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BMC Pediatrics Jun 2024Preterm born infants are at risk for brain injury and subsequent developmental delay. Treatment options are limited, but optimizing postnatal nutrition may improve... (Randomized Controlled Trial)
Randomized Controlled Trial
Dolphin CONTINUE: a multi-center randomized controlled trial to assess the effect of a nutritional intervention on brain development and long-term outcome in infants born before 30 weeks of gestation.
BACKGROUND
Preterm born infants are at risk for brain injury and subsequent developmental delay. Treatment options are limited, but optimizing postnatal nutrition may improve brain- and neurodevelopment in these infants. In pre-clinical animal models, combined supplementation of docosahexaenoic acid (DHA), choline, and uridine-5-monophosphate (UMP) have shown to support neuronal membrane formation. In two randomized controlled pilot trials, supplementation with the investigational product was associated with clinically meaningful improvements in cognitive, attention, and language scores. The present study aims to assess the effect of a similar nutritional intervention on brain development and subsequent neurodevelopmental outcome in infants born very and extremely preterm.
METHODS
This is a randomized, placebo-controlled, double-blinded, parallel-group, multi-center trial. A total of 130 infants, born at less than 30 weeks of gestation, will be randomized to receive a test or control product between term-equivalent age and 12 months corrected age (CA). The test product is a nutrient blend containing DHA, choline, and UMP amongst others. The control product contains only fractions of the active components. Both products are isocaloric powder supplements which can be added to milk and solid feeds. The primary outcome parameter is white matter integrity at three months CA, assessed using diffusion-tensor imaging (DTI) on MRI scanning. Secondary outcome parameters include volumetric brain development, cortical thickness, cortical folding, the metabolic and biochemical status of the brain, and product safety. Additionally, language, cognitive, motor, and behavioral development will be assessed at 12 and 24 months CA, using the Bayley Scales of Infant Development III and digital questionnaires (Dutch version of the Communicative Development Inventories (N-CDI), Ages and Stages Questionnaire 4 (ASQ-4), and Parent Report of Children's Abilities - Revised (PARCA-R)).
DISCUSSION
The investigated nutritional intervention is hypothesized to promote brain development and subsequent neurodevelopmental outcome in preterm born infants who have an inherent risk of developmental delay. Moreover, this innovative study may give rise to new treatment possibilities and improvements in routine clinical care.
TRIAL REGISTRATION
WHO International Clinical Trials Registry: NL-OMON56181 (registration assigned October 28, 2021).
Topics: Humans; Brain; Infant, Newborn; Choline; Double-Blind Method; Docosahexaenoic Acids; Dietary Supplements; Uridine Monophosphate; Infant; Child Development; Infant, Extremely Premature; Infant, Premature; Randomized Controlled Trials as Topic
PubMed: 38849784
DOI: 10.1186/s12887-024-04849-1 -
Nucleic Acids Research Jun 2024We present the nuclear magnetic resonance spectroscopy (NMR) solution structure of the 5'-terminal stem loop 5_SL1 (SL1) of the SARS-CoV-2 genome. SL1 contains two...
We present the nuclear magnetic resonance spectroscopy (NMR) solution structure of the 5'-terminal stem loop 5_SL1 (SL1) of the SARS-CoV-2 genome. SL1 contains two A-form helical elements and two regions with non-canonical structure, namely an apical pyrimidine-rich loop and an asymmetric internal loop with one and two nucleotides at the 5'- and 3'-terminal part of the sequence, respectively. The conformational ensemble representing the averaged solution structure of SL1 was validated using NMR residual dipolar coupling (RDC) and small-angle X-ray scattering (SAXS) data. We show that the internal loop is the major binding site for fragments of low molecular weight. This internal loop of SL1 can be stabilized by an A12-C28 interaction that promotes the transient formation of an A+•C base pair. As a consequence, the pKa of the internal loop adenosine A12 is shifted to 5.8, compared to a pKa of 3.63 of free adenosine. Furthermore, applying a recently developed pH-differential mutational profiling (PD-MaP) approach, we not only recapitulated our NMR findings of SL1 but also unveiled multiple sites potentially sensitive to pH across the 5'-UTR of SARS-CoV-2.
