PubMed

J Diabetes Metab Disord. 2021 Jan 20;23(2):1809-1816. doi: 10.1007/s40200-020-00714-x. eCollection 2024 Dec.ABSTRACTBACKGROUND: Endocrinology and Metabolism Research Institute (EMRI) is one of the biggest research institutes in Iran that was established to develop research strategies for managing endocrine and metabolic disorders such as diabetes. The aim of this study was to provide an overview of diabetes related research activities and achievements in the EMRI since its foundation.METHOD: A comprehensive search was conducted in the PubMed, Scopus, and EMBASE to find out diabetes-related research studies performed in the EMRI. After data extraction, articles were categorized based on their document types, levels of evidence, diabetes types, and subject areas and were presented in various charts.RESULT: After removing duplications and screening, 228 remained documents were categorized. The majority of diabetes investigations performed in the Diabetes Research Center (DRC) was on type 2 diabetes (T2D) (37%). Based on document types, most of these publications were original articles. Moreover, clinical studies constituted the greatest amount of evidence in the literature. According to the subject areas, most of the articles were on basic sciences and diabetes-related associated factors, followed by studies related to the management and prevention of diabetes.CONCLUSIONS: As one of the most comprehensive research institute, the EMRI has developed its national and international research activities to improve diabetes management and cure through developing new treatment strategies, improving translational research, and applying new emerging technologies such as regenerative medicine.PMID:39610497 | PMC:PMC11599651 | DOI:10.1007/s40200-020-00714-x

J Diabetes Metab Disord. 2024 Jul 20;23(2):2031-2042. doi: 10.1007/s40200-024-01462-y. eCollection 2024 Dec.ABSTRACTOBJECTIVES: Diabetic retinopathy (DR), an earnest complication of diabetes, is one of the most common causes of blindness worldwide. This study aimed to investigate the altered metabolites in the serum of non-DR (NDR) and DR including non-proliferative diabetic retinopathy (NPDR), and proliferative diabetic retinopathy (PDR) subjects.METHODS: In this study, the 1HNMR platform was applied to reveal the discriminating serum metabolites in three diabetic groups based on the status of their complications: T2D or NDR (n = 15), NPDR, (n = 15), and PDR (n = 15) groups. Multivariate analyses include principal component analysis (PCA) and Partial Least Structures-Discriminant Analysis (PLS-DA) analysis that were performed using R software. The main metabolic pathways were also revealed by KEGG pathway enrichment analysis.RESULTS: The results revealed the significantly different metabolites include 10 metabolites of the NPDR versus PDR group, 24 metabolites of the PDR versus NDR group, and 25 metabolites of the NPDR versus NDR group. The results showed that the significantly altered metabolites in DR compared with NDR serum samples mainly belonged to amino acids. The most important pathways between NPDR/PDR, and NDR/DR groups include ascorbate and aldarate metabolism, galactose metabolism, glutathione metabolism, and tryptophan metabolism, respectively. In addition, some metabolites were detected for the first time.CONCLUSIONS: We created a metabolomics profile for NDR, PDR and NPDR groups. The impairment in the ascorbate/aldarate, galactose, and especially amino acids metabolism was identified as metabolic dysregulation associated with DR, which may provide new insights into potential pathogenesis pathways for DR.PMID:39610496 | PMC:PMC11599686 | DOI:10.1007/s40200-024-01462-y

J Diabetes Metab Disord. 2021 Jan 19;23(2):1539-1544. doi: 10.1007/s40200-021-00727-0. eCollection 2024 Dec.ABSTRACTOBJECTIVE: The aim of this study was to evaluate the status of scientific research output of omics in regards to human diseases with more attention shifted toward endocrine and metabolism disorders in Iran, in order to find scientific gaps and also to design future plans for further investigations in this field.METHODS: Extensive search was performed in the electronic databases of Scopus and PubMed, and documents published by Iranian authors up to 27 December 2020 were extracted. Articles related to human diseases were included and categorized based on their types and topics.RESULTS: A total of 904 publications were found. Followed by checking their titles and abstracts, 327 studies were included. The trend of publication has been increasing during the past years. Regarding this subject, the highest number of publications was in the field of malignant disorders with 82 publications followed by reproductive system diseases and infectious diseases with 33 publications in each subject. Only 12 articles were found in the field of endocrinology and metabolism. The most popular techniques used in those reports were two-dimensional electrophoresis coupled with mass spectrometry (34.4 %) followed by NMR (22.6 %), LC/MS/MS (15 %).CONCLUSIONS: Omics studies in Iran are a relatively new approach and the number of original articles regarding endocrine disorders in humans is limited. Providing appropriate infrastructures including lab facilities with high technology instruments can improve the quality and quantity of basic and clinical researches in this field.PMID:39610495 | PMC:PMC11599483 | DOI:10.1007/s40200-021-00727-0

