-
Pathogens (Basel, Switzerland) Oct 2023Intracellular malaria parasites activate an ion and organic solute channel on their host erythrocyte membrane to acquire a broad range of essential nutrients. This... (Review)
Review
Intracellular malaria parasites activate an ion and organic solute channel on their host erythrocyte membrane to acquire a broad range of essential nutrients. This plasmodial surface anion channel (PSAC) facilitates the uptake of sugars, amino acids, purines, some vitamins, and organic cations, but remarkably, it must exclude the small Na ion to preserve infected erythrocyte osmotic stability in plasma. Although molecular, biochemical, and structural studies have provided fundamental mechanistic insights about PSAC and advanced potent inhibitors as exciting antimalarial leads, important questions remain about how nutrients and ions are transported. Here, I review PSAC's unusual selectivity and conductance properties, which should guide future research into this important microbial ion channel.
PubMed: 37887727
DOI: 10.3390/pathogens12101211 -
Science Advances Nov 2023Biallelic genetic variants in -acetylneuraminic acid synthase (), a critical enzyme in endogenous sialic acid biosynthesis, are clinically associated with...
Biallelic genetic variants in -acetylneuraminic acid synthase (), a critical enzyme in endogenous sialic acid biosynthesis, are clinically associated with neurodevelopmental disorders. However, the mechanism underlying the neuropathological consequences has remained elusive. Here, we found that mutation resulted in the absence of both sialic acid and protein polysialylation in the cortical organoids and notably reduced the proliferation and expansion of neural progenitors. mutation dysregulated neural migration and differentiation, disturbed synapse formation, and weakened neuronal activity. Single-cell RNA sequencing revealed that loss of function markedly altered transcriptional programs involved in neuronal differentiation and ribosomal biogenesis in various neuronal cell types. Similarly, heterozygous mice exhibited impaired cortical neurogenesis and neurobehavioral deficits. Collectively, our findings reveal a crucial role of NANS-mediated endogenous sialic acid biosynthesis in regulating multiple features of human cortical development, thus linking mutation with its clinically relevant neurodevelopmental disorders.
Topics: Humans; Mice; Animals; N-Acetylneuraminic Acid; Oxo-Acid-Lyases; Organoids; Mutation; Neurogenesis
PubMed: 38000033
DOI: 10.1126/sciadv.adf2772 -
Frontiers in Cellular and Infection... 2023is a commensal skin bacterium that forms host- and antibiotic-resistant biofilms that are a major cause of implant-associated infections. Most research has focused on...
is a commensal skin bacterium that forms host- and antibiotic-resistant biofilms that are a major cause of implant-associated infections. Most research has focused on studying the responses to host-imposed stresses on planktonic bacteria. In this work, we addressed the open question of how thrives on toxic concentrations of nitric oxide (NO) produced by host innate immune cells during biofilm assembly. We analyzed alterations of gene expression, metabolism, and matrix structure of biofilms of two clinical isolates of , namely, 1457 and RP62A, formed under NO stress conditions. In both strains, NO lowers the amount of biofilm mass and causes increased production of lactate and decreased acetate excretion from biofilm glucose metabolism. Transcriptional analysis revealed that NO induces , which is directly involved in polysaccharide intercellular adhesion (PIA) production, and genes encoding proteins of the amino sugar pathway ( and ) that link glycolysis to PIA synthesis. However, the strains seem to have distinct regulatory mechanisms to boost lactate production, as NO causes a substantial upregulation of gene in strain RP62A but not in strain 1457. The analysis of the matrix components of the staphylococcal biofilms, assessed by confocal laser scanning microscopy (CLSM), showed that NO stimulates PIA and protein production and interferes with biofilm structure in a strain-dependent manner, but independently of the Ldh level. Thus, NO resistance is attained by remodeling the staphylococcal matrix architecture and adaptation of main metabolic processes, likely providing fitness of biofilms contacting NO-proficient macrophages.
Topics: Humans; Staphylococcus epidermidis; Nitrosative Stress; Staphylococcal Infections; Biofilms; Staphylococcus
PubMed: 37469594
DOI: 10.3389/fcimb.2023.1200923 -
BMC Musculoskeletal Disorders Dec 2023Current research on autophagy is mainly focused on intervertebral disc tissues and cells, while there is few on human peripheral blood sample. therefore, this study...
BACKGROUND
Current research on autophagy is mainly focused on intervertebral disc tissues and cells, while there is few on human peripheral blood sample. therefore, this study constructed a diagnostic model to identify autophagy-related markers of intervertebral disc degeneration (IVDD).
