PubMed

Sci Rep. 2024 Oct 28;14(1):25853. doi: 10.1038/s41598-024-75785-4.ABSTRACTMicro- and nanoplastics can interact with various biologically active compounds forming aggregates of which the effects have yet to be understood. To this end, it is vital to characterize these aggregates of key compounds and micro- and nanoplastics. In this study, we examined the adsorption of the antibiotic tetracycline on four different nanoplastics, made of polyethylene (PE), polypropylene (PP), polystyrene (PS), and nylon 6,6 (N66) through chemical computation. Two separate approaches were employed to generate relevant conformations of the tetracycline-plastic complexes. In the first approach, we folded the plastic particle from individual polymer chains in the presence of the drug through multiple separate simulated annealing setups. In the second, more biased, approach, the neat plastic was pre-folded through simulated annealing, and the drug was placed at its surface in multiple orientations. The former approach was clearly superior to the other, obtaining lower energy conformations even with the antibiotic buried inside the plastic particle. Quantum chemical calculations on the structures revealed that the adsorption energies show a trend of decreasing affinity to the drug in the order of N66> PS> PP> PE. In vitro experiments on tetracycline-sensitive cell lines demonstrated that, in qualitative agreement with the calculations, the biological activity of tetracycline drops significantly in the presence of PS particles. Preliminary molecular dynamics simulations on two selected aggregates with each plastic served as first stability test of the aggregates under influence of temperature and in water. We found that all the selected cases persisted in water indicating that the aggregates may be stable also in more realistic environments. In summary, our data show that the interaction of micro- and nanoplastics with drugs can alter drug absorption, facilitate drug transport to new locations, and increase local antibiotic concentrations, potentially attenuating antibiotic effect and at the same time promoting antibiotic resistance.PMID:39468142 | DOI:10.1038/s41598-024-75785-4

Sci Rep. 2024 Oct 28;14(1):25825. doi: 10.1038/s41598-024-71439-7.ABSTRACTIn this study, a comprehensive methodology combining machine learning and statistical analysis was employed to investigate alterations in the metabolite profiles, including lipids, of breast cancer tissues and their subtypes. By integrating biological and machine learning feature selection techniques, along with univariate and multivariate analyses, a notable lipid signature was identified in breast cancer tissues. The results revealed elevated levels of saturated and monounsaturated phospholipids in breast cancer tissues, consistent with external validation findings. Additionally, lipidomics analysis in both the original and validation datasets indicated lower levels of most triacylglycerols compared to non-cancerous tissues, suggesting potential alterations in lipid storage and metabolism within cancer cells. Analysis of cancer subtypes revealed that levels of PC 30:0 were relatively reduced in HER2(-) samples that were ER(+) and PR(+) compared to those that were ER(-) and PR(-). Conversely, HER2(+) tumors, which were ER(-) and PR(-), exhibited increased concentrations of PC 30:0. This increase could potentially be linked to the role of Stearoyl-CoA-Desaturase 1 in breast cancer. Comprehensive metabolomic analyses of breast cancer can offer crucial insights into cancer development, aiding in early detection and treatment evaluation of this devastating disease.PMID:39468100 | DOI:10.1038/s41598-024-71439-7

Anal Bioanal Chem. 2024 Oct 29. doi: 10.1007/s00216-024-05563-8. Online ahead of print.ABSTRACTThe preparation of cellular metabolomics samples and how to achieve comprehensive coverage of different polar metabolites in cell samples in the analysis pose a challenge for cellular metabolomics. In this study, we optimized a metabolomics protocol based on ultra-high-performance liquid chromatography high-resolution mass spectrometry (UPLC/HRMS) for the extraction and detection of metabolites in A549 cells and exploration of the intervention effect of Qi-Yu-San-Long decoction (QYSLD) on A549 cells. The results indicate that the lowest level of ATP leakage was observed when A549 cells were quenched under liquid nitrogen. MeOH/chloroform/H2O (1:2:1) extraction yielded more chromatographic peaks and excellent reproducibility, and the relative extraction efficiency of most target metabolites was also high. And we optimized the chromatographic separation conditions in both HILIC and RPLC modes, enabling comprehensive detection and analysis of metabolites with varying polarities. Then, we applied the optimized method to UPLC-Q-TOF/MS-based metabolomics of A549 cells to study the mechanism of QYSLD intervention in non-small cell lung cancer (NSCLC). The CCK-8, EdU staining, and cell cycle assay showed that QYSLD inhibited the proliferation of A549 cells by interfering with the cell cycle and blocking them in the G1 phase. A total of 36 differential metabolites associated with the antitumor effects of QYSLD on NSCLC were identified, mainly involving nicotinate and nicotinamide metabolism, sphingolipid metabolism, and glycerophospholipid metabolism. And western blotting confirmed that the change in 1-methylnicotinamide levels after QYSLD intervention was associated with the inhibition of nicotinamide N-methyltransferase expression in A549 cells.PMID:39467912 | DOI:10.1007/s00216-024-05563-8