Public Health Nutr. 2024 Nov 29:1-13. doi: 10.1017/S1368980024002271. Online ahead of print.ABSTRACTOBJECTIVE: Neural tube defects (NTDs) are serious, life-threatening birth defects. Staple food fortification with folic acid (vitamin B9) is a proven, effective intervention to reduce NTD birth prevalence. Mandatory food fortification with folic acid was implemented in South Africa (SA) in 2003. This article provides an overview of NTD birth prevalence in SA, pre- and post-fortification, and evaluates current folic acid fortification regulations.DESIGN: Fortification effectiveness data in SA were reviewed using published studies and national reports on NTD birth prevalence pre- and post-folic acid fortification. Current folic acid fortification regulations in SA were evaluated by experts.SETTING: Regulations were assessed using national health guidelines, legislation and regulations. NTD birth prevalence data were sourced from the published literature.PARTICIPANTS: None.RESULTS: Significant reductions in the birth prevalence of spina bifida and anencephaly, and improved maternal folate levels have been achieved following the introduction of folic acid fortification in SA. However, there is poor overall regulatory compliance in some instances and a gap in current regulations that excludes the fortification of cake flour in SA.CONCLUSIONS: While the SA NTD birth prevalence has decreased post-fortification, the regulatory exclusion of cake flour fortification is a significant and growing issue. Proposed 2016 regulatory amendments to address this gap urgently require finalisation and enactment by government to prevent negating benefits achieved to date and to ensure continued improvement. Fortification monitoring requires strengthening to ensure widespread compliance with policies, particularly in underserved areas.PMID:39610362 | DOI:10.1017/S1368980024002271

Diabetes Metab J. 2024 Nov;48(6):1047-1055. doi: 10.4093/dmj.2024.0659. Epub 2024 Nov 21.ABSTRACTThe consumption of ultra-processed foods (UPFs) has surged globally, raising significant public health concerns due to their associations with a range of adverse health outcomes. This review aims to elucidate potential health impacts of UPF intake and underscore the importance of considering diet quality when interpreting study findings. UPF group, as classified by the Nova system based on the extent of industrial processing, contains numerous individual food items with a wide spectrum of nutrient profiles, as well as differential quality as reflected by their potential health effects. The quality of a given food may well misalign with the processing levels so that a UPF food can be nutritious and healthful whereas a non-UPF food can be of low quality and excess intake of which may lead to adverse health consequences. The current review argues that it is critical to focus on the nutritional content and quality of foods and their role within the overall dietary pattern rather than only the level of processing. Further research should dissect health effects of diet quality and food processing, investigate the health impacts of ingredients that render the UPF categorization, understand roles of metabolomics and the gut microbiome in mediating and modulating the health effects of food processing, and consider environmental sustainability in UPF studies. Emphasizing nutrient-dense healthful foods and dietary patterns shall remain the pivotal strategy for promoting overall health and preventing chronic diseases.PMID:39610133 | DOI:10.4093/dmj.2024.0659

