PubMed

Sleep. 2024 Nov 16:zsae240. doi: 10.1093/sleep/zsae240. Online ahead of print.ABSTRACTSTUDY OBJECTIVES: To examine the joint effect of obstructive sleep apnea (OSA) and objective excessive daytime sleepiness (EDS) on glucose metabolism and the underlying mechanisms.METHODS: We included 127 patients with OSA. The multiple sleep latency test (MSLT) and Epworth sleepiness scale (ESS) were used to assess objective and subjective EDS, respectively. Disordered glucose metabolism was defined as either a physician diagnosis or having fasting blood glucose levels ≥ 5.6 mmol/L. Values of fasting insulin and homeostasis model assessment of insulin resistance (HOMA-IR) higher than the median values of our sample were defined as high fasting insulin and insulin resistance. Serum metabolomics and fecal microbiota were used to explore underlying mechanisms.RESULTS: Lower MSLT values were associated with higher levels of fasting blood glucose, fasting insulin, and HOMA-IR. Furthermore, objective EDS was associated with increased odds of disordered glucose metabolism, elevated fasting insulin, and insulin resistance. Dysregulation of serum valine degradation and dysbiosis of fecal Bacteroides thetaiotaomicron were associated with impaired glucose metabolism in OSA with objective EDS. No association between subjective EDS and impaired glucose metabolism was observed.CONCLUSION: OSA with objective, but not subjective, EDS is associated with an increased risk of disordered glucose metabolism and insulin resistance. Dysregulation of valine degradation and dysbiosis of Bacteroides thetaiotaomicron appear to link objective EDS and disordered glucose metabolism in OSA.PMID:39549285 | DOI:10.1093/sleep/zsae240

STAR Protoc. 2024 Nov 15;5(4):103449. doi: 10.1016/j.xpro.2024.103449. Online ahead of print.ABSTRACTWe present a low-volume, direct analysis protocol for non-targeted gas chromatography-mass spectrometry (GC-MS) metabolomics, using 100 μL of urine. The steps include sample collection, stock solution preparation, metabolite extraction, two-step derivation with a drying phase, and analysis via two-dimensional GC time-of-flight MS (GCxGC-TOFMS). This protocol improves the efficiency and thoroughness of urinary metabolite analysis, contributing to advancements in metabolomics research, disease diagnosis, and biomarker discovery. For complete details on the use and execution of this protocol, please refer to Olivier et al.1.PMID:39549239 | DOI:10.1016/j.xpro.2024.103449

Metab Brain Dis. 2024 Nov 16;40(1):7. doi: 10.1007/s11011-024-01481-x.ABSTRACTThe biological basis for metabolic differences between unruptured and ruptured intracranial aneurysm (UIA and RIA) populations and their potential role in triggering IA rupture remain unclear. The aim of this study was to analyze the plasma metabolic profiles of patients with UIA and RIA using an untargeted metabolomic approach and to develop a model for early rupture classification. Plasma samples were analyzed using an ultra-high-performance liquid chromatography high-resolution tandem mass spectrometry-based platform. Least absolute shrinkage and selection operator regression and random forest machine learning methods were employed for metabolite feature selection and predictive model construction. Among 49 differential plasma metabolites identified, 31 were increased and 18 were decreased in the plasma of RIA patients. Five key metabolites-canrenone, piperine, 1-methyladenosine, betaine, and trigonelline-were identified as having strong potential to discriminate between UIA and RIA patients. This combination of metabolites demonstrated high diagnostic accuracy, with an area under the curve exceeding 0.95 in both the training and validation datasets. Our finding highlights the significance of plasma metabolites as potential biomarkers for early detection of IA rupture risk, offering new insights for clinical practice and future research on IA management.PMID:39549086 | DOI:10.1007/s11011-024-01481-x

