PubMed

J Chromatogr B Analyt Technol Biomed Life Sci. 2024 Jun 25;1243:124219. doi: 10.1016/j.jchromb.2024.124219. Online ahead of print.ABSTRACTThe variation of qualitative information among different types of mainstream hyphenated instruments of ultra-performance liquid chromatography coupled to high-resolution mass spectrometry (UPLC-HRMS) makes data sharing and standardization, and further comparison of results consistency in metabolite annotation not easy to attain. In this work, a quantitative study of correlation and difference was first achieved to systematically investigate the variation of retention time (tR), precursor ion (MS1), and product fragment ions (MS2) generated by three typical UPLC-HRMS instruments commonly used in metabolomics area. In terms of the findings of systematic and correlated variation of tR, MS1, and MS2 between different instruments, a computational strategy for integrated metabolite annotation was proposed to reduce the influence of differential ions, which made full use of the characteristic (common) and non-common fragments for scoring assessment. The regular variations of MS2 among three instruments under four collision energy voltages of high, medium, low, and hybrid levels were respectively inspected with three technical replicates at each level. These discoveries could improve general metabolite annotation with a known database and similarity comparison. It should provide the potential for metabolite annotation to generalize qualitative information obtained under different experimental conditions or using instruments from various manufacturers, which is still a big headache in untargeted metabolomics. The mixture of standard compounds and serum samples with the addition of standards were applied to demonstrate the principle and performance of the proposed method. The results showed that it could be an optional strategy for general use in HRMS-based metabolomics to offset the difference in metabolite annotation. It has some potential in untargeted metabolomics.PMID:38943690 | DOI:10.1016/j.jchromb.2024.124219

Plant J. 2024 Jun 29. doi: 10.1111/tpj.16896. Online ahead of print.ABSTRACTCold and saline-alkali stress are frequently encountered by plants, and they often occur simultaneously in saline-alkali soils at mid to high latitudes, constraining forage crop distribution and production. However, the mechanisms by which forage crops respond to the combination of cold and saline-alkali stress remain unknown. Alfalfa (Medicago sativa L.) is one of the most essential forage grasses in the world. In this study, we analyzed the complex response mechanisms of two alfalfa species (Zhaodong [ZD] and Blue Moon [BM]) to combined cold and saline-alkali stress using multi-omics. The results revealed that ZD had a greater ability to tolerate combined stress than BM. The tricarboxylic acid cycles of the two varieties responded positively to the combined stress, with ZD accumulating more sugars, amino acids, and jasmonic acid. The gene expression and flavonoid content of the flavonoid biosynthesis pathway were significantly different between the two varieties. Weighted gene co-expression network analysis and co-expression network analysis based on RNA-Seq data suggested that the MsMYB12 gene may respond to combined stress by regulating the flavonoid biosynthesis pathway. MsMYB12 can directly bind to the promoter of MsFLS13 and promote its expression. Moreover, MsFLS13 overexpression can enhance flavonol accumulation and antioxidant capacity, which can improve combined stress tolerance. These findings provide new insights into improving alfalfa resistance to combined cold and saline-alkali stress, showing that flavonoids are essential for plant resistance to combined stresses, and provide theoretical guidance for future breeding programs.PMID:38943631 | DOI:10.1111/tpj.16896

J Proteome Res. 2024 Jun 29. doi: 10.1021/acs.jproteome.4c00035. Online ahead of print.ABSTRACTTumor necrosis factor (TNF) has well-established roles in neuroinflammatory disorders, but the effect of TNF on the biochemistry of brain cells remains poorly understood. Here, we microinjected TNF into the brain to study its impact on glial and neuronal metabolism (glycolysis, pentose phosphate pathway, citric acid cycle, pyruvate dehydrogenase, and pyruvate carboxylase pathways) using 13C NMR spectroscopy on brain extracts following intravenous [1,2-13C]-glucose (to probe glia and neuron metabolism), [2-13C]-acetate (probing astrocyte-specific metabolites), or [3-13C]-lactate. An increase in [4,5-13C]-glutamine and [2,3-13C]-lactate coupled with a decrease in [4,5-13C]-glutamate was observed in the [1,2-13C]-glucose-infused animals treated with TNF. As glutamine is produced from glutamate by astrocyte-specific glutamine synthetase the increase in [4,5-13C]-glutamine reflects increased production of glutamine by astrocytes. This was confirmed by infusion with astrocyte substrate [2-13C]-acetate. As lactate is metabolized in the brain to produce glutamate, the simultaneous increase in [2,3-13C]-lactate and decrease in [4,5-13C]-glutamate suggests decreased lactate utilization, which was confirmed using [3-13C]-lactate as a metabolic precursor. These results suggest that TNF rearranges the metabolic network, disrupting the energy supply chain perturbing the glutamine-glutamate shuttle between astrocytes and the neurons. These insights pave the way for developing astrocyte-targeted therapeutic strategies aimed at modulating effects of TNF to restore metabolic homeostasis in neuroinflammatory disorders.PMID:38943617 | DOI:10.1021/acs.jproteome.4c00035