Diabetes Obes Metab. 2024 Oct 28. doi: 10.1111/dom.16039. Online ahead of print.NO ABSTRACTPMID:39467812 | DOI:10.1111/dom.16039

Sheng Wu Gong Cheng Xue Bao. 2024 Oct 25;40(10):3548-3560. doi: 10.13345/j.cjb.230852.ABSTRACTWith unique advantages, gibberellin GA4 has broad application prospects. To explore the regulatory mechanism for the biosynthesis of GA4, we combined liquid chromatography-mass spectrometry (LC-MS)-based metabolomics with principal component analysis (principal component analysis, PCA) and partial least squares-discriminant analysis (PLS-DA) to screen and identify the differential metabolites between the GA4-producing strains S (industrial high-yield strain CGMCC 17793) and wild-type strain Y (NRRL 13620) of Gibberella fujikuroi fermented for the same time and the differential metabolites of strain S fermented for different time periods. KEGG and MBROLE 2.0 were used to analyze the metabolic pathways involving the differential metabolites. The results showed that compared with strain Y, strain S significantly upregulated and downregulated 107 and 66, 136 and 47, and 94 and 65 metabolites on days 3, 6, and 9, respectively. Compared with that on day 3 of fermentation, strain S upregulated 29 metabolites and downregulated 40 metabolites on day 6 and upregulated 52 metabolites and downregulated 67 metabolites on day 9. The differential metabolites between strain S and strain Y after fermentation for the same time were mainly enriched in amino acid metabolism, tricarboxylic acid (TCA) cycle, and terpenoid biosynthesis. The differential metabolites of strain S after fermentation for different time periods were mainly enriched in amino acid and sugar metabolism pathways. Pathway annotation results indicated that strain S increased the production of acetyl-CoA by promoting amino acid and sugar metabolism and TCA cycle, thereby enhancing the mevalonic acid pathway and increasing the content of isopentenyl pyrophosphate (IPP), a precursor for the synthesis of terpenoids, which ultimately led to increased GA4 production. This study explored the metabolic rules of Gibberella fujikuroi GA4, providing a theoretical basis for regulating Gibberella fujikuroi to improve GA4 production.PMID:39467750 | DOI:10.13345/j.cjb.230852

Korean J Physiol Pharmacol. 2024 Nov 1;28(6):549-558. doi: 10.4196/kjpp.2024.28.6.549.ABSTRACTSepsis triggers a systemic inflammatory response that can lead to acute lung injury (ALI). Salidroside (SAL) has many pharmacological activities such as antiinflammatory and anti-oxidation. The objective of the study was to explore the mechanism of SAL on ALI caused by sepsis. A model of ALI in septic mice was established by cecal ligation and puncture. Following SAL treatment, the effect of SAL on the ferroptosis pathway in mice was analyzed. The pathological damage of lung tissue, the levels of inflammatory factors and apoptosis in bronchoalveolar lavage fluid (BALF) of mice were evaluated, and the changes of gene expression level and metabolite content abundance were explored by combining transcriptomics and metabolomics analysis. The effect of SAL on ferroptosis in mice with lung injury was observed by intraperitoneal injection of ferroptosis activator Erastin or ferroptosis inhibitor Ferrostatin-1 to promote or inhibit ferroptosis in mice. SAL significantly alleviated the pathological damage of lung tissue, decreased the number of TUNEL positive cells and the levels of TNF-α, IL-1β, IL-6 in BALF, and increased the level of IL- 10 in lung injury mice. Moreover, the Fe2+ content and malondialdehyde decreased significantly, the reactive oxygen species and glutathione content increased significantly, and the arachidonic acid metabolites 20-hydroxyeicosatetraenoic acid (20- HETE), (5Z, 8Z, 10E, 14Z)-12-Oxoeicosa-5,8,10,14-tetraenoic acid (12-OxOETE), (5Z, 8Z, 10E, 14Z)-(12S)-12-Hydroxyeicosa-5,8,10,14-tetraenoic acid (12(S)-HETE), (5Z, 8Z, 14Z)-11,12-Dihydroxyeicosa-5,8,14-trienoic acid (11,12-DHET), (5Z, 11Z, 14Z)-8,9- Dihydroxyeicosa-5,11,14-trienoic acid, Leukotriene B4, Leukotriene D4 were significantly up-regulated after SAL treatment. Salidroside alleviates ALI caused by sepsis by inhibiting ferroptosis.PMID:39467718 | DOI:10.4196/kjpp.2024.28.6.549

