PubMed

Ther Adv Endocrinol Metab. 2023 Oct 29;14:20420188231207544. doi: 10.1177/20420188231207544. eCollection 2023.ABSTRACTThis article aims to review current concepts in diagnosing and managing pheochromocytoma and paraganglioma (PPGL). Personalized genetic testing is vital, as 40-60% of tumors are linked to a known mutation. Tumor DNA should be sampled first. Next-generation sequencing is the best and most cost-effective choice and also helps with the expansion of current knowledge. Recent advancements have also led to the increased incorporation of regulatory RNA, metabolome markers, and the NETest in PPGL workup. PPGL presentation is highly volatile and nonspecific due to its multifactorial etiology. Symptoms mainly derive from catecholamine (CMN) excess or mass effect, primarily affecting the cardiovascular system. However, paroxysmal nature, hypertension, and the classic triad are no longer perceived as telltale signs. Identifying high-risk subjects and diagnosing patients at the correct time by using appropriate personalized methods are essential. Free plasma/urine catecholamine metabolites must be first-line examinations using liquid chromatography with tandem mass spectrometry as the gold standard analytical method. Reference intervals should be personalized according to demographics and comorbidity. The same applies to result interpretation. Threefold increase from the upper limit is highly suggestive of PPGL. Computed tomography (CT) is preferred for pheochromocytoma due to better cost-effectiveness and spatial resolution. Unenhanced attenuation of >10HU in non-contrast CT is indicative. The choice of extra-adrenal tumor imaging is based on location. Functional imaging with positron emission tomography/computed tomography and radionuclide administration improves diagnostic accuracy, especially in extra-adrenal/malignant or familial cases. Surgery is the mainstay treatment when feasible. Preoperative α-adrenergic blockade reduces surgical morbidity. Aggressive metastatic PPGL benefits from systemic chemotherapy, while milder cases can be managed with radionuclides. Short-term postoperative follow-up evaluates the adequacy of resection. Long-term follow-up assesses the risk of recurrence or metastasis. Asymptomatic carriers and their families can benefit from surveillance, with intervals depending on the specific gene mutation. Trials primarily focusing on targeted therapy and radionuclides are currently active. A multidisciplinary approach, correct timing, and personalization are key for successful PPGL management.PMID:37916027 | PMC:PMC10617285 | DOI:10.1177/20420188231207544

Front Cell Infect Microbiol. 2023 Oct 16;13:1255127. doi: 10.3389/fcimb.2023.1255127. eCollection 2023.ABSTRACTRecently, the hybrid Broussonetia papyrifera (BP) has been extensively cultivated and predominantly utilized in ruminants because of its high protein and bioactive compound content. In the present study, the effects of an ethanolic extract of BP leaves (BPE, 200 mg/kg) on mitigating 2% dextran sodium sulfate (DSS)-induced intestinal inflammation in mice were evaluated. BPE is rich in flavonoids, polyphenols, and polysaccharides, and displays potent antioxidant and antibacterial activities against pathogenic strains such as Clostridium perfringens, Salmonella Typhimurium, and Salmonella enterica subsp. enterica in vitro. In a mouse study, oral administration of DSS resulted in weight loss, incidence of diarrhea, enlargement of the liver and spleen, impaired colonic morphology, downregulation of both gene and protein expression related to intestinal antioxidant (Nrf2) and barrier function (ZO-1), decreased diversity of colonic microbiota, and 218 differentially altered colonic metabolites; however, co-treatment with BPE did not restore these modified aspects except for the liver index and colonic bacterial diversity. The singular treatment with BPE did not manifest evident side effects in normal mice but induced a mild occurrence of diarrhea and a notable alteration in the colonic metabolite profile. Moreover, a single BPE administration augmented the abundance of the commensal beneficial bacteria Faecalibaculum and Akkermansia genera. Overall, the extract of BP leaves did not demonstrate the anticipated effectiveness in alleviating DSS-induced intestinal inflammation.PMID:37915848 | PMC:PMC10616958 | DOI:10.3389/fcimb.2023.1255127