Plant J. 2024 Jun 29. doi: 10.1111/tpj.16905. Online ahead of print.ABSTRACTWhile it is known that increased dissolved CO2 concentrations and rising sea surface temperature (ocean warming) can act interactively on marine phytoplankton, the ultimate molecular mechanisms underlying this interaction on a long-term evolutionary scale are relatively unexplored. Here, we performed transcriptomics and quantitative metabolomics analyses, along with a physiological trait analysis, on the marine diatom Thalassiosira weissflogii adapted for approximately 3.5 years to warming and/or high CO2 conditions. We show that long-term warming has more pronounced impacts than elevated CO2 on gene expression, resulting in a greater number of differentially expressed genes (DEGs). The largest number of DEGs was observed in populations adapted to warming + high CO2, indicating a potential synergistic interaction between these factors. We further identified the metabolic pathways in which the DEGs function and the metabolites with significantly changed abundances. We found that ribosome biosynthesis-related pathways were upregulated to meet the increased material and energy demands after warming or warming in combination with high CO2. This resulted in the upregulation of energy metabolism pathways such as glycolysis, photorespiration, the tricarboxylic acid cycle, and the oxidative pentose phosphate pathway, as well as the associated metabolites. These metabolic changes help compensate for reduced photochemical efficiency and photosynthesis. Our study emphasizes that the upregulation of ribosome biosynthesis plays an essential role in facilitating the adaptation of phytoplankton to global ocean changes and elucidates the interactive effects of warming and high CO2 on the adaptation of marine phytoplankton in the context of global change.PMID:38943614 | DOI:10.1111/tpj.16905

Expert Opin Ther Targets. 2024 Jun 29. doi: 10.1080/14728222.2024.2375372. Online ahead of print.ABSTRACTINTRODUCTION: Systemic Lupus Erythematosus (SLE) is a multi-dimensional autoimmune disease involving numerous tissues throughout the body. The chromatin accessibility landscapes in immune cells play a pivotal role in governing their activation, function, and differentiation. Aberrant modulation of chromatin accessibility in immune cells is intimately associated with the onset and progression of SLE.AREAS COVERED: In this review, we described the chromatin accessibility landscapes in immune cells, summarized the recent evidence of chromatin accessibility related to the pathogenesis of SLE, and discussed the potential of chromatin accessibility as a valuable option to identify novel therapeutic targets for this disease.EXPERT OPINION: Dynamic changes in chromatin accessibility are intimately related to the pathogenesis of SLE and have emerged as a new direction for exploring its epigenetic mechanisms. The differently accessible chromatin regions in immune cells often contain binding sites for transcription factors (TFs) and cis-regulatory elements such as enhancers and promoters, which may be potential therapeutic targets for SLE. Larger scale cohort studies and integrating epigenomic, transcriptomic, and metabolomic data can provide deeper insights into SLE chromatin biology in the future.PMID:38943564 | DOI:10.1080/14728222.2024.2375372