Eur Respir J. 2024 Oct 28:2400298. doi: 10.1183/13993003.00298-2024. Online ahead of print.ABSTRACTBACKGROUND: Limited studies have investigated the influence of body mass index (BMI) trajectories on lung function covering the entire growth period.METHODS: We conducted a prospective study utilizing data from the Swedish BAMSE birth cohort. Latent class mixture modelling was employed to examine the diversity in BMI z-scores from birth to 24 years of age. Participants with four or more BMI z-scores were included (n=3204, 78·4%). Pre-bronchodilator (BD) spirometry was tested at 8, 16, and 24 years, while post-BD spirometry, multiple-breath nitrogen washout (for lung clearance index, LCI), and urinary metabolomics data were assessed at 24 years.RESULTS: Six distinct BMI development groups were identified. Compared to the stable normal BMI group, the accelerated increasing BMI group exhibited reduced pre- and post-BD FEV1/FVC ratio z scores (β=-0·26, 95% CI=[-0·44, -0·08], and -0·22, [ -0·39, -0·05], respectively), along with elevated LCI (0·30, [0·22, 0·42]) at 24 years. The persistent high BMI group demonstrated lower FEV1, and FVC z scores growth between 16 and 24 years (-0.24, [-0.42, -0.05], and -0.27, [-0.45, -0.01], respectively), and elevated LCI (0·20, [0·03, 0·39]) at 24 years. However, those impairments were not observed in the accelerated resolving BMI group. Conversely, the persistent low BMI group displayed persistently decreased FEV1, and FVC from 8 to 24 years, as well as decreased lung function growth. Additionally, histidine-related metabolites were associated with pre- and post-BD FEV1 (hypergeometric FDR=0.008 and <0.001, respectively).CONCLUSIONS: Early interventions aiming for normal BMI during childhood may contribute to improved lung health later in life.PMID:39467611 | DOI:10.1183/13993003.00298-2024

Lifestyle Genom. 2024 Oct 28:1-23. doi: 10.1159/000541909. Online ahead of print.ABSTRACTBACKGROUND: Cardiometabolic diseases pose a significant threat to global public health, with a substantial majority of cardiovascular disease mortality (more than three-quarters) occurring in low- and middle-income countries. There have been remarkable advances in recent years in identifying genetic variants that alter disease susceptibility by interacting with dietary factors. Despite the remarkable progress, several factors need to be considered before the translation of nutrigenetics insights to personalised and precision nutrition in ethnically diverse populations. Some of these factors include variations in genetic predispositions, cultural and lifestyle factors as well as socioeconomic factors.SUMMARY: This review aims to explore the factors that need to be considered in bridging the gap between existing nutrigenetics insights and the implementation of personalised and precision nutrition across diverse ethnicities. Several factors might influence variations among individuals with regards to dietary exposures and metabolic responses and these include genetic diversity, cultural and lifestyle factors as well as socioeconomic factors. A multi-omics approach involving disciplines such as metabolomics, epigenetics and the gut microbiome might contribute to improved understanding of the underlying mechanisms of gene-diet interactions and the implementation of precision nutrition although more research is needed to confirm the practicality and effectiveness of this approach. Conducting gene-diet interaction studies in diverse populations is essential and studies utilising large sample sizes are required as this improves the power to detect interactions with minimal effect sizes. Future studies should focus on replicating initial findings to enhance reliability and promote comparison across studies. Once findings have been replicated in independent samples, dietary intervention studies will be required to further strengthen the evidence and facilitate their application in clinical practice.KEY MESSAGES: Nutrigenetics has a potential role to play in the prevention and management of cardiometabolic diseases. Conducting gene-diet interaction studies in diverse populations is essential giving the genetic diversity and variations in dietary patterns. Integrating data from disciplines such as metabolomics, epigenetics and the gut microbiome could help in early identification of individuals at risk of cardiometabolic diseases as well as the implementation of precise dietary interventions for preventing and managing cardiometabolic diseases.PMID:39467522 | DOI:10.1159/000541909