Neural Regen Res. 2025 Oct 1;20(10):2982-2997. doi: 10.4103/NRR.NRR-D-23-01979. Epub 2024 Jun 26.ABSTRACTJOURNAL/nrgr/04.03/01300535-202510000-00028/figure1/v/2024-11-26T163120Z/r/image-tiff Alzheimer's disease not only affects the brain, but also induces metabolic dysfunction in peripheral organs and alters the gut microbiota. The aim of this study was to investigate systemic changes that occur in Alzheimer's disease, in particular the association between changes in peripheral organ metabolism, changes in gut microbial composition, and Alzheimer's disease development. To do this, we analyzed peripheral organ metabolism and the gut microbiota in amyloid precursor protein-presenilin 1 (APP/PS1) transgenic and control mice at 3, 6, 9, and 12 months of age. Twelve-month-old APP/PS1 mice exhibited cognitive impairment, Alzheimer's disease-related brain changes, distinctive metabolic disturbances in peripheral organs and fecal samples (as detected by untargeted metabolomics sequencing), and substantial changes in gut microbial composition compared with younger APP/PS1 mice. Notably, a strong correlation emerged between the gut microbiota and kidney metabolism in APP/PS1 mice. These findings suggest that alterations in peripheral organ metabolism and the gut microbiota are closely related to Alzheimer's disease development, indicating potential new directions for therapeutic strategies.PMID:39610107 | DOI:10.4103/NRR.NRR-D-23-01979

Environ Health. 2024 Nov 28;23(1):105. doi: 10.1186/s12940-024-01145-4.ABSTRACTBACKGROUND: Perfluoroalkyl and polyfluoroalkyl substances (PFAS) exposure has been associated with metabolic diseases, however, the underlying molecular pathogenesis remains to be understood. Integrated PFAS and lipidomic analysis has the potential to identify alterations in lipid metabolism pathways for exposome research.METHODS: A targeted LC-MS/MS method was developed for the quantification of 14 PFAS from human plasma samples (n = 96). Concurrently, high coverage lipidomics was conducted for the quantification of 665 lipid species in the same plasma samples. Linear regression models were implemented to study the association of PFAS with plasma lipidome.RESULTS: Women had lower levels of PFAS compared to men and Asian-Indians had lower levels of PFAS compared to both Chinese and Malay subjects. PFAS were positively associated with a number of lipid species from lysophospholipid, ceramide and triacylglycerol lipid classes. Phosphatidylinositol, acylcarnitine and sphingosine-1-phosphate were negatively associated with PFAS. Association studies revealed both shared and distinct relationship of PFAS with plasma lipids.CONCLUSIONS: We demonstrate that the circulating levels of PFAS vary with age, ethnicity and sex within a multi-ethnic Asian population with potential implications in future biomonitoring and mitigation. Our comprehensive lipidomics methodology and association studies enabled us to characterize the relationship of circulating PFAS and lipidomic profiles. These results will help in better understanding of the molecular basis of PFAS exposure on human health outcomes.PMID:39609840 | DOI:10.1186/s12940-024-01145-4

Cell Biosci. 2024 Nov 28;14(1):145. doi: 10.1186/s13578-024-01322-5.ABSTRACTBACKGROUND: The increasing incidence of childhood obesity annually has led to a surge in physical and mental health risks, making it a significant global public health concern. This study aimed to discover novel biomarkers of childhood simple obesity through integrative multi-omics analysis, uncovering their potential connections and providing fresh research directions for the complex pathogenesis and treatment strategies.METHODS: Transcriptome, untargeted metabolome, and 16 S rDNA sequencing were conducted on subjects to examine transcripts, metabolites in blood, and gut microflora in stool.RESULTS: Transcriptomic analysis identified 599 differentially expressed genes (DEGs), of which 25 were immune-related genes, and participated in immune pathways such as antimicrobial peptides, neutrophil degranulation, and interferons. The optimal random forest model based on these genes exhibited an AUC of 0.844. The metabolomic analysis examined 71 differentially expressed metabolites (DEMs), including 12 immune-related metabolites. Notably, lauric acid showed an extremely strong positive correlation with BMI and showed a good discriminative power for obesity (AUC = 0.82). DEMs were found to be significantly enriched in four metabolic pathways, namely "Aminoacyl-tRNA biosynthesis", "Valine leucine and isoleucine biosynthesis, and Glycine", "Serine and threonine metabolism", and "Biosynthesis of unsaturated fatty acids". Microbiome analysis revealed 12 differential gut microbiotas (DGMs) at the phylum and genus levels, with p_Firmicutes dominating in the obese group and g_Escherichia-Shigella in the normal group. Subsequently, a Random Forest model was developed based on the DEMs, immune-related DEGs, and metabolites with an AUC value of 0.912. The 14 indicators identified by this model could potentially serve as a set of biomarkers for obesity. The analysis of the inter-omics correlation network found 233 pairs of significant correlations. DEGs BPIFA1, BPI, and SAA1, DEMs Dimethy(tetradecyl)amine, Deoxycholic acid, Pathalic anhydride, and DL-Alanine, and DGMs g_Intestinimonas and g_Turicibacter showed strong connectivity within the network, constituting a large proportion of interactions.CONCLUSION: This study presents the first comprehensive description of the multi-omics characteristics of childhood simple obesity, recognizing promising biomarkers. Immune-related markers offer a new perspective for researching the immunological mechanisms underlying obesity and its associated complications. The revealed interactions among these biomarkers contribute to a deeper understanding the intricate biological regulatory networks associated with obesity.PMID:39609876 | DOI:10.1186/s13578-024-01322-5