Front Cell Infect Microbiol. 2023 Oct 16;13:1261284. doi: 10.3389/fcimb.2023.1261284. eCollection 2023.ABSTRACTINTRODUCTION: The lower respiratory tract microbiome is widely studied to pinpoint microbial dysbiosis of diversity or abundance that is linked to a number of chronic respiratory illnesses. However, it is vital to clarify how the microbiome, through the release of microbial metabolites, impacts lung health and oncogenesis.METHODS: In order to discover the powerful correlations between microbial metabolites and disease, we collected, under electronic bronchoscopy examinations, samples of paired bronchoalveolar lavage fluids (BALFs) from tumor-burden lung segments and ipsilateral non-tumor sites from 28 lung cancer participants, further performing metagenomic sequencing, short-chain fatty acid (SCFA) metabolomics, and multiomics analysis to uncover the potential correlations of the microbiome and SCFAs in lung cancer.RESULTS: In comparison to BALFs from normal lung segments of the same participant, those from lung cancer burden lung segments had slightly decreased microbial diversity in the lower respiratory tract. With 18 differentially prevalent microbial species, including the well-known carcinogens Campylobacter jejuni and Nesseria polysaccharea, the relative species abundance in the lower respiratory tract microbiome did not significantly differ between the two groups. Additionally, a collection of commonly recognized probiotic metabolites called short-chain fatty acids showed little significance in either group independently but revealed a strong predictive value when using an integrated model by machine learning. Multiomics also discovered particular species related to SCFAs, showing a positive correlation with Brachyspira hydrosenteriae and a negative one with Pseudomonas at the genus level, despite limited detection in lower airways. Of note, these distinct microbiota and metabolites corresponded with clinical traits that still required confirmation.CONCLUSIONS: Further analysis of metagenome functional capacity revealed that genes encoding environmental information processing and metabolism pathways were enriched in the lower respiratory tract metagenomes of lung cancer patients, further supporting the oncogenesis function of various microbial species by different metabolites. These findings point to a potent relationship between particular components of the integrated microbiota-metabolites network and lung cancer, with implications for screening and diagnosis in clinical settings.PMID:37915846 | PMC:PMC10617678 | DOI:10.3389/fcimb.2023.1261284

Front Genet. 2023 Oct 17;14:1251902. doi: 10.3389/fgene.2023.1251902. eCollection 2023.ABSTRACTIntroduction: The normal development of all heart valves requires highly coordinated signaling pathways and downstream mediators. While genomic variants can be responsible for congenital valve disease, environmental factors can also play a role. Later in life valve calcification is a leading cause of aortic valve stenosis, a progressive disease that may lead to heart failure. Current research into the causes of both congenital valve diseases and valve calcification is using a variety of high-throughput methodologies, including transcriptomics, proteomics and genomics. High quality genetic data from biological knowledge bases are essential to facilitate analyses and interpretation of these high-throughput datasets. The Gene Ontology (GO, http://geneontology.org/) is a major bioinformatics resource used to interpret these datasets, as it provides structured, computable knowledge describing the role of gene products across all organisms. The UCL Functional Gene Annotation team focuses on GO annotation of human gene products. Having identified that the GO annotations included in transcriptomic, proteomic and genomic data did not provide sufficient descriptive information about heart valve development, we initiated a focused project to address this issue. Methods: This project prioritized 138 proteins for GO annotation, which led to the curation of 100 peer-reviewed articles and the creation of 400 heart valve development-relevant GO annotations. Results: While the focus of this project was heart valve development, around 600 of the 1000 annotations created described the broader cellular role of these proteins, including those describing aortic valve morphogenesis, BMP signaling and endocardial cushion development. Our functional enrichment analysis of the 28 proteins known to have a role in bicuspid aortic valve disease confirmed that this annotation project has led to an improved interpretation of a heart valve genetic dataset. Discussion: To address the needs of the heart valve research community this project has provided GO annotations to describe the specific roles of key proteins involved in heart valve development. The breadth of GO annotations created by this project will benefit many of those seeking to interpret a wide range of cardiovascular genomic, transcriptomic, proteomic and metabolomic datasets.PMID:37915827 | PMC:PMC10616796 | DOI:10.3389/fgene.2023.1251902

