Integrative Molecular Phenotyping
INTEGRATIVE MOLECULAR
PHENOTYPING
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY

PubMed

Metabolic profiling stratifies colorectal cancer and reveals adenosylhomocysteinase as a therapeutic target

Mon, 14/08/2023 - 12:00
Nat Metab. 2023 Aug 14. doi: 10.1038/s42255-023-00857-0. Online ahead of print.ABSTRACTThe genomic landscape of colorectal cancer (CRC) is shaped by inactivating mutations in tumour suppressors such as APC, and oncogenic mutations such as mutant KRAS. Here we used genetically engineered mouse models, and multimodal mass spectrometry-based metabolomics to study the impact of common genetic drivers of CRC on the metabolic landscape of the intestine. We show that untargeted metabolic profiling can be applied to stratify intestinal tissues according to underlying genetic alterations, and use mass spectrometry imaging to identify tumour, stromal and normal adjacent tissues. By identifying ions that drive variation between normal and transformed tissues, we found dysregulation of the methionine cycle to be a hallmark of APC-deficient CRC. Loss of Apc in the mouse intestine was found to be sufficient to drive expression of one of its enzymes, adenosylhomocysteinase (AHCY), which was also found to be transcriptionally upregulated in human CRC. Targeting of AHCY function impaired growth of APC-deficient organoids in vitro, and prevented the characteristic hyperproliferative/crypt progenitor phenotype driven by acute deletion of Apc in vivo, even in the context of mutant Kras. Finally, pharmacological inhibition of AHCY reduced intestinal tumour burden in ApcMin/+ mice indicating its potential as a metabolic drug target in CRC.PMID:37580540 | DOI:10.1038/s42255-023-00857-0

Metabolites for monitoring symptoms and predicting remission in patients with depression who received electroconvulsive therapy: a pilot study

Mon, 14/08/2023 - 12:00
Sci Rep. 2023 Aug 14;13(1):13218. doi: 10.1038/s41598-023-40498-7.ABSTRACTThe lack of biomarkers to monitor and predict the efficacy of electroconvulsive therapy (ECT) has hindered its optimal use. To establish metabolomic markers for monitoring and predicting the treatment efficacy of ECT, we comprehensively evaluated metabolite levels in patients with major depressive disorder (MDD) by performing targeted and non-targeted metabolomic analyses using plasma samples before and after the first, third, and final ECT sessions, and 3-7 days after the final session. We compared the plasma metabolomes of age- and sex-matched healthy controls (HCs). Thirteen hospitalized patients with MDD and their corresponding HCs were included in this study. We observed that patients with MDD exhibited lower levels of amino acids, including gamma-aminobutyric acid (GABA), and metabolites involved in tryptophan metabolism and the kynurenine pathway, and higher levels of cortisol at baseline. Furthermore, we investigated the relationship between metabolite levels and depression severity across seven measurement timepoints along with one correlation analysis and found that amino acids, including GABA and tryptophan catabolites, were significantly correlated with the severity of depression. Despite the exploratory nature of this study due to the limited sample size necessitating further validation, our findings suggest that the blood metabolic profile has potential as a biomarker for ECT.PMID:37580528 | DOI:10.1038/s41598-023-40498-7

N-acetyl-L-leucine protects MPTP-treated Parkinson's disease mouse models by suppressing Desulfobacterota via the gut-brain axis