Food Chem. 2024 Oct 19;464(Pt 2):141713. doi: 10.1016/j.foodchem.2024.141713. Online ahead of print.ABSTRACTWithering is an important process for achieving high-quality flavor in tea. In this study, histological, metabolomics, transcriptomics, and biochemical analyses were combined to comprehensively explore the accumulation and molecular regulatory profiles of quality metabolites during tea withering. The results of tissue staining indicated that as the water content decreased, the vitality of the nucleus weakened, cytoplasmic content increased, flavone content decreased, and proteins degraded. Omics analysis showed that the total content of soluble sugars, free amino acids, and terpenoids increased, whereas that of catechins decreased significantly, although the caffeine content barely changed. Biochemical analysis revealed that the translated products of genes CSA010827 and CSA001819 catalyzed the biosynthesis of galactose and flavanol 3-O-glycosides, respectively, thereby increasing the content of soluble sugars and contributing to the astringent taste. Overall, by combining omics with histological and biochemical analyses, we revealed the metabolic profile and possible molecular mechanisms during the withering process of tea.PMID:39467504 | DOI:10.1016/j.foodchem.2024.141713

Talanta. 2024 Oct 24;283:127094. doi: 10.1016/j.talanta.2024.127094. Online ahead of print.ABSTRACTInvestigation of drug-microbial interactions has gained prominence due to the increasing need to study pharmacomicrobiomics. Previous research has revealed the microbiome's role in drug metabolism, influencing efficacy, bioavailability, and toxicity. Several potential interactions have reported between drugs and microbes, including bioaccumulation, biotransformation, and the influence of drugs on microbial growth. To facilitate the investigation of drug-microbial interactions, in this study, we present an integrated platform and procedure for investigating drug-microbial interactions, focusing on biotransformation, bioaccumulation, metabolomics, exometabolomics, lipidomics, and exolipidomics. To illustrate the feasibility of this platform, we examined the interactions between digoxin and Lactiplantibacillus pentosus (L. pentosus), revealing previously unknown interactions. Although the growth of L. pentosus was unaffected by digoxin, metabolomics, exometabolomics, lipidomics, and exolipidomics analyses revealed digoxin's impact on metabolites and lipids inside and outside L. pentosus. Additionally, we utilized a validated liquid chromatography-mass spectrometry quantification platform to evaluate digoxin biotransformation and bioaccumulation levels by L. pentosus. After accurately quantifying digoxin in the supernatant and pellet, we determined that approximately 8.7 % of digoxin was biotransformed by L. pentosus. Exolipidomics analysis further supported digoxin biotransformation, identifying digoxigenin and its metabolites. These findings elucidate the potential impact of L. pentosus on digoxin metabolism, underscoring the importance of considering microbial interactions in pharmacological research. We anticipate that the integrated platform could assist in more pharmacomicrobiomics studies and uncover unknown drug-microbial interactions.PMID:39467441 | DOI:10.1016/j.talanta.2024.127094