Front Nutr. 2023 Oct 17;10:1271817. doi: 10.3389/fnut.2023.1271817. eCollection 2023.ABSTRACTINTRODUCTION: With the internationalization of traditional Chinese medicine, the demand for medicinal and edible Codonopsis Radix (CR) has increased, and its medicinal resources have attracted attention. CR is a well-known traditional Chinese medicine with a long pharmaceutical and edible history. The Guizhou province in China has abundant CR resources, but in the absence of systematic studies on species identification and chemical compositions, the capacity of the capacity of the province to CR resource has not been fully utilized.METHODOLOGY: We used plant morphology and DNA barcoding techniques to identify Luodang (LD) and Weidang (WD) species. To investigate the differences in metabolites between LD and WD, as well as three Chinese Pharmacopeia CRs, and to predict pharmacological mechanisms of action for the dominant differential metabolites, we utilized widely targeted metabolomics and network pharmacology. The results also revealed the material basis for the excellent food properties of both LD and WD.RESULTS: The plant traits and DNA barcoding molecular identification results indicated that Luodang and Weidang from Guizhou were Codonopsis tangshen and Codonopsis pilosula, respectively. Widely targeted metabolomics analysis revealed that a total of 1,116 metabolites from 14 categories, including phenolic acids, lipids, flavonoids, were found in five CRs and shared 1,054 (94.4%) metabolites. LD and WD each contained 3 and 10 dominant differential metabolites, respectively, which were primarily flavonoids and amino acids. Amino acids, phenolic acids, and organic acids play important roles in their excellent food attributes. In CR, eight dominant differential metabolites were discovered for the first time, including isoorientin-7-O-(6″-feruloyl) glucoside, N-formyl-L-methionine, and cyclo (Phe-Glu), among others. Network pharmacology analyses showed that, in LD, dominant differential metabolites were closely related to anti-tumor, cardiovascular disease improvement, nervous system protection, and metabolic disease treatment, whereas in WD, they were closely related to nervous system protection and cardiovascular disease improvement.CONCLUSION: The species of LD and WD were included in the Chinese Pharmacopeia, and their metabolite profiles were remarkably similar to CR from traditional producing areas. Therefore, LD and WD can be used and promoted medicinally as CR, and they have potential value for new drug development. This study enriched the database of CR compounds and provided a reference for quality control, resource development, and new drug development of CR.PMID:37915621 | PMC:PMC10616484 | DOI:10.3389/fnut.2023.1271817

Front Plant Sci. 2023 Oct 17;14:1249456. doi: 10.3389/fpls.2023.1249456. eCollection 2023.ABSTRACTGastrodia elata Blume (Tianma in Chinese), a myco-heterotrophic orchid, is widely distributed in China. Tubers derived from this orchid are traditionally used as both medicinal and edible materials. At present, five primary varieties of G. elata are recorded in the "Flora of China." Among them, the three main varieties currently in artificial cultivation are G. elata f. elata (GR, red stem), G. elata f. glauca (GB, black stem), and G. elata f. viridis (GG, green stem). In our study, the metabolic profiles and chemical composition of these three varieties were determined via UPLC-MS/MS and HPLC-UV. In total, 11,132 metabolites were detected, from which multiple phytometabolites were identified as aromatic compounds, heteroatomic compounds, furans, carbohydrates, organic acids, and their derivatives. A number of differentially expressed metabolites (DEMs) were annotated as bioactive ingredients. Overall, parishins, vanilloloside, and gastrodin A/B in the GB group were markedly higher, whereas gastrodin, gastrol, and syringic acid were more enriched in the GG or GR groups. Moreover, HPLC fingerprint analysis also found six metabolites used as markers for the identification of Gastrodiae Rhizoma in the Chinese Pharmacopoeia, which were also typical DEMs in metabolomics. Of these, gastrodin, 4-hydroxybenzyl alcohol, citric acid, and adenosine were quantitatively detected, showing a similar result with the metabolomic data. In summary, our findings provide novel insights into the phytochemical ingredients of different G. elata varieties, highlighting diverse biological activities and healthcare value.PMID:37915510 | PMC:PMC10616830 | DOI:10.3389/fpls.2023.1249456

Toxicol Res (Camb). 2023 Sep 19;12(5):884-894. doi: 10.1093/toxres/tfad079. eCollection 2023 Oct.ABSTRACTBACKGROUND: Ionic liquids (ILs) have been recognized as potential environmentally friendly solvents; however, their potential toxicity to living organisms warrants thorough investigation, particularly for novel-generation ILs in mammalian models.METHODS: In this study, we examined the hepatic effects and disruption of lipid metabolism in mice exposed to 1-heptyl-3-methylimidazolium chloride (C7[MIM]Cl), a novel ILs. After four weeks of oral administration at different dosages (2.38, 5.95, and 11.9 mg/kg b.w.), we conducted clinical chemistry analysis and histopathological examination of the liver to assess biochemical and structural changes.RESULTS: The low-dose C7[MIM]Cl group exhibited a significant increase in alanine aminotransferase (ALT) levels, while aspartate aminotransferase (AST) levels were elevated in both low-dose and high-dose groups without statistical significance. Histopathological examination showed inflammatory cell infiltration and red blood cell aggregation in the livers of mice exposed to C7[MIM]Cl, particularly in the high-dose group. Oxidative stress levels showed moderate changes in response to C7[MIM]Cl exposure. Notably, hepatic biochemical parameters revealed a dose-dependent increase in triglycerides (TG) levels with statistically significant differences compared to the control group (P ≤ 0.01). Targeted lipidomic analysis revealed notable alterations in liver lipids of mice exposed to C7[MIM]Cl, with lysophosphatidylethanolamine (18:0), phosphatidylcholines (18:0), and phosphatidylcholines (19:0) identified as critical lipids associated with C7[MIM]Cl exposure. Furthermore, metabolic pathway analyses demonstrated significant disturbances in the glycerophospholipid metabolic pathway.CONCLUSION: These findings provide valuable insights into the hepatic effects of C7[MIM]Cl exposure and novel perspectives on the disruption of lipid metabolism underlying ILs toxicity.PMID:37915492 | PMC:PMC10615802 | DOI:10.1093/toxres/tfad079