J Diabetes Investig. 2024 Nov 16. doi: 10.1111/jdi.14355. Online ahead of print.ABSTRACTAIMS: This study aimed to identify metabolic markers for diabetic peripheral neuropathic pain (DPNP) in patients with type 2 diabetes mellitus (T2DM).MATERIALS AND METHODS: Blood metabolite levels in the amino acid, biogenic amine, sphingomyelin, phosphatidylcholine (PC), carnitines, and hexose classes were analyzed in nondiabetic control (n = 27), T2DM without DPNP (n = 58), and T2DM with DPNP (n = 29) using liquid chromatography tandem mass spectrometry. Variable importance projection (VIP) evaluation by partial least squares discriminant analysis was performed on clinical parameters and metabolites.RESULTS: Sixteen variables with VIP > 1.0 (P < 0.05) were identified across all patient groups, and 5 variables were identified to discriminate between the two T2DM groups. DPNP patients showed elevated fasting blood glucose, glutamate, PC aa C36:1, lysoPC a C18:1, and lysoPC a C18:2, while low-density lipoprotein cholesterol, phenylalanine, and tryptophan were reduced. Glutamate, lysoPC a C18:1, and lysoPC a C18:2 discriminated T2DM with DPNP from those without DPNP with an AUC of 0.671. The AUC was improved to 0.765 when ratios of metabolite pairs were considered.INTERPRETATION: Blood metabolites include glutamate, and phospholipid-related metabolites implicated in neuropathic pain may have the potential as biomarkers for DPNP. Further investigation is required to understand the mechanism of action of these altered metabolites in DPNP.PMID:39548809 | DOI:10.1111/jdi.14355

J Exp Bot. 2024 Nov 16:erae468. doi: 10.1093/jxb/erae468. Online ahead of print.ABSTRACTVirus infection brings about changes in the transcriptome, proteome and metabolome status of the infected plant wherein substantial alterations in the abundance of phytohormones and associated components involved in their signaling pathways have been observed. In the recent years, extensive research in the field of plant virology has showcased the undisputable significance of phytohormone signaling during plant-virus interactions. Apart from acting as growth regulators, phytohormones elicit robust immune response, which restricts the viral multiplication within the plant as well as its propagation by vector. Interestingly, these pathways have been shown to not only act as isolated mechanisms but as complex intertwined regulatory cascades where, the cross-talk among different phytohormones and with other antiviral pathways takes place during plant-virus interplay. Viruses cleverly disrupt phytohormone homeostasis via their multifunctional effectors that seems to be smart approach adopted by viruses to circumvent phytohormone-mediated plant immune responses. In this review, we summarize the current understanding of role of phytohormone signaling pathways during plant-virus interaction in activating antiviral immune responses of plant and also, how viruses exploit these signaling pathways favoring their pathogenesis.PMID:39548750 | DOI:10.1093/jxb/erae468

