PubMed

Adv Pharmacol Pharm Sci. 2023 Oct 11;2023:5932315. doi: 10.1155/2023/5932315. eCollection 2023.ABSTRACTBACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a crucial regulator of low-density lipoprotein cholesterol (LDL-c) levels, as it binds to and degrades the LDL receptor (LDLR) in the lysosome of hepatocytes. Elevated levels of PCSK9 have been linked to an increased LDL-c plasma levels, thereby increasing the risk of cardiovascular disease (CVD), making it an attractive target for therapeutic interventions. As a way to inhibit PCSK9 action, we searched for naturally derived small molecules which can block the binding of PCSK9 to the LDLR.METHODS: In this study, we carried out in silico studies which consist of virtual screening using an optimized pharmacophore model and molecular docking studies using Pyrx 0.98. Effects of the candidate compounds were evaluated using in vitro PCSK9-LDLR binding assays kit.RESULTS: Eleven natural compounds that bind to PCSK9 were virtually screened form HerbalDB database, including brazilin. Next, molecular docking studies using Pyrx 0.98 showed that brazilin had the highest binding affinity with PCSK9 at -9.0 (Kcal/mol), which was higher than that of the other ten compounds. Subsequent in vitro PCSK9-LDLR binding assays established that brazilin decreased the binding of PCSK9 to the EGF-A fragment of the LDLR in a dose-dependent manner, with an IC50 value of 2.19 μM.CONCLUSION: We have identified brazilin, which is derived from the Caesalpinia sappan herb, which can act as a small molecule inhibitor of PCSK9. Our findings suggest that screening for small molecules that can block the interaction between PCSK9 and the LDLR in silico and in vitro may be a promising approach for developing novel lipid-lowering therapy.PMID:37860715 | PMC:PMC10584496 | DOI:10.1155/2023/5932315

Chem Sci. 2023 Jun 26;14(40):11022-11032. doi: 10.1039/d3sc02226a. eCollection 2023 Oct 18.ABSTRACTAspergillus fumigatus is a serious human pathogen causing life-threatening Aspergillosis in immunocompromised patients. Secondary metabolites (SMs) play an important role in pathogenesis, but the products of many SM biosynthetic gene clusters (BGCs) remain unknown. In this study, we have developed a heterologous expression platform in Aspergillus nidulans, using a newly created genetic dereplication strain, to express a previously unknown BGC from A. fumigatus and determine its products. The BGC produces sartorypyrones, and we have named it the spy BGC. Analysis of targeted gene deletions by HRESIMS, NMR, and microcrystal electron diffraction (MicroED) enabled us to identify 12 products from the spy BGC. Seven of the compounds have not been isolated previously. We also individually expressed the polyketide synthase (PKS) gene spyA and demonstrated that it produces the polyketide triacetic acid lactone (TAL), a potentially important biorenewable platform chemical. Our data have allowed us to propose a biosynthetic pathway for sartorypyrones and related natural products. This work highlights the potential of using the A. nidulans heterologous expression platform to uncover cryptic BGCs from A. fumigatus and other species, despite the complexity of their secondary metabolomes.PMID:37860661 | PMC:PMC10583710 | DOI:10.1039/d3sc02226a

Heliyon. 2023 Oct 6;9(10):e20747. doi: 10.1016/j.heliyon.2023.e20747. eCollection 2023 Oct.ABSTRACTIn this study, we analyzed the chemical compositions of Alangium platanifolium (Sieb. et Zucc.) Harms (AP) using ultraperformance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) non-targeted plant metabolomics integration MolNetEnhancer strategy. A total of 75 compounds, including flavonoids, alkaloids, terpenes, C21 steroids, among others, were identified by comparing accurate mass-to-charge ratios, MS2 cleavage fragments, retention times, and MolNetenhancer-integrated analytical data, and the cleavage rules of the characteristic compounds were analyzed. A total of 125 potential cervical cancer (CC) therapeutic targets were obtained through Gene Expression Omnibus (GEO) data mining, differential analysis, and database screening. Hub targets were obtained by constructing protein-protein interaction (PPI) networks and CytoNCA topology analysis, including SRC, STAT3, TP53, PIK3R1, MAPK3, and PIK3CA. According to Gene ontology (GO) analysis, AP was primarily against CC by influencing gland development, oxidative stress processes, serine/threonine kinase, and tyrosine kinase activity. Enrichment analysis of the Kyoto Encyclopedia of Genes and Genomes (KEGG) indicated that the PI3K/AKT and MAPK signaling pathways play a crucial role in AP treatment for CC. The compound-target-pathway (C-T-P) network revealed that quercetin, methylprednisolone, and caudatin may play key roles in the treatment of CC. The results of molecular docking revealed that the core compound could bind significantly to the core target. In this study, the compounds in AP were systematically analyzed qualitatively, and the core components, core targets, and mechanisms of action of AP in the treatment of CC were screened through a combination of network pharmacology tools. Providing a scientific reference for the therapeutic material basis and quality control of AP.PMID:37860565 | PMC:PMC10582369 | DOI:10.1016/j.heliyon.2023.e20747

