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Nature Communications May 2024NADPH oxidase 5 (NOX5) catalyzes the production of superoxide free radicals and regulates physiological processes from sperm motility to cardiac rhythm. Overexpression...
NADPH oxidase 5 (NOX5) catalyzes the production of superoxide free radicals and regulates physiological processes from sperm motility to cardiac rhythm. Overexpression of NOX5 leads to cancers, diabetes, and cardiovascular diseases. NOX5 is activated by intracellular calcium signaling, but the underlying molecular mechanism of which - in particular, how calcium triggers electron transfer from NADPH to FAD - is still unclear. Here we capture motions of full-length human NOX5 upon calcium binding using single-particle cryogenic electron microscopy (cryo-EM). By combining biochemistry, mutagenesis analyses, and molecular dynamics (MD) simulations, we decode the molecular basis of NOX5 activation and electron transfer. We find that calcium binding to the EF-hand domain increases NADPH dynamics, permitting electron transfer between NADPH and FAD and superoxide production. Our structural findings also uncover a zinc-binding motif that is important for NOX5 stability and enzymatic activity, revealing modulation mechanisms of reactive oxygen species (ROS) production.
Topics: Humans; Binding Sites; Calcium; Cryoelectron Microscopy; Electron Transport; Enzyme Activation; Flavin-Adenine Dinucleotide; Molecular Dynamics Simulation; NADP; NADPH Oxidase 5; Protein Binding; Reactive Oxygen Species; Superoxides; Zinc
PubMed: 38734761
DOI: 10.1038/s41467-024-48467-y -
Nutrients Apr 2024(1) Background: Fortifying maize and wheat flours with folic acid has effectively reduced neural tube defect-affected births. However, maize and wheat flours may not be...
(1) Background: Fortifying maize and wheat flours with folic acid has effectively reduced neural tube defect-affected births. However, maize and wheat flours may not be widely consumed in all countries; further reduction in neural tube defect-affected births could benefit from the identification of alternative food vehicles. We aimed to use dietary intake or apparent consumption data to determine alternative food vehicles for large-scale fortification with folic acid in low-income and lower-middle-income countries (LILMICs) and identify current research related to examining the technological feasibility of fortifying alternative foods with folic acid. (2) Methods: We identified 81 LILMICs, defined by the World Bank's (WB) 2018 income classifications. To identify dietary intake or apparent consumption, we reviewed WB's Microdata Library and Global Health Data Exchange for national surveys from 1997-2018. We reviewed survey reports for dietary intake or apparent consumption data and analyzed survey datasets for population coverage of foods. We defined alternative food vehicles as those that may cover/be consumed by ≥30% of the population or households; cereal grains (maize and wheat flours and rice) were included as an alternative food vehicle if a country did not have existing mandatory fortification legislation. To identify current research on fortification with folic acid in foods other than cereal grains, we conducted a systematic review of published literature and unpublished theses, and screened for foods or food products. (3) Results: We extracted or analyzed data from 18 national surveys and countries. The alternative foods most represented in the surveys were oil ( = 16), sugar ( = 16), and salt ( = 14). The coverage of oil ranged from 33.2 to 95.7%, sugar from 32.2 to 98.4%, and salt from 49.8 to 99.9%. We found 34 eligible studies describing research on alternative foods. The most studied alternative foods for fortification with folic acid were dairy products ( = 10), salt ( = 6), and various fruit juices ( = 5). (4) Conclusions: Because of their high coverage, oil, sugar, and salt emerge as potential alternative foods for large-scale fortification with folic acid. However, except for salt, there are limited or no studies examining the technological feasibility of fortifying these foods with folic acid.
