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Marine Drugs Feb 2024Floridoside is a galactosyl-glycerol compound that acts to supply UDP-galactose and functions as an organic osmolyte in response to salinity in Rhodophyta....
Floridoside is a galactosyl-glycerol compound that acts to supply UDP-galactose and functions as an organic osmolyte in response to salinity in Rhodophyta. Significantly, the UDP-galactose pool is shared for sulfated cell wall galactan synthesis, and, in turn, affected by thallus development alongside carposporogenesis induced by volatile growth regulators, such as ethylene and methyl jasmonate, in the red seaweed . In this study, we monitored changes in the floridoside reservoir through gene expression controlling both the galactose pool and glyceride pool under different reproductive stages of and we considered changing salinity conditions. Floridoside synthesis was followed by expression analysis of () as UDP-galactose is obtained from UDP-glucose and glucose-1P, and through gene expression as degradation of floridoside occurs through the cleavage of galactosyl residues. Meanwhile, glycerol 3-phosphate is connected with the galactoglyceride biosynthetic pathway by glycerol 3-phosphate dehydrogenase (G3PD), monogalactosyl diacylglyceride synthase (MGDGS), and digalactosyl diacylglyceride synthase (DGDGS). The results of our study confirm that low transcripts are correlated with thalli softness to locate reproductive structures, as well as constricting the synthesis of UDP-hexoses for galactan backbone synthesis in the presence of two volatile regulators and methionine. Meanwhile, modulates expression according to cystocarp maturation, and we found high transcripts in late development stages, as occurred in the presence of methyljasmonate, compared to early stages in ethylene. Regarding the acylglyceride pool, the upregulation of , , and gene expression in treated with MEJA supports lipid remodeling, as high levels of transcripts for and provide membrane stability during late development stages of cystocarps. Similar behavior is assumed in three naturally collected thalli development stages-namely, fertile, fertilized, and fertile-under 65 psu salinity conditions. Low transcripts for and high for are reported in infertile and fertilized thalli, which is the opposite to high transcripts for and low for encountered in fertile thalli within visible cystocarps compared to each of their corresponding stages in 35 psu. No significant changes are reported for and . It is concluded that cystocarp and thallus development stages affect galactose and glycerides pools with interwoven effects on cell wall polysaccharides.
Topics: Seaweed; Glycerol; Galactose; alpha-Galactosidase; Rhodophyta; Galactans; Glucose; Uridine Diphosphate; Cyclopentanes; Glycerophosphates; Oxylipins
PubMed: 38535456
DOI: 10.3390/md22030115 -
The Korean Journal of Gastroenterology... Mar 2024This study compared the effectiveness and safety of glecaprevir/pibrentasvir (GLE/PIB) and sofosbuvir/ledipasvir (SOF/LDV) in real-life clinical practice.
BACKGROUND/AIMS
This study compared the effectiveness and safety of glecaprevir/pibrentasvir (GLE/PIB) and sofosbuvir/ledipasvir (SOF/LDV) in real-life clinical practice.
METHODS
The data from genotype 1 or 2 chronic hepatitis C patients treated with GLE/PIB or sofosbuvir + ribavirin or SOF/LDV in South Korea were collected retrospectively. The analysis included the treatment completion rate, sustained virologic response at 12 weeks (SVR12) test rate, treatment effectiveness, and adverse events.
RESULTS
Seven hundred and eighty-two patients with genotype 1 or 2 chronic hepatitis C who were treated with GLE/PIB (n=575) or SOF/LDV (n=207) were included in this retrospective study. The baseline demographic and clinical characteristics revealed significant statistical differences in age, genotype, ascites, liver cirrhosis, and hepatocellular carcinoma between the GLE/PIB and SOF/LDV groups. Twenty-two patients did not complete the treatment protocol. The treatment completion rate was high for both regimens without statistical significance (97.7% vs. 95.7%, p=0.08). The overall SVR12 of intention-to-treat analysis was 81.2% vs. 80.7% without statistical significance (p=0.87). The overall SVR12 of per protocol analysis was 98.7% vs. 100% without statistical significance (p=0.14). Six patients treated with GLE/PIB experienced treatment failure. They were all male, genotype 2, and showed a negative hepatitis C virus RNA level at the end of treatment. Two patients treated with GLE/PIB stopped medication because of fever and abdominal discomfort.