Front Med (Lausanne). 2023 Oct 17;10:1256238. doi: 10.3389/fmed.2023.1256238. eCollection 2023.ABSTRACTBACKGROUND AND OBJECTIVE: With the development of global population aging, comorbidity (≥2 diseases) is a common health problem among elderly people. Osteoarthritis (OA) and osteoporosis (OP) are common in elderly individuals. There is a lack of drug therapy for OA and OP comorbidities. The purpose of this study was to explore the efficacy and mechanism of Longbie capsule (LBJN), which contains various plant herbs, in treating OA and OP comorbidities (OA + OP) in rats using metabolomics techniques.METHODS: We created an OA + OP rat model through bilateral oophorectomy combined with meniscus instability surgery. Thirty SD rats were randomly divided into five groups (six in each group), namely, the sham group, OA group, OA + OP group, LBJN low-dose group (0.625 g/kg, OA + OP+LB-L group) and LBJN high-dose group (1.25 g/kg, OA + OP+LB-H group). After 8 weeks of intervention, we used micro-CT to detect bone microstructure status, ELISA to measure bone metabolism indicators, and UPLC-MS technology for metabolomics analysis. Finally, the screened differentially expressed metabolites were subjected to Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and functional enrichment analysis.RESULTS: The micro-CT results showed that LBJN significantly improved the bone mineral density (BMD) and bone quality of subchondral bone in OA + OP rats, and LBJN regulated the expression of bone alkaline phosphatase (BALP), osteoprotegerin (OPG), and tartrate-resistant acid phosphatase (TRACP) in serum to maintain bone metabolism balance. Metabolomics analysis showed that the metabolic trajectory of OA + OP rats after intervention in the OA + OP+LB-H group showed significant changes, and 107 potential biomarkers could be identified. Among them, 50 metabolites were upregulated (such as zeranol) and 57 were downregulated (such as vanillactic acid). The KEGG functional enrichment results indicated that the differentially expressed metabolites are mainly involved in amino acid metabolism, lipid metabolism, and carbohydrate metabolism. The KEGG pathway enrichment results indicated that LBJN may exert therapeutic effects on OA + OP rats by regulating the cAMP signaling pathway, and the FoxO signaling pathway.CONCLUSION: LBJN can maintain bone metabolism balance by regulating serum lipid metabolism, amino acid metabolism, carbohydrate metabolism, and estrogen, thereby reducing bone loss in subchondral bone, which may be a potential mechanism through which LBJN treats OA + OP.PMID:37915330 | PMC:PMC10616798 | DOI:10.3389/fmed.2023.1256238

Sci Rep. 2023 Nov 1;13(1):18860. doi: 10.1038/s41598-023-46134-8.ABSTRACTGlansreginin A has been reported to be an indicator of the quality of walnuts (Juglans spp.). However, bioactive properties of glansreginin A have not been adequately explored. In the present study, we quantified concentrations of glansreginin A in black walnuts (Juglans nigra) using high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) and performed an array of in vitro bioassays to characterize biological activities (e.g., antibacterial, antioxidant, anticancer capacities) of this compound. Results from HPLC-MS/MS analysis indicated that glansreginin A was presented in all 12 black cultivars examined and its contents were variable among black walnut cultivars, ranged from 6.8 mg/kg (Jackson) to 47.0 mg/kg (Hay). Glansreginin A possessed moderate antibacterial activities against Gram-positive pathogens (Staphylococcus aureus and Bacillus anthracis). This compound exhibited no antioxidant activities, did not induce the activity of antioxidant response element signaling pathways, and exerted no antiproliferative effects on tumorigenic alveolar epithelial cells and non-tumorigenic lung fibroblast cells.PMID:37914763 | DOI:10.1038/s41598-023-46134-8