Topics: Folic Acid; Food, Fortified; Humans; Neural Tube Defects; Triticum; Edible Grain; Flour; Zea mays; Developing Countries
PubMed: 38732559
DOI: 10.3390/nu16091312 -
Anemia in Breastfeeding Women and Its Impact on Offspring's Health in Indonesia: A Narrative Review.Nutrients Apr 2024Anemia in breastfeeding women is a neglected global health issue with significant implications for maternal and child health. Despite its widespread occurrence and... (Review)
Review
Anemia in breastfeeding women is a neglected global health issue with significant implications for maternal and child health. Despite its widespread occurrence and adverse effects, this problem remains largely unknown and overlooked on the global health agenda. Despite efforts to improve health access coverage and provide iron and folic acid supplementation, anemia persists. This underscores the need for a comprehensive approach to address the problem. Urgent action must be taken to prioritize education and awareness campaigns, ensure access to nutritious food, and enhance healthcare services. Education programs should focus on promoting iron-rich diets, dispelling cultural myths, and providing practical guidance. Improving healthcare services requires increasing availability, ensuring a consistent supply of iron supplements, and providing adequate training for healthcare providers. A successful implementation relies on a strong collaboration between the government, healthcare providers, and community. It is crucial that we acknowledge that high coverage alone is insufficient for solving the issue, emphasizing the importance of targeted interventions and a strategic implementation. By adopting a comprehensive approach and addressing the underlying causes of anemia, Indonesia can make significant progress in reducing its prevalence and improving the overall health of its population, particularly among breastfeeding women.
Topics: Humans; Breast Feeding; Indonesia; Female; Dietary Supplements; Anemia; Anemia, Iron-Deficiency; Infant; Child Health; Iron; Folic Acid
PubMed: 38732532
DOI: 10.3390/nu16091285 -
International Journal of Molecular... May 2024One-carbon (1-C) metabolic deficiency impairs homeostasis, driving disease development, including infertility. It is of importance to summarize the current evidence... (Review)
Review
One-carbon (1-C) metabolic deficiency impairs homeostasis, driving disease development, including infertility. It is of importance to summarize the current evidence regarding the clinical utility of 1-C metabolism-related biomolecules and methyl donors, namely, folate, betaine, choline, vitamin B12, homocysteine (Hcy), and zinc, as potential biomarkers, dietary supplements, and culture media supplements in the context of medically assisted reproduction (MAR). A narrative review of the literature was conducted in the PubMed/Medline database. Diet, ageing, and the endocrine milieu of individuals affect both 1-C metabolism and fertility status. In vitro fertilization (IVF) techniques, and culture conditions in particular, have a direct impact on 1-C metabolic activity in gametes and embryos. Critical analysis indicated that zinc supplementation in cryopreservation media may be a promising approach to reducing oxidative damage, while female serum homocysteine levels may be employed as a possible biomarker for predicting IVF outcomes. Nonetheless, the level of evidence is low, and future studies are needed to verify these data. One-carbon metabolism-related processes, including redox defense and epigenetic regulation, may be compromised in IVF-derived embryos. The study of 1-C metabolism may lead the way towards improving MAR efficiency and safety and ensuring the lifelong health of MAR infants.
Topics: Humans; Reproductive Techniques, Assisted; Carbon; Vitamin B 12; Fertilization in Vitro; Female; Homocysteine; Folic Acid; Dietary Supplements; Choline; Zinc; Betaine; Biomarkers
PubMed: 38732193
DOI: 10.3390/ijms25094977 -
International Journal of Molecular... Apr 2024Non-muscle invasive bladder cancer is a common tumour in men and women. In case of resistance to the standard therapeutic agents, gemcitabine can be used as off-label...
Non-muscle invasive bladder cancer is a common tumour in men and women. In case of resistance to the standard therapeutic agents, gemcitabine can be used as off-label instillation therapy into the bladder. To reduce potential side effects, continuous efforts are made to optimise the therapeutic potential of drugs, thereby reducing the effective dose and consequently the pharmacological burden of the medication. We recently demonstrated that it is possible to significantly increase the therapeutic efficacy of mitomycin C against a bladder carcinoma cell line by exposure to non-toxic doses of blue light (453 nm). In the present study, we investigated whether the therapeutically supportive effect of blue light can be further enhanced by the additional use of the wavelength-specific photosensitiser riboflavin. We found that the gemcitabine-induced cytotoxicity of bladder cancer cell lines (BFTC-905, SW-1710, RT-112) was significantly enhanced by non-toxic doses of blue light in the presence of riboflavin. Enhanced cytotoxicity correlated with decreased levels of mitochondrial ATP synthesis and increased lipid peroxidation was most likely the result of increased oxidative stress. Due to these properties, blue light in combination with riboflavin could represent an effective therapy option with few side effects and increase the success of local treatment of bladder cancer, whereby the dose of the chemotherapeutic agent used and thus the chemical load could be significantly reduced with similar or improved therapeutic success.
