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Environmental Health : a Global Access... Jun 2024Spina bifida, a developmental malformation of the spinal cord, is associated with high rates of mortality and disability. Although folic acid-based preventive strategies...
BACKGROUND
Spina bifida, a developmental malformation of the spinal cord, is associated with high rates of mortality and disability. Although folic acid-based preventive strategies have been successful in reducing rates of spina bifida, some areas continue to be at higher risk because of chemical exposures. Bangladesh has high arsenic exposures through contaminated drinking water and high rates of spina bifida. This study examines the relationships between mother's arsenic exposure, folic acid, and spina bifida risk in Bangladesh.
METHODS
We conducted a hospital-based case-control study at the National Institute of Neurosciences & Hospital (NINS&H) in Dhaka, Bangladesh, between December 2016 and December 2022. Cases were infants under age one year with spina bifida and further classified by a neurosurgeon and imaging. Controls were drawn from children seen at NINS&H and nearby Dhaka Shishu Hospital. Mothers reported folic acid use during pregnancy, and we assessed folate status with serum assays. Arsenic exposure was estimated in drinking water using graphite furnace atomic absorption spectrophotometry (GF-AAS) and in toenails using inductively coupled plasma mass spectrometry (ICP-MS). We used logistic regression to examine the associations between arsenic and spina bifida. We used stratified models to examine the associations between folic acid and spina bifida at different levels of arsenic exposure.
RESULTS
We evaluated data from 294 cases of spina bifida and 163 controls. We did not find a main effect of mother's arsenic exposure on spina bifida risk. However, in stratified analyses, folic acid use was associated with lower odds of spina bifida (adjusted odds ratio [OR]: 0.50, 95% confidence interval [CI]: 0.25-1.00, p = 0.05) among women with toenail arsenic concentrations below the median value of 0.46 µg/g, and no association was seen among mothers with toenail arsenic concentrations higher than 0.46 µg/g (adjusted OR: 1.09, 95% CI: 0.52-2.29, p = 0.82).
CONCLUSIONS
Mother's arsenic exposure modified the protective association of folic acid with spina bifida. Increased surveillance and additional preventive strategies, such as folic acid fortification and reduction of arsenic, are needed in areas of high arsenic exposure.
Topics: Humans; Folic Acid; Bangladesh; Spinal Dysraphism; Case-Control Studies; Female; Arsenic; Infant; Male; Adult; Infant, Newborn; Pregnancy; Water Pollutants, Chemical; Maternal Exposure; Young Adult; Drinking Water
PubMed: 38831396
DOI: 10.1186/s12940-024-01091-1 -
Cell Death & Disease Jun 2024Vitamin B6 is a water-soluble vitamin which possesses antioxidant properties. Its catalytically active form, pyridoxal 5'-phosphate (PLP), is a crucial cofactor for DNA...
Vitamin B6 is a water-soluble vitamin which possesses antioxidant properties. Its catalytically active form, pyridoxal 5'-phosphate (PLP), is a crucial cofactor for DNA and amino acid metabolism. The inverse correlation between vitamin B6 and cancer risk has been observed in several studies, although dietary vitamin B6 intake sometimes failed to confirm this association. However, the molecular link between vitamin B6 and cancer remains elusive. Previous work has shown that vitamin B6 deficiency causes chromosome aberrations (CABs) in Drosophila and human cells, suggesting that genome instability may correlate the lack of this vitamin to cancer. Here we provide evidence in support of this hypothesis. Firstly, we show that PLP deficiency, induced by the PLP antagonists 4-deoxypyridoxine (4DP) or ginkgotoxin (GT), promoted tumorigenesis in eye larval discs transforming benign Ras tumors into aggressive forms. In contrast, PLP supplementation reduced the development of tumors. We also show that low PLP levels, induced by 4DP or by silencing the sgll gene involved in PLP biosynthesis, worsened the tumor phenotype in another Drosophila cancer model generated by concomitantly activating Ras and downregulating Discs-large (Dlg) gene. Moreover, we found that Ras eye discs from larvae reared on 4DP displayed CABs, reactive oxygen species (ROS) and low catalytic activity of serine hydroxymethyltransferase (SHMT), a PLP-dependent enzyme involved in thymidylate (dTMP) biosynthesis, in turn required for DNA replication and repair. Feeding Ras 4DP-fed larvae with PLP or ascorbic acid (AA) plus dTMP, rescued both CABs and tumors. The same effect was produced by overexpressing catalase in Ras Dlg 4DP-fed larvae, thus allowing to establish a relationship between PLP deficiency, CABs, and cancer. Overall, our data provide the first in vivo demonstration that PLP deficiency can impact on cancer by increasing genome instability, which is in turn mediated by ROS and reduced dTMP levels.