METHODS
GSE150408 and GSE124272 datasets were acquired from the Gene Expression Omnibus database, and differential expression analysis was performed. The IVDD-autophagy genes were obtained using Weighted Gene Coexpression Network Analysis, and a diagnostic model was constructed and validated, followed by Gene Set Variation Analysis (GSVA) and Gene Set Enrichment Analysis (GSEA). Meanwhile, miRNA-gene and transcription factor-gene interaction networks were constructed. In addition, drug-gene interactions and target genes of methylprednisolone and glucosamine were analyzed.
RESULTS
A total of 1,776 differentially expressed genes were identified between IVDD and control samples, and the composition of the four immune cell types was significantly different between the IVDD and control samples. The Meturquoise and Mebrown modules were significantly related to immune cells, with significant differences between the control and IVDD samples. A diagnostic model was constructed using five key IVDD-autophagy genes. The area under the curve values of the model in the training and validation datasets were 0.907 and 0.984, respectively. The enrichment scores of the two pathways were significantly different between the IVDD and healthy groups. Eight pathways in the IVDD and healthy groups had significant differences. A total of 16 miRNAs and 3 transcription factors were predicted to be of great value. In total, 84 significantly related drugs were screened for five key IVDD-autophagy genes in the diagnostic model, and three common autophagy-related target genes of methylprednisolone and glucosamine were predicted.
CONCLUSION
This study constructs a reliable autophagy-related diagnostic model that is strongly related to the immune microenvironment of IVD. Autophagy-related genes, including PHF23, RAB24, STAT3, TOMM5, and DNAJB9, may participate in IVDD pathogenesis. In addition, methylprednisolone and glucosamine may exert therapeutic effects on IVDD by targeting CTSD, VEGFA, and BAX genes through apoptosis, as well as the sphingolipid and AGE-RAGE signaling pathways in diabetic complications.
Topics: Humans; Intervertebral Disc Degeneration; Intervertebral Disc; Transcription Factors; Autophagy; Methylprednisolone; Glucosamine; Membrane Proteins; Molecular Chaperones; HSP40 Heat-Shock Proteins; Homeodomain Proteins
PubMed: 38041088
DOI: 10.1186/s12891-023-06886-w -
Environment International Aug 2023Breast cancer is now the most common cancer globally, accounting for 12% of all new annual cancer cases worldwide. Despite epidemiologic studies having established a...
Breast cancer is now the most common cancer globally, accounting for 12% of all new annual cancer cases worldwide. Despite epidemiologic studies having established a number of risk factors, knowledge of chemical exposure risks is limited to a relatively small number of chemicals. In this exposome research study, we used non-targeted, high-resolution mass spectrometry of pregnancy cohort biospecimens in the Child Health and Development Studies to test for associations with breast cancer identified via the California Cancer Registry. Second and third trimester archival samples were analyzed from 182 women who subsequently developed breast cancer and 384 randomly selected women who did not develop breast cancer. Environmental chemicals were annotated with the Toxin and Toxin-Target Database for chemical signals that were higher in breast cancer cases and used with an exposome epidemiology analytic framework to identify suspect chemicals and associated metabolic networks. Network and pathway enrichment analyses showed consistent linkage in both second and third trimesters to inflammation pathways, including linoleate, arachidonic acid and prostaglandins, and identified new suspect environmental chemicals associated with breast cancer, i.e., an N-substituted piperidine insecticide and a common commercial product, 2,4-dinitrophenol, linked to variations in amino acid and nucleotide pathways in second trimester and benzo[a]carbazole and a benzoate derivative linked to glycan and amino sugar metabolism in third trimester. The results identify new suspect environmental chemical risk factors for breast cancer and provide an exposome epidemiology framework for discovery of suspect environmental chemicals and potential mechanistic associations with breast cancer.
Topics: Female; Humans; Pregnancy; Amino Acids; Breast Neoplasms; Environmental Exposure; Exposome; Mass Spectrometry
PubMed: 37517180
DOI: 10.1016/j.envint.2023.108112 -
Foods (Basel, Switzerland) Jul 2023With the increasing global nutritional bar market, developing and formulating innovative high-energy and protein bars to compensate for nutrients using date fruits is...