Bratisl Lek Listy. 2024;125(7):457-462. doi: 10.4149/BLL_2024_70.ABSTRACTIncreased serum lactate dehydrogenase (LDH) activity is considered as a marker of cellular necrosis and serves as a metabolomic diagnostic marker in several types of cancer including head and neck squamous cell carcinoma (HNSCC). LDH, an enzyme involved in the glycolytic cycle, is correlated not only with the activation of oncogenes such as HIF-α and Myc, but also with effects such as tumor proliferation and metastasis. Serum alkaline phosphatase (ALP) is a marker of cell differentiation and tumor induction. Albumin-to-alkaline phosphatase ratio (AAPR) could be an advantageous biomarker due to its easily accessible dynamics and cost-effectiveness. Elevated values of AAPR could be associated with longer overall survival (OS) in cases with solid tumors. Diabetes mellitus (DM) could influence the outcome of patients with HNSCC by contributing to insulin resistance and chronic inflammation, and by being involved in various aspects of carcinogenesis, disease progression and metastasis. However, the use of antihyperglycemic medications (metformin) can have beneficial effects by inhibiting tumor metabolic pathways. The biomarker role of LDH and AAPR in HNSCC patients with DM has been less evaluated. The purpose of the study was to assess the prognostic value of pretreatment serum lactate dehydrogenase (LDH) and albumin-to-alkaline phosphatase ratio (AAPR) in predicting the duration of non-surgical oncological treatment and glycemic control in cases of head and neck cancers patients with DM, including cases selected from the database of the oncology clinic and oncology outpatient clinic of the Craiova County Hospital. Both LDH and AAPR can be used as pre-treatment biomarkers predictive of treatment response, or prognostic tools included in complex multi-parametric models in HNC associated with DM. However, given the impact of short-term glycemic control on the LDH level, it is necessary to evaluate these biomarkers after assessing and controlling for DM, and with the recommended cut-off value set around 0.5. Due to the limited number of cases, it is necessary to validate the results in multicentric trials with a larger number of patients (Tab. 5, Ref. 50). Keywords: diabetes mellitus, HNC, LDH, AAPR, biomarkers, predictive, head and neck cancers, lactate dehydrogenase, albumin-to-alkaline phosphatase ratio.PMID:38943508 | DOI:10.4149/BLL_2024_70

Anim Microbiome. 2024 Jun 28;6(1):37. doi: 10.1186/s42523-024-00325-4.ABSTRACTBACKGROUND: Pinus koraiensis cone essential oil (PEO) contains functional compounds such as monoterpene hydrocarbons, and the administration of PEO reduced methane (CH4) emissions during growing phase of goats. However, the mode of action of PEO driven CH4 reduction is not known, especially how the administration of PEO can affect rumen microbiota and host metabolism in goats during the fattening phase. This study aimed to elucidate the potential microbial and host responses PEO supplementation in goats using metataxonomics (prokaryotes and protozoa) and metabolomics (rumen fluid and serum).RESULTS: Ten fattening Korean native goats were divided into two dietary groups: control (CON; basal diet without additives) and PEO (basal diet + 1.5 g/d of PEO) with a 2 × 2 crossover design and the treatment lasted for 11 weeks. Administration of PEO reduced CH4 concentrations in the exhaled gas from eructation by 12.0-13.6% (P < 0.05). Although the microbial composition of prokaryotes (bacteria and archaea) and protozoa in the rumen was not altered after PEO administration. MaAsLin2 analysis revealed that the abundance of Selenomonas, Christensenellaceae R-7 group, and Anaerovibrio were enriched in the rumen of PEO supplemented goats (Q < 0.1). Co-occurrence network analysis revealed that Lachnospiraceae AC2044 group and Anaerovibrio were the keystone taxa in the CON and PEO groups, respectively. Methane metabolism (P < 0.05) was enriched in the CON group, whereas metabolism of sulfur (P < 0.001) and propionate (P < 0.1) were enriched in the PEO group based on microbial predicted functions. After PEO administration, the abundance of 11 rumen and 4 serum metabolites increased, whereas that of 25 rumen and 14 serum metabolites decreased (P < 0.1). Random forest analysis identified eight ruminal metabolites that were altered after PEO administration, among which four were associated with propionate production, with predictive accuracy ranging from 0.75 to 0.88. Additionally, we found that serum sarcosine (serum metabolite) was positively correlated with CH4 emission parameters and abundance of Methanobrevibacter in the rumen (|r|≥ 0.5, P < 0.05).CONCLUSIONS: This study revealed that PEO administration reduced CH4 emission from of fattening goats with altered microbial interactions and metabolites in the rumen and host. Importantly, PEO administration affected utilizes various mechanisms such as formate, sulfur, methylated amines metabolism, and propionate production, collectively leading to CH4 reduction. The knowledge is important for future management strategies to maintain animal production and health while mitigate CH4 emission.PMID:38943213 | DOI:10.1186/s42523-024-00325-4