Heliyon. 2023 Oct 5;9(10):e20661. doi: 10.1016/j.heliyon.2023.e20661. eCollection 2023 Oct.ABSTRACTBACKGROUND: Whether the mechanism of thyroid papillary carcinoma (PTC) is the same in patients with a Hashimoto's thyroiditis (HT) background as compared with patients with a normal background remains a highly debated and controversial issue. In this study, we aimed to analyze the differences and similarities of the metabolic mechanism of PTC in normal and HT background, and to explore the relationship between HT and PTC.METHODS: The ultra performance liquid chromatography-quadrupole-time of flight-mass spectrometry (UPLC-Q-TOF/MS) technology was used to analyze 61 PTC patient tissues (31 HT background and 30 normal tissue (NC) background). Potential biomarkers were screened from principal component analysis (PCA) to orthogonal partial least square (OPLS) discriminant analysis. HMDB was searched to identify potential differential metabolites and final metabolic pathway analysis was performed by MetaboAnalyst 5.0. We analyzed the differential metabolites diagnostic accuracy through receiver operating characteristic (ROC) curves analysis.RESULTS: Seven different metabolites were screened from HT group and NC group, including arginine, glutamic acid, cysteine, citric acid, malic acid, uracil and taurine. Logistic regression model combined with ROC analysis of these 7 biomarkers had good discriminability for PTC (area under operating characteristic curve of HT group and NC group were 0.867 and 0.973, respectively). The HT group had specific metabolic pathways, including aminoacyl-tRNA biosynthesis, glycine, serine and threonine metabolism.CONCLUSIONS: The metabolic profiles of the NC and HT groups had important similarities and differences in PTC. The correlation of PTC with HT may be related to aminoacyl-tRNA biosynthesis, serine and threonine metabolism.PMID:37860538 | PMC:PMC10582305 | DOI:10.1016/j.heliyon.2023.e20661

J Healthc Eng. 2023 Oct 11;2023:9823469. doi: 10.1155/2023/9823469. eCollection 2023.ABSTRACT[This retracts the article DOI: 10.1155/2021/7600835.].PMID:37860348 | PMC:PMC10584444 | DOI:10.1155/2023/9823469

Oncoimmunology. 2023 Oct 16;12(1):2271693. doi: 10.1080/2162402X.2023.2271693. eCollection 2023.ABSTRACTBCL2 robustly preserves mitochondrial integrity, hence inhibiting innate immune signaling and apoptotic cell death in several cell types. Here, we comment on our recent data demonstrating that BCL2 also limits the ability of dendritic cells to elicit adaptive immune responses, lending support to a universal immunosuppressive function for the mitochondrial immune checkpoint.PMID:37860277 | PMC:PMC10583618 | DOI:10.1080/2162402X.2023.2271693