Microbiome. 2024 Nov 16;12(1):242. doi: 10.1186/s40168-024-01962-2.ABSTRACTBACKGROUND: Long-distance road transportation is a common practice in the beef industry, frequently resulting in bovine respiratory disease (BRD) and compromised growth performance. However, a comprehensive investigation integrating clinical performance, physiological conditions, and nasopharyngeal microflora remains lacking.METHODS: This study aimed to evaluate the respiratory health and immunometabolic status of 54 beef calves subjected to a 3000-km journey. The respiratory health of calves was monitored over 60 days post-arrival using a modified clinical scoring system. Nasopharyngeal microflora and venous blood samples were collected at 3 time points: before transportation (A), 30 days post-arrival (B), and 60 days post-arrival (C), for 16S rRNA microbiomics, whole-blood transcriptomics, serum metabolomics, and laboratory assays.RESULT: Within the first week post-arrival, the appetite and mental scores of calves dropped to zero, while other respiratory-related scores progressively declined over the 60 days. The α-diversity of nasopharyngeal microflora in calves was similar at time points A and B, both significantly higher than at time point C. The structure of these microbial communities varied significantly across different time points, with a notably higher relative abundance of BRD-related genera, such as Pasteurella and Mannheimia, detected at time point A compared to B and C. The composition and gene expression profiles of circulating blood cells at time point A were significantly different from those at B and C. Specifically, higher expression levels of oxidative- and inflammatory-related genes, cytokines, and enzymes were observed at time point A compared to B and C. Higher levels of catabolism-related metabolites and enzymes were detected at time point A, while higher levels of anabolism-related metabolites and enzymes were observed at time points B and C. Additionally, significant correlations were found among microorganisms, genes, and metabolites with differing abundances, expression levels, and concentrations across time points. Stronger correlations were observed between calves' performance and nasopharyngeal microflora and immunometabolic status at time point A compared to B or C.CONCLUSIONS: Collectively, these results confirm that 3000 km of road transportation significantly alters the composition and gene expression profiles of circulating white blood cells in calves, affects their metabolic processes, disrupts the balance of the respiratory microbial community, and leads to pronounced respiratory symptoms that persist for at least 60 days. During this period, the influenced composition and gene expression of circulating blood cells, metabolic processes, and nasopharyngeal microbial community gradually return to equilibrium, and the respiratory symptoms gradually diminish. This observational research indicates that transportation induces BRD in calves by disrupting the homeostasis of their immune function, metabolic processes, and nasopharyngeal microbial community. However, these results and their underlying molecular mechanisms warrant further validation through well-designed in vivo and in vitro confirmatory experiments with larger sample size. Video Abstract.PMID:39548602 | DOI:10.1186/s40168-024-01962-2

Microbiome. 2024 Nov 16;12(1):241. doi: 10.1186/s40168-024-01960-4.ABSTRACTBACKGROUND: Vestimentiferan tubeworms are deep-sea colonizers, in which chemoautotrophic symbiosis was first observed. These animals are gutless and depend on endosymbiotic bacteria for organic compound synthesis and nutrition supply. Taxonomically, vestimentiferans belong to Siboglinidae and Annelida. Compared with other siboglinids, vestimentiferans are distinguished by high tolerance of the prevailing hydrogen sulfide in hydrothermal vents, rapid growth in local habitats, and a physical structure consisting of a thick chitinous tube. The metabolic mechanisms contributing to these features remain elusive.RESULTS: Comparative genomics revealed that unlike other annelids, vestimentiferans possessed trehaloneogenesis and lacked gluconeogenesis. Transcriptome and metabolome analyses detected the expression of trehalose-6-phosphate synthase/phosphatase (TPSP), the key enzyme of trehaloneogenesis, and trehalose production in vestimentiferan tissues. In addition to trehaloneogenesis, glycogen biosynthesis evidenced by packed glycogen granules was also found in vestimentiferan symbionts, but not in other Siboglinidae symbionts. Data mining and analyses of invertebrate TPSP revealed that the TPSP in Vestimentifera, as well as Cnidaria, Rotifera, Urochordata, and Cephalochordata, likely originated from Arthropoda, possibly as a result of transposon-mediated inter-phyla gene transfer.CONCLUSION: This study indicates a critical role of bacterial glycogen biosynthesis in the highly efficient symbiont - vestimentiferan cooperation. This study provides a new perspective for understanding the environmental adaptation strategies of vestimentiferans and adds new insights into the mechanism of metabolic evolution in Metazoa. Video Abstract.PMID:39548600 | DOI:10.1186/s40168-024-01960-4