Topics: Animals; Vitamin B 6 Deficiency; Drosophila Proteins; Vitamin B 6; Drosophila melanogaster; Drosophila; Pyridoxal Phosphate; Reactive Oxygen Species; Carcinogenesis; ras Proteins; Neoplasms; Larva; Humans
PubMed: 38830901
DOI: 10.1038/s41419-024-06787-3 -
International Journal of Biological... Jun 2024Cellulose nanofibres (CNFs), also known as nano-fibrillated cellulose, have emerged as highly promising sustainable biomaterials owing to their numerous advantages,...
Cellulose nanofibres (CNFs), also known as nano-fibrillated cellulose, have emerged as highly promising sustainable biomaterials owing to their numerous advantages, including high accessibility, long-term sustainability, low toxicity, and mechanical properties. Recently, marine organisms have been explored as novel and environmentally friendly sources of cellulose fibers (CFs) due to their easy cultivation, extraction and biocompatibility. Dinoflagellates, a group of marine phytoplankton, have gained particular attention due to their unique cellulosic morphology and lignin-free biomass. Previously, we showed that the unique amorphous nature of dinoflagellate-derived cellulose offers various benefits. This study further explores the potential of dinoflagellate-derived CFs as a sustainable and versatile CNF source. Extracted dinoflagellate cellulose is effectively converted into CNFs via one-step TEMPO oxidation without significant polymer degradation. In addition, the biological compatibility of the CNFs is improved by amine-grafting using putrescine and folic acid. The products are characterised by conductometric titration, zeta potential measurements, TGA, GPC, FTIR, SEM/TEM, XRD, and XPS. Finally, in a proof-of-principle study, the application of the functionalised CNFs in drug delivery is tested using methylene blue as a drug model. Our findings suggest that dinoflagellate-derived CNFs provide an eco-friendly platform that can be easily functionalised for various applications, including drug delivery.
Topics: Dinoflagellida; Cellulose; Nanofibers; Cyclic N-Oxides; Folic Acid
PubMed: 38825272
DOI: 10.1016/j.ijbiomac.2024.132804 -
Microbial Cell Factories May 2024Bacillus subtilis is widely used in industrial-scale riboflavin production. Previous studies have shown that targeted mutagenesis of the ribulose 5-phosphate 3-epimerase...
BACKGROUND
Bacillus subtilis is widely used in industrial-scale riboflavin production. Previous studies have shown that targeted mutagenesis of the ribulose 5-phosphate 3-epimerase in B. subtilis can significantly enhance riboflavin production. This modification also leads to an increase in purine intermediate concentrations in the medium. Interestingly, B. subtilis exhibits remarkable efficiency in purine nucleoside synthesis, often exceeding riboflavin yields. These observations highlight the importance of the conversion steps from inosine-5'-monophosphate (IMP) to 2,5-diamino-6-ribosylamino-4(3 H)-pyrimidinone-5'-phosphate (DARPP) in riboflavin production by B. subtilis. However, research elucidating the specific impact of these reactions on riboflavin production remains limited.
RESULT
We expressed the genes encoding enzymes involved in these reactions (guaB, guaA, gmk, ndk, ribA) using a synthetic operon. Introduction of the plasmid carrying this synthetic operon led to a 3.09-fold increase in riboflavin production compared to the control strain. Exclusion of gmk from the synthetic operon resulted in a 36% decrease in riboflavin production, which was further reduced when guaB and guaA were not co-expressed. By integrating the synthetic operon into the genome and employing additional engineering strategies, we achieved riboflavin production levels of 2702 mg/L. Medium optimization further increased production to 3477 mg/L, with a yield of 0.0869 g riboflavin per g of sucrose.