IMA Fungus. 2024 Nov 28;15(1):38. doi: 10.1186/s43008-024-00167-4.ABSTRACTFungi are known to produce many chemically diversified metabolites, yet their ecological roles are not always fully understood. The blue cheese fungus Penicillium roqueforti thrives in different ecological niches and is known to produce a wide range of metabolites, including mycotoxins. Three P. roqueforti populations have been domesticated for cheese production and two populations thrive in other anthropized environments, i.e., food, lumber and silage. In this study, we looked for differences in targeted and untargeted metabolite production profiles between populations using HPLC-HR-Q-TOF and UHPLC-Q-TOF-HR-MS/MS. The non-cheese populations produced several fatty acids and different terpenoids, lacking in cheese strains. The Termignon cheese population displayed intermediate metabolite profiles between cheese and non-cheese populations, as previously shown for other traits. The non-Roquefort cheese population with the strongest domestication syndrome, produced the lowest quantities of measured metabolites, including mycophenolic acid (MPA), andrastin A and PR toxin. Its inability to produce MPA was due to a deletion in the mpaC gene, while a premature stop codon in ORF 11 of the PR toxin gene cluster explained PR toxin absence and the accumulation of its intermediates, i.e., eremofortins A and B. In the Roquefort population, we detected no PR toxin nor eremofortins A or B, but found no indel or frameshift mutation, suggesting downregulation. The hypotoxigenic trait of domesticated cheese populations can be hypothesized to be linked to the loss of this ability through trait degeneration and/or the selection of low toxin producers. It may also be due to the fact that populations from other anthropized environments maintained high metabolite diversity as the bioactivities of these compounds are likely important in these ecological niches.PMID:39609866 | DOI:10.1186/s43008-024-00167-4

J Transl Med. 2024 Nov 28;22(1):1077. doi: 10.1186/s12967-024-05796-2.ABSTRACTBACKGROUND: Although research has indicated correlations between lipids, cerebrospinal fluid (CSF) metabolites, and Late-Onset Alzheimer's Disease (LOAD), the specific causal relationships among these elements, as well as the roles and mechanisms of the cerebrospinal fluid metabolites, remain unclear.METHODS: Statistical datasets derived from Genome-Wide Association Studies (GWAS) were utilized to assess the bidirectional causal relationships between lipids and LOAD. Subsequently, genetic variants associated with CSF metabolites and established lipids underwent a two-step Mendelian randomization (MR) analysis to explore potential mediators and analyze mediation effects. Sensitivity analyses were employed to assess the robustness of the detection systems.RESULTS: Genetically predicted cholesterol (IVW OR = 0.989; 95% CI 0.982-0.996) was found to reduce the risk of LOAD, whereas Phosphatidylcholine (PC) (18:1_0:0) (IVW OR = 1.015; 95% CI 1.005-1.025) posed a risk factor. The potential mediator, CSF metabolite N-acetylneuraminate (NeuAC), was identified with a mediation proportion of 21.02% (3.25%, 45.50%). No pleiotropy or heterogeneity was detected across MR analyses.CONCLUSIONS: The findings underscore the pivotal role of CSF metabolomics in elucidating the lipid-mediated pathogenesis of LOAD, highlighting potential diagnostic and preventative biomarkers.PMID:39609832 | DOI:10.1186/s12967-024-05796-2