Nat Commun. 2023 Oct 31;14(1):6934. doi: 10.1038/s41467-023-42532-8.ABSTRACTThe human plasma lipidome captures risk for cardiometabolic diseases. To discover new lipid-associated variants and understand the link between lipid species and cardiometabolic disorders, we perform univariate and multivariate genome-wide analyses of 179 lipid species in 7174 Finnish individuals. We fine-map the associated loci, prioritize genes, and examine their disease links in 377,277 FinnGen participants. We identify 495 genome-trait associations in 56 genetic loci including 8 novel loci, with a considerable boost provided by the multivariate analysis. For 26 loci, fine-mapping identifies variants with a high causal probability, including 14 coding variants indicating likely causal genes. A phenome-wide analysis across 953 disease endpoints reveals disease associations for 40 lipid loci. For 11 coronary artery disease risk variants, we detect strong associations with lipid species. Our study demonstrates the power of multivariate genetic analysis in correlated lipidomics data and reveals genetic links between diseases and lipid species beyond the standard lipids.PMID:37907536 | PMC:PMC10618167 | DOI:10.1038/s41467-023-42532-8

Eur Respir Rev. 2023 Nov 1;32(170):230063. doi: 10.1183/16000617.0063-2023. Print 2023 Dec 31.ABSTRACTAsthma is the most common chronic disease within the paediatric population. Although it is multifactorial, its onset may be linked to early-life exposures with subsequent impact on immune system development. Microbial and dietary metabolic products have been implicated in the development and exacerbation of paediatric asthma. Linoleic acid is the most common omega-6 polyunsaturated fatty acid in the Western diet. In this review, we summarise the literature regarding the involvement of linoleic acid in the development of and its impact on existing paediatric asthma. First, we summarise the existing knowledge surrounding the relationship between human microbial metabolism and allergic diseases in children. Next, we examine cellular or animal model-based mechanistic studies that investigated the impact of dietary- and microbial-derived linoleic acid metabolites on asthma. Finally, we review the literature investigating the impact of linoleic acid metabolites on the development and exacerbation of childhood asthma. While there is conflicting evidence, there is growing support for a role of linoleic acid in the onset and pathophysiology of asthma. We recommend that additional cellular, animal, and longitudinal studies are performed that target linoleic acid and its metabolites.PMID:37914192 | DOI:10.1183/16000617.0063-2023

Glob Chang Biol. 2023 Nov 1. doi: 10.1111/gcb.16987. Online ahead of print.ABSTRACTOcean warming has caused coral mass bleaching and mortality worldwide and the persistence of symbiotic reef-building corals requires rapid acclimation or adaptation. Experimental evolution of the coral's microalgal symbionts followed by their introduction into coral is one potential method to enhance coral thermotolerance. Heat-evolved microalgal symbionts of the generalist species, Cladocopium proliferum (strain SS8), were exposed to elevated temperature (31°C) for ~10 years, and were introduced into four genotypes of chemically bleached adult fragments of the scleractinian coral, Galaxea fascicularis. Two of the four coral genotypes acquired SS8. The new symbionts persisted for the 5 months of the experiment and enhanced adult coral thermotolerance, compared with corals that were inoculated with the wild-type C. proliferum strain. Thermotolerance of SS8-corals was similar to that of coral fragments from the same colony hosting the homologous symbiont, Durusdinium sp., which is naturally heat tolerant. However, SS8-coral fragments exhibited faster growth and recovered cell density and photochemical efficiency more quickly following chemical bleaching and inoculation under ambient temperature relative to Durusdinium-corals. Mass spectrometry imaging suggests that algal pigments involved in photobiology and oxidative stress were the greatest contributors to the thermotolerance differences between coral hosting heat-evolved versus wild-type C. proliferum. These pigments may have increased photoprotection in the heat-evolved symbionts. This is the first laboratory study to show that thermotolerance of adult corals (G. fascicularis) can be enhanced via the uptake of exogenously supplied, heat-evolved symbionts, without a trade-off against growth under ambient temperature. Importantly, heat-evolved C. proliferum remained in the corals in moderate abundance 2 years after first inoculation, suggesting long-term stability of this novel symbiosis and potential long-term benefits to coral thermotolerance.PMID:37913765 | DOI:10.1111/gcb.16987