Gut Pathog. 2024 Nov 15;16(1):69. doi: 10.1186/s13099-024-00662-4.ABSTRACTBACKGROUND: Cow milk, which is sometimes consumed raw, hosts a plethora of microorganisms, some of which are beneficial, while others raise food safety concerns. In this study, the draft genome of an extended-spectrum β-lactamase-producing Klebsiella pneumoniae subsp. pneumoniae strain Cow102, isolated from raw cow milk used to produce traditional foods in Nigeria, is reported.RESULT: The genome has a total length of 5,359,907 bp, with 70 contigs and a GC content of 57.35%. A total of 5,244 protein coding sequences were detected with 31% mapped to a subsystem, and genes coding for amino acids and derivatives being the most prevalent. Multilocus sequence typing revealed that the strain had new allelic profile assigned to the novel 6914 sequence type possessing capsular and lipopolysaccharide antigen K locus 122 with an unknown K type (KL122) and O locus O1/O2v2 with type O2afg, respectively. A total of 28 resistance-related genes, 98 virulence-related genes, two plasmids and five phages were identified in the genome. The resistance genes oqxA, oqxB and an IS3 belonging to cluster 204 were traced to bacteriophage Escher 500,465. Comparative analysis predicted one strain specific orthologous group comprising three genes.CONCLUSION: This report of a novel sequence type (ST6914) in K. pneumoniae presents a new allelic profile, indicating ongoing evolution and diversification within the species. Its uniqueness suggests it may represent a locally evolved lineage, although further sampling would be necessary to confirm this hypothesis. The strain's multidrug resistance, virulence gene repertoire, and isolation from animal milk render it a potentially significant public health concern, underscoring the importance of genomic surveillance in non-clinical settings to detect emerging strains. Further research is required to fully characterise the capsular K type of ST6914.PMID:39548558 | DOI:10.1186/s13099-024-00662-4

J Transl Med. 2024 Nov 15;22(1):1028. doi: 10.1186/s12967-024-05786-4.ABSTRACTPURPOSE: Intestinal flora promotes the pathogenesis of colorectal cancer (CRC) through microorganisms and their metabolites. This study aimed to investigate the composition of intestinal flora in different stages of CRC progression and the effect of fecal microbiota transplantation (FMT) on CRC mice.METHODS: The fecal microbiome from healthy volunteers (HC), colorectal adenoma (CRA), inflammatory bowel disease (IBD), and CRC patients were analyzed by 16s rRNA gene sequencing. In an azoxymethane (AOM)/dextran-sulfate-sodium (DSS)-induced CRC mouse, the effect of FMT from HC, CRA, CRC, and IBD patients on CRC mice was assessed by histological analysis. Expression of inflammation- EMT-associated proteins and Wnt/β-catenin pathway were assessed using qRT-PCR and western blot. The ratio of the fecal microorganisms and metabolomics alteration after FMT were also assessed.RESULT: Prevotella, Faecalibacterium, Phascolarctobacterium, Veillonella, Alistipes, Fusobacterium, Oscillibacter, Blautia, and Ruminococcus abundance was different among HC, IBD, CRC, and CRA patients. HC-FMT alleviated disease progression and inflammatory response in CRC mice, inhibited splenic T help (Th)1 and Th17 cell numbers, and suppressed the EMT and Wnt/β-catenin pathways in tumor tissues of CRC mice. IBD-FMT, CRA-FMT, and CRC-FMT played deleterious roles; the CRC-FMT mice exhibited the most malignant phenotype. Compared with the non-FMT CRC mice, Muribaculaceae abundance was lower after FMT, especially lowest in the IBD-FMT group; while Lactobacillus abundance was higher after FMT and especially high in HC-FMT. Akkermansia and Ileibacterium abundance increased after FMT-HC compared to other groups. Metabolite correlation analysis revealed that Muribaculaceae abundance was significantly correlated with metabolites such as Betaine, LysoPC, and Soyasaponin III. Lactobacillus abundance was positively correlated with Taurocholic acid 3-sulfate, and Ileibacterium abundance was positively correlated with Linoleoyl ethanolamide.CONCLUSION: The different intestinal microbiota communities of HC, IBD, CRA, and CRC patients may be attributed to the different modulation effects of FMT on CRC mice. CRC-FMT promoted, while HC-FMT inhibited the progress of CRC. Increased linoleoyl ethanolamide levels and abundance of Muribaculaceae, Akkermansia, and Ileibacterium and reduced Fusobacterium might participate in inhibiting CRC initiation and development. This study demonstrated that FMT intervention could restore the intestinal microbiota and metabolomics of CRC mice, suggesting FMT as a potential strategy for CRC therapy.PMID:39548468 | DOI:10.1186/s12967-024-05786-4