Adv Clin Neurosci Rehabil. 2023 Aug 8;22(2):WVJZ9783. doi: 10.47795/WVJZ9783.ABSTRACTMeningioma are the most common primary brain tumour. Classically, meningioma are phenotypically grouped using the World Health Organisation (WHO) classification system. However, it is now understood that the WHO approach overfits tumours into three grades, resulting in similarly graded tumours displaying phenotypically distinct behaviour. There is a growing body of research investigating the molecular biology of these tumours, including genomic, transcriptomic, metabolomic, proteomic, and methylomic profiling. Such advancements in molecular profiling of meningioma are providing greater accuracy in prognostication of tumours. Furthermore, a clearer understanding of tumour molecular biology highlights potential targets for pharmacotherapies. Currently, the routine application of in-depth tumour molecular analysis is limited, however as it becomes more widely available it will likely result in improved patient care. This review seeks to explore the important developments in meningioma molecular biology, discussed in the context of their clinical importance.PMID:37860270 | PMC:PMC7615222 | DOI:10.47795/WVJZ9783

Front Plant Sci. 2023 Oct 4;14:1210850. doi: 10.3389/fpls.2023.1210850. eCollection 2023.ABSTRACTINTRODUCTION: High levels of toxic steroidal glycoalkaloids (SGAs) in potato tubers constitute a recognized food quality problem. Tuber SGA levels vary between potato cultivars and can increase after post-harvest stresses such as wounding and light exposure. A few cultivars, e.g., 'Magnum Bonum' and 'Lenape,' have been withdrawn from commercial sales due to excessive SGA levels during some cultivation years. However, these sudden SGA increases are diffucult to predict, and their causes are not understood. To identify external and genetic factors that underlie sudden SGA increases in certain potato cultivars, we have here in a 2-year study investigated 'Magnum Bonum' and five additional table potato cultivars for their SGA levels after wounding and light exposure.RESULTS AND METHODS: Results showed that 'Magnum Bonum' has an unusual strong SGA response to light exposure, but not to wounding, whereas 'Bintje' displayed an opposite regulation. Levels of calystegine alkaloids were not significantly altered by treatments, implicating independent metabolic regulation of SGA and calystegine levels also under conditions of high SGA accumulation. Metabolomic and transcriptomic analyses identified a small number of key genes whose expression correlated with SGA differences between cultivars. Overexpression of two key genes in transgenic low-SGA potato cultivars increased their leaf SGA levels significantly.DISCUSSION: The results show that a strong response to light can underlie the SGA peaks that occasionally occur in certain potato cultivars and indicate that a between-cultivar variation in the expression of single SGA key genes can account for cultivar SGA differerences. We propose that current attempts to mitigate the SGA hazard will benefit from an increased consideration of cultivar-dependent SGA responses to post-harvest conditions, particularly light exposure. The identified key SGA genes can now be used as a molecular tool in this work.PMID:37860257 | PMC:PMC10582707 | DOI:10.3389/fpls.2023.1210850

Front Med (Lausanne). 2023 Oct 4;10:1259182. doi: 10.3389/fmed.2023.1259182. eCollection 2023.ABSTRACTBACKGROUND: Heart failure (HF) is characterized by reduced ventricular filling or ejection function due to organic or non-organic cardiovascular diseases. Danhong injection (DHI) is a medicinal material used clinically to treat HF for many years in China. Although prior research has shown that Danhong injection can improve cardiac function and structure, the biological mechanism has yet to be determined.METHODS: Serum metabolic analysis was conducted via ultra-high-performance liquid chromatography-quadrupole time-of-flight/mass spectrometry (UHPLC-QE/MS) to explore underlying protective mechanisms of DHI in the transverse aortic constriction (TAC)-induced heart failure. Multivariate statistical techniques were used in the research, such as unsupervised principal component analysis (PCA) and orthogonal projection to latent structures discriminant analysis (OPLS-DA). MetaboAnalyst and Kyoto Encyclopedia of Genes and Genomes (KEGG) were employed to pinpoint pertinent metabolic pathways.RESULTS: After DHI treatment, cardiac morphology and function as well as the metabolism in model rats were improved. We identified 17 differential metabolites and six metabolic pathways. Two biomarkers, PC(18:3(6Z,9Z,12Z)/24:0) and L-Phenylalanine, were identified for the first time as strong indicators for the significant effect of DHI.CONCLUSION: This study revealed that DHI could regulate potential biomarkers and correlated metabolic pathway, which highlighted therapeutic potential of DHI in managing HF.PMID:37859859 | PMC:PMC10582331 | DOI:10.3389/fmed.2023.1259182