Mon, 14/08/2023 - 12:00
Brain Res Bull. 2023 Aug 12:110729. doi: 10.1016/j.brainresbull.2023.110729. Online ahead of print.ABSTRACTParkinson's disease (PD) is the second most common neurodegenerative disease, and communication between the gut and brain (the gut-brain axis) has been found to be essential in behavior and cognitive function. However, the exact mechanisms underlying microbiota dysbiosis in PD progression have not yet been elucidated. Our study aimed to investigate the correlation between gut microbiota disturbances and feces metabolic disorders in Parkinson's disease (PD). We used 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to induce PD models and observed mice's motor symptoms, dopaminergic (DA) neuron death, and gastrointestinal dysfunction. To identify alterations in microbiota and metabolome, feces were collected from mice and analyzed using 16S ribosomal RNA sequencing feces metabolomics. Pearson analysis was utilized to investigate correlations between the abundances of gut microbiota components and the levels of gut microbiota metabolites, displaying their interaction networks. Our findings revealed a significant increase in Desulfobacterota in the PD mouse model and 151 differentially expressed fecal metabolites between PD and vehicle mice. Moreover, Pearson correlation analysis suggested that the protective factor N-acetyl-L-leucine (NALL) may be associated with neuroinflammation in the striatum and substantia nigra, which also had a negative relationship with the concentration of Desulfobacterota. Additionally, we found that oral administration of NALL alleviated MPTP-Induced Motor Impairments and DA neuronal deficits. All in all, we concluded that the decrease of NALL might lead to a significant increase of Desulfobacterota in the MPTP model mouse and subsequently result in the damage of DA neurons via the gut-brain aix pathway.PMID:37579888 | DOI:10.1016/j.brainresbull.2023.110729

Biochar-assisted degradation of oxytetracycline by Achromobacter denitrificans and underlying mechanisms

Mon, 14/08/2023 - 12:00
Bioresour Technol. 2023 Aug 12:129673. doi: 10.1016/j.biortech.2023.129673. Online ahead of print.ABSTRACTContamination of the environment with large amounts of residual oxytetracycline (OTC) and the corresponding resistance genes poses a potential threat to natural ecosystems and human health. In this study, an effective OTC-degrading strain, identified as Achromobacter denitrificans OTC-F, was isolated from activated sludge. In the degradation experiment, the degradation rates of OTC in the degradation systems with and without biochar addition were 95.01-100% and 73.72-99.66%, respectively. Biochar promotes the biodegradation of OTC, particularly under extreme environmental conditions. Toxicity evaluation experiments showed that biochar reduced biotoxicity and increased the proportion of living cells by 17.36%. Additionally, biochar increased the activity of antioxidant enzymes by 34.1-91.0%. Metabolomic analysis revealed that biochar promoted the secretion of antioxidant substances such as glutathione and tetrahydrofolate, which effectively reduced oxidative stress induced by OTC. This study revealed the mechanism at the molecular level and provided new strategies for the bioremediation of OTC in the environment.PMID:37579863 | DOI:10.1016/j.biortech.2023.129673

Discovery of candidate biomarkers to discriminate between Korean and Japanese red seabream (Pagrus major) using metabolomics

Mon, 14/08/2023 - 12:00
Food Chem. 2023 Aug 11;431:137129. doi: 10.1016/j.foodchem.2023.137129. Online ahead of print.ABSTRACTRed seabream (Pagrus major) is widely consumed in East Asia. As nuclear wastewater is discharged into Japanese waterbodies, the country of origin of marine products must be accurately labeled. Here, we aimed to discover candidate metabolite biomarkers to discriminate between Korean and Japanese red seabream using LC-Orbitrap mass spectrometry. In total, 95 and 138 putative metabolites were detected via chromatographic separation of fish sampled in the warm and cold seasons, respectively. The spectrometric and chromatographic data were analyzed using principal component analysis and orthogonal partial least squares discriminant analysis. We identified 12 and 19 influential metabolites to discriminate between each origin fish in the warm and cold seasons, respectively, using variable importance in projection scores and p values. Anserine was further selected as a candidate biomarker based on receiver operating characteristic curve analysis. This study provides a basis for using anserine to determine the geographic origin of red seabream.PMID:37579607 | DOI:10.1016/j.foodchem.2023.137129

Metabolic and oxidative stress response of sea cucumber Apostichopus japonicus exposed to acute high concentration of bisphenol AF