Aquat Toxicol. 2023 Oct 28;264:106736. doi: 10.1016/j.aquatox.2023.106736. Online ahead of print.ABSTRACTPlastic is undoubtedly the most useful and versatile polymeric material that man has developed in the last two centuries Despite the societal benefits, plastic is now a serious global issue because it is persistent and may bioaccumulate into aquatic biota as microplastics (MPs). This study was designed to evaluate the daily uptake and cellular effects due to a short-term (up to 72 h) exposure to 3 μm red polystyrene MPs (50 beads/mL) in the gills of the Mediterranean mussel Mytilus galloprovincialis, chosen as model species for its ecological and commercial relevance. After measuring the daily uptake of MPs and detecting their presence within the branchial epithelium at all the exposure time-points (T24, T48, T72), some cleaning mechanisms were observed by neutral and acid mucous secretions at mussel gills. The protonic Nuclear Magnetic Resonance (1H NMR)-based metabolomics, combined with chemometrics, allowed to comprehensively explore the time-dependent metabolic disorders triggered by MPs in mussel gills over the short-term trial. Specifically, the clear clustering between MP-treated mussel gills and those from control, together with the grouping for experimental time-points as depicted by the Principal Component Analysis (PCA), were due to changes in the amino acids and energy metabolism, disturbances in the osmoregulatory processes, as well as in the cholinergic neurotransmission. Moreover, as evidenced by enzymatic assays, even the oxidative defense systems and lipid metabolism were hampered by MP exposure. Overall, these findings provides the first insights into the early time-dependent mechanisms of toxicity of polystyrene MPs in marine mussels, and underline the potential environment and human health risk posed by MPs contamination.PMID:37913686 | DOI:10.1016/j.aquatox.2023.106736

Atherosclerosis. 2023 Oct 11;385:117340. doi: 10.1016/j.atherosclerosis.2023.117340. Online ahead of print.ABSTRACTBACKGROUND AND AIMS: Lipids play an important role in atherosclerotic plaque development and are interesting candidate predictive biomarkers. However, the link between circulating lipids, accumulating lipids in the vessel wall, and plaque destabilization processes in humans remains largely unknown. This study aims to provide new insights into the role of lipids in atherosclerosis using lipidomics and mass spectrometry imaging to investigate lipid signatures in advanced human carotid plaque and plasma samples.METHODS: We used lipidomics and desorption electrospray ionization mass spectrometry imaging (DESI-MSI) to investigate lipid signatures of advanced human carotid plaque and plasma obtained from patients who underwent carotid endarterectomy (n = 14 out of 17 whose plaque samples were analyzed by DESI-MSI). Multivariate data analysis and unsupervised clustering were applied to identify lipids that were the most discriminative species between different patterns in plaque and plasma. These patterns were interpreted by quantitative comparison with conventional histology.RESULTS: Lipidomics detected more than 300 lipid species in plasma and plaque, with markedly different relative abundances. DESI-MSI visualized the spatial distribution of 611 lipid-related m/z features in plaques, of which 330 m/z features could be assigned based on exact mass, comparison to the lipidomic data, and high mass resolution MSI. Matching spatial lipid patterns to histological areas of interest revealed several molecular species that were colocalized with pertinent disease processes in plaque including specific sphingomyelin and ceramide species with calcification, phospholipids and free fatty acids with inflammation, and triacylglycerols and phosphatidylinositols with fibrin-rich areas.CONCLUSIONS: By comparing lipid species in plaque and plasma, we identified those circulating species that were also prominently present in plaque. Quantitative comparison of lipid spectral patterns with histology revealed the presence of specific lipid species in destabilized plaque areas, corroborating previous in vitro and animal studies.PMID:37913561 | DOI:10.1016/j.atherosclerosis.2023.117340

Sci Transl Med. 2023 Nov;15(720):eadg3049. doi: 10.1126/scitranslmed.adg3049. Epub 2023 Nov 1.ABSTRACTLipid peroxidation-dependent ferroptosis has become an emerging strategy for tumor therapy. However, current strategies not only selectively induce ferroptosis in malignant cells but also trigger ferroptosis in immune cells simultaneously, which can compromise anti-tumor immunity. Here, we used In-Cell Western assays combined with an unbiased drug screening to identify the compound N6F11 as a ferroptosis inducer that triggered the degradation of glutathione peroxidase 4 (GPX4), a key ferroptosis repressor, specifically in cancer cells. N6F11 did not cause the degradation of GPX4 in immune cells, including dendritic, T, natural killer, and neutrophil cells. Mechanistically, N6F11 bound to the RING domain of E3 ubiquitin ligase tripartite motif containing 25 (TRIM25) in cancer cells to trigger TRIM25-mediated K48-linked ubiquitination of GPX4, resulting in its proteasomal degradation. Functionally, N6F11 treatment caused ferroptotic cancer cell death that initiated HMGB1-dependent antitumor immunity mediated by CD8+ T cells. N6F11 also sensitized immune checkpoint blockade that targeted CD274/PD-L1 in advanced cancer models, including genetically engineered mouse models of pancreatic cancer driven by KRAS and TP53 mutations. These findings may establish a safe and efficient strategy to boost ferroptosis-driven antitumor immunity.PMID:37910602 | DOI:10.1126/scitranslmed.adg3049