CONCLUSION
The conversion steps from IMP to DARPP play a critical role in riboflavin production by B. subtilis. Our overexpression strategies have demonstrated their effectiveness in overcoming these limiting factors and enhancing riboflavin production.
Topics: Riboflavin; Bacillus subtilis; Purines; Metabolic Engineering; Biosynthetic Pathways; Operon; Bacterial Proteins
PubMed: 38822377
DOI: 10.1186/s12934-024-02426-w -
Scientific Reports May 2024Fluorescent detection in cells has been tremendously developed over the years and now benefits from a large array of reporters that can provide sensitive and specific...
Fluorescent detection in cells has been tremendously developed over the years and now benefits from a large array of reporters that can provide sensitive and specific detection in real time. However, the intracellular monitoring of metabolite levels still poses great challenges due to the often complex nature of detected metabolites. Here, we provide a systematic analysis of thiamin pyrophosphate (TPP) metabolism in Escherichia coli by using a TPP-sensing riboswitch that controls the expression of the fluorescent gfp reporter. By comparing different combinations of reporter fusions and TPP-sensing riboswitches, we determine key elements that are associated with strong TPP-dependent sensing. Furthermore, by using the Keio collection as a proxy for growth conditions differing in TPP levels, we perform a high-throughput screen analysis using high-density solid agar plates. Our study reveals several genes whose deletion leads to increased or decreased TPP levels. The approach developed here could be applicable to other riboswitches and reporter genes, thus representing a framework onto which further development could lead to highly sophisticated detection platforms allowing metabolic screens and identification of orphan riboswitches.
Topics: Riboswitch; Biosensing Techniques; Escherichia coli; Thiamine Pyrophosphate; Metabolic Networks and Pathways; Green Fluorescent Proteins; Genes, Reporter; Gene Expression Regulation, Bacterial; Genome, Bacterial
PubMed: 38821978
DOI: 10.1038/s41598-024-61980-w -
BMC Oral Health May 2024The present study aimed to evaluate nutritional intake among a group of male patients in the dental clinic with and without periodontal disease to search for...
BACKGROUND
The present study aimed to evaluate nutritional intake among a group of male patients in the dental clinic with and without periodontal disease to search for associations between nutritional profile and periodontal health.
METHODS
To this purpose, nutritional intake of macronutrients, fiber, vitamins, and minerals were compared evaluating both clinical parameters and periodontal status. Non periodontitis patients were compared with stage III and IV periodontitis and its extension according to the 2017 classification.
RESULTS
After multivariate analysis, statistically significant associations were found between the dietary intake of energy, total fat, cholesterol, calcium, saturated fat, monounsaturated fat and folic acid and iodine and periodontitis status. This study reports an inverse association between cholesterol and iodine and periodontitis and a direct association with saturated fat, monounsaturated fat, and folic acid.
CONCLUSIONS
Maintaining an adequate intake of fat, iodine, calcium, and cholesterol and avoiding an excessive intake of energy, saturated fat, monounsaturated fat, and folic acid could be important to controlling periodontitis.
