combination, to discriminate between different grades of HCC.
MATERIALS AND METHODS
From July 2017 to February 2020, 96 patients (male, 83; mean age, 53.67 years; age range, 29-71 years) clinically diagnosed with HCC were included in the present study. All patients underwent Gd-EOB-DTPA-enhanced magnetic resonance imaging (MRI, including T1 mapping sequence) before surgery or biopsy. All the patients were categorized into 3 groups according to the pathological results (including 24 cases of well-differentiated HCCs, 59 cases of moderately differentiated HCCs, 13 cases of and poorly differentiated HCCs). The mean Gd-EOB-DTPA enhanced T1 values (ΔT1=[(T1pre-T1post)/T1pre]×100%) and ADC values between different grading groups of HCC were calculated and compared. The area under the characteristics curve (AUC), the diagnostic threshold, sensitivity, and specificity of ΔT1 and ADC for differential diagnosis were analyzed.
RESULTS
Mean ΔT1 was 58% for well-differentiated HCCs, 50% for moderately-differentiated HCCs, and 43% for poorly-differentiated HCCs. ΔT1 showed statistical differences between the groups (P<0.001). The mean ADC values of the 3 groups were 1.11×10-3 mm2/s, 0.91×10-3 mm2/s, and 0.80×10-3mm2/s, respectively. ADC showed statistical differences between the groups (P<0.001). In discriminating well- differentiated group from the moderately differentiated group, the AUC of ΔT1 was 0.751 (95% CI: 0.642, 0.859), the AUC of ADC was 0.782 (95% CI: 0.671, 0.894), the AUC of combined model was 0.811 (95% CI: 0.709, 0.914). In discriminating the poorly differentiated group from the moderately differentiated group, the AUC of ΔT1 was 0.768 (95% CI: 0.634, 0.902), the AUC of ADC was 0.754 (95% CI: 0.603, 0.904), and the AUC of the combined model was 0.841 (95% CI: 0.729, 0.953).
CONCLUSION
Gd-EOB-DTPA enhanced T1 mapping, and ADC values have complementary effects on the sensitivity and specificity for identifying different HCC grades. A combined model of Gd-EOB-DTPA-enhanced MRI T1 mapping and ADC values could improve diagnostic performance for predicting HCC grades.
.Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Middle Aged; Gadolinium DTPA; Male; Female; Aged; Adult; Contrast Media; Neoplasm Grading; Diffusion Magnetic Resonance Imaging; Magnetic Resonance Imaging; Retrospective Studies; Sensitivity and Specificity; ROC Curve
PubMed: 38918998
DOI: 10.2174/0115734056259418231112102249 -
Cell & Bioscience Jun 2024Polyamines (PA) are polycations with pleiotropic functions in cellular physiology and pathology. In particular, PA have been involved in the regulation of cell... (Review)
Review
Polyamines (PA) are polycations with pleiotropic functions in cellular physiology and pathology. In particular, PA have been involved in the regulation of cell homeostasis and proliferation participating in the control of fundamental processes like DNA transcription, RNA translation, protein hypusination, autophagy and modulation of ion channels. Indeed, their dysregulation has been associated to inflammation, oxidative stress, neurodegeneration and cancer progression. Accordingly, PA intracellular levels, derived from the balance between uptake, biosynthesis, and catabolism, need to be tightly regulated. Among the mechanisms that fine-tune PA metabolic enzymes, emerging findings highlight the importance of noncoding RNAs (ncRNAs). Among the ncRNAs, microRNA, long noncoding RNA and circRNA are the most studied as regulators of gene expression and mRNA metabolism and their alteration have been frequently reported in pathological conditions, such as cancer progression and brain diseases. In this review, we will discuss the role of ncRNAs in the regulation of PA genes, with a particular emphasis on the changes of this modulation observed in health disorders.
PubMed: 38918813
DOI: 10.1186/s13578-024-01235-3 -
Biomacromolecules Jun 2024Carbonyl cross-linkers are used to modify textiles and form resins, and are produced annually in megatonne volumes. Due to their toxicity toward the environment and...
Carbonyl cross-linkers are used to modify textiles and form resins, and are produced annually in megatonne volumes. Due to their toxicity toward the environment and human health, however, less harmful biobased alternatives are needed. This study introduces carbonyl groups to lactose and galactose using galactose oxidase from (GalOx) and pyranose dehydrogenase from (PDH1) to produce four cross-linkers. Differential scanning calorimetry was used to compare cross-linker reactivity, most notably resulting in a 34 °C decrease in reaction peak temperature (72 °C) for GalOx-oxidized galactose compared to unmodified galactose. Attenuated total reflectance Fourier-transform infrared (ATR-FTIR) spectroscopy, X-ray photoelectron spectroscopy (XPS), and proton nuclear magnetic resonance (H NMR) spectroscopy were used to verify imine formation and amine and aldehyde depletion. Cross-linkers were shown to form gels when mixed with polyallylamine, with GalOx-oxidized lactose forming gels more effectively than all other cross-linkers, including glutaraldehyde. Further development of carbohydrate cross-linker technologies could lead to their adoption in various applications, including in adhesives, resins, and textiles.