Elife. 2023 Nov 1;12:e84235. doi: 10.7554/eLife.84235.ABSTRACTCardiac muscle has the highest mitochondrial density of any human tissue, but mitochondrial dysfunction is not a recognized cause of isolated cardiomyopathy. Here, we determined that the rare mitofusin (MFN) 2 R400Q mutation is 15-20× over-represented in clinical cardiomyopathy, whereas this specific mutation is not reported as a cause of MFN2 mutant-induced peripheral neuropathy, Charcot-Marie-Tooth disease type 2A (CMT2A). Accordingly, we interrogated the enzymatic, biophysical, and functional characteristics of MFN2 Q400 versus wild-type and CMT2A-causing MFN2 mutants. All MFN2 mutants had impaired mitochondrial fusion, the canonical MFN2 function. Compared to MFN2 T105M that lacked catalytic GTPase activity and exhibited normal activation-induced changes in conformation, MFN2 R400Q and M376A had normal GTPase activity with impaired conformational shifting. MFN2 R400Q did not suppress mitochondrial motility, provoke mitochondrial depolarization, or dominantly suppress mitochondrial respiration like MFN2 T105M. By contrast to MFN2 T105M and M376A, MFN2 R400Q was uniquely defective in recruiting Parkin to mitochondria. CRISPR editing of the R400Q mutation into the mouse Mfn2 gene induced perinatal cardiomyopathy with no other organ involvement; knock-in of Mfn2 T105M or M376V did not affect the heart. RNA sequencing and metabolomics of cardiomyopathic Mfn2 Q/Q400 hearts revealed signature abnormalities recapitulating experimental mitophagic cardiomyopathy. Indeed, cultured cardiomyoblasts and in vivo cardiomyocytes expressing MFN2 Q400 had mitophagy defects with increased sensitivity to doxorubicin. MFN2 R400Q is the first known natural mitophagy-defective MFN2 mutant. Its unique profile of dysfunction evokes mitophagic cardiomyopathy, suggesting a mechanism for enrichment in clinical cardiomyopathy.PMID:37910431 | DOI:10.7554/eLife.84235

Obes Surg. 2023 Nov 1. doi: 10.1007/s11695-023-06905-8. Online ahead of print.ABSTRACTPURPOSE: Remission of type 2 diabetes (T2D) can be achieved by many, but not all, people following bariatric/metabolic surgery. The mechanisms underlying T2D remission remain incompletely understood. This observational study aimed to identify novel weight-loss independent clinical, metabolic and genetic factors that associate with T2D remission using comprehensive phenotyping.MATERIALS AND METHODS: Ten patients without T2D remission (non-remitters) were matched to 10 patients with T2D remission (remitters) for age, sex, type of surgery, body weight, BMI, post-operative weight loss, duration from surgery and duration of T2D. Detailed body composition assessed using magnetic resonance imaging, gut hormones, serum metabolomics, insulin sensitivity, and genetic risk scores for T2D and anthropometric traits were assessed.RESULTS: Remitters had significantly greater β-cell function and circulating acyl ghrelin levels, but lower visceral adipose tissue (VAT): subcutaneous adipose tissue (SAT) ratio than non-remitters. Branched-chain amino acids (BCAAs) and VLDL particle size were the most discriminant metabolites between groups. A significant positive correlation between, VAT area, VAT:SAT ratio and circulating levels of BCAAs was observed, whereas a significant negative correlation between BCAAs and β-cell function was revealed.CONCLUSION: We highlight a potentially novel relationship between VAT and BCAAs, which may play a role in glucoregulatory control. Improvement in β-cell function, and the role ghrelin plays in its recovery, is likely another key factor influencing T2D remission post-surgery. These findings suggest that adjunctive approaches that target VAT loss and restoration of BCAA metabolism might achieve higher rates of long-term T2D remission post-surgery.PMID:37910328 | DOI:10.1007/s11695-023-06905-8

