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Saudi Journal of Kidney Diseases and... Nov 2023Patients with end-stage renal disease (ESRD) are at an increased risk of hepatitis C virus (HCV) infection. This study evaluated the prevalence of HCV infection in...
Prevalence of Hepatitis C Virus Infection and Efficacy of Sofosbuvir-Velpatasvir and Sofosbuvir-Daclatasvir Treatment Regimens in End-stage Renal Disease Patients on Maintenance Hemodialysis.
Patients with end-stage renal disease (ESRD) are at an increased risk of hepatitis C virus (HCV) infection. This study evaluated the prevalence of HCV infection in patients with ESRD on maintenance hemodialysis (MHD) and studied the effectiveness of sofosbuvir-velpatasvir and sofosbuvir-daclatasvir regimens in these patients. This study included patients with ESRD on MHD between January 2019 and December 2021 who were screened for HCV serology status. HCV-positive patients received sofosbuvir-velpatasvir or sofosbuvir-daclatasvir. Efficacy was assessed by the sustained virological response (SVR), and safety assessments included monitoring adverse events and laboratory parameters. Out of 1330 patients, 188 patients (14.1%) were positive for anti-HCV, with Genotype 1 being the most common genotype. Of these, 106 patients were included. The majority were males (61.3%), and the mean age was 48.4 years. Hypertension (45.3%) was the most common cause of renal failure, followed by diabetes (31.1%). Most patients (63.2%) were positive for HCV in the first 2 years of their dialysis treatment. Out of 106 patients, only 54 had received blood transfusions. Ninety-four (88.7%) patients received sofosbuvir-velpatasvir, whereas 12 (11.3%) received sofosbuvir-daclatasvir. SVR at 12 and 24 weeks after stopping treatment was seen in all (100%) patients. Asthenia and fatigue were the most common adverse events (11.2%). No patients reported on-treatment virologic failure or discontinuation of treatment because of adverse events. The prevalence of HCV infection in this population was 14.1%, and treatment of HCV infection using sofosbuvir-velpatasvir or sofosbuvir-daclatasvir regimens was well tolerated and effective.
Topics: Humans; Male; Female; Middle Aged; Sofosbuvir; Imidazoles; Renal Dialysis; Kidney Failure, Chronic; Carbamates; Valine; Pyrrolidines; Antiviral Agents; Heterocyclic Compounds, 4 or More Rings; Drug Combinations; Adult; Prevalence; Treatment Outcome; Hepatitis C; Aged; Hepacivirus; Sustained Virologic Response; Saudi Arabia; Hepatitis C, Chronic
PubMed: 38725207
DOI: 10.4103/sjkdt.sjkdt_19_23 -
Nucleic Acids Research Jun 2024In recent years, several noncanonical RNA caps derived from cofactors and metabolites have been identified. Purine-containing RNA caps have been extensively studied,...
In recent years, several noncanonical RNA caps derived from cofactors and metabolites have been identified. Purine-containing RNA caps have been extensively studied, with multiple decapping enzymes identified and efficient capture and sequencing protocols developed for nicotinamide adenine dinucleotide (NAD)-RNA, which allowed for a stepwise elucidation of capping functions. Despite being identified as an abundant noncanonical RNA-cap, UDP-sugar-capped RNA remains poorly understood, which is partly due to its complex in vitro preparation. Here, we describe a scalable synthesis of sugar-capped uridine-guanosine dinucleotides from readily available protected building blocks and their enzymatic conversion into several cell wall precursor-capped dinucleotides. We employed these capped dinucleotides in T7 RNA polymerase-catalyzed in vitro transcription reactions to efficiently generate RNAs capped with uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), its N-azidoacetyl derivative UDP-GlcNAz, and various cell wall precursors. We furthermore identified four enzymes capable of processing UDP-GlcNAc-capped RNA in vitro: MurA, MurB and MurC from Escherichia coli can sequentially modify the sugar-cap structure and were used to introduce a bioorthogonal, clickable moiety, and the human Nudix hydrolase Nudt5 was shown to efficiently decap UDP-GlcNAc-RNA. Our findings underscore the importance of efficient synthetic methods for capped model RNAs. Additionally, we provide useful enzymatic tools that could be utilized in the development and application of UDP-GlcNAc capture and sequencing protocols. Such protocols are essential for deepening our understanding of the widespread yet enigmatic GlcNAc modification of RNA and its physiological significance.