Phytomedicine. 2024 Oct 22;135:156179. doi: 10.1016/j.phymed.2024.156179. Online ahead of print.ABSTRACTBACKGROUND: Xianglian pill (XLP) is a traditional Chinese medicine (TCM) that is widely used to treat ulcerative colitis (UC). However, its mechanism of action in UC is unclear.PURPOSE: This study aimed to investigate the mechanism of action of XLP in treating UC and role of M1 macrophage polarization in this process.STUDY DESIGN: In vivo experiments were performed using UC mice while in vitro experiments were conducted using RAW264.7 cells.METHODS: Mice were administered 3 % dextran sulfate to induce UC model and then treated with XLP. Changes in histopathology and pro-inflammatory cytokines were evaluated. The levels of M1 macrophages in mesenteric lymph nodes were detected by flow cytometry. Colon metabolite levels were analyzed using an energy metabolomic assay. To assess itaconate's impact, both in vivo (mice) and in vitro (RAW264.7 cells) models were employed. Immunofluorescence staining was used to measure the expression levels of TNF-α, IL-6, and iNOS, while qRT-PCR was utilized to quantify the mRNA levels of TET2, STAT1, and Nfkbiz.RESULTS: XLP alleviated ulcerative damage and reduced TNF-α and IL-6 levels in colon, and also downregulated the levels of M1 macrophages and modulated the state of energy metabolism. Specifically, XLP significantly increased ITA level in colonic tissue and this increase was significantly associated with decreased levels of M1 macrophages and alleviation of UC following XLP treatment. Moreover, ITA directly suppressed the polarization of macrophage from M0 to M1 phenotype, accompanied by the decrease of TNF-α, IL-6, and iNOS levels. Further, ITA decreased inflammatory responses in M1 macrophage by inhibiting the TET2/STAT1 and TET2/NF-κB signaling pathways.CONCLUSION: XLP can treat UC by suppressing M1 macrophage polarization via increasing the level of energy metabolite ITA.PMID:39467429 | DOI:10.1016/j.phymed.2024.156179

Neurol Neuroimmunol Neuroinflamm. 2024 Nov;11(6):e200312. doi: 10.1212/NXI.0000000000200312. Epub 2024 Oct 28.ABSTRACTBACKGROUND AND OBJECTIVES: In multiple sclerosis (MS), immune cells invade the CNS and destroy myelin. Macrophages contribute to demyelination and myelin repair, and their role in each process depends on their ability to acquire specific phenotypes in response to external signals. In this article, we assess whether defects in MS patient macrophage responses may lead to increased inflammation or lack of neuroregenerative effects.METHODS: CD14+CD16- monocytes from patients with MS and healthy controls (HCs) were activated in vitro to obtain homeostatic-like, proinflammatory, and proregenerative macrophages. Macrophage activation profiles were assessed through RNA sequencing and metabolomics. Surface molecule expression of CD14, CD16, and HLA-DR and myelin phagocytic capacity were evaluated with flow cytometry. Macrophage supernatant capacity to influence oligodendrocyte precursor cell differentiation toward an astrocytic or oligodendroglia fate was also tested.RESULTS: We observed that MS patient monocytes ex vivo recapitulate their preferential activation toward the CD16+ phenotype, a subset of proinflammatory cells overrepresented in MS lesions. Functionally, MS patient macrophages display a decreased capacity to phagocytose human myelin and a deficit of processing myelin after ingestion. In addition, MS patient macrophage supernatant favors astrocytes over oligodendrocyte differentiation when compared with HC macrophage supernatant. Furthermore, even when exposed to homeostatic or proregenerative stimuli, MS patient macrophages uphold a proinflammatory transcriptomic profile with higher levels of cytokine/chemokine. Of interest, MS patient macrophages exhibit a distinct metabolic signature with a mitochondrial energy metabolism blockage. Transcriptomic data are further substantiated by metabolomics studies that reveal perturbations in the corresponding metabolic pathways.DISCUSSION: Our results show an intrinsic defect of MS patient macrophages, reminiscent of innate immune cell memory in MS, lifting macrophage importance in the disease and as potential therapeutic targets.PMID:39467238 | DOI:10.1212/NXI.0000000000200312