PubMed: 38842942
DOI: 10.1093/nar/gkae477 -
Antiviral Research Jul 2024Hepatitis E is an underestimated disease, leading to estimated 20 million infections and up to 70,000 deaths annually. Infections are mostly asymptomatic, but can reach...
Hepatitis E is an underestimated disease, leading to estimated 20 million infections and up to 70,000 deaths annually. Infections are mostly asymptomatic, but can reach mortality rates up to 25% in pregnant women or become chronic in immunocompromised patients. Hepatitis E virus (HEV) infection have been associated with a range of extrahepatic manifestations, including a spectrum of neurological symptoms. Current therapy options are limited to non-specific antivirals like ribavirin, but recently, repurposed viral polymerase inhibitors like sofosbuvir and NITD008 were described to inhibit HEV replication. Here, we evaluated the efficacy of these drugs in various neuronal-derived cell lines to determine their potency outside the liver. Our findings indicate that both drugs, especially sofosbuvir, exhibited reduced efficacy in neuronal cells compared to hepatic cells. These results should be taken into account in the development of direct-acting antivirals for HEV and their potency at extrahepatic replication sites.
Topics: Sofosbuvir; Antiviral Agents; Humans; Hepatitis E virus; Virus Replication; Neurons; Cell Line; Hepatitis E; Adenosine
PubMed: 38825018
DOI: 10.1016/j.antiviral.2024.105922 -
International Journal of Medical... 2024Citicoline can be used to reduce acute ischemic stroke injury via venous infusion, however, its protective effects in the brain extracellular space remain largely...
Citicoline can be used to reduce acute ischemic stroke injury via venous infusion, however, its protective effects in the brain extracellular space remain largely unknown. Herein, we investigated the brain protective effects of citicoline administered via the brain extracellular space and sought precise effective dosage range that can protect against ischemic injury after experimental ischemic stroke in rats. : Fifty-six Sprague-Dawley rats were randomly divided into control, intraperitoneal (IP), caudate-putamen (CPu)-25, CPu-40, CPu-50, CPu-60 and CPu-75 groups based on the infusion site and concentration of citicoline. Two hours after the administration of citicoline, the rats were subjected to a permanent middle cerebral artery occlusion to mimic acute ischemic stroke. Then, the brain infarct volume in rats after stroke was measured and their neurological deficiency was evaluated to explain the protective effects and effective dosage range of citicoline. Compared to the control and IP groups, brain infarct volume of rats in CPu-40, CPu-50, and CPu-60 groups is significant smaller. Furthermore, the brain infarct volume of rats in CPu-50 is the least. Here, we showed that citicoline can decrease the brain infarct volume, thus protecting the brain from acute ischemic stroke injury. We also found that the appropriate effective citicoline dose delivered via the brain extracellular space is 50 mM. Our study provides novel insights into the precise treatment of acute ischemic stroke by citicoline via the brain extracellular space, further guiding the treatment of brain disease.
Topics: Animals; Cytidine Diphosphate Choline; Rats; Ischemic Stroke; Disease Models, Animal; Extracellular Space; Male; Rats, Sprague-Dawley; Brain; Neuroprotective Agents; Humans; Infarction, Middle Cerebral Artery; Brain Ischemia
PubMed: 38818467
DOI: 10.7150/ijms.93482 -
World Journal of Hepatology May 2024Metabolic-dysfunction associated steatotic liver disease (MASLD) is a hepatic manifestation of metabolic syndrome. Studies suggest ornithine aspartate (LOLA) as drug...
BACKGROUND
Metabolic-dysfunction associated steatotic liver disease (MASLD) is a hepatic manifestation of metabolic syndrome. Studies suggest ornithine aspartate (LOLA) as drug therapy.