CONCLUSIONS
Both regimens had similar treatment completion rates, effectiveness, and safety profiles. Therefore, the SOF/LDV regimen can also be considered a viable DAA for the treatment of patients with genotype 1 or 2 chronic hepatitis C.
Topics: Humans; Male; Sofosbuvir; Antiviral Agents; Hepatitis C, Chronic; Hepacivirus; Retrospective Studies; Treatment Outcome; Liver Neoplasms; Genotype; Drug Therapy, Combination; Sulfonamides; Pyrrolidines; Fluorenes; Quinoxalines; Aminoisobutyric Acids; Benzimidazoles; Lactams, Macrocyclic; Cyclopropanes; Leucine; Proline
PubMed: 38522854
DOI: 10.4166/kjg.2023.141 -
International Journal of Infectious... Jun 2024Yellow fever (YF) is a potentially lethal viral hemorrhagic fever that can be prevented with the 17D live attenuated YF vaccine. However, this vaccination can cause...
Yellow fever (YF) is a potentially lethal viral hemorrhagic fever that can be prevented with the 17D live attenuated YF vaccine. However, this vaccination can cause severe adverse reactions including vaccine-associated YF. Here, we describe the case of a 32-year-old female who was permanently immunosuppressed with an anti-CD20 antibody due to multiple sclerosis. Following YF vaccination, the patient developed a variety of symptoms such as febrile temperatures, muscle and joint pain, headaches, and dysuria. A vaccine-associated YF with viremia was diagnosed. To avoid a potentially severe course of the disease, sofosbuvir was used as antiviral treatment followed by the resolution of symptoms and serological response. As travelers with chronic diseases and immunosuppression will increasingly engage in long distance travel, this case demonstrates the importance of assessing patient history prior to the administration of live vaccines and points towards a possible therapeutic approach in those suffering from vaccine-associated YF.
Topics: Adult; Female; Humans; Antiviral Agents; Immunocompromised Host; Rituximab; Sofosbuvir; Yellow Fever; Yellow Fever Vaccine; Antigens, CD20; Multiple Sclerosis
PubMed: 38521450
DOI: 10.1016/j.ijid.2024.107017 -
PLoS Genetics Mar 2024Enterococci are commensal members of the gastrointestinal tract and also major nosocomial pathogens. They possess both intrinsic and acquired resistance to many...
Enterococci are commensal members of the gastrointestinal tract and also major nosocomial pathogens. They possess both intrinsic and acquired resistance to many antibiotics, including intrinsic resistance to cephalosporins that target bacterial cell wall synthesis. These antimicrobial resistance traits make enterococcal infections challenging to treat. Moreover, prior therapy with antibiotics, including broad-spectrum cephalosporins, promotes enterococcal proliferation in the gut, resulting in dissemination to other sites of the body and subsequent infection. As a result, a better understanding of mechanisms of cephalosporin resistance is needed to enable development of new therapies to treat or prevent enterococcal infections. We previously reported that flow of metabolites through the peptidoglycan biosynthesis pathway is one determinant of enterococcal cephalosporin resistance. One factor that has been implicated in regulating flow of metabolites into cell wall biosynthesis pathways of other Gram-positive bacteria is GlmR. In enterococci, GlmR is encoded as the middle gene of a predicted 3-gene operon along with YvcJ and YvcL, whose functions are poorly understood. Here we use genetics and biochemistry to investigate the function of the enterococcal yvcJ-glmR-yvcL gene cluster. Our results reveal that YvcL is a DNA-binding protein that regulates expression of the yvcJ-glmR-yvcL operon in response to cell wall stress. YvcJ and GlmR bind UDP-GlcNAc and reciprocally regulate cephalosporin resistance in E. faecalis, and binding of UDP-GlcNAc by YvcJ appears essential for its activity. Reciprocal regulation by YvcJ/GlmR is essential for fitness during exposure to cephalosporin stress. Additionally, our results indicate that enterococcal GlmR likely acts by a different mechanism than the previously studied GlmR of Bacillus subtilis, suggesting that the YvcJ/GlmR regulatory module has evolved unique targets in different species of bacteria.