Topics: Humans; Riboflavin; Urinary Bladder Neoplasms; Gemcitabine; Deoxycytidine; Cell Line, Tumor; Light; Photosensitizing Agents; Oxidative Stress; Cell Survival; Lipid Peroxidation; Adenosine Triphosphate; Mitochondria; Blue Light
PubMed: 38732087
DOI: 10.3390/ijms25094868 -
International Journal of Molecular... Apr 2024Dolutegravir (DTG) is one of the most prescribed antiretroviral drugs for treating people with HIV infection, including women of child-bearing potential or pregnant....
Dolutegravir (DTG) is one of the most prescribed antiretroviral drugs for treating people with HIV infection, including women of child-bearing potential or pregnant. Nonetheless, neuropsychiatric symptoms are frequently reported. Early reports suggested that, probably in relation to folic acid (FA) shortage, DTG may induce neural tube defects in infants born to women taking the drug during pregnancy. Subsequent reports did not definitively confirm these findings. Recent studies in animal models have highlighted the association between DTG exposure in utero and congenital anomalies, and an increased risk of neurologic abnormalities in children exposed during in utero life has been reported. Underlying mechanisms for DTG-related neurologic symptoms and congenital anomalies are not fully understood. We aimed to deepen our knowledge on the neurodevelopmental effects of DTG exposure and further explore the protective role of FA by the use of zebrafish embryos. We treated embryos at 4 and up to 144 h post fertilization (hpf) with a subtherapeutic DTG concentration (1 μM) and observed the disruption of the anterior-posterior axis and several morphological malformations in the developing brain that were both prevented by pre-exposure (2 hpf) and rescued by post-exposure (10 hpf) with FA. By whole-mount in situ hybridization with riboprobes for genes that are crucial during the early phases of neurodevelopment (, , , ) and by in vivo visualization of the transgenic Tg(:EGFP) zebrafish line, we found that DTG induced severe neurodevelopmental defects over time in most regions of the nervous system (notochord, midbrain-hindbrain boundary, eye, forebrain, midbrain, hindbrain, spinal cord) that were mostly but not completely rescued by FA supplementation. Of note, we observed the disruption of expression in the dopaminergic regions of the developing forebrain, spinal cord neurons and spinal motor neuron projections, with the depletion of the tyrosine hydroxylase (TH) dopaminergic neurons of the dorsal diencephalon and the strong reduction in larvae locomotion. Our study further supports previous evidence that DTG can interfere with FA pathways in the developing brain but also provides new insights regarding the mechanisms involved in the increased risk of DTG-associated fetal neurodevelopmental defects and adverse neurologic outcomes in in utero exposed children, suggesting the impairment of dopaminergic pathways.
Topics: Animals; Zebrafish; Heterocyclic Compounds, 3-Ring; Folic Acid; Oxazines; Pyridones; Piperazines; Embryo, Nonmammalian; Neural Tube Defects; Neurogenesis; Female
PubMed: 38731859
DOI: 10.3390/ijms25094640 -
Molecules (Basel, Switzerland) Apr 2024Leishmaniasis and Human African trypanosomiasis pose significant public health threats in resource-limited regions, accentuated by the drawbacks of the current...