AIM
To analyze the influence of LOLA intake on gut microbiota using a nutritional model of MASLD.
METHODS
Adult male Sprague Dawley rats were randomized into three groups: Control (10 rats fed with a standard diet), MASLD (10 rats fed with a high-fat and choline-deficient diet), and LOLA (10 rats receiving 200 mg/kg/d LOLA, after the 16 week receiving high-fat and choline-deficient diet). After 28 wk of the experiment, animals were euthanized, and feces present in the intestine were collected. Following fecal DNA extraction, the V4 region of the 16S rRNA gene was amplified followed by sequencing in an Ion S5™ system.
RESULTS
Alpha and beta diversity metrics were comparable between MASLD and LOLA. 3 OTUs were differentially abundant between MASLD and LOLA, which belong to the species , , and . The functional prediction provided two different metabolic profiles between MASLD and LOLA. The 9 pathways differentially abundant in MASLD are related to a change in energy source, adenosine/purine nucleotides degradation as well as guanosine and adenosine deoxyribonucleotides biosynthesis. The 14 pathways differentially abundant in LOLA are associated with four major metabolic functions primarily influenced by L-aspartate, including tricarboxylic acid cycle pathways, purine/guanosine nucleotides biosynthesis, pyrimidine ribonucleotides biosynthesis and salvage as well as lipid IVA biosynthesis.
CONCLUSION
Although LOLA had no influence on alpha and beta diversity in this nutritional model of MASLD, it was associated with changes in specific gut microbes and their related metabolic pathways.
PubMed: 38818297
DOI: 10.4254/wjh.v16.i5.832 -
Nucleosides, Nucleotides & Nucleic Acids May 2024In this communication, an innovative and straightforward protocol for the one-pot catalytic synthesis of bis(indolyl)pyrimidine derivatives and their DNA binding...
Investigation of bisindole-linked pyrimidine moieties: synthesis using strantium-aluminum supported strontium aluminate nanophosphors catalyst, DNA reactivity, and molecular docking studies.
In this communication, an innovative and straightforward protocol for the one-pot catalytic synthesis of bis(indolyl)pyrimidine derivatives and their DNA binding abilities is presented. The synthesis involves the condensation of indole with diverse substituted pyrimidine-5-carbaldehydes, employing cost-effective and reusable Sr-Al supported nanophosphors, specifically strontium aluminate (SrAlO), as a catalyst. In particular, this method does not require the use of toxic solvents. The Sr-Al supported nanophosphorus catalyst exhibited sustained activity over multiple cycles and showed no significant decline while maintaining its strictly heterogeneous properties. The bis(indolyl)pyrimidine derivatives were extensively characterized using spectroscopic and analytical techniques. Furthermore, the interaction between these derivatives and CT-DNA was investigated by absorption spectroscopy, viscosity measurement, and molecular docking studies. Photoinduced cleavage studies demonstrated the photonuclease activity of the compound against pUC19 DNA upon exposure to UV-visible radiation.
PubMed: 38817089
DOI: 10.1080/15257770.2024.2358901 -
Haematologica May 2024T-cell acute lymphoblastic leukemia (T-ALL) is a cancer of the immune system. Approximately 20% of paediatric and 50% of adult T-ALL patients have refractory disease or...
T-cell acute lymphoblastic leukemia (T-ALL) is a cancer of the immune system. Approximately 20% of paediatric and 50% of adult T-ALL patients have refractory disease or relapse and die from the disease. To improve patient outcome new therapeutics are needed. With the aim to identify new therapeutic targets, we combined the analysis of T-ALL gene expression and metabolism to identify the metabolic adaptations that T-ALL cells exhibit. We found that glutamine uptake is essential for T-ALL proliferation. Isotope tracing experiments showed that glutamine fuels aspartate synthesis through the TCA cycle and that glutamine and glutamine-derived aspartate together supply three nitrogen atoms in purines and all but one atom in pyrimidine rings. We show that the glutamate-aspartate transporter EAAT1 (SLC1A3), which is normally expressed in the central nervous system, is crucial for glutamine conversion to aspartate and nucleotides and that T-ALL cell proliferation depends on EAAT1 function. Through this work, we identify EAAT1 as a novel therapeutic target for T-ALL treatment.