Topics: Uridine Diphosphate N-Acetylglucosamine; RNA Caps; Endoribonucleases; DNA-Directed RNA Polymerases; Humans; Escherichia coli; Viral Proteins
PubMed: 38716860
DOI: 10.1093/nar/gkae353 -
Journal of Drugs in Dermatology : JDD May 2024This study aimed to investigate the ultraviolet (UV) protection/repair benefits of a patented Amino Acid Complex (AAComplex).
OBJECTIVE
This study aimed to investigate the ultraviolet (UV) protection/repair benefits of a patented Amino Acid Complex (AAComplex).
METHODS
I) AAComplex was incubated with dermal fibroblasts, with/without UVA, and collagen I was measured with a GlasBoxPlus device. II) A lotion, with/without AAComplex (1%) was applied topically to skin explants, following UVA irradiation, and quantified for health-related biomarkers (TNFalpha, histamine, and MMP-1). III) A broad spectrum sunscreen with SPF 46 and a skincare serum containing AAComplex (2%) were assessed using epidermal equivalents, in the presence of UV irradiation, for effects on IL-1alpha, thymine dimers, Ki-67, filaggrin and Nrf2.
RESULTS
I) Collagen I synthesis in dermal fibroblasts was significantly decreased after UVA compared to without UV. The presence of AAComplex prevented this decrease. II) UVA irradiation of skin explants increased histamine, TNFα, and MMP-1. Hydrocortisone aceponate cream significantly decreases all 3 biomarkers. AAComplex contained lotion also significantly decreased all 3 biomarkers, the no AAComplex control lotion only reduced histamine. III) With the regimen of sunscreen + AAComplex contained skincare serum, the significant reduction in IL-1alpha was observed along with a complete recovery of Ki-67 and stimulation of filaggrin and Nrf2T. No thymine dimer positive cell was observed indicating the most positive skin impact from the regiment. Conclusion: This research using different human skin models demonstrated that AAComplex can provide protection and damage repair caused by UV, at the ingredient level also when formulated in a serum or lotion formula. Skin may be best protected from UV damage when the regimen is used. J Drugs Dermatol. 2024;23(5):366-375. doi:10.36849/JDD.7916.
Topics: Humans; Filaggrin Proteins; Ultraviolet Rays; Fibroblasts; Matrix Metalloproteinase 1; Tumor Necrosis Factor-alpha; Skin; Sunscreening Agents; Amino Acids; Interleukin-1alpha; Histamine; Skin Cream; Biomarkers; Collagen Type I; Intermediate Filament Proteins; Ki-67 Antigen; Pyrimidine Dimers; Cells, Cultured; NF-E2-Related Factor 2
PubMed: 38709706
DOI: 10.36849/JDD.7916 -
Advances in Therapy Jun 2024This study aimed to investigate the tolerability of high-viscosity diquafosol tetrasodium (DQS) ophthalmic solution (DIQUAS LX; DQSLX) and examine its usability and...
INTRODUCTION
This study aimed to investigate the tolerability of high-viscosity diquafosol tetrasodium (DQS) ophthalmic solution (DIQUAS LX; DQSLX) and examine its usability and effect on clinical findings in patients with dry eye disease (DED).
METHODS
This interventional retrospective study included 66 eyes of 66 patients with DED who switched from conventional DQS to DQSLX ophthalmic solution. Tear function assessments (tear film breakup time [BUT], keratoconjunctival vital staining [VS] score), evaluations of DED symptom relief, and a four-item usability questionnaire ("comfort upon instillation," "irritation upon instillation," "eye mucus discharge," "convenience of instillation frequency") assessed using a visual analog scale from 0 (worst) to 10 (best) were administered 4 weeks after switching to DQSLX. Factors associated with drug tolerability were assessed using multiple regression analysis.
RESULTS
The symptoms improved by 64.2% after switching to DQSLX. The BUT value, VS score, and the questionnaire items "comfort upon instillation" and "convenience of instillation frequency" were significantly improved after switching to DQSLX. DQSLX tolerability was reported as acceptable in 56 (84.8%) and unacceptable in 10 (15.2%) patients. Overall, DQSLX tolerability was significantly associated with "comfort upon instillation" and "convenience of instillation frequency" and tended to be associated with a VS score ≥ 1. DQSLX tolerability depended on symptom and VS score improvements and absence of excessive "eye mucus discharge" in patients with a VS score ≥ 1 (39 patients), but on "comfort upon instillation" and absence of excessive "eye mucus discharge" in patients with a VS score = 0 (27 patients).
