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Food Chemistry May 2024Manuka honey (MH) is a highly prized natural product from the nectar of Leptospermum scoparium flowers. Increased competition on the global market drives MH product... (Review)
Review
Manuka honey (MH) is a highly prized natural product from the nectar of Leptospermum scoparium flowers. Increased competition on the global market drives MH product innovations. This review updates comparative and non-comparative studies to highlight nutritional, therapeutic, bioengineering, and cosmetic values of MH. MH is a good source of phenolics and unique chemical compounds, such as methylglyoxal, dihydroxyacetone, leptosperin glyoxal, methylsyringate and leptosin. Based on the evidence from in vitro, in vivo and clinical studies, multifunctional bioactive compounds of MH have exhibited anti-oxidative, anti-inflammatory, immunomodulatory, anti-microbial, and anti-cancer activities. There are controversial topics related to MH, such as MH grading, safety/efficacy, implied benefits, and maximum levels of contaminants concerned. Artificial intelligence can optimize MH studies related to chemical analysis, toxicity prediction, multi-functional mechanism exploration and product innovation.
Topics: Honey; Artificial Intelligence; Plant Nectar; Flowers; Pyruvaldehyde; Leptospermum
PubMed: 38211407
DOI: 10.1016/j.foodchem.2023.138060 -
Journal of Translational Medicine Aug 2023ABCA4, the gene implicated in Stargardt disease (STGD1), contains 50 exons, of which 17 contain multiples of three nucleotides. The impact of in-frame exon skipping is...
BACKGROUND
ABCA4, the gene implicated in Stargardt disease (STGD1), contains 50 exons, of which 17 contain multiples of three nucleotides. The impact of in-frame exon skipping is yet to be determined. Antisense oligonucleotides (AONs) have been investigated in Usher syndrome-associated genes to induce skipping of in-frame exons carrying severe variants and mitigate their disease-linked effect. Upon the identification of a STGD1 proband carrying a novel exon 17 canonical splice site variant, the activity of ABCA4 lacking 22 amino acids encoded by exon 17 was examined, followed by design of AONs able to induce exon 17 skipping.
METHODS
A STGD1 proband was compound heterozygous for the splice variant c.2653+1G>A, that was predicted to result in in-frame skipping of exon 17, and a null variant [c.735T>G, p.(Tyr245*)]. Clinical characteristics of this proband were studied using multi-modal imaging and complete ophthalmological examination. The aberrant splicing of c.2653+1G>A was investigated in vitro in HEK293T cells with wild-type and mutant midigenes. The residual activity of the mutant ABCA4 protein lacking Asp864-Gly885 encoded by exon 17 was analyzed with all-trans-retinal-activated ATPase activity assay, along with its subcellular localization. To induce exon 17 skipping, the effect of 40 AONs was examined in vitro in WT WERI-Rb-1 cells and 3D human retinal organoids.
RESULTS
Late onset STGD1 in the proband suggests that c.2653+1G>A does not have a fully deleterious effect. The in vitro splice assay confirmed that this variant leads to ABCA4 transcripts without exon 17. ABCA4 Asp864_Gly863del was stable and retained 58% all-trans-retinal-activated ATPase activity compared to WT ABCA4. This sequence is located in an unstructured linker region between transmembrane domain 6 and nucleotide-binding domain-1 of ABCA4. AONs were designed to possibly reduce pathogenicity of severe variants harbored in exon 17. The best AON achieved 59% of exon 17 skipping in retinal organoids.
CONCLUSIONS
Exon 17 deletion in ABCA4 does not result in the absence of protein activity and does not cause a severe STGD1 phenotype when in trans with a null allele. By applying AONs, the effect of severe variants in exon 17 can potentially be ameliorated by exon skipping, thus generating partial ABCA4 activity in STGD1 patients.