PubMed: 38813748
DOI: 10.3324/haematol.2023.283471 -
Analytical Chemistry Jun 2024It is the scientific basis of precision medicine to study all of the targets of drugs based on the interaction between drugs and proteins. It is worth paying attention...
It is the scientific basis of precision medicine to study all of the targets of drugs based on the interaction between drugs and proteins. It is worth paying attention to unknown proteins that interact with drugs to find new targets for the design of new drugs. Herein, we developed a protein profiling strategy based on drug-protein interactions and drug-modified magnetic nanoparticles and took hepatitis C virus (HCV) and its corresponding drug sofosbuvir (SOF) as an example. A SOF-modified magnetic separation medium (FeO@POSS@SOF) was prepared, and a gradient elution strategy was employed and optimized to profile specific proteins interacted with SOF. A series of proteomic analyses were performed to profile proteins based on SOF-protein interactions (SPIs) in the serum of HCV patients to evaluate the specificity of the profiling strategy. As a result, five proteins were profiled with strong SPIs and exhibited high relevance with liver tissue, which were potentially new drug targets. Among them, HSP60 was used to confirm the highly specific interactions between the SOF and its binding proteins by Western blotting analysis. Besides, 124 and 29 differential proteins were profiled by SOF material from three HCV patient serum and pooled 20 HCV patient serum, respectively, by comparing with healthy human serum. In comparison with those profiled by the polyhedral oligomeric silsesquioxane (POSS) material, differential proteins profiled by the SOF material were highly associated with liver diseases through GO analysis and pathway analysis. Furthermore, four common differential proteins profiled by SOF material but not by POSS material were found to be identical and expressed consistently in both pooled serum samples and independent serum samples, which might potentially be biomarkers of HCV infection. Taken together, our study proposes a highly specific protein profiling strategy to display distinctive proteomic profiles, providing a novel idea for drug design and development.
Topics: Humans; Sofosbuvir; Hepacivirus; Antiviral Agents; Hepatitis C; Magnetite Nanoparticles; Proteomics; Blood Proteins
PubMed: 38804236
DOI: 10.1021/acs.analchem.4c00993 -
Infectious Diseases of Poverty May 2024Migrants, mainly undocumented and low-income refugees, are at high risk of hepatitis C virus (HCV) infection, but are a difficult-to-reach and to-treat population. The...
BACKGROUND
Migrants, mainly undocumented and low-income refugees, are at high risk of hepatitis C virus (HCV) infection, but are a difficult-to-reach and to-treat population. The aim of the study was to evaluate the effectiveness of a test and treat model with direct-acting antiviral for HCV infection in these migrants coming from low-income and living in southern Italy.
METHODS
A prospective, multicenter, collaborative study based on a four-phase-program (educational counseling, screening, linkage-to-care and treatment) was designed in southern Italy; the study started in June 2018, was stopped in February 2020 because of the outbreak of SARS-CoV2 infection in Italy and was resumed in February 2021 until November 2021. After educational counseling on infectious diseases that are transmitted through blood or sexually pseudonymized HCV screening was offered to all undocumented migrants and low-income refugees observed at one of the 1st level clinical centers. The HCV-RNA-positive subjects were referred to one of the 3rd level units of Infectious Diseases (ID) and treated with a 12-week course of sofosbuvir-velpatasvir and observed for 12 weeks after the end of direct antiviral agents (DAA) treatment.