CONCLUSION
The high-viscosity DQSLX ophthalmic solution was generally considered acceptable in the study population. However, drug tolerability seemingly differed between patients with DED with and without epithelial damage. The former were affected by improvements in symptoms and clinical findings, whereas the latter were affected by comfort upon instillation.
TRIAL REGISTRATION
University Hospital Medical Information Network identifier, UMIN000051390.
Topics: Humans; Dry Eye Syndromes; Male; Female; Uracil Nucleotides; Ophthalmic Solutions; Middle Aged; Retrospective Studies; Aged; Polyphosphates; Tears; Adult; Delayed-Action Preparations; Treatment Outcome; Surveys and Questionnaires
PubMed: 38709396
DOI: 10.1007/s12325-024-02871-4 -
Scientific Reports May 2024Access to Hepatis C treatment in Sub-Saharan Africa is a clinical, public health and ethical concern. The multi-country open-label trial TAC ANRS 12311 allowed assessing... (Clinical Trial)
Clinical Trial
Access to Hepatis C treatment in Sub-Saharan Africa is a clinical, public health and ethical concern. The multi-country open-label trial TAC ANRS 12311 allowed assessing the feasibility, safety, efficacy of a specific care model of HCV treatment and retreatment in patients with hepatitis C in Sub Saharan Africa. Between November 2015 and March 2017, with follow-up until mid 2019, treatment-naïve patients with HCV without decompensated cirrhosis or liver cancer were recruited to receive 12 week-treatment with either sofosbuvir + ribavirin (HCV genotype 2) or sofosbuvir + ledipasvir (genotype 1 or 4) and retreatment with sofosbuvir + velpatasvir + voxilaprevir in case of virological failure. The primary outcome was sustained virological response at 12 weeks after end of treatment (SVR12). Secondary outcomes included treatment adherence, safety and SVR12 in patients who were retreated due to non-response to first-line treatment. The model of care relied on both viral load assessment and educational sessions to increase patient awareness, adherence and health literacy. The study recruited 120 participants, 36 HIV-co-infected, and 14 cirrhotic. Only one patient discontinued treatment because of return to home country. Neither death nor severe adverse event occurred. SVR12 was reached in 107 patients (89%): (90%) in genotype 1 or 2, and 88% in GT-4. All retreated patients (n = 13) reached SVR12. HCV treatment is highly acceptable, safe and effective under this model of care. Implementation research is now needed to scale up point-of-care HCV testing and SVR assessment, along with community involvement in patient education, to achieve HCV elimination in Sub-Saharan Africa.
Topics: Adult; Female; Humans; Male; Middle Aged; Africa, Central; Africa, Western; Aminoisobutyric Acids; Antiviral Agents; Benzimidazoles; Benzopyrans; Carbamates; Cyclopropanes; Drug Therapy, Combination; Feasibility Studies; Fluorenes; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Heterocyclic Compounds, 4 or More Rings; Lactams, Macrocyclic; Leucine; Proline; Quinoxalines; Ribavirin; Sofosbuvir; Sulfonamides; Sustained Virologic Response; Treatment Outcome
PubMed: 38702350
DOI: 10.1038/s41598-024-57013-1 -
The Journal of Physical Chemistry. B May 2024Resistance to available antibiotics poses a growing challenge to modern medicine, as this often disallows infections to be controlled. This problem can only be...
Resistance to available antibiotics poses a growing challenge to modern medicine, as this often disallows infections to be controlled. This problem can only be alleviated by the development of new drugs. Nisin, a natural lantibiotic with broad antimicrobial activity, has shown promise as a potential candidate for combating antibiotic-resistant bacteria. However, nisin is poorly soluble and barely stable at physiological pH, which despite attempts to address these issues through mutant design has restricted its use as an antibacterial drug. Therefore, gaining a deeper understanding of the antimicrobial effectiveness, which relies in part on its ability to form pores, is crucial for finding innovative ways to manage infections caused by resistant bacteria. Using large-scale molecular dynamics simulations, we find that the bacterial membrane-specific lipid II increases the stability of pores formed by nisin and that the interplay of nisin and lipid II reduces the overall integrity of bacterial membranes by changing the local thickness and viscosity.
Topics: Nisin; Molecular Dynamics Simulation; Uridine Diphosphate N-Acetylmuramic Acid; Anti-Bacterial Agents; Cell Membrane; Lipid Bilayers
PubMed: 38696215
DOI: 10.1021/acs.jpcb.4c01249 -
Alimentary Pharmacology & Therapeutics Jul 2024Sofosbuvir, velpatasvir and voxilaprevir (SOF/VEL/VOX) is the recommended rescue therapy for patients with chronic hepatitis C infection who fail direct-acting...