Sci Rep. 2024 Nov 28;14(1):29621. doi: 10.1038/s41598-024-81321-1.ABSTRACTDiet is a potentially modifiable neurodegenerative disease risk factor. We studied the effects of a typical Western diet (WD; high in refined carbohydrates, cholesterol and saturated fat), relative to a heart-healthy diet (HHD; high in unrefined carbohydrates, polyunsaturated fat and fiber, and low in cholesterol) on brain microvessel transcriptomics and brain metabolomics of the temporal region in Ossabaw minipigs. Thirty-two pigs (16 male and 16 females) were fed a WD or HHD starting at the age of 4 months for a period of 6 months. The WD and HHD were isocaloric and had a similar macronutrient content but differed in macronutrient quality. Within each dietary group, half of the pigs also received atorvastatin. Relative to HHD-fed pigs, WD-fed pigs had 175 genes differentially expressed (fold change > 1.3, FDR < 0.05) by diet, 46 upregulated and 129 downregulated. Gene Set Enrichment Analysis identified 22 gene sets enriched in WD-fed pigs, comprising pathways related to inflammation, angiogenesis, and apoptosis, and 53 gene sets enriched in the HHD-fed pigs, including cell energetics, neurotransmission, and inflammation resolution pathways. Metabolite analysis showed enrichment in arginine, tyrosine, and lysine in WD-fed pigs, and ergothioneine and S-adenosyl methionine in HHD-fed pigs. Atorvastatin treatment did not affect gene expression. These results suggest a likely contribution of diet to brain pathologies characterized by neuroinflammation and neurodegeneration.PMID:39609531 | DOI:10.1038/s41598-024-81321-1

Sci Rep. 2024 Nov 28;14(1):29570. doi: 10.1038/s41598-024-80955-5.ABSTRACTMass spectrometry (MS)-based metabolomics analysis is a powerful tool, but it comes with its own set of challenges. The MS workflow involves multiple steps before its interpretation in what is denominate data mining. Data mining consists of a two-step process. First, the MS data is ordered, arranged, and presented for filtering before being analyzed. Second, the filtered and reduced data are analyzed using statistics to remove further variability. This holds true particularly for MS-based untargeted metabolomics studies, which focused on understanding fold changes in metabolic networks. Since the task of filtering and identifying changes from a large dataset is challenging, automated techniques for mining untargeted MS-based metabolomic data are needed. The traditional statistics-based approach tends to overfilter raw data, which may result in the removal of relevant data and lead to the identification of fewer metabolomic changes. This limitation of the traditional approach underscores the need for a new method. In this work, we present a novel deep learning approach using node embeddings (powered by GNNs), edge embeddings, and anomaly detection algorithm to analyze the data generated by mass spectrometry (MS)-based metabolomics called GEMNA (Graph Embedding-based Metabolomics Network Analysis), for example for an untargeted volatile study on Mentos candy, the data clusters produced by GEMNA were better than the ones used traditional tools, i.e., GEMNA has [Formula: see text], vs. the traditional approach has [Formula: see text].PMID:39609505 | DOI:10.1038/s41598-024-80955-5

Sci Rep. 2024 Nov 28;14(1):29632. doi: 10.1038/s41598-024-78537-6.NO ABSTRACTPMID:39609490 | DOI:10.1038/s41598-024-78537-6

Cell Death Discov. 2024 Nov 28;10(1):484. doi: 10.1038/s41420-024-02232-8.ABSTRACTArrhythmogenic Cardiomyopathy (ACM) is a life-threatening, genetically determined disease primarily caused by mutations in desmosomal genes, such as PKP2. Currently, there is no etiological therapy for ACM due to its complex and not fully elucidated pathogenesis. Various cardiac cell types affected by the genetic mutation, such as cardiomyocytes (CM) and cardiac mesenchymal stromal cells (cMSC), individually contribute to the ACM phenotype, driving functional abnormalities and fibro-fatty substitution, respectively. However, the relative importance of the CM and cMSC alterations, as well as their reciprocal influence in disease progression remain poorly understood. We hypothesised that ACM-dependent phenotypes are driven not only by alterations in individual cell types but also by the reciprocal interactions between CM and cMSC, which may further impact disease pathogenesis. We utilized a patient-specific, multicellular cardiac system composed of either control or PKP2-mutated CM and cMSC to assess the mutation's role in fibro-fatty phenotype by immunofluorescence, and contractile behaviour of co-cultures using cell motion detection software. Additionally, we investigated reciprocal interactions both in silico and via multi-targeted proteomics. We demonstrated that ACM CM can promote fibro-adipose differentiation of cMSC. Conversely, ACM cMSC contribute to increasing the rate of abnormal contractile events with likely arrhythmic significance. Furthermore, we showed that an ACM-causative mutation alters the CM-cMSC interaction pattern. We identified the CM-sourced DLK1 as a novel regulator of fibro-adipose remodelling in ACM. Our study challenges the paradigm of exclusive cell-specific mechanisms in ACM. A deeper understanding of the cell-cell influence is crucial for identifying novel therapeutic targets for ACM, and this concept is exploitable for other cardiomyopathies.PMID:39609399 | DOI:10.1038/s41420-024-02232-8