Topics: Cephalosporins; Cephalosporin Resistance; Anti-Bacterial Agents; Enterococcus faecalis; Operon; Uridine Diphosphate
PubMed: 38512984
DOI: 10.1371/journal.pgen.1011215 -
Carbohydrate Research Apr 2024Moraxella nonliquefaciens is a commensal of the human upper respiratory tract (URT) but on rare occasions is recovered in cases of ocular, septic and pulmonary...
Moraxella nonliquefaciens is a commensal of the human upper respiratory tract (URT) but on rare occasions is recovered in cases of ocular, septic and pulmonary infections. Hence there is interest in the pathogenic determinants of M. nonliquefaciens, of which outer membrane (OM) structures such as fimbriae and two capsular polysaccharide (CPS) structures, →3)-β-D-GalpNAc-(1→5)-β-Kdop-(2→ and →8)-α-NeuAc-(2→, have been reported in the literature. To further characterise its surface virulence factors, we isolated a novel CPS from M. nonliquefaciens type strain CCUG 348T. This structure was elucidated using NMR data obtained from CPS samples that were subjected to various degrees of mild acid hydrolysis. Together with GLC-MS data, the structure was resolved as a linear polymer composed of two GalfNAc residues consecutively added to Kdo, →3)-β-D-GalfNAc-(1→3)-α-D-GalfNAc-(1→5)-α-(8-OAc)Kdop-(2→. Supporting evidence for this material being CPS was drawn from the proposed CPS biosynthetic locus which encoded a potential GalfNAc transferase, a UDP-GalpNAc mutase for UDP-GalfNAc production and a putative CPS polymerase with predicted GalfNAc and Kdo transferase domains. This study describes a unique CPS composition reported in Moraxella spp. and offers genetic insights into the synthesis and expression of GalfNAc residues, which are rare in bacterial OM glycans.
Topics: Humans; Polysaccharides; Moraxella; Transferases; Uridine Diphosphate; Bacterial Capsules; Polysaccharides, Bacterial
PubMed: 38507941
DOI: 10.1016/j.carres.2024.109095 -
Chemical Research in Toxicology Apr 2024is a useful model organism to study the xenobiotic detoxification pathways of various natural and synthetic toxins, but the mechanisms of phase II detoxification are...
is a useful model organism to study the xenobiotic detoxification pathways of various natural and synthetic toxins, but the mechanisms of phase II detoxification are understudied. 1-Hydroxyphenazine (1-HP), a toxin produced by the bacterium , kills . We previously showed that detoxifies 1-HP by adding one, two, or three glucose molecules in N2 worms. Our current study evaluates the roles that some UDP-glycosyltransferase () genes play in 1-HP detoxification. We show that and knockout mutants are more sensitive to 1-HP than reference strains N2 or PD1074. Our data also show that knockout mutants produce reduced amounts of the trisaccharide sugars, while the knockout mutants produce reduced amounts of all 1-HP derivatives except for the glucopyranosyl product compared to the reference strains. We characterized the structure of the trisaccharide sugar phenazines made by and showed that one of the sugar modifications contains an -acetylglucosamine (GlcNAc) in place of glucose. This implies broad specificity regarding UGT function and the role of genes other than in adding GlcNAc, at least in small-molecule detoxification.
Topics: Animals; Glycosylation; Caenorhabditis elegans; Glycosyltransferases; Phenazines; Uridine Diphosphate; Glucose; Sugars; Trisaccharides
PubMed: 38488606
DOI: 10.1021/acs.chemrestox.3c00410 -
International Journal of Molecular... Feb 2024The uridine diphosphate glycosyltransferase (UGT) superfamily plays a key role in the metabolism of xenobiotics and metabolic wastes, which is essential for detoxifying... (Review)
Review
The uridine diphosphate glycosyltransferase (UGT) superfamily plays a key role in the metabolism of xenobiotics and metabolic wastes, which is essential for detoxifying those species. Over the last several decades, a huge effort has been put into studying human and mammalian UGT homologs, but family members in other organisms have been explored much less. Potentially, other UGT homologs can have desirable substrate specificity and biological activities that can be harnessed for detoxification in various medical settings. In this review article, we take a plant UGT homology, UGT71G1, and compare its structural and biochemical properties with the human homologs. These comparisons suggest that even though mammalian and plant UGTs are functional in different environments, they may support similar biochemical activities based on their protein structure and function. The known biological functions of these homologs are discussed so as to provide insights into the use of UGT homologs from other organisms for addressing human diseases related to UGTs.