Mon, 14/08/2023 - 12:00
Aquat Toxicol. 2023 Aug 11;262:106654. doi: 10.1016/j.aquatox.2023.106654. Online ahead of print.ABSTRACTBisphenols are known as endocrine disruptor that affect the development, and growth of marine creatures, including human. There were plenty of manuscripts evaluated the toxicology of bisphenol A (BPA) and its analogues such as bisphenol F (BPF), bisphenol AF (BPAF), and bisphenol S (BPS), but limits of them studied the effects of bisphenol analogues on echinoderms. In this study, we used metabolomics to investigate the metabolic response of sea cucumber (Apostichopus japonicus) exposed to BPAF, and the activities of glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD) were determined. The results demonstrated alterations in lipid metabolism, glycerophospholipid metabolism, and biosynthesis of amino acids following BPAF treatment. Sea cucumbers upregulated the glycerophospholipid metabolism to repair the destruction of intestine cellular homeostasis. Six metabolites were selected as the potential biomarkers for the exposure of BPAF. This study revealed the metabolic response and oxidative response of sea cucumber arising from BPAF exposure, and provided theoretical support for the risk assessment of bisphenol analogues on economically important echinoderms, such as A. japonicus.PMID:37579560 | DOI:10.1016/j.aquatox.2023.106654

Shaping the tumor immune microenvironment of SCLC: Mechanisms, and opportunities for immunotherapy

Mon, 14/08/2023 - 12:00
Cancer Treat Rev. 2023 Aug 7;120:102606. doi: 10.1016/j.ctrv.2023.102606. Online ahead of print.ABSTRACTSmall-cell lung cancer (SCLC) is a very aggressive neuroendocrine tumor with a poor prognosis. Whereas immunotherapy has emerged as a promising approach for treating SCLC, its unique tumor immune microenvironment (TIME) might limit patient responses. To fully characterize the TIME and understand the mechanism of its formation with respect to SCLC is crucial. The recent rapid development of multi-omics technologies has rapidly advanced knowledge of TIME features and the regulatory mechanisms associated with SCLC. This review summarizes the TIME features of SCLC as well as shaping the TIME according to the genomics, epigenomics, and metabolomics of tumors. Future opportunities and challenges for immunotherapy are also discussed.PMID:37579532 | DOI:10.1016/j.ctrv.2023.102606

Aggregated Molecular Phenotype Scores: Enhancing Assessment and Visualization of Mass Spectrometry Imaging Data for Tissue-Based Diagnostics

Mon, 14/08/2023 - 12:00
Anal Chem. 2023 Aug 14. doi: 10.1021/acs.analchem.3c02389. Online ahead of print.ABSTRACTMass spectrometry imaging (MSI) has gained increasing popularity for tissue-based diagnostics due to its ability to identify and visualize molecular characteristics unique to different phenotypes within heterogeneous samples. Data from MSI experiments are often assessed and visualized using various supervised and unsupervised statistical approaches. However, these approaches tend to fall short in identifying and concisely visualizing subtle, phenotype-relevant molecular changes. To address these shortcomings, we developed aggregated molecular phenotype (AMP) scores. AMP scores are generated using an ensemble machine learning approach to first select features differentiating phenotypes, weight the features using logistic regression, and combine the weights and feature abundances. AMP scores are then scaled between 0 and 1, with lower values generally corresponding to class 1 phenotypes (typically control) and higher scores relating to class 2 phenotypes. AMP scores, therefore, allow the evaluation of multiple features simultaneously and showcase the degree to which these features correlate with various phenotypes. Due to the ensembled approach, AMP scores are able to overcome limitations associated with individual models, leading to high diagnostic accuracy and interpretability. Here, AMP score performance was evaluated using metabolomic data collected from desorption electrospray ionization MSI. Initial comparisons of cancerous human tissues to their normal or benign counterparts illustrated that AMP scores distinguished phenotypes with high accuracy, sensitivity, and specificity. Furthermore, when combined with spatial coordinates, AMP scores allow visualization of tissue sections in one map with distinguished phenotypic borders, highlighting their diagnostic utility.PMID:37579019 | DOI:10.1021/acs.analchem.3c02389