BMJ Med. 2023 Oct 12;2(1):e000548. doi: 10.1136/bmjmed-2023-000548. eCollection 2023.ABSTRACTPolycystic ovary syndrome is characterised by excessive levels of androgens and ovulatory dysfunction, and is a common endocrine disorder in women of reproductive age. Polycystic ovary syndrome arises as a result of polygenic susceptibility in combination with environmental influences that might include epigenetic alterations and in utero programming. In addition to the well recognised clinical manifestations of hyperandrogenism and ovulatory dysfunction, women with polycystic ovary syndrome have an increased risk of adverse mental health outcomes, pregnancy complications, and cardiometabolic disease. Unlicensed treatments have limited efficacy, mostly because drug development has been hampered by an incomplete understanding of the underlying pathophysiological processes. Advances in genetics, metabolomics, and adipocyte biology have improved our understanding of key changes in neuroendocrine, enteroendocrine, and steroidogenic pathways, including increased gonadotrophin releasing hormone pulsatility, androgen excess, insulin resistance, and changes in the gut microbiome. Many patients with polycystic ovary syndrome have high levels of 11-oxygenated androgens, with high androgenic potency, that might mediate metabolic risk. These advances have prompted the development of new treatments, including those that target the neurokinin-kisspeptin axis upstream of gonadotrophin releasing hormone, with the potential to lessen adverse clinical sequelae and improve patient outcomes.PMID:37859784 | PMC:PMC10583117 | DOI:10.1136/bmjmed-2023-000548

J Agric Food Chem. 2023 Oct 19. doi: 10.1021/acs.jafc.3c04515. Online ahead of print.ABSTRACTThe gastrointestinal tract (GIT) is the target of assorted pathological conditions, and dietary components are known to affect its functionality and health. In previous in vitro studies, we observed that reducing sugars induced protein glycoxidation and impaired protein digestibility. To gain further insights into the pathophysiological effects of dietary sugars, Wistar rats were provided with a 30% (w/v) fructose water solution for 10 weeks. Upon slaughter, in vivo protein digestibility was assessed, and the entire GIT (digests and tissues) was analyzed for markers of oxidative stress and untargeted metabolomics. Additionally, the impact of sustained fructose intake on colonic microbiota was also evaluated. High fructose intake for 10 weeks decreased protein digestibility and promoted changes in the physiological digestion of proteins, enhancing intestinal digestion rather than stomach digestion. Moreover, at colonic stages, the oxidative stress was harmfully increased, and both the microbiota and the intraluminal colonic metabolome were modified.PMID:37859404 | DOI:10.1021/acs.jafc.3c04515

Comb Chem High Throughput Screen. 2023 Oct 5. doi: 10.2174/0113862073238503230924180432. Online ahead of print.ABSTRACTBACKGROUND AND AIM: Nonalcoholic fatty liver disease (NAFLD) is not only the top cause of liver diseases but also a hepatic-correlated metabolic syndrome. This study performed untargeted metabolomics analysis of NAFLD hamsters to identify the key metabolites to discriminate different stages of NAFLD.METHODS: Hamsters were fed a high-fat diet (HFD) to establish the NAFLD model with different stages (six weeks named as the NAFLD1 group and twelve weeks as the NAFLD2 group, respectively). Those liver samples were analyzed by untargeted metabolomics (UM) analysis to investigate metabolic changes and metabolites to discriminate different stages of NAFLD.RESULTS: The significant liver weight gain in NAFLD hamsters was observed, accompanied by significantly increased levels of serum triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), alanine aminotransferase (ALT), and aspartate aminotransferase (AST). Moreover, the levels of TG, LDL-C, ALT, and AST were significantly higher in the NAFLD2 group than in the NAFLD1 group. The UM analysis also revealed the metabolic changes; 27 differently expressed metabolites were detected between the NAFLD2 and NAFLD1 groups. More importantly, the levels of N-methylalanine, allantoin, glucose, and glutamylvaline were found to be significantly different between any two groups (control, NAFLD2 and NAFLD1). Receiver operating characteristic curve (ROC) curve results also showed that these four metabolites are able to distinguish control, NAFLD1 and NAFLD2 groups.CONCLUSION: This study indicated that the process of NAFLD in hamsters is accompanied by different metabolite changes, and these key differently expressed metabolites may be valuable diagnostic biomarkers and responses to therapeutic interventions.PMID:37859316 | DOI:10.2174/0113862073238503230924180432