Lipids Health Dis. 2024 Nov 15;23(1):380. doi: 10.1186/s12944-024-02322-7.ABSTRACTBACKGROUND: The year of 2023 displayed the highest average global temperatures since it has been recorded-the duration and severity of extreme heat are projected to increase. Rising global temperatures represent a major public health threat, especially to occupations exposed to hot environments, such as construction and agricultural workers, and first responders. Despite efforts of the scientific community, there is still a need to characterize the pathophysiological processes leading to heat related illness and develop biomarkers that can predict its onset.METHODS: Liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based lipidomics analysis was performed on plasma from male and female subjects who underwent exertional heat tolerance testing (HTT), consisting of a 2-h treadmill walk at 5 km/h with 2.0% incline at a controlled temperature of 40ºC. From HTT, heat tolerance was calculated using the physiological strain index (PSI).RESULTS: Nearly half of all 995 detected lipids from 27 classes were responsive to HTT. Lipid classes related to substrate utilization were predominantly affected by HTT, with a downregulation of triacylglycerols and upregulation of free fatty acids and acyl-carnitines (CARs). Even chain CAR 4:0, 14:0 and 16:1, suggested by-products of incomplete beta oxidation, and diacylglycerols displayed the highest correlation to PSI. PSI did not correlate with plasma lactate levels, suggesting that correlations between even chain CARs and PSI are related to metabolic efficiency versus physical exertion.CONCLUSIONS: Overall, HTT displays a strong impact on the human plasma lipidome and lipid metabolic inefficiencies may underlie reduced heat tolerance.PMID:39548465 | DOI:10.1186/s12944-024-02322-7

BMC Womens Health. 2024 Nov 15;24(1):608. doi: 10.1186/s12905-024-03448-7.ABSTRACTMenopausal syndrome, occurring during the menopausal stage in women, manifests as symptoms stemming from decreased estrogen levels, such as hot flashes, insomnia, mental disorders (anxiety, depression), and osteoporosis. The bulk of studies have indicated alterations in the gut microbiota of those experiencing menopause syndrome compared to healthy women. However, This article focuses on the alterations in gut microbiota in perimenopausal women. Our study utilized 16 s rRNA sequencing to determine the differences in the gut microbiota and metabolites among 44 menopausal syndrome women. The distribution of gut microbiota in postmenopausal women varies based on the level of follicle stimulating hormone, with changes in gut microbiota abundance taking precedence over symptom onset. Fecal metabolites reveal changes in several metabolites, including Amino acid metabolism (Tyrosine, Tryptophan), Lipid metabolism (Alpha linolenic acid metabolism), and other metabolites. Disturbances in lipid metabolism, triggered by hormonal level fluctuations, can contribute to the development of osteoporosis.PMID:39548431 | DOI:10.1186/s12905-024-03448-7

BMC Genomics. 2024 Nov 15;25(1):1091. doi: 10.1186/s12864-024-11016-4.ABSTRACTBACKGROUND: Bivalves represent a vital economic resource in aquaculture for their high productivity and extensive market demand. Growth is one of the most important and desired aquaculture traits for bivalves, regulated by multiple levels, notably intricate metabolic processes. However, the understanding of the metabolic profiles that influence bivalve growth is limited, particularly from a multi-tissue perspective.RESULTS: In this study, metabolic profiles of multiple tissues of Chlamys farreri with different growth performance were systematically investigated by ultraperformance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). Through comparing the metabolic variation between fast-growing (FG) scallops and slow-growing (SG) scallops, 613, 509, 105, and 192 significantly different metabolites (SDMs) were identified in the mantle, gill, adductor muscle, and digestive gland, respectively. Growth-related metabolic pathways including sphingolipid metabolism, fatty acid biosynthesis, and ABC transporter pathway, along with 11 SDMs associated with growth traits were identified in all four tissues, implying they were involved in the growth of multiple tissues in scallops. Tissue-specific metabolic profiling indicated that sulfur-containing amino acid metabolism in the mantle potentially contributed to shell growth, while the gill synergistically participated with the mantle through various metabolic processes, such as tyrosine metabolism, glycine, serine, and threonine metabolism and melanogenesis; energy metabolism was crucial for adductor muscle growth; and nutrients digestion and absorption in the digestive gland were linked to scallop growth.CONCLUSIONS: Our results represent the first comprehensive analysis of the crucial pathways and metabolites associated with the growth of C. farreri, offering valuable insights for future bivalve aquaculture production.PMID:39548384 | DOI:10.1186/s12864-024-11016-4