PubMed: 38917058
DOI: 10.1021/acs.biomac.4c00457 -
ELife Jun 2024The emergence of new protein functions is crucial for the evolution of organisms. This process has been extensively researched for soluble enzymes, but it is largely...
The emergence of new protein functions is crucial for the evolution of organisms. This process has been extensively researched for soluble enzymes, but it is largely unexplored for membrane transporters, even though the ability to acquire new nutrients from a changing environment requires evolvability of transport functions. Here, we demonstrate the importance of environmental pressure in obtaining a new activity or altering a promiscuous activity in members of the amino acid-polyamine-organocation (APC)-type yeast amino acid transporters family. We identify APC members that have broader substrate spectra than previously described. Using in vivo experimental evolution, we evolve two of these transporter genes, and , toward new substrate specificities. Single mutations on these transporters are found to be sufficient for expanding the substrate range of the proteins, while retaining the capacity to transport all original substrates. Nonetheless, each adaptive mutation comes with a distinct effect on the fitness for each of the original substrates, illustrating a trade-off between the ancestral and evolved functions. Collectively, our findings reveal how substrate-adaptive mutations in membrane transporters contribute to fitness and provide insights into how organisms can use transporter evolution to explore new ecological niches.
Topics: Mutation; Saccharomyces cerevisiae; Amino Acid Transport Systems; Substrate Specificity; Evolution, Molecular; Polyamines; Saccharomyces cerevisiae Proteins; Genetic Fitness; Amino Acids
PubMed: 38916596
DOI: 10.7554/eLife.93971 -
BioRxiv : the Preprint Server For... Jun 2024Microbes must adapt to diverse biotic and abiotic factors encountered in host environments. Polyamines are an abundant class of aliphatic molecules that play essential...
Microbes must adapt to diverse biotic and abiotic factors encountered in host environments. Polyamines are an abundant class of aliphatic molecules that play essential roles in fundamental cellular processes across the tree of life. Surprisingly, the bacterial pathogen is highly sensitive to polyamines encountered during infection, and acquisition of a polyamine resistance locus has been implicated in spread of the prominent USA300 methicillin-resistant lineage. At present, alternative pathways of polyamine resistance in staphylococci are largely unknown. Here we applied experimental evolution to identify novel mechanisms and consequences of adaption when exposed to increasing concentrations of the polyamine spermine. Evolved populations of exhibited striking evidence of parallel adaptation, accumulating independent mutations in the potassium transporter genes and . Mutations in either or are sufficient to confer polyamine resistance and function in an additive manner. Moreover, we find that ktr mutations provide increased resistance to multiple classes of unrelated cationic antibiotics, suggesting a common mechanism of resistance. Consistent with this hypothesis, ktr mutants exhibit alterations in cell surface charge indicative of reduced affinity and uptake of cationic molecules. Finally, we observe that laboratory-evolved ktr mutations are also present in diverse natural isolates, suggesting these mutations may contribute to antimicrobial resistance during human infections. Collectively this study identifies a new role for potassium transport in polyamine resistance with consequences for susceptibility to both host-derived and clinically-used antimicrobials.
PubMed: 38915543
DOI: 10.1101/2024.06.15.599172 -
International Journal of Biological... Jun 2024In this report, we present a dual crosslinking hydrogel fiber made from polyamine saccharides chitosan (CS), synthesized through UV polymerization. This process utilizes...
On the dual crosslinking for functionality enhancement of poly (acrylamide-co-acrylic acid)/chitosan-aluminum (III) ions and its characterization and sensory hydrogel fibers.
In this report, we present a dual crosslinking hydrogel fiber made from polyamine saccharides chitosan (CS), synthesized through UV polymerization. This process utilizes Irgacure 2959 and N,N'-Methylenebisacrylamide (MBAA) as initiators, followed by immersion in an aluminum chloride (AlCl) solution. The resulting hydrogel incorporates a dual crosslinking mechanism, quantitatively studied via Nuclear Magnetic Resonance (NMR) spectroscopy. This mechanism involves chemical crosslinking through radical graft polymerization of acrylamide and acrylic acid onto CS in the presence of MBAA, and physical crosslinking through hydrogen bonding interactions between P(AAm-co-AA) and a metal coordination bond. The mechanical properties of the hydrogel fiber enable it to withstand stresses up to 656 kPa and strains exceeding 300 %. Additionally, the hydrogel fiber exhibits conductivity at 1.96 Scm. Serving as a multifunctional material, it acts as a strain sensor and finds utility in optics. Remarkably, it demonstrates the capability to detect human motions such as finger bending and minor deformations like vibrations of the vocal cords. Furthermore, its ability to guide dynamic light makes it promising for optical applications. Consequently, this multifunctional hydrogel fiber emerges as a highly promising candidate for diverse applications in fields such as bioengineering and electronics.