Topics: Humans; Male; Periodontitis; Middle Aged; Adult; Energy Intake; Nutritional Status; Folic Acid; Diet; Dietary Fats; Dietary Fiber
PubMed: 38816851
DOI: 10.1186/s12903-024-04384-6 -
Scientific Reports May 2024Nanoliposomal irinotecan with fluorouracil and folinic acid (NFF) is a standard regimen after gemcitabine-based therapy for patients with unresectable or recurrent... (Observational Study)
Observational Study
Nanoliposomal irinotecan with fluorouracil and folinic acid (NFF) is a standard regimen after gemcitabine-based therapy for patients with unresectable or recurrent pancreatic cancer. However, there are limited clinical data on its efficacy and safety in the real-world. We therefore initiated a retrospective and prospective observational study (NAPOLEON-2). The results of the retrospective part were reported herein. In this retrospective study, we evaluated 161 consecutive patients who received NFF as second-or-later-line regimen. The main endpoint was overall survival (OS), and the other endpoints were response rate, disease control rate, progression-free survival (PFS), dose intensity, and adverse events (AEs). The median age was 67 years (range, 38-85 years). The median OS and PFS were 8.1 and 3.4 months, respectively. The objective response and disease control rates were 5% and 52%, respectively. The median relative dose intensity was 81.6% for nanoliposomal irinotecan and 82.9% for fluorouracil. Grade 3 or 4 hematological and nonhematological AEs occurred in 47 and 42 patients, respectively. Common grade 3 or 4 AEs included neutropenia (24%), anorexia (12%), and leukocytopenia (12%). Subanalysis of patients treated with second-line and third-or-later-line demonstrated no statistical significant difference in OS (7.6 months vs. 9.1 months, respectively; hazard ratio, 0.92; 95% confidence interval, 0.64-1.35; p = 0.68). In conclusion, NFF has acceptable efficacy and safety profile even in real-world clinical settings. The prospective study is in progress to validate these findings.
Topics: Humans; Fluorouracil; Aged; Leucovorin; Irinotecan; Female; Middle Aged; Male; Pancreatic Neoplasms; Aged, 80 and over; Retrospective Studies; Adult; Liposomes; Antineoplastic Combined Chemotherapy Protocols; Treatment Outcome; Prospective Studies
PubMed: 38816500
DOI: 10.1038/s41598-024-63172-y -
World Journal of Gastroenterology May 2024The advent of cutting-edge systemic therapies has driven advances in the treatment of hepatocellular carcinoma (HCC), and therapeutic strategies with multiple modes of...
BACKGROUND
The advent of cutting-edge systemic therapies has driven advances in the treatment of hepatocellular carcinoma (HCC), and therapeutic strategies with multiple modes of delivery have been shown to be more efficacious than monotherapy. However, the mechanisms underlying this innovative treatment modality have not been elucidated.
AIM
To evaluate the clinical efficacy of targeted therapy plus immunotherapy combined with hepatic arterial infusion chemotherapy (HAIC) of FOLFOX in patients with unresectable HCC.
METHODS
We enrolled 53 patients with unresectable HCC who received a combination of targeted therapy, immunotherapy, and HAIC of FOLFOX between December 2020 and June 2021 and assessed the efficacy and safety of the treatment regimen.
RESULTS
The objective response rate was 60.4% (32/53), complete response was 24.5% (13/53), partial response was 35.9% (19/53), and stable disease was 39.6% (21/53). The median duration of response and median progression-free survival were 9.1 and 13.9 months, respectively. The surgical conversion rate was 34.0% (18/53), and 1-year overall survival was 83.0% without critical complicating diseases or adverse events (AEs).
CONCLUSION
The regimen of HAIC of FOLFOX, targeted therapy, and immunotherapy was curative for patients with unresectable HCC, with no serious AEs and a high rate of surgical conversion.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Male; Female; Antineoplastic Combined Chemotherapy Protocols; Middle Aged; Fluorouracil; Infusions, Intra-Arterial; Leucovorin; Aged; Adult; Hepatic Artery; Organoplatinum Compounds; Treatment Outcome; Molecular Targeted Therapy; Progression-Free Survival; Retrospective Studies; Immunotherapy; Combined Modality Therapy
PubMed: 38813052
DOI: 10.3748/wjg.v30.i17.2321 -
PloS One 2024Benfotiamine provides an important novel therapeutic direction in Alzheimer's disease (AD) with possible additive or synergistic effects to amyloid targeting therapeutic... (Randomized Controlled Trial)
Randomized Controlled Trial
Protocol for a seamless phase 2A-phase 2B randomized double-blind placebo-controlled trial to evaluate the safety and efficacy of benfotiamine in patients with early Alzheimer's disease (BenfoTeam).
BACKGROUND
Benfotiamine provides an important novel therapeutic direction in Alzheimer's disease (AD) with possible additive or synergistic effects to amyloid targeting therapeutic approaches.