BACKGROUND
Sofosbuvir, velpatasvir and voxilaprevir (SOF/VEL/VOX) is the recommended rescue therapy for patients with chronic hepatitis C infection who fail direct-acting antivirals (DAAs). Data are limited on the effectiveness of this treatment after the current first-line therapies. Our aim was to analyse the effectiveness and safety of SOF/VEL/VOX among patients failing sofosbuvir/velpatasvir (SOF/VEL) or glecaprevir/pibrentasvir (GLE/PIB).
METHODS
Retrospective multicentre study (26 Spanish hospitals), including chronic hepatitis C patients unsuccessfully treated with SOF/VEL or GLE/PIB, and retreated with SOF/VEL/VOX ± ribavirin for 12 weeks between December 2017 and December 2022.
RESULTS
In total, 142 patients included: 100 (70.4%) had failed SOF/VEL and 42 (29.6%) GLE/PIB. Patients were mainly men (84.5%), White (93.9%), with hepatitis C virus genotype (GT) 3 (49.6%) and 47.2% had liver cirrhosis. Sustained virological response (SVR) was evaluated in 132 patients who completed SOF/VEL/VOX and were followed 12 weeks after end of treatment; 117 (88.6%) achieved SVR. There were no significant differences in SVR rates according to initial DAA treatment (SOF/VEL 87.9% vs. GLE/PIB 90.2%, p = 0.8), cirrhosis (no cirrhosis 90% vs. cirrhosis 87.1%, p = 0.6) or GT3 infection (non-GT3 91.9% vs. GT3 85.5%, p = 0.3). However, when considering the concurrent presence of SOF/VEL treatment, cirrhosis and GT3 infection, SVR rates dropped to 82.8%. Ribavirin was added in 8 (6%) patients, all achieved SVR.
CONCLUSION
SOF/VEL/VOX is an effective rescue therapy for failures to SOF/VEL or GLE/PIB, with an SVR of 88.6%. Factors previously linked to lower SVR rates, such as GT3 infection, cirrhosis and first-line therapy with SOF/VEL were not associated with lower SVRs.
Topics: Humans; Male; Female; Hepatitis C, Chronic; Heterocyclic Compounds, 4 or More Rings; Antiviral Agents; Sofosbuvir; Carbamates; Middle Aged; Retrospective Studies; Sulfonamides; Benzimidazoles; Quinoxalines; Aminoisobutyric Acids; Proline; Cyclopropanes; Aged; Sustained Virologic Response; Pyrrolidines; Lactams, Macrocyclic; Drug Combinations; Leucine; Drug Therapy, Combination; Treatment Outcome; Hepacivirus; Benzopyrans
PubMed: 38695095
DOI: 10.1111/apt.18020 -
The Journal of Physical Chemistry. B May 2024This study elucidated the mechanism of formation of a tripartite complex containing daptomycin (Dap), lipid II, and phospholipid phosphatidylglycerol in the bacterial...
This study elucidated the mechanism of formation of a tripartite complex containing daptomycin (Dap), lipid II, and phospholipid phosphatidylglycerol in the bacterial septum membrane, which was previously reported as the cause of the antibacterial action of Dap against gram-positive bacteria via molecular dynamics and enhanced sampling methods. Others have suggested that this transient complex ushers in the inhibition of cell wall synthesis by obstructing the downstream polymerization and cross-linking processes involving lipid II, which is absent in the presence of cardiolipin lipid in the membrane. In this work, we observed that the complex was stabilized by Ca-mediated electrostatic interactions between Dap and lipid head groups, hydrophobic interaction, hydrogen bonds, and salt bridges between the lipopeptide and lipids and was associated with Dap concentration-dependent membrane depolarization, thinning of the bilayer, and increased lipid tail disorder. Residues Orn6 and Kyn13, along with the DXDG motif, made simultaneous contact with constituent lipids, hence playing a crucial role in the formation of the complex. Incorporating cardiolipin into the membrane model led to its competitively displacing lipid II away from the Dap, reducing the lifetime of the complex and the nonexistence of lipid tail disorder and membrane depolarization. No evidence of water permeation inside the membrane hydrophobic interior was noted in all of the systems studied. Additionally, it was shown that using hydrophobic contacts between Dap and lipids as collective variables for enhanced sampling gave rise to a free energy barrier for the translocation of the lipopeptide. A better understanding of Dap's antibacterial mechanism, as studied through this work, will help develop lipopeptide-based antibiotics for rising Dap-resistant bacteria.