PubMed: 38914395
DOI: 10.1016/j.ijbiomac.2024.133383 -
Gene Jun 2024Products from stingless bees are rich reservoirs of microbial diversity, including yeasts with fermentative potential. Previously, two Saccharomyces cerevisiae strains,...
Products from stingless bees are rich reservoirs of microbial diversity, including yeasts with fermentative potential. Previously, two Saccharomyces cerevisiae strains, JP14 and IP9, were isolated from Jataí (Tetragonisca angustula) and Iraí (Nannotrigona testaceicornis) bees, respectively, aiming at mead production. Both strains presented great osmotic and sulfite tolerance, and ethanol production, although they have a high free amino nitrogen demand. Herein, their genomes were sequenced, assembled, and annotated, and the variants were compared to the S. cerevisiae S288c reference strain. The final assembly of IP9 and JP14 presented high N50 and BUSCO scores, and more than 6430 protein-coding genes. Additionally, nQuire predicted the ploidy of IP9 as diploid, but the results were not enough to determine the ploidy of JP14. The mitochondrial genomes of IP9 and JP14 presented the same gene content as S288c but the genes were rearranged and fragmented in different patterns. Meanwhile, the genes with mutations of high impact (e.g., indels, gain of stop codon) for both yeasts were enriched for transmembrane transport, electron transfer, oxidoreductase, heme binding, fructose, mannose, and glucose transport, activities related to the respiratory chain and sugar metabolism. The IP9 strain presented copy number gains in genes related to sugar transport and cell morphogenesis; in JP14, genes were enriched for disaccharide metabolism and transport, response to reactive oxygen species, and polyamine transport. On the other hand, IP9 presented copy number losses related to disaccharide, thiamine, and aldehyde metabolism, while JP14 presented depletions related to disaccharide, oligosaccharide, asparagine, and aspartate metabolism. Notably, both strains presented a killer toxin gene, annotated from the assembling of unmapped reads, representing a potential mechanism for the control of other microorganisms population in the environment. Therefore, the annotated genomes of JP14 and IP9 presented a high selective pressure for sugar and nitrogen metabolism and stress response, consistent with their isolation source and fermentative properties.
PubMed: 38914244
DOI: 10.1016/j.gene.2024.148722 -
Acta Oncologica (Stockholm, Sweden) Jun 2024The delineation of intraprostatic lesions is vital for correct delivery of focal radiotherapy boost in patients with prostate cancer (PC). Errors in the delineation... (Comparative Study)
Comparative Study
BACKGROUND
The delineation of intraprostatic lesions is vital for correct delivery of focal radiotherapy boost in patients with prostate cancer (PC). Errors in the delineation could translate into reduced tumour control and potentially increase the side effects. The purpose of this study is to compare PET-based delineation methods with histopathology.
MATERIALS AND METHODS
The study population consisted of 15 patients with confirmed high-risk PC intended for prostatectomy. [68Ga]-PSMA-PET/MR was performed prior to surgery. Prostate lesions identified in histopathology were transferred to the in vivo [68Ga]-PSMA-PET/MR coordinate system. Four radiation oncologists manually delineated intraprostatic lesions based on PET data. Various semi-automatic segmentation methods were employed, including absolute and relative thresholds, adaptive threshold, and multi-level Otsu threshold.
RESULTS
The gross tumour volumes (GTVs) delineated by the oncologists showed a moderate level of interobserver agreement with Dice similarity coefficient (DSC) of 0.68. In comparison with histopathology, manual delineations exhibited the highest median DSC and the lowest false discovery rate (FDR) among all approaches. Among semi-automatic approaches, GTVs generated using standardized uptake value (SUV) thresholds above 4 (SUV > 4) demonstrated the highest median DSC (0.41), with 0.51 median lesion coverage ratio, FDR of 0.66 and the 95th percentile of the Hausdorff distance (HD95%) of 8.22 mm.
INTERPRETATION
Manual delineations showed a moderate level of interobserver agreement. Compared to histopathology, manual delineations and SUV > 4 exhibited the highest DSC and the lowest HD95% values. The methods that resulted in a high lesion coverage were associated with a large overestimation of the size of the lesions.
Topics: Humans; Male; Prostatic Neoplasms; Gallium Radioisotopes; Tumor Burden; Gallium Isotopes; Positron-Emission Tomography; Aged; Prostatectomy; Middle Aged; Radiopharmaceuticals; Oligopeptides; Magnetic Resonance Imaging; Edetic Acid
PubMed: 38912830
DOI: 10.2340/1651-226X.2024.39041