Topics: Animals; Humans; Glycosyltransferases; Uridine Diphosphate; Plants; Phylogeny; Mammals
PubMed: 38474028
DOI: 10.3390/ijms25052782 -
International Journal of Molecular... Feb 2024UDP-glycosyltransferases (UGTs) form a large enzyme family that is found in a wide range of organisms. These enzymes are known for accepting a wide variety of...
UDP-glycosyltransferases (UGTs) form a large enzyme family that is found in a wide range of organisms. These enzymes are known for accepting a wide variety of substrates, and they derivatize xenobiotics and metabolites for detoxification. However, most UGT homologs have not been well characterized, and their potential for biomedical and environmental applications is underexplored. In this work, we have used a fluorescent assay for screening substrates of a plant UGT homolog by monitoring the formation of UDP. We optimized the assay such that it could be used for high-throughput screening of substrates of the UGT enzyme, UGT71G1, and our results show that 34 of the 159 screened compound samples are potential substrates. With an LC-MS/MS method, we confirmed that three of these candidates indeed were glycosylated by UGT71G1, which includes bisphenol A (BPA) and 7-Ethyl-10-hydroxycamptothecin (SN-38); derivatization of these toxic compounds can lead to new environmental and medical applications. This work suggests that UGT homologs may recognize a substrate profile that is much broader than previously anticipated. Additionally, it demonstrates that this screening method provides a new means to study UDP-glycosyltransferases, facilitating the use of these enzymes to tackle a wide range of problems.
Topics: Glycosyltransferases; Chromatography, Liquid; Tandem Mass Spectrometry; Plants; Uridine Diphosphate
PubMed: 38473971
DOI: 10.3390/ijms25052725 -
MBio Apr 2024Multidrug-resistant bacteria such as the opportunistic pathogen , which causes life-threatening infections especially in immunocompromised individuals and cystic...
Multidrug-resistant bacteria such as the opportunistic pathogen , which causes life-threatening infections especially in immunocompromised individuals and cystic fibrosis patients, pose an increasing threat to public health. In the search for new treatment options, uridine diphosphate-glucose pyrophosphorylase (PaUGP) has been proposed as a novel drug target because it is required for the biosynthesis of important virulence factors and linked to pathogenicity in animal models. Here, we show that UGP-deficient exhibits severely reduced virulence against human lung tissue and cells, emphasizing the enzyme's suitability as a drug target. To establish a basis for the development of selective PaUGP inhibitors, we solved the product-bound crystal structure of tetrameric PaUGP and conducted a comprehensive structure-function analysis, identifying key residues at two different molecular interfaces that are essential for tetramer integrity and catalytic activity and demonstrating that tetramerization is pivotal for PaUGP function. Importantly, we show that part of the PaUGP oligomerization interface is uniquely conserved across bacterial UGPs but does not exist in the human enzyme, therefore representing an allosteric site that may be targeted to selectively inhibit bacterial UGPs.IMPORTANCEInfections with the opportunistic bacterial pathogen are becoming increasingly difficult to treat due to multidrug resistance. Here, we show that the enzyme uridine diphosphate-glucose pyrophosphorylase (UGP) is involved in virulence toward human lung tissue and cells, making it a potential target for the development of new antibacterial drugs. Our exploration of (Pa)UGP structure-function relationships reveals that the activity of PaUGP depends on the formation of a tetrameric enzyme complex. We found that a molecular interface involved in tetramer formation is conserved in all bacterial UGPs but not in the human enzyme, and therefore hypothesize that it provides an ideal point of attack to selectively inhibit bacterial UGPs and exploit them as drug targets.
Topics: Animals; Humans; Virulence Factors; Pseudomonas aeruginosa; Anti-Bacterial Agents; Pseudomonas Infections; Glucose; Uridine Diphosphate
PubMed: 38470050
DOI: 10.1128/mbio.02114-23