Nat Commun. 2024 Nov 28;15(1):9903. doi: 10.1038/s41467-024-54137-w.ABSTRACTLipidomics and metabolomics communities comprise various informatics tools; however, software programs handling multimodal mass spectrometry (MS) data with structural annotations guided by the Lipidomics Standards Initiative are limited. Here, we provide MS-DIAL 5 for in-depth lipidome structural elucidation through electron-activated dissociation (EAD)-based tandem MS and determining their molecular localization through MS imaging (MSI) data using a species/tissue-specific lipidome database containing the predicted collision-cross section values. With the optimized EAD settings using 14 eV kinetic energy, the program correctly delineated lipid structures for 96.4% of authentic standards, among which 78.0% had the sn-, OH-, and/or C = C positions correctly assigned at concentrations exceeding 1 μM. We showcased our workflow by annotating the sn- and double-bond positions of eye-specific phosphatidylcholines containing very-long-chain polyunsaturated fatty acids (VLC-PUFAs), characterized as PC n-3-VLC-PUFA/FA. Using MSI data from the eye and n-3-VLC-PUFA-supplemented HeLa cells, we identified glycerol 3-phosphate acyltransferase as an enzyme candidate responsible for incorporating n-3 VLC-PUFAs into the sn1 position of phospholipids in mammalian cells, which was confirmed using EAD-MS/MS and recombinant proteins in a cell-free system. Therefore, the MS-DIAL 5 environment, combined with optimized MS data acquisition methods, facilitates a better understanding of lipid structures and their localization, offering insights into lipid biology.PMID:39609386 | DOI:10.1038/s41467-024-54137-w

Phytochem Anal. 2024 Nov 28. doi: 10.1002/pca.3481. Online ahead of print.ABSTRACTINTRODUCTION: Determining the bittering profile of hops is a prerequisite for their use in beer making industry. To fully grasp the brewing potential of Corsican hops, it is therefore essential to perform a precise quantification of the molecules responsible for their bittering power.OBJECTIVE: The aim of this study is highlighting of the bittering profile of Corsican hops.METHODOLOGY: A method for the characterization and quantification of α-acids, β-acids, and phenolic compounds in Corsican hops using high performance liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) has been developed. In addition to the six α- and β-acids commonly quantified in hops, seven others hop acids were identified using a new methodology based on the analysis of their fragmentation pattern in full-scan detection mode. The compounds were then quantified as humulone or lupulone equivalents. Subsequently, a metabolomic analysis of hop cones was conducted using the method of molecular networking.RESULTS: A total of 28 compounds were quantified. The influence of both annual climate variations and transplantation on the chemical composition of hops extractives was highlighted. The molecular network elucidation led to the identification of 34 compounds. Among them, eight were previously undescribed in hops, including one previously unknown to the literature.CONCLUSION: The methodologies developed in this study have shed light on the "bittering" potential of Corsican hops which represents a significant economic opportunity for the local brewing industry potentially establishing a new, sustainable, and profitable hops market. This work focuses extensively on the phenolic compounds and the bittering acids of Corsican hops, aiming to highlight their unique organoleptic characteristics and the influence of the Corsican terroir on their chemical composition and abundance.PMID:39609247 | DOI:10.1002/pca.3481