Sci Rep. 2024 Nov 15;14(1):28179. doi: 10.1038/s41598-024-71546-5.ABSTRACTAjuga turkestanica preparations are used as anti-aging cosmeceuticals and for medicinal purposes. Herein we describe the characterization and quantification of its metabolites in different organs using UHPLC-MS and NMR spectroscopy. A total of 51 compounds belonging to various phytochemical classes (11 flavonoids, 10 ecdysteroids, 9 diterpenes, 6 fatty acids, 5 iridoids, 3 phenylpropanoids, 3 sugars, 2 phenolics, 1 coumarin, 1 triterpene) were annotated and tentatively identified by UHPLC-ESI-QqTOF-MS/MS of methanolic extracts obtained separately from the organs. 1D and 2D NMR spectroscopy independently confirmed the identity of six major compounds. The abundances of these main constituents in flowers, fruits, leaves, roots, seeds, and stems were compared and quantified using 1H NMR. The results showed that 8-O-acetylharpagide, 20-hydroxyecdysone (ecdysterone) and ajugachin B were the most abundant constituents in the species. The two major compounds, 8-O-acetylharpagide and 20-hydroxyecdysone, were chosen as the markers for the quality assessment of A. turkestanica material. The methanolic extract of the aerial parts of A. turkestanica showed no noteworthy anthelmintic (antihelmintic), antifungal, or cytotoxic effect in in vitro assays.PMID:39548128 | DOI:10.1038/s41598-024-71546-5

Nat Microbiol. 2024 Nov 15. doi: 10.1038/s41564-024-01843-2. Online ahead of print.ABSTRACTChemical cues mediate interactions between marine phytoplankton and bacteria, underpinning ecosystem-scale processes including nutrient cycling and carbon fixation. Phage infection alters host metabolism, stimulating the release of chemical cues from intact plankton, but how these dynamics impact ecology and biogeochemistry is poorly understood. Here we determine the impact of phage infection on dissolved metabolite pools from marine cyanobacteria and the subsequent chemotactic response of heterotrophic bacteria using time-resolved metabolomics and microfluidics. Metabolites released from intact, phage-infected Synechococcus elicited strong chemoattraction from Vibrio alginolyticus and Pseudoalteromonas haloplanktis, especially during early infection stages. Sustained bacterial chemotaxis occurred towards live-infected Synechococcus, contrasted by no discernible chemotaxis towards uninfected cyanobacteria. High-throughput microfluidics identified 5'-deoxyadenosine and 5'-methylthioadenosine as key attractants. Our findings establish that, before lysis, phage-infected picophytoplankton release compounds that attract motile heterotrophic bacteria, suggesting a mechanism for resource transfer that might impact carbon and nutrient fluxes across trophic levels.PMID:39548345 | DOI:10.1038/s41564-024-01843-2