With the increasing global nutritional bar market, developing and formulating innovative high-energy and protein bars to compensate for nutrients using date fruits is beneficial for health-conscious individuals. The current research was undertaken to study the composition and physicochemical characteristics of innovative high-energy and high-protein bars using two combinations of Sukkari dates or fruit mixtures as a base. Fifty percent of either Sukkari date paste or dried fruit mixture (25% raisin, 12.5% fig, and 12.5% apricot) combined with other different ingredients was used to produce a date-based bar (DBB) or fruit-based bar (FBB). Proximate composition, sugar content, amino and fatty acid profiles, minerals and vitamins, phytochemicals, antioxidant activity, and visual color parameters of the DBB and the FBB were determined and statistically compared. Proximate analysis revealed higher moisture and fat content in the FBB than the DBB, while ash and crude fiber were higher in the DBB than the FBB. The protein content in the DBB and the FBB was not statistically different. Both prepared bars exuded around 376-378 kcal 100 g fresh weight. Sugar profile analysis of the DBB and the FBB showed dependable changes based on date or fruit content. Fructose, glucose, and maltose contents were higher in the FBB than in the DBB, while sucrose content was higher in the DBB than in the FBB. The DBB showed significantly higher content in Ca, Cu, Fe, Zn, Mn, and Se and significantly lower content in Mg, K, and Na than the FBB, with no variation in phosphorus content. The DBB and the FBB contained both essential (EAA) and non-essential (NEAA) amino acids. The DBB scored higher Lysine, Methionine, Histidine, Threonine, Phenylalanine, Isoleucine, and Cystine contents than the FBB, while the FBB scored only higher Leucine and Valine contents than the DBB. Seventeen saturated fatty acids were identified in the DBB and the FBB, with Palmitic acid (C16:0) as the predominant fatty acid. Oleic acid (C18:1n9c) was predominant among seven determined monounsaturated fatty acids. Linoleic fatty acid (C18:2n6c) was predominant among eight identified polyunsaturated fatty acids. In addition, α-Linolenic (C18:3n3) was detected in a considerable amount. However, in both the DBB and the FBB, the content and distribution of fatty acids were not remarkably changed. Regarding phytochemicals and bioactive compounds, the FBB was significantly higher in total phenolic content (TPC), total flavonoids (TF), and total flavonols (TFL) contents and scavenging activity against DPPH and ABTS free radicals than the DBB. The DBB and the FBB showed positive a* values, indicating a reddish color. The b* values were 27.81 and 28.54 for the DBB and the FBB, respectively. The DBB is affected by the lower L* value and higher browning index (BI) to make its color brownish. Sensory evaluation data showed that panelists significantly preferred the DBB over the FBB. In conclusion, processing and comparing these bars indicated that using Sukkari dates is a nutrient-dense, convenient, economical, and better sugar alternative that helps combat the calorie content. Thus, scaling up the use of dates instead of fruits in producing high-energy and protein bars commercially is highly recommended.
PubMed: 37509869
DOI: 10.3390/foods12142777 -
Nature Chemical Biology May 2024Amyloid-forming proteins such α-synuclein and tau, which are implicated in Alzheimer's and Parkinson's disease, can form different fibril structures or strains with...
Amyloid-forming proteins such α-synuclein and tau, which are implicated in Alzheimer's and Parkinson's disease, can form different fibril structures or strains with distinct toxic properties, seeding activities and pathology. Understanding the determinants contributing to the formation of different amyloid features could open new avenues for developing disease-specific diagnostics and therapies. Here we report that O-GlcNAc modification of α-synuclein monomers results in the formation of amyloid fibril with distinct core structure, as revealed by cryogenic electron microscopy, and diminished seeding activity in seeding-based neuronal and rodent models of Parkinson's disease. Although the mechanisms underpinning the seeding neutralization activity of the O-GlcNAc-modified fibrils remain unclear, our in vitro mechanistic studies indicate that heat shock proteins interactions with O-GlcNAc fibril inhibit their seeding activity, suggesting that the O-GlcNAc modification may alter the interactome of the α-synuclein fibrils in ways that lead to reduce seeding activity in vivo. Our results show that posttranslational modifications, such as O-GlcNAc modification, of α-synuclein are key determinants of α-synuclein amyloid strains and pathogenicity.