Biomed Chromatogr. 2023 Oct 19:e5763. doi: 10.1002/bmc.5763. Online ahead of print.ABSTRACTAlisol B 23-acetate (AB23A) has been demonstrated to have beneficial effects on nonalcoholic steatohepatitis (NASH). However, the mechanisms of AB23A on NASH remain unclear. This study aimed to investigate the mechanisms underlying the metabolic regulatory effects of AB23A on NASH. We used AB23A to treat mice with NASH, which was induced by a methionine and choline deficient (MCD) diet. We initially investigated therapeutic effect and resistance to oxidation and inflammation of AB23A on NASH. Subsequently, we performed untargeted metabolomic analyses and relative validation assessments to evaluate the metabolic regulatory effects of AB23A. AB23A reduced lipid accumulation, ameliorated oxidative stress and decreased pro-inflammatory cytokines in the liver. Untargeted metabolomic analysis found that AB23A altered the metabolites of liver. A total of 55 differential metabolites and three common changed pathways were screened among the control, model and AB23A treatment groups. Further tests validated the effects of AB23A on modulating common changed pathway-involved factors. AB23A treatment can ameliorate NASH by inhibiting oxidative stress and inflammation. The mechanism of AB23A on NASH may be related to the regulation of alanine, aspartate and glutamate metabolism, d-glutamine and d-glutamate metabolism, and arginine biosynthesis pathways.PMID:37858975 | DOI:10.1002/bmc.5763

Toxicology. 2023 Oct 17:153652. doi: 10.1016/j.tox.2023.153652. Online ahead of print.ABSTRACTAflatoxin B1 (AFB1) is a fungal metabolite found in animal feeds and human foods. It is one of the most toxic and carcinogenic of aflatoxins and is classified as a Group 1 carcinogen. Dietary exposure to AFB1 and infection with chronic Hepatitis B Virus (HBV) make up two of the major risk factors for hepatocellular carcinoma (HCC). These two major risk factors raise the probability of synergism between the two agents. This review proposes some collaborative molecular mechanisms underlying the interaction between AFB1 and HBV in accelerating or magnifying the effects of HCC. The HBx viral protein of HBV is one of the main viral proteins of HBV and has many carcinogenic qualities that are involved with HCC. AFB1, when metabolized by CYP450, becomes AFB1-exo-8,9-epoxide (AFBO), an extremely toxic compound that can form adducts in DNA sequences and induce mutations. With possible synergisms that exist between HBV and AFB1 in mind, it is best to treat both agents simultaneously to reduce the risk by HCC.PMID:37858775 | DOI:10.1016/j.tox.2023.153652

Brain Behav Immun. 2023 Oct 17:S0889-1591(23)00316-1. doi: 10.1016/j.bbi.2023.10.016. Online ahead of print.ABSTRACTThe mechanism by which SARS-CoV-2 causes neurological post-acute sequelae of SARS-CoV-2 (neuro-PASC) remains unclear. Herein, we conducted proteomic and metabolomic analyses of cerebrospinal fluid (CSF) samples from 21 neuro-PASC patients, 45 healthy volunteers, and 26 inflammatory neurological diseases patients. Our data showed 69 differentially expressed metabolites and six differentially expressed proteins between neuro-PASC patients and healthy individuals. Elevated sphinganine, ST1A1, sphingolipid metabolism disorder, and attenuated inflammatory responses may contribute to the occurrence of neuro-PASC, whereas decreased levels of 7,8-dihydropterin and activation of steroid hormone biosynthesis may play a role in the repair process. Additionally, a biomarker cohort consisting of sphinganine, 7,8-dihydroneopterin, and ST1A1 was preliminarily demonstrated to have high value in diagnosing neuro-PASC. In summary, our study represents the first attempt to integrate the diagnostic benefits of CSF with the methodological advantages of multi-omics, thereby offering valuable insights into the pathogenesis of neuro-PASC and facilitating the work of neuroscientists in disclosing different neurological dimensions associated with COVID-19.PMID:37858739 | DOI:10.1016/j.bbi.2023.10.016