FASEB J. 2024 Oct;38(20):e70135. doi: 10.1096/fj.202401160RR.ABSTRACTThe intake of high dietary fat has been correlated with the progression of age-related macular degeneration (AMD), affecting the function of the retinal pigment epithelium through oxidative stress. A high-fat diet (HFD) can lead to lipid metabolism disorders, excessive production of circulating free fatty acids, and systemic inflammation by aggravating the degree of oxidative stress. Deletion of the retinal G-protein-coupled receptor (RGR-d) has been identified in drusen. In this study, we investigated how the RGR-d exacerbates AMD-like changes under oxidative stress, both in vivo and in vitro. Fundus atrophy became evident, at 12 months old, particularly in the RGR-d + HFD group, and fluorescence angiography revealed narrower retinal vessels and a reduced perfusion area in the peripheral retina. Although rod electroretinography revealed decreasing trends in the a- and b-wave amplitudes in the RGR-d + HFD group at 12 months, the changes were not statistically significant. Mice in the RGR-d + HFD group showed a significantly thinner and more fragile retinal morphology than those in the WT + HFD group, with disordered and discontinuous pigment distribution in the RGR-d + HFD mice. Transmission electron microscopy revealed a thickened Bruch's membrane along the choriocapillaris endothelial cell wall in the RGR-d + HFD mice, and the outer nuclear layer structure appeared disorganized, with reduced nuclear density. Kyoto Encyclopedia of Genes and Genomes pathway analysis indicated significantly lower levels of 25(OH)-vitamin D3 metabolites in the RGR-d + HFD group. Under oxidative stress, RGR-d localized to the mitochondria and reduced the levels of the PINK1-parkin pathway. RGR-d mice fed an HFD were used as a new animal model of dry AMD. Under high-fat-induced oxidative stress, RGR-d accumulated in the mitochondria, disrupting normal mitophagy and causing cellular damage, thus exacerbating AMD-like changes both in vivo and in vitro.PMID:39467145 | DOI:10.1096/fj.202401160RR

Adv Sci (Weinh). 2024 Oct 28:e2409499. doi: 10.1002/advs.202409499. Online ahead of print.ABSTRACTMyocardial ischemia-reperfusion injury (MIRI) significantly worsens the outcomes of patients with cardiovascular diseases. Dexmedetomidine (Dex) is recognized for its cardioprotective properties, but the related mechanisms, especially regarding metabolic reprogramming, have not been fully clarified. A total of 60 patients with heart valve disease are randomly assigned to Dex or control group. Blood samples are collected to analyze cardiac injury biomarkers and metabolomics. In vivo and vitro rat models of MIRI are utilized to assess the effects of Dex on cardiac function, lactate production, and mitochondrial function. It is found that postoperative CK-MB and cTNT levels are significantly lower in the Dex group. Metabolomics reveals that Dex regulates metabolic reprogramming and reduces lactate level. In Dex-treated rats, the myocardial infarction area is reduced, and myocardial contractility is improved. Dex inhibits glycolysis, reduces lactate, and improves mitochondrial function following MIRI. Lactylation proteomics identifies that Dex reduces the lactylation of Malate Dehydrogenase 2（MDH2), thus alleviating myocardial injury. Further studies reveal that MDH2 lactylation induces ferroptosis, leading to MIRI by impairing mitochondrial function. Mechanistic analyses reveal that Dex upregulates Nuclear Receptor Subfamily 3 Group C Member 1（NR3C1) phosphorylation, downregulates Pyruvate Dehydrogenase Kinase 4 (PDK4), and reduces lactate production and MDH2 lactylation. These findings provide new therapeutic targets and mechanisms for the treatment for MIRI.PMID:39467114 | DOI:10.1002/advs.202409499

Adv Sci (Weinh). 2024 Oct 28:e2407677. doi: 10.1002/advs.202407677. Online ahead of print.ABSTRACTHeart failure is a leading cause of mortality worldwide, necessitating the development of novel therapeutic and lifestyle interventions. Recent studies highlight a potential role of time-restricted feeding (TRF) in the prevention and treatment of cardiac diseases. Here, it is found that TRF protected against heart failure at different stages in mice. Metabolomic profiling revealed that TRF upregulated most circulating amino acids, and amino acid supplementation protected against heart failure. In contrast, TRF showed a mild effect on cardiac amino acid profile, but increased cardiac amino acid utilization and activated the cardiac urea cycle through upregulating argininosuccinate lyase (ASL) expression. Cardiac-specific ASL knockout abolished the cardioprotective effects afforded by TRF. Circulating amino acids also protected against heart failure through activation of the urea cycle. Additionally, TRF upregulated cardiac ASL expression through transcription factor Yin Yang 1, and urea cycle-derived NO contributes to TRF-afforded cardioprotection. Furthermore, arteriovenous gradients of circulating metabolites across the human hearts were measured, and found that amino acid utilization and urea cycle activity were impaired in patients with decreased cardiac function. These results suggest that TRF is a promising intervention for heart failure, and highlight the importance of urea cycle in regulation of cardiac function.PMID:39467073 | DOI:10.1002/advs.202407677