OBJECTIVE
To conduct a seamless phase 2A-2B proof of concept trial investigating tolerability, safety, and efficacy of benfotiamine, a prodrug of thiamine, as a first-in-class small molecule oral treatment for early AD.
METHODS
This is the protocol for a randomized, double-blind, placebo-controlled 72-week clinical trial of benfotiamine in 406 participants with early AD. Phase 2A determines the highest safe and well-tolerated dose of benfotiamine to be carried forward to phase 2B. During phase 2A, real-time monitoring of pre-defined safety stopping criteria in the first approximately 150 enrollees will help determine which dose (600 mg or 1200 mg) will be carried forward into phase 2B. The phase 2A primary analysis will test whether the rate of tolerability events (TEs) is unacceptably high in the high-dose arm compared to placebo. The primary safety endpoint in phase 2A is the rate of TEs compared between active and placebo arms, at each dose. The completion of phase 2A will seamlessly transition to phase 2B without pausing or stopping the trial. Phase 2B will assess efficacy and longer-term safety of benfotiamine in a larger group of participants through 72 weeks of treatment, at the selected dose. The co-primary efficacy endpoints in phase 2B are CDR-Sum of Boxes and ADAS-Cog13. Secondary endpoints include safety and tolerability measures; pharmacokinetic measures of thiamine and its esters, erythrocyte transketolase activity as blood markers of efficacy of drug delivery; ADCS-ADL-MCI; and MoCA.
CONCLUSION
The BenfoTeam trial utilizes an innovative seamless phase 2A-2B design to achieve proof of concept. It includes an adaptive dose decision rule, thus optimizing exposure to the highest and best-tolerated dose.
TRIAL REGISTRATION
ClinicalTrials.gov identifier: NCT06223360, registered on January 25, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT06223360.
Topics: Humans; Alzheimer Disease; Thiamine; Double-Blind Method; Male; Female; Aged; Middle Aged; Treatment Outcome; Prodrugs
PubMed: 38809849
DOI: 10.1371/journal.pone.0302998 -
Frontiers in Endocrinology 2024The effects of vitamin B12 metabolism on musculoskeletal health and the exact mechanism have not been fully determined. Our study aimed to assess the association of...
INTRODUCTION
The effects of vitamin B12 metabolism on musculoskeletal health and the exact mechanism have not been fully determined. Our study aimed to assess the association of vitamin B12 and its biomarkers with musculoskeletal health in middle-aged and older adults.
METHODS
The data from the National Health and Nutrition Examination Survey 2001-2002 were used to investigate the effects of serum vitamin B12 and its biomarkers (homocysteine and methylmalonic acid) on skeletal muscle health. Bone mineral density (BMD), lean mass, gait speed and knee extensor strength were used as indicators for musculoskeletal health.
RESULTS
Serum vitamin B12 level was positively correlated with the total and appendicular lean mass (β = 584.83, = 0.044; β = 291.65, = 0.043) in older adults over 65 years of age. In the full population, plasma homocysteine was associated with total lean mass, appendicular lean mass, gait speed, and knee extensor strength (all < 0.05). Among older adults over 65 years of age, homocysteine level was significantly negatively correlated with gait speed and knee extensor strength (β = -12.75, = 0.019; β = -0.06, 0.001). Plasma methylmalonic acid was negatively associated with total BMD and femur BMD in the full population (β = -0.01, = 0.018; β = -0.01, = 0.004). In older adults, methylmalonic acid significantly affected total BMD, femur BMD and knee extensor strength (β = -0.01, = 0.048; β = -0.01, = 0.025; β = -7.53, = 0.015).
CONCLUSIONS
Vitamin B12 and its biomarkers are closely related to BMD, body composition, muscle strength and physical function in middle-aged and older adults. Vitamin B12 may be an important indicator of musculoskeletal health in the elderly.
Topics: Humans; Vitamin B 12; Aged; Female; Male; Biomarkers; Middle Aged; Bone Density; Homocysteine; Methylmalonic Acid; Muscle Strength; Muscle, Skeletal; Nutrition Surveys; Body Composition; Cross-Sectional Studies; Aged, 80 and over
PubMed: 38808112
DOI: 10.3389/fendo.2024.1387035