Mol Nutr Food Res. 2023 Nov 1:e2200525. doi: 10.1002/mnfr.202200525. Online ahead of print.ABSTRACTSCOPE: Aged laying hen is recently suggested as a more attractive animal model than rodent for studying nonalcoholic fatty liver disease (NAFLD) of humans. This study aims to reveal effects and metabolic regulation mechanisms of taurine alleviating NAFLD by using the aged laying hen model.METHODS AND RESULTS: Liver histomorphology and biochemical indices showe 0.02% taurine effectively alleviates fat deposition and liver damage. Comparative liver lipidomics and gene expressions analyses reveal taurine promoted lipolysis, fatty acids oxidation, lipids transport, and reduced oxidative stress in liver. Furthermore, comparative serum metabolomics screen six core metabolites negatively correlated with NAFLD, including linoleic acid, gamma-linolenic acid, pantothenate, L-methionine, 2-methylbutyroylcarnitine, L-carnitine; and two core metabolites positively correlated with NAFLD, including lysophosphatidylcholine (14:0/0:0) and lysophosphatidylcholine (16:0/0:0). Metabolic pathway analysis reveals taurine mainly regulated linoleic acid metabolism, cysteine and methionine metabolism, carnitine metabolism, pantothenic acid and coenzyme A biosynthesis metabolism, and glycerophospholipid metabolism to up-adjust levels of six negatively correlated metabolites and down-adjust two positively correlated metabolites for alleviating NAFLD of aged hens.CONCLUSION: This study firstly reveals underlying metabolic mechanisms of taurine alleviating NAFLD using the aged hen model, thereby laying the foundation for taurine's application in the prevention of NAFLD in both human and poultry.PMID:37909476 | DOI:10.1002/mnfr.202200525

Food Funct. 2023 Nov 1. doi: 10.1039/d3fo03031h. Online ahead of print.ABSTRACTSea cucumber peptides (SCPs) have been proven to have many active functions; however, their impact on testosterone synthesis and the corresponding mechanism are not yet clear. This study attempts to explore the effects of SCPs on sex hormone regulation in acute exhaustive swimming (AES) male mice and the possible mechanisms. In the present study, SCP intervention significantly prolonged exhaustive swimming time and reduced exercise metabolite accumulation. The reproductive ability-related parameters including penile index, mating ability, testicular morphology, and sperm storage were dramatically improved by SCP intervention. Notably, SCPs markedly reversed the AES-induced decrease in serum testosterone (T), estradiol (E2), and follicle-stimulating hormone (FSH) levels. Moreover, treatment with a high dose of SCP (0.6 mg per g bw) significantly enhanced the expression of testosterone synthesis-related proteins in testis, meanwhile markedly increasing the gene expression of StAR, Hsd17b3, Hsd17b2, Ldlr, and Cyp19a1. Serum metabolomics results indicated that SCP intervention notably upregulated the expression of 1-stearoyl-2-arachidonoyl-sn-glycerol but downregulated the concentrations of succinate and DL-lactate. Furthermore, serum metabolomics combined with testicular transcriptome, western blot, and correlation analyses demonstrated that SCPs may regulate testosterone synthesis via the Ca2+/PKA signaling pathway. This study indicated that the SCP could be a potential dietary supplement to improve the symptoms of decreased sex hormones related to exercise fatigue.PMID:37909356 | DOI:10.1039/d3fo03031h

Immunity. 2023 Oct 26:S1074-7613(23)00418-1. doi: 10.1016/j.immuni.2023.09.013. Online ahead of print.ABSTRACTDimeric IgA (dIgA) can move through cells via the IgA/IgM polymeric immunoglobulin receptor (PIGR), which is expressed mainly on mucosal epithelia. Here, we studied the ability of dIgA to target commonly mutated cytoplasmic oncodrivers. Mutation-specific dIgA, but not IgG, neutralized KRASG12D within ovarian carcinoma cells and expelled this oncodriver from tumor cells. dIgA binding changed endosomal trafficking of KRASG12D from accumulation in recycling endosomes to aggregation in the early/late endosomes through which dIgA transcytoses. dIgA targeting of KRASG12D abrogated tumor cell proliferation in cell culture assays. In vivo, KRASG12D-specific dIgA1 limited the growth of KRASG12D-mutated ovarian and lung carcinomas in a manner dependent on CD8+ T cells. dIgA specific for IDH1R132H reduced colon cancer growth, demonstrating effective targeting of a cytoplasmic oncodriver not associated with surface receptors. dIgA targeting of KRASG12D restricted tumor growth more effectively than small-molecule KRASG12D inhibitors, supporting the potential of this approach for the treatment of human cancers.PMID:37909039 | DOI:10.1016/j.immuni.2023.09.013