Topics: Humans; Stargardt Disease; HEK293 Cells; Retinaldehyde; Exons; Mutant Proteins; Adenosine Triphosphatases; ATP-Binding Cassette Transporters
PubMed: 37587475
DOI: 10.1186/s12967-023-04406-x -
MBio Aug 2023is a major human pathogen and the causative agent of tuberculosis disease. is able to persist in the face of host-derived antimicrobial molecules nitric oxide (NO) and...
is a major human pathogen and the causative agent of tuberculosis disease. is able to persist in the face of host-derived antimicrobial molecules nitric oxide (NO) and copper (Cu). However, with defective proteasome activity is highly sensitive to NO and Cu, making the proteasome an attractive target for drug development. Previous work linked NO susceptibility with the accumulation of -hydroxybenzaldehyde (HBA) in mutants with defective proteasomal degradation. In this study, we found that HBA accumulation was also responsible for Cu sensitivity in these strains. We showed that exogenous addition of HBA to wild-type cultures sensitized bacteria to Cu to a degree similar to that of a proteasomal degradation mutant. We determined that HBA reduced the production and function of critical Cu resistance proteins of the egulated n opper epressor (RicR) regulon. Furthermore, we extended these Cu-sensitizing effects to an aldehyde that may face within the macrophage. Collectively, this study is the first to mechanistically propose how aldehydes can render susceptible to an existing host defense and could support a broader role for aldehydes in controlling infections. IMPORTANCE is a leading cause of death by a single infectious agent, causing 1.5 million deaths annually. An effective vaccine for infections is currently lacking, and prior infection does not typically provide robust immunity to subsequent infections. Nonetheless, immunocompetent humans can control infections for decades. For these reasons, a clear understanding of how mammalian immunity inhibits mycobacterial growth is warranted. In this study, we show aldehydes can increase susceptibility to copper, an established antibacterial metal used by immune cells to control and other microbes. Given that activated macrophages produce increased amounts of aldehydes during infection, we propose host-derived aldehydes may help control bacterial infections, making aldehydes a previously unappreciated antimicrobial defense.
Topics: Animals; Humans; Mycobacterium tuberculosis; Copper; Aldehydes; Proteasome Endopeptidase Complex; Tuberculosis; Anti-Bacterial Agents; Mammals
PubMed: 37350636
DOI: 10.1128/mbio.00363-23 -
Genome Biology Oct 2023Technologies to study localized host-pathogen interactions are urgently needed. Here, we present a spatial transcriptomics approach to simultaneously capture host and...
Technologies to study localized host-pathogen interactions are urgently needed. Here, we present a spatial transcriptomics approach to simultaneously capture host and pathogen transcriptome-wide spatial gene expression information from human formalin-fixed paraffin-embedded (FFPE) tissue sections at a near single-cell resolution. We demonstrate this methodology in lung samples from COVID-19 patients and validate our spatial detection of SARS-CoV-2 against RNAScope and in situ sequencing. Host-pathogen colocalization analysis identified putative modulators of SARS-CoV-2 infection in human lung cells. Our approach provides new insights into host response to pathogen infection through the simultaneous, unbiased detection of two transcriptomes in FFPE samples.
Topics: Humans; Transcriptome; Tissue Fixation; Formaldehyde; COVID-19; SARS-CoV-2
PubMed: 37858234
DOI: 10.1186/s13059-023-03080-y -
Journal of Inorganic Biochemistry Oct 2023Two oligonucleotide conjugates sharing the same sequence but incorporating a different 5'-terminal organometallic moiety were synthesized, by either direct mercuration...
Two oligonucleotide conjugates sharing the same sequence but incorporating a different 5'-terminal organometallic moiety were synthesized, by either direct mercuration in solution or oximation with an organomercury aldehyde on solid support. The potential of these conjugates to serve as new type of artificial ribonucleases was tested with a complementary 2´-O-methyl-RNA target sequence featuring a single cleavable RNA phosphodiester linkage. Both organomercury oligonucleotides greatly outperformed their metal-free counterparts as well as the previously reported small molecule organomercury RNA cleaving agent in catalytic activity, providing an important proof-of-concept. Compared to state-of-the-art metal-dependent artificial ribonucleases, however, the observed activity was modest.
Topics: Aldehydes; Oligonucleotides; RNA; Ribonucleases
PubMed: 37480764
DOI: 10.1016/j.jinorgbio.2023.112331 -
Scientific Reports Sep 2023Malondialdehyde (MDA) is generated in oxidized LDL. It forms covalent protein adducts, and is recognized by antibodies (anti-MDA). We previously studied IgM anti-MDA,...