Int Breastfeed J. 2024 Jun 28;19(1):45. doi: 10.1186/s13006-024-00652-x.ABSTRACTBACKGROUND: Despite global public health organizations endorsing breastfeeding or human milk (HM) as the optimal source of nutrition for infants, detailed knowledge of how HM composition influences infant growth is lacking. In this commentary we summarize and interpret the key findings of a large systematic review on HM components and child growth (N = 141 articles included). We highlight the most consistent associations, discuss study quality issues, explore socio-economic and time trends in this body of research, and identify gaps and future research directions.KEY FINDINGS OF SYSTEMATIC REVIEW: We grouped HM components into three categories: micronutrients (28 articles), macronutrients (57 articles), and bioactives (75 articles). Overall, we struggled to find consistent associations between HM components and infant growth. The majority of studies (85%) were of moderate or low-quality, with inconsistent HM collection and analysis strategies being identified as the most substantial quality concerns. Additional quality issues included failing to account for potential confounding by factors such as breastfeeding exclusivity and maternal body mass index.CONSIDERATIONS FOR FUTURE HUMAN MILK RESEARCH: Many opportunities exist for the future of HM research. Using untargeted metabolomics will expand our understanding of HM components beyond previously defined and well-understood components. Machine learning will allow researchers to investigate HM as an integrated system, rather than a collection of individual components. Future research on HM composition should incorporate evidence-based HM sampling strategies to encompass circadian variation as well as infant consumption. Additionally, researchers need to focus on developing high quality growth data using consistent growth metrics and definitions. Building multidisciplinary research teams will help to ensure that outcomes are meaningful and clinically relevant.CONCLUSION: Despite a large body of literature, there is limited quality evidence on the relationship between HM composition and infant growth. Future research should engage in more accurate collection of breastfeeding data, use standardized HM collection strategies and employ assays that are validated for HM. By systematically evaluating the existing literature and identifying gaps in existing research methods and practice, we hope to inspire standardized methods and reporting guidelines to support robust strategies for examining relationships between HM composition and child growth.PMID:38943170 | DOI:10.1186/s13006-024-00652-x

Cardiovasc Diabetol. 2024 Jun 28;23(1):223. doi: 10.1186/s12933-024-02298-9.ABSTRACTBACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT-2i) are glucose-lowering agents used for the treatment of type 2 diabetes mellitus, which also improve heart failure and decrease the risk of cardiovascular complications. Epicardial adipose tissue (EAT) dysfunction was suggested to contribute to the development of heart failure. We aimed to elucidate a possible role of changes in EAT metabolic and inflammatory profile in the beneficial cardioprotective effects of SGLT-2i in subjects with severe heart failure.METHODS: 26 subjects with severe heart failure, with reduced ejection fraction, treated with SGLT-2i versus 26 subjects without treatment, matched for age (54.0 ± 2.1 vs. 55.3 ± 2.1 years, n.s.), body mass index (27.8 ± 0.9 vs. 28.8 ± 1.0 kg/m2, n.s.) and left ventricular ejection fraction (20.7 ± 0.5 vs. 23.2 ± 1.7%, n.s.), who were scheduled for heart transplantation or mechanical support implantation, were included in the study. A complex metabolomic and gene expression analysis of EAT obtained during surgery was performed.RESULTS: SGLT-2i ameliorated inflammation, as evidenced by the improved gene expression profile of pro-inflammatory genes in adipose tissue and decreased infiltration of immune cells into EAT. Enrichment of ether lipids with oleic acid noted on metabolomic analysis suggests a reduced disposition to ferroptosis, potentially further contributing to decreased oxidative stress in EAT of SGLT-2i treated subjects.CONCLUSIONS: Our results show decreased inflammation in EAT of patients with severe heart failure treated by SGLT-2i, as compared to patients with heart failure without this therapy. Modulation of EAT inflammatory and metabolic status could represent a novel mechanism behind SGLT-2i-associated cardioprotective effects in patients with heart failure.PMID:38943140 | DOI:10.1186/s12933-024-02298-9