Evaluation of Data-Dependent MS/MS Acquisition Parameters for Non-Targeted Metabolomics and Molecular Networking of Environmental Samples: Focus on the Q Exactive Platform

Mon, 14/08/2023 - 12:00
Anal Chem. 2023 Aug 14. doi: 10.1021/acs.analchem.3c01202. Online ahead of print.ABSTRACTNon-targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) is a widely used tool for metabolomics analysis, enabling the detection and annotation of small molecules in complex environmental samples. Data-dependent acquisition (DDA) of product ion spectra is thereby currently one of the most frequently applied data acquisition strategies. The optimization of DDA parameters is central to ensuring high spectral quality, coverage, and number of compound annotations. Here, we evaluated the influence of 10 central DDA settings of the Q Exactive mass spectrometer on natural organic matter samples from ocean, river, and soil environments. After data analysis with classical and feature-based molecular networking using MZmine and GNPS, we compared the total number of network nodes, multivariate clustering, and spectrum quality-related metrics such as annotation and singleton rates, MS/MS placement, and coverage. Our results show that automatic gain control, microscans, mass resolving power, and dynamic exclusion are the most critical parameters, whereas collision energy, TopN, and isolation width had moderate and apex trigger, monoisotopic selection, and isotopic exclusion minor effects. The insights into the data acquisition ergonomics of the Q Exactive platform presented here can guide new users and provide them with initial method parameters, some of which may also be transferable to other sample types and MS platforms.PMID:37578818 | DOI:10.1021/acs.analchem.3c01202

Stratifying Ferroptosis Sensitivity in Cells and Tissues with PALP

Mon, 14/08/2023 - 12:00
Methods Mol Biol. 2023;2712:9-17. doi: 10.1007/978-1-0716-3433-2_2.ABSTRACTFerroptosis is emerging as a promising strategy for suppressing multiple types of human cancers. Rapid and accurate assessment of the relative sensitivity to ferroptosis in biological samples will accelerate the development of ferroptosis-targeted therapies. We previously demonstrated that photochemical activation of membrane lipid peroxidation (PALP) that uses high-power lasers to induce localized polyunsaturated fatty acyl (PUFA)-lipid peroxidation can efficiently report ferroptosis sensitivity in live cells and tissues in situ. Here, we describe the experimental details for PALP analysis, including preparation of tissue sections, preparation of fluorescent lipid peroxidation reporter, sample staining, lipid peroxidation induced by laser source, and data processing. We envision predicting the relative sensitivity to ferroptosis of cellular and tissue samples is potentially useful for basic research and clinical investigations.PMID:37578692 | DOI:10.1007/978-1-0716-3433-2_2

Gut microbiome-serum metabolic profiles: insight into the hypoglycemic effect of <em>Porphyra haitanensis</em> glycoprotein on hyperglycemic mice

Mon, 14/08/2023 - 12:00
Food Funct. 2023 Aug 14. doi: 10.1039/d3fo02040a. Online ahead of print.ABSTRACTThe hypoglycemic activity of natural algal glycoproteins has attracted interest, but studies of their mechanism of regulating glucose metabolism are lacking. This study investigated the hypoglycemic activity of Porphyra haitanensis glycoprotein (PG) in a mouse hyperglycemia model. The underlying mechanism was elucidated by monitoring changes in the gut microbiome and untargeted serum metabolomics. The results indicated that 30-300 mg kg-1 PG regulated blood glucose levels by increasing insulin secretion, reducing glycated hemoglobin, and improving streptozotocin-induced hyperglycemia in a concentration-dependent manner. In particular, 300 mg kg-1 PG decreased fasting blood glucose by 63.11% and glycosylated hemoglobin by 24.50% and increased insulin secretion by 163.97%. The mechanism of the improvement of hyperglycemia by PG may involve regulating beneficial intestinal bacteria (e.g., norank_f__Muribaculaceae and Lachnospiraceae) and altering the serum metabolic profile (e.g., upregulation of hypotaurine, 3-hydroxy-2-naphthoic acid, and L-glycine), to regulate taurine and hypotaurine, the TCA cycle, AMPK, and pyruvate metabolism. Our findings supported the development of Porphyra haitanensis and its glycoprotein as novel natural antidiabetic compounds to regulate the glycemic balance.PMID:37578326 | DOI:10.1039/d3fo02040a