ACS Nano. 2024 Nov 28. doi: 10.1021/acsnano.4c12801. Online ahead of print.ABSTRACTIntestinal dysbiosis and the associated l-tryptophan metabolic disorder are pivotal in inflammatory bowel disease progression, leading to a compromised intestinal barrier integrity. Remedying the dysfunction in tryptophan metabolism has emerged as a promising therapeutic strategy. Herein, we reprogram the tryptophan metabolism in situ by EcN-TRP@A/G, encapsulating the engineered probiotic, EcN-TRP, with enhanced tryptophan synthesis capacity, for sustained modulation, thereby restoring intestinal barrier function and microbial homeostasis. The pH-responsive dual-layered EcN-TRP@A/G microcapsule developed via high-voltage electrospraying and liquid interface self-assembly, preserved probiotic viability in the harsh gastrointestinal milieu, and facilitated targeted colon release. Bioluminescent tracking in mice reveals a 22.84-fold increase in EcN-TRP@A/G viability and distribution compared to naked EcN-TRP. Targeted metabolomics highlights EcN-TRP@A/G's modulation of the tryptophan-indole pathway. Oral administration of EcN-TRP@A/G sustained elevates indole metabolites, particularly indole-3-acetic acid and indole-3-propionic acid, in colon tissue for up to 7 days. In IBD mice, EcN-TRP@A/G improves intestinal permeability, reduces inflammation, and recovers the gut microbiome by enhancing beneficial bacteria abundance like Prevotellaceae_UCG-001 and Anaerostipes while suppressing pathogenic strains like Escherichia-Shigella. Our findings offer a cost-effective approach, harnessing the probiotic metabolic potential in situ through engineered modifications for effective IBD treatment.PMID:39609102 | DOI:10.1021/acsnano.4c12801

BMJ Open. 2024 Nov 27;14(11):e078660. doi: 10.1136/bmjopen-2023-078660.ABSTRACTINTRODUCTION: Dementia is one of the leading causes of disability among older people aged 60 years and above, with majority eventually being diagnosed with Alzheimer's disease (AD). Pharmacological agents approved for dementia include acetylcholinesterase enzyme (AChE) inhibitors like rivastigmine, donepezil and galantamine and the N-methyl-D-aspartate (NMDA) receptor antagonist memantine, prescribed as monotherapy or in combination with each other, depending on the severity of disease. There is currently no available study demonstrating the clinical response to these drugs for AD in the Filipino population. Hence, this protocol aims to characterise the clinical, genetic, microbial and metabolic factors associated with drug responses to donepezil, rivastigmine and/or memantine for AD in a cohort of Filipinos with late-onset AD.METHODS AND ANALYSIS: This protocol involves a multisite descriptive study that will use two study designs: (1) a descriptive, cross-sectional study to characterise the clinical profile of Filipino dementia patients with AD and (2) an exploratory prospective cohort study to investigate drug response-related genetic, gut microbiome and metabolome signatures of a subset of the recruited AD patients. At least 153 patients with mild or moderate AD aged 65 years old and above will be recruited regardless of their treatment status. A subset of these patients (n=60) who meet inclusion and exclusion criteria will be included further in the exploratory cohort study. These patients will be grouped according to their baseline medications and will be observed for treatment response in 6 months. The cognitive, functional and behavioural domains of patients and levels of functioning will be measured using different assessment tools. Drug responses of Filipino patients will then be investigated employing multi-omics technology to characterise genetic variations via whole exome sequencing, gut microbiome profile via shotgun metagenomic sequencing and metabolome profile via liquid chromatography with mass spectrometry.ETHICS AND DISSEMINATION: The study has received ethical clearance from the Department of Health Single Joint Research Ethics Board (SJREB-2022-15). Results of psychometric scales will be made available to enrolled patients. The study results will be presented at national/international conferences and published in international peer-reviewed scientific journals, and summaries of the results will be provided to the study funders and institutional review boards of the three tertiary referral hospitals.TRIAL REGISTRATION NUMBER: Philippine Health Research Registry ID PHRR230220-0054116; ClinicalTrials.gov ID NCT05801380.PMID:39608999 | DOI:10.1136/bmjopen-2023-078660