NPJ Precis Oncol. 2024 Nov 15;8(1):262. doi: 10.1038/s41698-024-00752-1.ABSTRACTThis study profiled global single cell-spatial-bulk transcriptome landscapes of hepatocellular carcinoma (HCC) ecosystem from six HCC cases and a non-carcinoma liver control donor. We discovered that intratumoral heterogeneity mainly derived from HCC cells diversity and pervaded the genome-transcriptome-proteome-metabolome network. HCC cells are the core driving force of taming tumor-associated macrophages (TAMs) with pro-tumorigenic phenotypes for favor its dominant growth. Remarkably, M1-types TAMs had been characterized by disturbance of metabolism, poor antigen-presentation and immune-killing abilities. Besides, we found simultaneous cirrhotic and HCC lesions in an individual patient shared common origin and displayed parallel clone evolution via driving disparate immune reprograms for better environmental adaptation. Moreover, endothelial cells exhibited phenotypically conserved but executed differential functions in a space-dependent manner. Further, the spatiotemporal traits of rapid recurrence niche genes were identified and validated by immunohistochemistry. Our data unravels the great significance of HCC cells in shaping vibrant tumor ecosystems corresponding to clinical scenarios.PMID:39548284 | DOI:10.1038/s41698-024-00752-1

Mol Cell Endocrinol. 2024 Nov 13:112414. doi: 10.1016/j.mce.2024.112414. Online ahead of print.ABSTRACTPurine metabolism is upregulated in various cancers including colorectal cancer (CRC). While previous work has elucidated the role of estrogen (E2) in metabolic reprogramming and ATP production, the effect of E2 on purine metabolism remains largely unknown. Herein, the impact of E2 signalling on purine metabolism in CRC cells was investigated using metabolome and transcriptome profiling of cell extracts derived from E2-treated HCT-116 cells with intact or silenced estrogen receptor alpha (ERα). Purine metabolic pathway enrichment analysis showed that 27 genes in the de novo purine synthesis pathway were downregulated in E2-treated CRC cells. Downstream consequences of E2 treatment including the induction of DNA damage, cell cycle arrest, and apoptosis were all shown to be ERα-dependent. These findings demonstrate, for the first time, that E2 exerts a significant anti-growth and survival effect in CRC cells by targeting the purine synthesis pathway in a ERα-dependent manner, meriting further investigation of the therapeutic utility of E2 signalling in CRC.PMID:39547645 | DOI:10.1016/j.mce.2024.112414

Int J Biol Macromol. 2024 Nov 13:137630. doi: 10.1016/j.ijbiomac.2024.137630. Online ahead of print.ABSTRACTBronchial asthma is the most common multifactorial and heterogeneous disease in childhood. The glucocorticoid dexamethasone is a classic treatment for asthma. Research indicates that group 2 innate lymphoid cells (ILC2s) are crucial to the pathogenesis of asthma. However, few studies have focused on ILC2s metabolism and transcription. This study aims to establish an ovalbumin (OVA)-induced asthma model and a dexamethasone-treated asthma model to explore the regulation of lung ILC2s at the genetic and metabolic levels during the progression and remission of asthma, utilizing single-cell metabolomics and transcriptomics approaches. The results showed that ILC2s regulated the metabolic pathways and transcriptional levels of amino acids (such as arginine, proline, and histidine) and linoleic acid, as well as the metabolic biomarkers of arginine, urocanic acid, and linoleic acid in asthma. Additionally, the cytokine pathways and NF-γB pathways have been altered at the genetic level. At the same time, we revealed that dexamethasone regulates ILC2s amino acid and aminoacyl tRNA metabolism, as well as related genes, thereby alleviating asthma symptoms. Furthermore, we identified the genes Eno3 and Tap1, which are significantly associated with asthma. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to verify the accuracy of the RNA sequencing results. This study, for the first time, revealed the mechanistic changes of ILC2s in the development and treatment of asthma using multiomics techniques, laying a foundation for targeted therapies in asthma.PMID:39547613 | DOI:10.1016/j.ijbiomac.2024.137630