Malondialdehyde (MDA) is generated in oxidized LDL. It forms covalent protein adducts, and is recognized by antibodies (anti-MDA). We previously studied IgM anti-MDA, and here we focus on IgG, IgG1 and IgG2 anti-MDA in predicting cardiovascular disease (CVD). We determined, by ELISA, anti-MDA in a 7-year follow-up of 60-year-old men and women from Stockholm County (2039 men, 2193 women). We identified 210 incident CVD cases (defined as new events of myocardial infarction (MI), and hospitalization for angina pectoris) and ischemic stroke, and 620 age- and sex-matched controls. IgG anti-MDA was not associated with CVD. Median values only differed significantly for IgG1 anti-MDA among men, with lower levels among cases than controls (p = 0.039). High IgG1 anti-MDA (above 75th percentile) was inversely associated with CVD risk after adjustment for smoking, body mass index, type 2 diabetes, hyperlipidemia, and hypertension, (OR and 95% CI: 0.59; 0.40-0.89). After stratification by sex, this association emerged in men (OR and 95% CI: 0.46; 0.27-0.77), but not in women. IgG2 anti-MDA were associated with protection in the whole group and among men though weaker than IgG1 anti-MDA. IgG2 anti-MDA above the 75th percentile was associated with an increased risk of MI/angina in women (OR and 95% CI: 2.57; (1.08-6.16)). IgG1 and less so IgG2 anti-MDA are protection markers for CVD and MI/angina in the whole group and among men. However, IgG2 anti-MDA was a risk marker for MI/angina among women. These findings could have implications for both prediction and therapy.
Topics: Male; Female; Humans; Middle Aged; Cardiovascular Diseases; Malondialdehyde; Diabetes Mellitus, Type 2; Immunoglobulin G; Myocardial Infarction; Angina Pectoris
PubMed: 37697019
DOI: 10.1038/s41598-023-42264-1 -
Nature Sep 2023Plywood is widely used in construction, such as for flooring and interior walls, as well as in the manufacture of household items such as furniture and cabinets. Such...
Plywood is widely used in construction, such as for flooring and interior walls, as well as in the manufacture of household items such as furniture and cabinets. Such items are made of wood veneers that are bonded together with adhesives such as urea-formaldehyde and phenol-formaldehyde resins. Researchers in academia and industry have long aimed to synthesize lignin-phenol-formaldehyde resin adhesives using biomass-derived lignin, a phenolic polymer that can be used to substitute the petroleum-derived phenol. However, lignin-phenol-formaldehyde resin adhesives are less attractive to plywood manufacturers than urea-formaldehyde and phenol-formaldehyde resins owing to their appearance and cost. Here we report a simple and practical strategy for preparing lignin-based wood adhesives from lignocellulosic biomass. Our strategy involves separation of uncondensed or slightly condensed lignins from biomass followed by direct application of a suspension of the lignin and water as an adhesive on wood veneers. Plywood products with superior performances could be prepared with such lignin adhesives at a wide range of hot-pressing temperatures, enabling the use of these adhesives as promising alternatives to traditional wood adhesives in different market segments. Mechanistic studies indicate that the adhesion mechanism of such lignin adhesives may involve softening of lignin by water, filling of vessels with softened lignin and crosslinking of lignins in adhesives with those in the cell wall.