Topics: Daptomycin; Anti-Bacterial Agents; Phospholipids; Molecular Dynamics Simulation; Uridine Diphosphate N-Acetylmuramic Acid; Cell Membrane; Phosphatidylglycerols; Hydrophobic and Hydrophilic Interactions; Cardiolipins
PubMed: 38690887
DOI: 10.1021/acs.jpcb.4c00332 -
Proceedings of the National Academy of... May 2024Phytophagous insects have evolved sophisticated detoxification systems to overcome the antiherbivore chemical defenses produced by many plants. However, how these...
Phytophagous insects have evolved sophisticated detoxification systems to overcome the antiherbivore chemical defenses produced by many plants. However, how these biotransformation systems differ in generalist and specialist insect species and their role in determining insect host plant range remains an open question. Here, we show that UDP-glucosyltransferases (UGTs) play a key role in determining the host range of insect species within the genus. Comparative genomic analyses of species that differ in host plant breadth identified a relatively conserved number of UGT genes in generalist species but high levels of UGT gene pseudogenization in the specialist . CRISPR-Cas9 knockouts of the three main UGT gene clusters of revealed that UGT33 genes play an important role in allowing this species to utilize the poaceous plants maize, wheat, and rice, while UGT40 genes facilitate utilization of cotton. Further functional analyses in vivo and in vitro identified the UGT SfUGT33F32 as the key mechanism that allows generalist to detoxify the benzoxazinoid DIMBOA (2,4-dihydroxy-7-methoxy-2H-1,4-benzoxazin-3(4H)-one), a potent insecticidal phytotoxin produced by poaceous plants. However, while this detoxification capacity is conserved in several generalist species, , which specializes on plants, is unable to detoxify DIMBOA due to a nonfunctionalizing mutation in . Collectively, these findings provide insight into the role of insect UGTs in host plant adaptation, the mechanistic basis of evolutionary transitions between generalism and specialism and offer molecular targets for controlling a group of notorious insect pests.
Topics: Animals; Spodoptera; Glycosyltransferases; Host Specificity; Uridine Diphosphate; Insect Proteins; Phylogeny
PubMed: 38683998
DOI: 10.1073/pnas.2402045121 -
The Plant Journal : For Cell and... Jul 2024L-Arabinose (L-Ara) is a plant-specific sugar found in cell wall polysaccharides, proteoglycans, glycoproteins, and small glycoconjugates, which play physiologically...
L-Arabinose (L-Ara) is a plant-specific sugar found in cell wall polysaccharides, proteoglycans, glycoproteins, and small glycoconjugates, which play physiologically important roles in cell proliferation and other essential cellular processes. L-Ara is synthesized as UDP-L-arabinose (UDP-L-Ara) from UDP-xylose (UDP-Xyl) by UDP-Xyl 4-epimerases (UXEs), a type of de novo synthesis of L-Ara unique to plants. In Arabidopsis, the Golgi-localized UXE AtMUR4 is the main contributor to UDP-L-Ara synthesis. However, cytosolic bifunctional UDP-glucose 4-epimerases (UGEs) with UXE activity, AtUGE1, and AtUGE3 also catalyze this reaction. For the present study, we first examined the physiological importance of bifunctional UGEs in Arabidopsis. The uge1 and uge3 mutants enhanced the dwarf phenotype of mur4 and further reduced the L-Ara content in cell walls, suggesting that bifunctional UGEs contribute to UDP-L-Ara synthesis. Through the introduction of point mutations exchanging corresponding amino acid residues between AtUGE1 with high UXE activity and AtUGE2 with low UXE activity, two mutations that increase relative UXE activity of AtUGE2 were identified. The crystal structures of AtUGE2 in complex forms with NAD and NAD/UDP revealed that the UDP-binding domain of AtUGE2 has a more closed conformation and smaller sugar-binding site than bacterial and mammalian UGEs, suggesting that plant UGEs have the appropriate size and shape for binding UDP-Xyl and UDP-L-Ara to exhibit UXE activity. The presented results suggest that the capacity for cytosolic synthesis of UDP-L-Ara was acquired by the small sugar-binding site and several mutations of UGEs, enabling diversified utilization of L-Ara in seed plants.
Topics: Arabidopsis; Arabidopsis Proteins; Cytosol; Uridine Diphosphate Sugars; Cell Wall; UDPglucose 4-Epimerase; Mutation; Uridine Diphosphate Xylose
PubMed: 38678521
DOI: 10.1111/tpj.16779