Topics: alpha-Synuclein; Amyloid; Humans; Animals; Mice; Parkinson Disease; Acetylglucosamine; Protein Processing, Post-Translational; Cryoelectron Microscopy; Neurons
PubMed: 38347213
DOI: 10.1038/s41589-024-01551-2 -
Foods (Basel, Switzerland) Aug 2023Wheat is a staple crop, consumed worldwide as a major source of starch and protein. Global intake of wheat has increased in recent years, and overall, wheat is... (Review)
Review
Wheat is a staple crop, consumed worldwide as a major source of starch and protein. Global intake of wheat has increased in recent years, and overall, wheat is considered to be a healthy food, particularly when products are made from whole grains. However, wheat is almost invariably processed before it is consumed, usually via baking and/or toasting, and this can lead to the formation of toxic processing contaminants, including acrylamide, 5-hydroxymethylfurfural (HMF) and polycyclic aromatic hydrocarbons (PAHs). Acrylamide is principally formed from free (soluble, non-protein) asparagine and reducing sugars (glucose, fructose and maltose) within the Maillard reaction and is classified as a Group 2A carcinogen (probably carcinogenic to humans). It also has neurotoxic and developmental effects at high doses. HMF is also generated within the Maillard reaction but can also be formed via the dehydration of fructose or caramelisation. It is frequently found in bread, biscuits, cookies, and cakes. Its molecular structure points to genotoxicity and carcinogenic risks. PAHs are a large class of chemical compounds, many of which are genotoxic, mutagenic, teratogenic and carcinogenic. They are mostly formed during frying, baking and grilling due to incomplete combustion of organic matter. Production of these processing contaminants can be reduced with changes in recipe and processing parameters, along with effective quality control measures. However, in the case of acrylamide and HMF, their formation is also highly dependent on the concentrations of precursors in the grain. Here, we review the synthesis of these contaminants, factors impacting their production and the mitigation measures that can be taken to reduce their formation in wheat products, focusing on the role of genetics and agronomy. We also review the risk management measures adopted by food safety authorities around the world.
PubMed: 37685197
DOI: 10.3390/foods12173264 -
Biomedicine & Pharmacotherapy =... Oct 2023Lung injury and pulmonary fibrosis contribute to morbidity and mortality, and, in particular, are characterized as leading cause on confirmed COVID-19 death. To date,...
Lung injury and pulmonary fibrosis contribute to morbidity and mortality, and, in particular, are characterized as leading cause on confirmed COVID-19 death. To date, efficient therapeutic approach for such lung diseases is lacking. N-Acetylglucosamine (NAG), an acetylated derivative of glucosamine, has been proposed as a potential protector of lung function in several types of lung diseases. The mechanism by which NAG protects against lung injury, however, remains unclear. Here, we show that NAG treatment improves pulmonary function in bleomycin (BLM)-induced lung injury model measured by flexiVent system. At early phase of lung injury, NAG treatment results in silenced immune response by targeting ARG1 macrophages activation, and, consequently, blocks KRT8 transitional stem cell in the alveolar region to stimulate PDGF Rβ fibroblasts hyperproliferation, thereby attenuating the pulmonary fibrosis. This combinational depression of immune response and extracellular matrix deposition within the lung mitigates lung injury and pulmonary fibrosis induced by BLM. Our findings provide novel insight into the protective role of NAG in lung injury.
Topics: Humans; Pulmonary Fibrosis; Lung Injury; Acetylglucosamine; Bleomycin; COVID-19
PubMed: 37633052
DOI: 10.1016/j.biopha.2023.115069 -
Journal of Translational Medicine Mar 2024Intratumoral bacteria might play essential roles in tumorigenesis in different cancer types. However, its features and potential roles in hepatocellular carcinoma (HCC)...
BACKGROUND
Intratumoral bacteria might play essential roles in tumorigenesis in different cancer types. However, its features and potential roles in hepatocellular carcinoma (HCC) are largely unknown.
METHODS
In this study, we assessed bacterial RNA by 16S rRNA fluorescence in situ hybridization and detected bacterial lipopolysaccharide (LPS) via immunohistochemistry. Hepa1-6 cells were used to establish orthotopic HCC models in mice. 2bRAD sequencing for microbiome was performed to determine the intratumoral bacterial characteristics, and liquid chromatography-mass spectrometry was conducted to explore the metabolic profile. The potential association between different intratumoral microbiota and metabolites were evaluated.
RESULTS
We detected bacterial 16S rRNA and LPS in HCC tissues from the patients with HCC. In HCC mouse model, we found that the intratumor bacteria in HCC tissues were significantly different to adjacent nontumor tissues. Furthermore, we observed different metabolites in HCC tissues and adjacent nontumor tissues, such as N-acetyl-D-glucosamine and a-lactose. Our results showed that several bacteria were significantly associated with metabolites, such as Pseudomonas koreensis, which was positively correlated with N-acetyl-D-glucosamine and negatively correlated with citrulline.
CONCLUSIONS
This study confirmed the close association between different bacteria and metabolites, which might provide novel opportunities for developing new biomarkers and therapeutic targets for HCC.
Topics: Humans; Mice; Animals; Carcinoma, Hepatocellular; RNA, Ribosomal, 16S; Acetylglucosamine; In Situ Hybridization, Fluorescence; Lipopolysaccharides; Liver Neoplasms; Mice, Inbred Strains; Bacteria
PubMed: 38439045
DOI: 10.1186/s12967-024-05036-7