Topics: Adhesives; Formaldehyde; Lignin; Phenols; Urea; Water; Wood; Biomass; Hot Temperature
PubMed: 37553075
DOI: 10.1038/s41586-023-06507-5 -
PloS One 2023Sickle cell disease (SCD) is an inherited blood disorder in which sickle hemoglobin (HbS) polymerizes, leading to red blood cell sickling and chronic hemolytic anemia,... (Meta-Analysis)
Meta-Analysis
Sickle cell disease (SCD) is an inherited blood disorder in which sickle hemoglobin (HbS) polymerizes, leading to red blood cell sickling and chronic hemolytic anemia, vaso-occlusive crises, and end-organ damage associated with early mortality. Despite standard of care, patients with SCD still experience complications and early mortality, highlighting remaining unmet treatment needs. Voxelotor is a first-in-class HbS polymerization inhibitor approved by the US Food and Drug Administration as a treatment for SCD and by the European Medicines Agency for hemolytic anemia due to SCD. In clinical studies, voxelotor has been shown to increase hemoglobin (Hb) and decrease hemolytic markers in patients with SCD. The objective of this study was to estimate the impact of voxelotor on the burden of SCD in France using a modeling approach, accounting for its anticipated adoption and diffusion over the next 5 years. We designed a sequential multi-cohort model to project and compare the cumulative incidence of SCD complications over a 20-year time horizon in a world with and without voxelotor. A distribution of patients was simulated across various levels of Hb response based on the phase 3 HOPE trial results, and relative risk reduction was adjusted using published meta-analysis results that projected risk reduction due to a 1 g/dL increase in Hb. In 6100 modeled patients with SCD treated with voxelotor, the model projected the number of deaths to decrease by 39.4%, with an increase of 1.8% in life-years gained. The model also projected life expectancy to increase by 15.8%, and incident cases of stroke, pulmonary hypertension, and chronic kidney disease to decrease by 19.8%, 24.5%, and 25.1%, respectively. The model suggests that improving Hb using a treatment such as voxelotor may have a positive public health impact by reducing the burden of SCD for patients and the healthcare system.
Topics: United States; Humans; Public Health; Anemia, Sickle Cell; Benzaldehydes; Hemoglobin, Sickle; France
PubMed: 37703228
DOI: 10.1371/journal.pone.0291211 -
Archives of Biochemistry and Biophysics Apr 2024Phospholipids are key biomolecules with important roles as components of membranes, lipoproteins and as signalling molecules. However, phospholipids are quite prone to... (Review)
Review
Phospholipids are key biomolecules with important roles as components of membranes, lipoproteins and as signalling molecules. However, phospholipids are quite prone to oxidation. Upon oxidation they generate several types of oxidation products including long chain oxidation products, as hydroperoxyl and hydroxy derivatives, and highly reactive oxidation products, like small aldehydes and truncated oxidized phospholipids. The formation of protein adducts with small electrophilic aldehydes (like malondialdehyde) is now well studied, however, the aggregation of proteins with truncated oxidized phospholipids lacks research. This paper provides a short overview of the formation of protein adducts with truncated oxidized phospholipids as well as a gathering of the research on this topic. The literature found reports the synthesis, detection and fragmentation of this type of adducts, mainly focusing on truncated oxidized phospholipid' products from phosphatidylcholine class and few peptides and proteins, as human serum albumin and Apo B100, leaving unattended the screening in vivo and in disease correlation, thus lacking possible association with their biological role. These adducts are a consequence of oxidative modifications to important biomolecules and their involvement in the organism is still unclear, revealing the urgent need for more investigation in this area.
Topics: Humans; Phospholipids; Oxidation-Reduction; Lipoproteins; Peptides; Aldehydes
PubMed: 38458481
DOI: 10.1016/j.abb.2024.109956 -
Genome Biology Nov 2023Spatial transcriptomic technologies, such as the Visium platform, measure gene expression in different regions of tissues. Here, we describe new software, STmut, to...
Spatial transcriptomic technologies, such as the Visium platform, measure gene expression in different regions of tissues. Here, we describe new software, STmut, to visualize somatic point mutations, allelic imbalance, and copy number alterations in Visium data. STmut is tested on fresh-frozen Visium data, formalin-fixed paraffin-embedded (FFPE) Visium data, and tumors with and without matching DNA sequencing data. Copy number is inferred on all conditions, but the chemistry of the FFPE platform does not permit analyses of single nucleotide variants. Taken together, we propose solutions to add the genetic dimension to spatial transcriptomic data and describe the limitations of different datatypes.
Topics: Humans; Formaldehyde; Transcriptome; Paraffin Embedding; Neoplasms; Gene Expression Profiling; High-Throughput Nucleotide Sequencing
PubMed: 38037084
DOI: 10.1186/s13059-023-03121-6