BMC Microbiol. 2024 Jun 28;24(1):229. doi: 10.1186/s12866-024-03385-3.ABSTRACTBACKGROUND: Lactobacillus plantarum has been found to play a significant role in maintaining the balance of intestinal flora in the human gut. However, it is sensitive to commonly used antibiotics and is often incidentally killed during treatment. We attempted to identify a means to protect L. plantarum ATCC14917 from the metabolic changes caused by two commonly used antibiotics, ampicillin, and doxycycline. We examined the metabolic changes under ampicillin and doxycycline treatment and assessed the protective effects of adding key exogenous metabolites.RESULTS: Using metabolomics, we found that under the stress of ampicillin or doxycycline, L. plantarum ATCC14917 exhibited reduced metabolic activity, with purine metabolism a key metabolic pathway involved in this change. We then screened the key biomarkers in this metabolic pathway, guanine and adenosine diphosphate (ADP). The exogenous addition of each of these two metabolites significantly reduced the lethality of ampicillin and doxycycline on L. plantarum ATCC14917. Because purine metabolism is closely related to the production of reactive oxygen species (ROS), the results showed that the addition of guanine or ADP reduced intracellular ROS levels in L. plantarum ATCC14917. Moreover, the killing effects of ampicillin and doxycycline on L. plantarum ATCC14917 were restored by the addition of a ROS accelerator in the presence of guanine or ADP.CONCLUSIONS: The metabolic changes of L. plantarum ATCC14917 under antibiotic treatments were determined. Moreover, the metabolome information that was elucidated can be used to help L. plantarum cope with adverse stress, which will help probiotics become less vulnerable to antibiotics during clinical treatment.PMID:38943061 | DOI:10.1186/s12866-024-03385-3

Environ Pollut. 2024 Jun 26:124458. doi: 10.1016/j.envpol.2024.124458. Online ahead of print.ABSTRACTCyanobacterial blooms have emerged as a significant environmental issue worldwide in recent decades. However, the toxic effects of microcystin-LR (MC-LR) on aquatic organisms, such as frogs, have remained poorly understood. In this study, frogs (Pelophylax nigromaculatus) were exposed to environmentally relevant concentrations of MC-LR (0, 1, and 10 μg/L) for 21 days. Subsequently, we assessed the impact of MC-LR on the histomorphology of the frogs' livers and conducted a global MS-based nontarget metabolomics analysis, followed by the determination of substances involved in lipid metabolism. Results showed that MC-LR significantly induced histological alterations in the frogs' hepatopancreas. Over 200 differentially expressed metabolites were identified, primarily enriched in lipid metabolism. Biochemical analysis further confirmed that MC-LR exposure led to a disorder in lipid metabolism in the frogs. This study laid the groundwork for a mechanistic understanding of MC-LR toxicity in frogs and potentially other aquatic organisms.PMID:38942276 | DOI:10.1016/j.envpol.2024.124458

Cell Rep Med. 2024 Jun 20:101624. doi: 10.1016/j.xcrm.2024.101624. Online ahead of print.ABSTRACTPrior studies indicate no correlation between the gut microbes of healthy first-degree relatives (HFDRs) of patients with Crohn's disease (CD) and the development of CD. Here, we utilize HFDRs as controls to examine the microbiota and metabolome in individuals with active (CD-A) and quiescent (CD-R) CD, thereby minimizing the influence of genetic and environmental factors. When compared to non-relative controls, the use of HFDR controls identifies fewer differential taxa. Faecalibacterium, Dorea, and Fusicatenibacter are decreased in CD-R, independent of inflammation, and correlated with fecal short-chain fatty acids (SCFAs). Validation with a large multi-center cohort confirms decreased Faecalibacterium and other SCFA-producing genera in CD-R. Classification models based on these genera distinguish CD from healthy individuals and demonstrate superior diagnostic power than models constructed with markers identified using unrelated controls. Furthermore, these markers exhibited limited discriminatory capabilities for other diseases. Finally, our results are validated across multiple cohorts, underscoring their robustness and potential for diagnostic and therapeutic applications.PMID:38942021 | DOI:10.1016/j.xcrm.2024.101624

Comput Biol Med. 2024 Jun 27;178:108775. doi: 10.1016/j.compbiomed.2024.108775. Online ahead of print.ABSTRACTBACKGROUND: CDD-2103 is an herbal prescription used to treat ulcerative colitis (UC). This study aimed to uncover its mechanism by integrating metabolomics and serum-feces pharmacochemistry-based network pharmacology.METHODS: A DSS-induced chronic colitis mice model was used to evaluate the anti-colitis effect of CDD-2103. Serum and feces metabolomics were conducted to identify differential metabolites and pathways. In the serum-feces pharmacochemistry study, biological samples were collected from rats treated with CDD-2103. Then, network pharmacology was utilized to predict the targets of the identified compounds. Critical genes were extracted through the above-integrated analysis. The interactions between targets, CDD-2103, and its compounds were validated through molecular docking, immunoblotting, and enzyme activity assays.RESULTS: CDD-2103 alleviated ulcerous symptoms and colonic injuries in colitis mice. Metabolomics study identified differential metabolites associated with tryptophan, glycerophospholipid, and linoleic acid metabolisms. The serum-feces pharmacochemistry study revealed twenty-three compounds, which were subjected to network pharmacology analysis. Integration of these results identified three key targets (AHR, PLA2, and PTGS2). Molecular docking showed strong affinities between the compounds and targets. PTGS2 was identified as a hub gene targeted by most CDD-2103 compounds. Immunoblotting and enzyme activity assays provided further evidence that CDD-2103 alleviates UC, potentially through its inhibitory effect on cyclooxygenase-2 (COX-2, encoded by PTGS2), with alkaloids and curcuminoids speculated as crucial anti-inflammatory compounds.CONCLUSION: This integrated strategy reveals the mechanism of CDD-2103 and provides insights for developing herbal medicine-based therapies for UC.PMID:38941901 | DOI:10.1016/j.compbiomed.2024.108775