Leishmaniasis and Human African trypanosomiasis pose significant public health threats in resource-limited regions, accentuated by the drawbacks of the current antiprotozoal treatments and the lack of approved vaccines. Considering the demand for novel therapeutic drugs, a series of BODIPY derivatives with several functionalizations at the , 2 and/or 6 positions of the core were synthesized and characterized. The in vitro activity against and parasites was carried out alongside a human healthy cell line (MRC-5) to establish selectivity indices (SIs). Notably, the -substituted BODIPY, with 1-dimethylaminonaphthalene () and anthracene moiety (), were the most active against , displaying IC = 4.84 and 5.41 μM, with a 16 and 18-fold selectivity over MRC-5 cells, respectively. In contrast, the mono-formylated analogues and exhibited the highest toxicity (IC = 2.84 and 6.17 μM, respectively) and selectivity (SI = 24 and 11, respectively) against . Further insights on the activity of these compounds were gathered from molecular docking studies. The results suggest that these BODIPYs act as competitive inhibitors targeting the NADPH/NADP linkage site of the pteridine reductase (PR) enzyme. Additionally, these findings unveil a range of quasi-degenerate binding complexes formed between the PRs and the investigated BODIPY derivatives. These results suggest a potential correlation between the anti-parasitic activity and the presence of multiple configurations that block the same site of the enzyme.
Topics: Boron Compounds; Trypanosoma brucei brucei; Humans; Molecular Docking Simulation; Antiprotozoal Agents; Leishmania major; Drug Design; Structure-Activity Relationship; Cell Line; Molecular Structure; Trypanocidal Agents; Oxidoreductases
PubMed: 38731562
DOI: 10.3390/molecules29092072 -
Pediatric Rheumatology Online Journal May 2024Etanercept has been studied in doses up to 0.8 mg/kg/week (max 50 mg/week) in juvenile idiopathic arthritis (JIA) patients. In clinical practice higher doses are used... (Randomized Controlled Trial)
Randomized Controlled Trial
Increasing the etanercept dose in a treat-to-target approach in juvenile idiopathic arthritis: does it help to reach the target? A post-hoc analysis of the BeSt for Kids randomised clinical trial.
BACKGROUND
Etanercept has been studied in doses up to 0.8 mg/kg/week (max 50 mg/week) in juvenile idiopathic arthritis (JIA) patients. In clinical practice higher doses are used off-label, but evidence regarding the relation with outcomes is lacking. We describe the clinical course of JIA-patients receiving high-dose etanercept (1.6 mg/kg/week; max 50 mg/week) in the BeSt for Kids trial.
METHODS
92 patients with oligoarticular JIA, RF-negative polyarticular JIA or juvenile psoriatic arthritis were randomised across three treat-to-target arms: (1) sequential DMARD-monotherapy (sulfasalazine or methotrexate (MTX)), (2) combination-therapy MTX + 6 weeks prednisolone and (3) combination therapy MTX + etanercept. In any treatment-arm, patients could eventually escalate to high-dose etanercept alongside MTX 10mg/m/week.
RESULTS
32 patients received high-dose etanercept (69% female, median age 6 years (IQR 4-10), median 10 months (7-16) from baseline). Median follow-up was 24.6 months. Most clinical parameters improved within 3 months after dose-increase: median JADAS10 from 7.2 to 2.8 (p = 0.008), VAS-physician from 12 to 4 (p = 0.022), VAS-patient/parent from 38.5 to 13 (p = 0.003), number of active joints from 2 to 0.5 (p = 0.12) and VAS-pain from 35.5 to 15 (p = 0.030). Functional impairments (CHAQ-score) improved more gradually and ESR remained stable. A comparable pattern was observed in 11 patients (73% girls, median age 8 (IQR 6-9)) who did not receive high-dose etanercept despite eligibility (comparison group). In both groups, 56% reached inactive disease at 6 months. No severe adverse events (SAEs) occurred after etanercept dose-increase. In the comparison group, 2 SAEs consisting of hospital admission occurred. Rates of non-severe AEs per subsequent patient year follow-up were 2.27 in the high-dose and 1.43 in the comparison group.
CONCLUSIONS
Escalation to high-dose etanercept in JIA-patients who were treated to target was generally followed by meaningful clinical improvement. However, similar improvements were observed in a smaller comparison group who did not escalate to high-dose etanercept. No SAEs were seen after escalation to high-dose etanercept. The division into the high-dose and comparison groups was not randomised, which is a potential source of bias. We advocate larger, randomised studies of high versus regular dose etanercept to provide high level evidence on efficacy and safety.