Biochim Biophys Acta Rev Cancer. 2023 Oct 17:188999. doi: 10.1016/j.bbcan.2023.188999. Online ahead of print.ABSTRACTRecent multi-omics studies, including proteomics, transcriptomics, genomics, and metabolomics have revealed the critical role of post-translational modifications (PTMs) in the progression and pathogenesis of Glioblastoma multiforme (GBM). Further, PTMs alter the oncogenic signaling events and offer a novel avenue in GBM therapeutics research through PTM enzymes as potential biomarkers for drug targeting. In addition, PTMs are critical regulators of chromatin architecture, gene expression, and tumor microenvironment (TME), that play a crucial function in tumorigenesis. Moreover, the implementation of artificial intelligence and machine learning algorithms enhances GBM therapeutics research through the identification of novel PTM enzymes and residues. Herein, we briefly explain the mechanism of protein modifications in GBM etiology, and in altering the biologics of GBM cells through chromatin remodeling, modulation of the TME, and signaling pathways. In addition, we highlighted the importance of PTM enzymes as therapeutic biomarkers and the role of artificial intelligence and machine learning in protein PTM prediction.PMID:37858622 | DOI:10.1016/j.bbcan.2023.188999

Mol Cell Endocrinol. 2023 Oct 17:112086. doi: 10.1016/j.mce.2023.112086. Online ahead of print.ABSTRACTThyroid hormones (THs) are crucial in bodily functions, while iron is essential for processes like oxygen transport. Specialized proteins maintain iron balance, including ferritin, transferrin, ferroportin, and hepcidin. Research suggests that THs can influence iron homeostasis by affecting mRNA and protein expression, such as ferritin and transferrin. Our study focused on male rats to assess mRNA expression of iron homeostasis-related proteins and metabolomics in thyroid dysfunction. We found altered gene expression across various tissues (liver, duodenum, spleen, and kidney) and identified disrupted metabolite patterns in thyroid dysfunction. These findings highlight tissue-specific effects of thyroid dysfunction on essential iron homeostasis proteins and provide insights into associated metabolic changes. Our research contributes to understanding the intricate interplay between thyroid hormones and iron balance. By unveiling tissue-specific gene expression alterations and metabolic disruptions caused by thyroid dysfunction, our work lays a foundation for future investigations to explore underlying mechanisms and develop targeted strategies for managing iron-related complications in thyroid disorders.PMID:37858610 | DOI:10.1016/j.mce.2023.112086

Cell Rep. 2023 Oct 12:113248. doi: 10.1016/j.celrep.2023.113248. Online ahead of print.ABSTRACTThe emergence of three highly pathogenic human coronaviruses-severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003, Middle Eastern respiratory syndrome (MERS)-CoV in 2012, and SARS-CoV-2 in 2019-underlines the need to develop broadly active vaccines against the Merbecovirus and Sarbecovirus betacoronavirus subgenera. While SARS-CoV-2 vaccines protect against severe COVID-19, they do not protect against other sarbecoviruses or merbecoviruses. Here, we vaccinate mice with a trivalent sortase-conjugate nanoparticle (scNP) vaccine containing the SARS-CoV-2, RsSHC014, and MERS-CoV receptor-binding domains (RBDs), which elicited live-virus neutralizing antibody responses. The trivalent RBD scNP elicited serum neutralizing antibodies against bat zoonotic Wuhan Institute of Virology-1 (WIV-1)-CoV, SARS-CoV, SARS-CoV-2 BA.1, SARS-CoV-2 XBB.1.5, and MERS-CoV live viruses. The monovalent SARS-CoV-2 RBD scNP vaccine only protected against Sarbecovirus challenge, whereas the trivalent RBD scNP vaccine protected against both Merbecovirus and Sarbecovirus challenge in highly pathogenic and lethal mouse models. This study demonstrates proof of concept for a single pan-sarbecovirus/pan-merbecovirus vaccine that protects against three highly pathogenic human coronaviruses spanning two betacoronavirus subgenera.PMID:37858337 | DOI:10.1016/j.celrep.2023.113248