PLoS One. 2024 Oct 28;19(10):e0311136. doi: 10.1371/journal.pone.0311136. eCollection 2024.ABSTRACTJasmonate is an essential phytohormone involved in plant development and stress responses. Its perception occurs through the CORONATINE INSENSITIVE (COI) nuclear receptor allowing to target the Jasmonate-ZIM domain (JAZ) repressors for degradation by the 26S proteasome. Consequently, repressed transcription factors are released and expression of jasmonate responsive genes is induced. In rice, three OsCOI genes have been identified, OsCOI1a and the closely related OsCOI1b homolog, and OsCOI2. While the roles of OsCOI1a and OsCOI1b in plant defense and leaf senescence are well-established, the significance of OsCOI2 in plant development and jasmonate signaling has only emerged recently. To unravel the role of OsCOI2 in regulating jasmonate signaling, we examined the transcriptomic and metabolomic responses of jasmonate-treated rice lines mutated in both the OsCOI1a and OsCOI1b genes or OsCOI2. RNA-seq data highlight OsCOI2 as the primary driver of the extensive transcriptional reprogramming observed after a jasmonate challenge in rice roots. A series of transcription factors exhibiting an OsCOI2-dependent expression were identified, including those involved in root development or stress responses. OsCOI2-dependent expression was also observed for genes involved in specific processes or pathways such as cell-growth and secondary metabolite biosynthesis (phenylpropanoids and diterpene phytoalexins). Although functional redundancy exists between OsCOI1a/b and OsCOI2 in regulating some genes, oscoi2 plants generally exhibit a weaker response compared to oscoi1ab plants. Metabolic data revealed a shift from the primary metabolism to the secondary metabolism primarily governed by OsCOI2. Additionally, differential accumulation of oryzalexins was also observed in oscoi1ab and oscoi2 lines. These findings underscore the pivotal role of OsCOI2 in jasmonate signaling and suggest its involvement in the control of the growth-defense trade-off in rice.PMID:39466751 | DOI:10.1371/journal.pone.0311136

ACS Appl Mater Interfaces. 2024 Oct 28. doi: 10.1021/acsami.4c15042. Online ahead of print.ABSTRACTRespiratory syncytial virus (RSV) is a common pathogen that causes respiratory infections in infants and children worldwide, significantly impacting hospitalization rates in this age group. Zinc ions are considered to have broad-spectrum antiviral potential against RNA viruses, including RSV. However, poor organism absorption and low intracellular accumulation of zinc require repeated high-dose supplementation, which may lead to unnecessary toxic side effects. In this research, a Zn2+-mediated glycyrrhizinic acid (GA)-based hydrogel (ZnGA Gel) was introduced and potentially developed to be a clinically available drug candidate for RSV therapy. ZnGA Gel was fabricated based on the cooperation of two potential RSV inhibiting molecules (Zn2+ and GA), where Zn2+ promoted self-assembly of GA and reduced its gel concentration and GA promoted zinc absorption and distribution in lung tissue in vivo. The facile construction of supramolecular hydrogel by the self-assembled coordination complex made it an injectable, temperature-sensitive, and pH-responsive controlled-release drug delivery for Zn2+. Most importantly, GA was observed to enhance organism absorption and intracellular accumulation of Zn2+ and was identified as a zinc ionophore for the first time. GA can colonize on the cell membrane and disturb cell membrane potential, resulting in an enhanced cell membrane permeability. In the presence of GA, more than 4.7-fold increasing Zn2+ concentrations materialized in the intracellular cytoplasm, compared to Zn2+ alone administration. This intracellular Zn2+ accumulation directly boosted the antiviral activities through improved inhibition of RSV replication-associated proteins and significantly inhibited RSV replication. Oral administration of ZnGA Gel on the RSV-infected mice model achieved an ideal therapeutic effect by effectively lowering viral load in the lungs, alleviating lung injury symptoms, and reducing inflammatory cell infiltration at pathological sites. The mechanism involved the inhibition of RSV replication-related proteins, aligning with our in vitro results. Additionally, ZnGA Gel had demonstrated biocompatibility, and reasonable supplementation of zinc was acceptable and effective for infants and children in clinical practice. Hence, the ZnGA Gel developed by us holds promise as an effective anti-RSV medicine in the future.PMID:39466722 | DOI:10.1021/acsami.4c15042