TRIAL REGISTRATION
Dutch Trial Register; NTR1574; 3 December 2008; https://onderzoekmetmensen.nl/en/trial/26585 .
Topics: Humans; Arthritis, Juvenile; Etanercept; Female; Male; Child; Antirheumatic Agents; Methotrexate; Drug Therapy, Combination; Child, Preschool; Dose-Response Relationship, Drug; Treatment Outcome; Prednisolone; Sulfasalazine
PubMed: 38730442
DOI: 10.1186/s12969-024-00989-x -
Scientific Reports May 2024Type III collagen gene expression is upregulated in the synovium of patients with rheumatoid arthritis (RA) presenting the fibroid phenotype. The soluble type III...
Type III collagen gene expression is upregulated in the synovium of patients with rheumatoid arthritis (RA) presenting the fibroid phenotype. The soluble type III collagen formation biomarker, PRO-C3, is known to measure fibrogenesis in fibrotic diseases. In this exploratory study, we aimed to investigate the association between fibrogenesis (PRO-C3) and the disease- and treatment response in patients with RA. We measured PRO-C3 in subsets of two clinical trials assessing the effect of the anti-interleukin-6 (IL-6) receptor treatment tocilizumab (TCZ) as monotherapy or polytherapy with methotrexate. PRO-C3 levels had weak or very weak correlations with the clinical parameters (Spearman's). However, when the patients were divided into Disease Activity Score-28 groups characterized by the erythrocyte sedimentation rate (DAS28-ESR), there was a statistical difference between the PRO-C3 levels of the different groups (p < 0.05). To determine the response in relation to PRO-C3, a cut-off based on PRO-C3 levels and patients in remission (DAS28-ESR ≤ 2.6) was identified. This showed that a reduction in PRO-C3 after treatment initiation was associated with decreased DAS28-ESR and a higher response rate in patients with low PRO-C3 levels than in those with high PRO-C3 levels. This indicates that a fibrotic component affects the responsiveness of patients.
Topics: Humans; Arthritis, Rheumatoid; Female; Receptors, Interleukin-6; Male; Middle Aged; Antibodies, Monoclonal, Humanized; Antirheumatic Agents; Methotrexate; Phenotype; Biomarkers; Adult; Aged; Treatment Outcome
PubMed: 38730088
DOI: 10.1038/s41598-024-61435-2 -
ENeuro Jun 2024Intracerebral hemorrhage (ICH), the most common subtype of hemorrhagic stroke, leads to cognitive impairment and imposes significant psychological burdens on patients....
Intracerebral hemorrhage (ICH), the most common subtype of hemorrhagic stroke, leads to cognitive impairment and imposes significant psychological burdens on patients. Hippocampal neurogenesis has been shown to play an essential role in cognitive function. Our previous study has shown that tetrahydrofolate (THF) promotes the proliferation of neural stem cells (NSCs). However, the effect of THF on cognition after ICH and the underlying mechanisms remain unclear. Here, we demonstrated that administration of THF could restore cognition after ICH. Using Nestin-GFP mice, we further revealed that THF enhanced the proliferation of hippocampal NSCs and neurogenesis after ICH. Mechanistically, we found that THF could prevent ICH-induced elevated level of PTEN and decreased expressions of phosphorylated AKT and mTOR. Furthermore, conditional deletion of PTEN in NSCs of the hippocampus attenuated the inhibitory effect of ICH on the proliferation of NSCs and abnormal neurogenesis. Taken together, these results provide molecular insights into ICH-induced cognitive impairment and suggest translational clinical therapeutic strategy for hemorrhagic stroke.
Topics: Animals; Neurogenesis; Hippocampus; Cognitive Dysfunction; PTEN Phosphohydrolase; Male; Signal Transduction; Neural Stem Cells; Tetrahydrofolates; Mice; Hemorrhagic Stroke; Mice, Inbred C57BL; Mice, Transgenic; Cell Proliferation
PubMed: 38729764
DOI: 10.1523/ENEURO.0021-24.2024