Fluids Barriers CNS. 2023 Oct 19;20(1):74. doi: 10.1186/s12987-023-00473-w.ABSTRACTThe meninges surround the brain and spinal cord, affording physical protection while also serving as a niche of neuroimmune activity. Though possessing stromal qualities, its complex cellular and extracellular makeup has yet to be elaborated, and it remains unclear whether the meninges vary along the neuroaxis. Hence, studies were carried-out to elucidate the protein composition and structural organization of brain and spinal cord meninges in normal, adult Biozzi ABH mice. First, shotgun, bottom-up proteomics was carried-out. Prominent proteins at both brain and spinal levels included Type II collagen and Type II keratins, representing extracellular matrix (ECM) and cytoskeletal categories, respectively. While the vast majority of total proteins detected was shared between both meningeal locales, more were uniquely detected in brain than in spine. This pattern was also seen when total proteins were subdivided by cellular compartment, except in the case of the ECM category where brain and spinal meninges each had near equal number of unique proteins, and Type V and type III collagen registered exclusively in the spine. Quantitative analysis revealed differential expression of several collagens and cytoskeletal proteins between brain and spinal meninges. High-resolution immunofluorescence and immunogold-scanning electronmicroscopy on sections from whole brain and spinal cord - still encased within bone -identified major proteins detected by proteomics, and highlighted their association with cellular and extracellular elements of variously shaped arachnoid trabeculae. Western blotting aligned with the proteomic and immunohistological analyses, reinforcing differential appearance of proteins in brain vs spinal meninges. Results could reflect regional distinctions in meninges that govern protective and/or neuroimmune functions.PMID:37858244 | DOI:10.1186/s12987-023-00473-w

Clin Epigenetics. 2023 Oct 19;15(1):166. doi: 10.1186/s13148-023-01578-7.ABSTRACTBACKGROUND: B vitamins such as folate (B9), B6, and B12 are key in one carbon metabolism, which generates methyl donors for DNA methylation. Several studies have linked differential methylation to self-reported intakes of folate and B12, but these estimates can be imprecise, while metabolomic biomarkers can offer an objective assessment of dietary intakes. We explored blood metabolomic biomarkers of folate and vitamins B6 and B12, to carry out epigenome-wide analyses across up to three European cohorts. Associations between self-reported habitual daily B vitamin intakes and 756 metabolites (Metabolon Inc.) were assessed in serum samples from 1064 UK participants from the TwinsUK cohort. The identified B vitamin metabolomic biomarkers were then used in epigenome-wide association tests with fasting blood DNA methylation levels at 430,768 sites from the Infinium HumanMethylation450 BeadChip in blood samples from 2182 European participants from the TwinsUK and KORA cohorts. Candidate signals were explored for metabolite associations with gene expression levels in a subset of the TwinsUK sample (n = 297). Metabolomic biomarker epigenetic associations were also compared with epigenetic associations of self-reported habitual B vitamin intakes in samples from 2294 European participants.RESULTS: Eighteen metabolites were associated with B vitamin intakes after correction for multiple testing (Bonferroni-adj. p < 0.05), of which 7 metabolites were available in both cohorts and tested for epigenome-wide association. Three metabolites - pipecolate (metabolomic biomarker of B6 and folate intakes), pyridoxate (marker of B6 and folate) and docosahexaenoate (DHA, marker of B6) - were associated with 10, 3 and 1 differentially methylated positions (DMPs), respectively. The strongest association was observed between DHA and DMP cg03440556 in the SCD gene (effect = 0.093 ± 0.016, p = 4.07E-09). Pyridoxate, a catabolic product of vitamin B6, was inversely associated with CpG methylation near the SLC1A5 gene promoter region (cg02711608 and cg22304262) and with SLC7A11 (cg06690548), but not with corresponding changes in gene expression levels. The self-reported intake of folate and vitamin B6 had consistent but non-significant associations with the epigenetic signals.CONCLUSION: Metabolomic biomarkers are a valuable approach to investigate the effects of dietary B vitamin intake on the human epigenome.PMID:37858220 | DOI:10.1186/s13148-023-01578-7