J Vet Intern Med. 2024 Oct 28. doi: 10.1111/jvim.17217. Online ahead of print.ABSTRACTBACKGROUND: Milk fever (MF), a metabolic disorder in dairy cows characterized by low blood calcium concentrations postpartum, is well-recognized clinically. However, comprehensive data on the alteration of metabolites associated with this condition remains sparse.HYPOTHESIS: Delineate serum metabolite profiles and metabolic pathways preceding, coinciding with, and after the onset of MF.ANIMALS: Twenty-six cows, including 20 healthy cows and 6 cows initially affected by MF. Because of culling, the number of MF-affected cows decreased to 4 at MF week, +4 weeks, and +8 weeks postpartum.METHODS: A nested case-control longitudinal study was conducted, with blood samples collected at -8 and -4 weeks prepartum, MF week, and +4 and +8 weeks postpartum. Serum analysis utilized direct injection/liquid chromatography/tandem mass spectrometry (DI/LC/MS/MS) techniques.RESULTS: Key findings included the identification of diverse metabolites such as hexose, amino acids, phosphatidylcholines, lysophosphatidylcholines, and sphingomyelin, which varied between studied groups (P < .05). The most marked metabolic alterations were observed 4 weeks prepartum. In total, 42, 56, 38, 29, and 24 metabolites distinguished the MF group at the respective time points (P < .05). Additionally, 33 metabolic pathways, including amino acid, antioxidant metabolism, fatty acid degradation, and carbohydrate processing, were impacted (P < .05).CONCLUSIONS AND CLINICAL IMPORTANCE: Metabolic disruptions in dairy cows begin several weeks before the clinical manifestation of MF and persist up to 8 weeks postpartum. These findings emphasize the complexity of MF, extending beyond only hypocalcemia and indicate the necessity for preemptive monitoring in dairy herd management.PMID:39466655 | DOI:10.1111/jvim.17217

J Proteome Res. 2024 Oct 28. doi: 10.1021/acs.jproteome.4c00559. Online ahead of print.ABSTRACTWe aimed to investigate the correlation between plasma proteins and metabolites and the occurrence of future strokes using mass spectrometry and bioinformatics as well as to identify other biomarkers that could predict stroke risk in hypertensive patients. In a nested case-control study, baseline plasma samples were collected from 50 hypertensive subjects who developed stroke and 50 gender-, age- and body mass index-matched controls. Plasma untargeted metabolomics and data independent acquisition-based proteomics analysis were performed in hypertensive patients, and 19 metabolites and 111 proteins were found to be differentially expressed. Integrative analyses revealed that molecular changes in plasma indicated dysregulation of protein digestion and absorption, salivary secretion, and regulation of actin cytoskeleton, along with significant metabolic suppression. C4BPA, Caprolactam, Col15A1, and HBB were identified as predictors of stroke occurrence, and the Support Vector Machines (SVM) model was determined to be the optimal predictive model by integrating six machine-learning classification models. The SVM model showed strong performance in both the internal validation set (area under the curve [AUC]: 0.977, 95% confidence interval [CI]: 0.941-1.000) and the external independent validation set (AUC: 0.973, 95% CI: 0.921-0.999).PMID:39466185 | DOI:10.1021/acs.jproteome.4c00559

Explor Target Antitumor Ther. 2024;5(6):1199-1222. doi: 10.37349/etat.2024.00271. Epub 2024 Sep 20.ABSTRACTImmune checkpoint inhibitors (ICI)-based combinations have become the standard first-line treatment for advanced clear cell renal cell carcinoma (ccRCC). Despite significant improvements in survival and the achievement of sustained long-term responses, a subset of patients remains refractory to ICI, and most will eventually develop resistance. Thus, identifying predictive biomarkers for ICI efficacy and resistance is essential for optimizing therapeutic strategies. Up to now, tissue-based biomarkers have not been successful as predictive biomarkers in RCC. Circulating blood-based biomarkers offer a promising alternative. These biomarkers, including circulating immune cells, soluble factors, tumor-derived markers, and those based on metabolomics, are less invasive, offer reproducibility over time, and provide a comprehensive assessment of tumor biology and patient immune status, as well as allow dynamic monitoring during treatment. This review aims to evaluate the current evidence on the different candidate circulating biomarkers being investigated for their potential to predict ICI efficacy in RCC patients.PMID:39465007 | PMC:PMC11502076 | DOI:10.37349/etat.2024.00271