Phytomedicine. 2024 Jun 20;132:155834. doi: 10.1016/j.phymed.2024.155834. Online ahead of print.ABSTRACTBACKGROUND: Non-alcoholic fatty liver disease (NAFLD) poses a significant global public health concern. Liupao tea (LPT) is a Chinese national geographical indication product renowned for its lipid-lowering properties. However, the precise mechanisms and active constituents contributing to the efficacy of LPT against NAFLD remain unclear.PURPOSE: This study aims to comprehensively explore the therapeutic potential of Liupao tea extract (LPTE) in alleviating NAFLD through an integrated strategy.METHODS: Initially, network pharmacology analysis was conducted based on LPTE chemical ingredient analysis, identifying core targets and key components. Potential active ingredients were validated through chemical standards based on LC-MS/MS. To confirm the pharmacological efficacy of LPTE in NAFLD, NAFLD mice models were employed. Alterations in hepatic lipid metabolism were comprehensively elucidated through integration of metabolomics, lipidomics, network pharmacology analysis, and real-time PCR analysis. To further explore the binding interactions between key components and core targets, molecular docking and microscale thermophoresis (MST) analysis were employed. Furthermore, to investigate LPTE administration effectiveness on gut microbiota in NAFLD mice, a comprehensive approach was employed. This included Metorigin analysis, 16S rRNA sequencing, molecular docking, and fecal microbiome transplantation (FMT).RESULTS: Study identified naringenin, quercetin, luteolin, and kaempferol as the potential active ingredients of LPTE. These compounds exhibited therapeutic potential for NAFLD by targeting key proteins such as PTGS2, CYP3A4, and ACHE, which are involved in the metabolic pathways of hepatic linoleic acid (LA) and glycerophospholipid (GP) metabolism. The therapeutic effectiveness of LPTE was observed to be comparable to that of simvastatin. Furthermore, LPTE exhibited notable efficacy in alleviating NAFLD by influencing alterations in gut microbiota composition (Proteobacteria phylum, Lactobacillus and Dubosiella genus) that perhaps impact LA and GP metabolic pathways.CONCLUSION: LPTE could be effective in preventing high-fat diet (HFD)-induced NAFLD by modulating hepatic lipid metabolism and gut microbiota. This study firstly integrated bioinformatics and multi-omics technologies to identify the potential active components and key microbiota associated with LPTE's effects, while also primally elucidating the action mechanisms of LPTE in alleviating NAFLD. The findings offer a conceptual basis for LPTE's potential transformation into an innovative pharmaceutical agent for NAFLD prevention.PMID:38941818 | DOI:10.1016/j.phymed.2024.155834

Talanta. 2024 Jun 26;278:126479. doi: 10.1016/j.talanta.2024.126479. Online ahead of print.ABSTRACTArtificial photosynthesis by microbe-semiconductor biohybrid systems has been demonstrated as a valuable strategy in providing sustainable energy and in carbon fixation. However, most of the developed biohybrid systems for light harvesting employ heavy metal materials, especially cadmium sulfide (CdS), which normally cause environmental pollution and restrict the widespread of the systems. Herein, we constructed an environmentally friendly biohybirid system based on a typical acetogenic bacteria, Moorella thermoacetica, coupling with a carbon-based semiconductor, graphitic carbon nitride (g-C3N4), to realize light-driven carbon fixation. The proposed biohybrid system displayed outstanding acetate productivity with a quantum yield of 2.66 ± 0.43 %. Non-targeted proteomic analysis indicated that the physiological activity of the bacteria was improved, coupling with the non-toxic material. We further proposed the mechanisms of energy generation, electron transfer and CO2 fixation of the irradiated biohybrid system by proteomic and metabolomic characterization. With the photoelectron generated in g-C3N4 under illumination, CO2 is finally converted to acetate via the Wood-Ljungdahl pathway (WLP). Other associated pathways were also proved to be activated, providing extra energy or substrates for acetate production. The study reveals that the future focus of the development of biohybrid systems for light harvesting can be on the metal-free biocompatible material, which can activate the expression of the key enzymes involved in the electron transfer and carbon metabolism under light irradiation.PMID:38941811 | DOI:10.1016/j.talanta.2024.126479