J Biol Chem. 2024 Nov 26:108019. doi: 10.1016/j.jbc.2024.108019. Online ahead of print.ABSTRACTBenzoxazinoids (BXDs) are important defense compounds produced by a number of species from different, evolutionarily unrelated plant families. While BXD biosynthesis has been extensively studied in the grasses (monocots) and core eudicots, the mechanism of BXD synthesis in the basal eudicots is still unclear. We used an integrated metabolomics and transcriptomics approach to elucidate the BXD pathway in Consolida orientalis, a Ranunculaceae species known to produce the BXD DIBOA-Glc. Overexpression of candidate genes in Nicotiana benthamiana identified a flavin-dependent monooxygenase (CoBX2-3) and two cytochrome P450 enzymes (CoBX4 and CoBX5) that catalyze the oxidation steps that transform indole into DIBOA. Co-expression of CoBx2-3, CoBx4, and CoBx5 with the previously described indole synthase gene CoBx1 and the UDP-glucosyltransferase gene CoBx8 in N. benthamiana resulted in the reconstitution of a fully active BXD pathway. The fact that CoBX2-3, CoBX4, and CoBX5 are not phylogenetically related to their counterparts in the grasses and core eudicots suggests independent evolution of benzoxazinoids biosynthesis in these three angiosperm lineages.PMID:39608711 | DOI:10.1016/j.jbc.2024.108019

J Ethnopharmacol. 2024 Nov 26:119160. doi: 10.1016/j.jep.2024.119160. Online ahead of print.ABSTRACTBACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial inflammation, bone and cartilage damage, musculoskeletal pain, swelling, and stiffness. Inflammation is one of the key factors that induce RA. Jingfang Granule (JFG) is a traditional Chinese medicine (TCM) with significant anti-inflammatory effects. Clinical studies have confirmed that JFG can be used to treat RA, but the mechanism is still vague.PURPOSE: This study was designed to evaluate the protective function and the mechanism of JFG on rats with RA.STUDY DESIGN AND METHODS: Complete Freud's Adjuvant (CFA) was used to establish a rat RA model, and JFG or Diclofenac Sodium (Dic) was orally administered. Foot swelling and hematoxylin eosin (H&E) staining were used to test the therapeutic effect of JFG on RA treatment, while ELISA kits were used to detect serum cytokines. Malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), catalase (CAT), and reactive oxygen species (ROS) were used to evaluate oxidative stress levels. The integration of label free proteomics, fecal short chain fatty acid (SCFA) targeted metabolomics, peripheral blood SCFA, medium and long chain fatty acid targeted metabolomics, and 16S rDNA sequencing of gut microbiota were used to screen the mechanism. Western blot technology was used to validate the results of multiple omics studies. Serum D-Lactic acid, lipopolysaccharide specific IgA antibody (LPS IgA), diamine oxidase (DAO), and colon Claudin 5 and ZO-1 were used to evaluate the intestinal barrier.RESULTS: The results confirmed that JFG effectively protected rats from RA injury, which was confirmed by improved foot swelling and synovial pathology. At the same time, JFG reduced the levels of TNF-α, IL-1β, and IL-6 in serum by inhibiting the NLRP3 inflammasome signaling pathway and TLR4/NF-κB signaling pathway in synovial tissue. Multiple omics studies indicated that JFG increased the abundance of gut microbiota and regulated the number of gut bacteria, thereby increased the levels of Acetic acid, Propionic acid, and Butyric acid in the gut and serum of RA rats, which activated AMPK to regulate fatty acid metabolism and fatty acid biosynthesis, thereby inhibited lipid oxidative stress induced ferroptosis to improve tissue damage caused by RA. Meanwhile, JFG improved the intestinal barrier by upregulating the expresses of Claudin 5 and ZO-1, which was confirmed by low concentrations of D-Lactic acid, LPS-SIgA and DAO in serum.CONCLUSIONS: This study confirmed that JFG improved the disturbance of fatty acid metabolism by modulating gut microbiota and the production of fecal SCFAs to activate AMPK, and then inhibited ferroptosis caused by lipid oxidative stress in synovium tissue and prevented AR injury. This study proposes for the first time to investigate the mechanism of JFG treatment for RA from the perspective of the "Gut-joint" axis, and provides a promising approach for the treatment of RA.PMID:39608616 | DOI:10.1016/j.jep.2024.119160