Metabolism. 2024 Nov 13:156064. doi: 10.1016/j.metabol.2024.156064. Online ahead of print.ABSTRACTPCSK9 is a serine protease that regulates plasma levels of low-density lipoprotein (LDL) and cholesterol by mediating the endolysosomal degradation of LDL receptor (LDLR) in the liver. When PCSK9 functions unchecked, it leads to increased degradation of LDLR, resulting in elevated circulatory levels of LDL and cholesterol. This dysregulation contributes to lipid and cholesterol metabolism abnormalities, foam cell formation, and the development of various diseases, including cardiovascular disease (CVD), viral infections, cancer, and sepsis. Emerging clinical and experimental evidence highlights an imperative role for PCSK9 in metabolic anomalies such as hypercholesterolemia and hyperlipidemia, as well as inflammation, and disturbances in mitochondrial homeostasis. Moreover, metabolic hormones - including insulin, glucagon, adipokines, natriuretic peptides, and sex steroids - regulate the expression and circulatory levels of PCSK9, thus influencing cardiovascular and metabolic functions. In this comprehensive review, we aim to elucidate the regulatory role of PCSK9 in lipid and cholesterol metabolism, pathophysiology of diseases such as CVD, infections, cancer, and sepsis, as well as its pharmaceutical and non-pharmaceutical targeting for therapeutic management of these conditions.PMID:39547595 | DOI:10.1016/j.metabol.2024.156064

Free Radic Biol Med. 2024 Nov 13:S0891-5849(24)01055-4. doi: 10.1016/j.freeradbiomed.2024.11.021. Online ahead of print.ABSTRACTPolycystic ovary syndrome (PCOS) is a common endocrine disorder marked by ovarian dysfunction and metabolic abnormality. This study explores the therapeutic potential of leonurine (SCM-198) in PCOS. Our results show that SCM-198 treatment significantly improved ovarian function, hormone disorders and insulin resistance while reducing granulosa cell ferroptosis. This study provides the first evidence that SCM-198 modulates the gut microbiota composition, increases the abundance of Christensenella minuta, and boosts butyrate levels. Transcriptomic and metabolomic analyses revealed that PCOS patients exhibit granulosa cell ferroptosis and decreased butyrate levels in follicular fluid. Butyrate was shown to alleviate ferroptosis in granulosa cells via the SLC7A11/TXNRD1/GPX4 pathway, as confirmed in vitro with KGN cells. The therapeutic mechanism of SCM-198 in the management of PCOS via the gut-ovary axis involves the enhancement of intestinal microbiota and its metabolites. This intervention improves ovarian function and alleviates PCOS symptoms by targeting ferroptosis in granulosa cells.PMID:39547522 | DOI:10.1016/j.freeradbiomed.2024.11.021

Biochim Biophys Acta Mol Basis Dis. 2024 Nov 13:167569. doi: 10.1016/j.bbadis.2024.167569. Online ahead of print.ABSTRACTMitochondrial diseases, often caused by defects in complex I (CI) of the oxidative phosphorylation system, currently lack curative treatments. Human-relevant, high-throughput drug screening platforms are crucial for the discovery of effective therapeutics, with induced pluripotent stem cells (iPSCs) emerging as a valuable technology for this purpose. Here, we present a novel iPSC model of NDUFS4-related CI deficiency that displays a strong metabolic phenotype in the pluripotent state. Human iPSCs were edited using CRISPR-Cas9 to target the NDUFS4 gene, generating isogenic NDUFS4 knockout (KO) cell lines. Sanger sequencing detected heterozygous biallelic deletions, whereas no indel mutations were found in isogenic control cells. Western blotting confirmed the absence of NDUFS4 protein in KO iPSCs and CI enzyme kinetics showed a ~56 % reduction in activity compared to isogenic controls. Comprehensive metabolomic profiling revealed a distinct metabolic phenotype in NDUFS4 KO iPSCs, predominantly associated with an elevated NADH/NAD+ ratio, consistent with alterations observed in other models of mitochondrial dysfunction. Additionally, β-lapachone, a recognized NAD+ modulator, alleviated reductive stress in KO iPSCs by modifying the redox state in both the cytosol and mitochondria. Although undifferentiated iPSCs cannot fully replicate the complex cellular dynamics of the disease seen in vivo, these findings highlight the utility of iPSCs in providing a relevant metabolic milieu that can facilitate early-stage, high-throughput exploration of therapeutic strategies for mitochondrial dysfunction.PMID:39547516 | DOI:10.1016/j.bbadis.2024.167569