J Chromatogr B Analyt Technol Biomed Life Sci. 2024 Jun 25;1243:124192. doi: 10.1016/j.jchromb.2024.124192. Online ahead of print.ABSTRACTPig bile- and Fructus Evodiae sauce-processed Rhizoma Coptidis (Danhuanglian, DHL; Yuhuanglian, YHL, respectively) are two types of processed Rhizoma Coptidis (Huanglian, HL) in traditional Chinese medicine (TCM). DHL and YHL are representative of HL generated from the subordinate and counter system processing methods, respectively, both noted for their anti-inflammatory effects. How these processing methods can affect the medicinal efficacy of HL remains a hot topic. Here, we discussed the influence of the two methods on the efficacy of final HL products (i.e., DHL and YHL) by comparing their components and anti-inflammatory mechanisms. Enzyme-linked immunosorbent assay was employed to measure inflammatory factors in RAW264.7 cells induced by lipopolysaccharide, and UPLC-Q-Exactive Orbitrap-MS was utilized to analyze the endogenous differential metabolites of RAW264.7 cells treated with HL, YHL, and DHL, and thus to identify the related metabolic pathways. Finally, using network pharmacology, we constructed a "disease-target-differential metabolites-active ingredients" network map. Compared with the control, all three products, HL, YHL, and DHL, significantly reduced IL-6, TNF-α, and IL-1β levels. 12 differential metabolites related to inflammation were identified and 25 target proteins were overlapping among the three groups. Notably, the anti-inflammatory effects of DHL and YHL were mediated by metabolic pathways such as aminoacyl-tRNA biosynthesis, arginine and proline metabolism, alanine, aspartate and glutamate metabolism, and arginine biosynthesis. Specifically, DHL significantly impacted free fatty acid levels, which was not observed with HL and YHL. On screening, DHL had 9 active ingredients, including three from pig bile, and YHL had 12 active ingredients, with six from the processing excipient Fructus Evodiae. The distinct anti-inflammatory mechanisms and material basis of YHL and DHL were characterized by consistency and distinctiveness. Thus, this study underscores the significant influence of processing methods on the medicinal efficacy of TCMs by revealing their regulatory mechanisms and material bases.PMID:38941716 | DOI:10.1016/j.jchromb.2024.124192

Bioorg Chem. 2024 Jun 22;150:107587. doi: 10.1016/j.bioorg.2024.107587. Online ahead of print.ABSTRACTMolecular hybridization between structural fragments from the structures of curcumin (1) and resveratrol (2) was used as a designing tool to generate a new N-acyl-cinnamoyl-hydrazone hybrid molecular architecture. Twenty-eight new compounds were synthesized and evaluated for multifunctional activities related to Parkinson's disease (PD), including neuroprotection, antioxidant, metal chelating ability, and Keap1/Nrf2 pathway activation. Compounds 3b (PQM-161) and 3e (PQM-164) were highlighted for their significant antioxidant profile, acting directly as induced free radical stabilizers by DPPH and indirectly by modulating intracellular inhibition of t-BOOH-induced ROS formation in neuronal cells. The mechanism of action was determined as a result of Keap1/Nrf2 pathway activation by both compounds and confirmed by different experiments. Furthermore, compound 3e (PQM-164) exhibited a significant effect on the accumulation of α-synuclein and anti-inflammatory activity, leading to an expressive decrease in gene expression of iNOS, IL-1β, and TNF-α. Overall, these results highlighted compound 3e as a promising and innovative multifunctional drug prototype candidate for PD treatment.PMID:38941700 | DOI:10.1016/j.bioorg.2024.107587