STATISTICAL ANALYSIS
For the descriptive analysis, the categorical variables were reported as absolute numbers and relative frequencies. Continuous variables were summarized as mean and standard deviation (SD) if normally distributed, or as a median and interquartile range (IQR) if not normally distributed. We used Pearson chi-square or Fisher's exact test for categorical variables and Student's t test or Mann-Whitney test for continuous variables. A P value < 0.05 was considered to be statistically significant. Analyses were performed with SPSS 21.0.
RESULTS
Of the 3501migrants observed in the study period, 3417 (97.6%) agreed to be screened; 185 (4.7%) were anti-HCV-positive and, of these, 53 (28.6%) were HCV-RNA-positive. Of these 53 subjects, 48 (90.5%) were referred to an ID unit and started DAA treatment. The HCV-RNA-positive-subjects were older [median 36 years (IQR: 32-21) vs 27.19 (IQR: 30.5-19.25); P = 0.001], and less frequently males [35 (66.03 %) vs 119 (90.1%), P < 0 .0001] than seronegative participants. They more frequently came from Eastern Europe (70.8%) stayed longer in Italy [months of stay in Italy, mean ± SD: 51.02 ± 52.84 vs 25.7 ± 42.65, P = 0.001], and had more years of schooling [years of schooling, mean ± SD: 9.61±2.81 vs 7.10 ± 4, P = 0.0001]. HCV-RNA-positive-subjects less frequently reported piercing, tattoos and tribal scars as risk factors (23.6%). Of these 48 HCV RNA positive subjects who started DAA, 47 (97.9%) showed a sustained virological response and one dropped-out in follow-up after DAA treatment. No subject had any adverse event.
CONCLUSIONS
This model of HCV screening and linkage to care seems effective to eliminate HCV infectionin a difficult-to-reach and to-treat population, such as undocumented migrants and low-income refugees. The participation of cultural mediators in the study made possible a better interaction between migrants and physicians, as is evident from the large number of subjects enrolled. Eliminating HCV among migrants will have a long-term positive impact from a public health and healthcare perspective by reducing the number of individuals who potentially develop HCV-related complications such as liver cirrhosis and hepatocellular carcinoma and reducing the circulation of HCV in the regions that host them which often, as in the case of Italy, are low endemic for HCV infection.
Topics: Humans; Italy; Antiviral Agents; Prospective Studies; Male; Female; Adult; Middle Aged; Hepatitis C; Transients and Migrants; Hepacivirus; Sofosbuvir; Young Adult; Mass Screening; Refugees; Poverty
PubMed: 38802954
DOI: 10.1186/s40249-024-01200-9 -
Molecules (Basel, Switzerland) May 2024Azido-modified nucleosides have been extensively explored as substrates for click chemistry and the metabolic labeling of DNA and RNA. These compounds are also of... (Review)
Review
Azido-modified nucleosides have been extensively explored as substrates for click chemistry and the metabolic labeling of DNA and RNA. These compounds are also of interest as precursors for further synthetic elaboration and as therapeutic agents. This review discusses the chemistry of azidonucleosides related to the generation of nitrogen-centered radicals (NCRs) from the azido groups that are selectively inserted into the nucleoside frame along with the subsequent chemistry and biological implications of NCRs. For instance, the critical role of the sulfinylimine radical generated during inhibition of ribonucleotide reductases by 2'-azido-2'-deoxy pyrimidine nucleotides as well as the NCRs generated from azidonucleosides by radiation-produced (prehydrated and aqueous) electrons are discussed. Regio and stereoselectivity of incorporation of an azido group ("radical arm") into the frame of nucleoside and selective generation of NCRs under reductive conditions, which often produce the same radical species that are observed upon ionization events due to radiation and/or other oxidative conditions that are emphasized. NCRs generated from nucleoside-modified precursors other than azidonucleosides are also discussed but only with the direct relation to the same/similar NCRs derived from azidonucleosides.
Topics: Nucleosides; Azides; Nitrogen; Free Radicals; Click Chemistry
PubMed: 38792171
DOI: 10.3390/molecules29102310