Nat Med. 2024 Jun 28. doi: 10.1038/s41591-024-03075-7. Online ahead of print.ABSTRACTMetastasis occurs frequently after resection of pancreatic cancer (PaC). In this study, we hypothesized that multi-parametric analysis of pre-metastatic liver biopsies would classify patients according to their metastatic risk, timing and organ site. Liver biopsies obtained during pancreatectomy from 49 patients with localized PaC and 19 control patients with non-cancerous pancreatic lesions were analyzed, combining metabolomic, tissue and single-cell transcriptomics and multiplex imaging approaches. Patients were followed prospectively (median 3 years) and classified into four recurrence groups; early (<6 months after resection) or late (>6 months after resection) liver metastasis (LiM); extrahepatic metastasis (EHM); and disease-free survivors (no evidence of disease (NED)). Overall, PaC livers exhibited signs of augmented inflammation compared to controls. Enrichment of neutrophil extracellular traps (NETs), Ki-67 upregulation and decreased liver creatine significantly distinguished those with future metastasis from NED. Patients with future LiM were characterized by scant T cell lobular infiltration, less steatosis and higher levels of citrullinated H3 compared to patients who developed EHM, who had overexpression of interferon target genes (MX1 and NR1D1) and an increase of CD11B+ natural killer (NK) cells. Upregulation of sortilin-1 and prominent NETs, together with the lack of T cells and a reduction in CD11B+ NK cells, differentiated patients with early-onset LiM from those with late-onset LiM. Liver profiles of NED closely resembled those of controls. Using the above parameters, a machine-learning-based model was developed that successfully predicted the metastatic outcome at the time of surgery with 78% accuracy. Therefore, multi-parametric profiling of liver biopsies at the time of PaC diagnosis may determine metastatic risk and organotropism and guide clinical stratification for optimal treatment selection.PMID:38942992 | DOI:10.1038/s41591-024-03075-7

Sci Rep. 2024 Jun 28;14(1):14957. doi: 10.1038/s41598-024-65733-7.ABSTRACTThe tobacco alkaloid nicotine is known for its activation of neuronal nicotinic acetylcholine receptors. Nicotine is consumed in different ways such as through conventional smoking, e-cigarettes, snuff or nicotine pouches. The use of snuff has been associated with several adverse health effects, such as inflammatory reactions of the oral mucosa and oral cavity cancer. We performed a metabolomic analysis of nicotine-exposed THP-1 human monocytes. Cells were exposed to 5 mM of the alkaloid for up to 4 h, and cell extracts and medium subjected to untargeted liquid chromatography high-resolution mass spectrometry. Raw data processing revealed 17 nicotine biotransformation products. Among these, cotinine and nornicotine were identified as the two major cellular biotransformation products. The application of multi- and univariate statistical analyses resulted in the annotation, up to a certain level of identification, of 12 compounds in the cell extracts and 13 compounds in the medium that were altered by nicotine exposure. Of these, four were verified as methylthioadenosine, cytosine, uric acid, and L-glutamate. Methylthioadenosine levels were affected in both cells and the medium, while cytosine, uric acid, and L-glutamate levels were affected in the medium only. The effects of smoking on the pathways involving these metabolites have been previously demonstrated in humans. Most of the other discriminating compounds, which were merely tentatively or not fully identified, were amino acids or amino acid derivatives. In conclusion, our preliminary data suggest that some of the potentially adverse effects related to smoking may also be expected when nicotine is consumed via snuff or nicotine pouches.PMID:38942832 | DOI:10.1038/s41598-024-65733-7

Nat Commun. 2024 Jun 28;15(1):5473. doi: 10.1038/s41467-024-49781-1.ABSTRACTIndividuals with Down syndrome, the genetic condition caused by trisomy 21, exhibit strong inter-individual variability in terms of developmental phenotypes and diagnosis of co-occurring conditions. The mechanisms underlying this variable developmental and clinical presentation await elucidation. We report an investigation of human chromosome 21 gene overexpression in hundreds of research participants with Down syndrome, which led to the identification of two major subsets of co-expressed genes. Using clustering analyses, we identified three main molecular subtypes of trisomy 21, based on differential overexpression patterns of chromosome 21 genes. We subsequently performed multiomics comparative analyses among subtypes using whole blood transcriptomes, plasma proteomes and metabolomes, and immune cell profiles. These efforts revealed strong heterogeneity in dysregulation of key pathophysiological processes across the three subtypes, underscored by differential multiomics signatures related to inflammation, immunity, cell growth and proliferation, and metabolism. We also observed distinct patterns of immune cell changes across subtypes. These findings provide insights into the molecular heterogeneity of trisomy 21 and lay the foundation for the development of personalized medicine approaches for the clinical management of Down syndrome.PMID:38942750 | DOI:10.1038/s41467-024-49781-1