Methodology to Metabolically Inactivate Bacteria for Caenorhabditis elegans Research

Mon, 14/08/2023 - 12:00
J Vis Exp. 2023 Jul 28;(197). doi: 10.3791/65775.ABSTRACTCaenorhabditis elegans is a common model organism for research in genetics, development, aging, metabolism, and behavior. Because C. elegans consume a diet of live bacteria, the metabolic activity of their food source can confound experiments looking for the direct effects of various interventions on the worm. To avoid the confounding effects of bacterial metabolism, C. elegans researchers have used multiple methods to metabolically inactivate bacteria, including ultraviolet (UV)-irradiation, heat-killing, and antibiotics. UV treatment is relatively low-throughput and cannot be used in liquid culture because each plate must be examined for successful bacterial killing. A second treatment method, heat-killing, negatively affects the texture and nutritional quality of the bacteria, leading to the developmental arrest of C. elegans. Finally, antibiotic treatment can directly alter C. elegans physiology in addition to preventing bacterial growth. This manuscript describes an alternative method to metabolically inactivate bacteria using paraformaldehyde (PFA). PFA treatment cross-links proteins within bacterial cells to prevent metabolic activity while preserving cellular structure and nutritional content. This method is high-throughput and can be used in liquid culture or solid plates, as testing one plate of PFA-treated bacteria for growth validates the whole batch. Metabolic inactivation through PFA treatment can be used to eliminate the confounding effects of bacterial metabolism on studies of drug or metabolite supplementation, stress resistance, metabolomics, and behavior in C. elegans.PMID:37578251 | DOI:10.3791/65775

Metabolomic changes associated with acquired resistance to <em>Ixodes scapularis</em>

Mon, 14/08/2023 - 12:00
bioRxiv. 2023 Jul 31:2023.07.31.551287. doi: 10.1101/2023.07.31.551287. Preprint.ABSTRACTGuinea pigs repeatedly exposed to Ixodes scapularis develop acquired resistance to the ticks (ATR). The molecular mechanisms of ATR have not been fully elucidated, and partially involve immune responses to proteins in tick saliva. In this study, we examined the metabolome of sera of guinea pigs during the development of ATR. Induction of components of the tyrosine metabolic pathway, including hydroxyphenyllactic acid (HPLA), were associated with ATR. We therefore administered HPLA to mice, an animal that does not develop ATR, and exposed the animals to I. scapularis . We also administered nitisinone, a known inhibitor of tyrosine degradation, to another group of mice. The mortality of I. scapularis that fed on mice given HPLA or nitisinone was 26% and 72% respectively, compared with 2% mortality among ticks that fed on control animals. These data indicate that metabolic changes that occur after tick bites contribute to ATR.PMID:37577710 | PMC:PMC10418055 | DOI:10.1101/2023.07.31.551287

FAM210A mediates an inter-organelle crosstalk essential for protein synthesis and muscle growth in mouse

Mon, 14/08/2023 - 12:00
bioRxiv. 2023 Aug 5:2023.08.03.551853. doi: 10.1101/2023.08.03.551853. Preprint.ABSTRACTMitochondria are not only essential for energy production in eukaryocytes but also a key regulator of intracellular signaling. Here, we report an unappreciated role of mitochondria in regulating cytosolic protein translation in skeletal muscle cells (myofibers). We show that the expression of mitochondrial protein FAM210A (Family With Sequence Similarity 210 Member A) is positively associated with muscle mass in mice and humans. Muscle-specific Myl1 Cre -driven Fam210a knockout ( Fam210a MKO ) in mice reduces mitochondrial density and function, leading to progressive muscle atrophy and premature death. Metabolomic and biochemical analyses reveal that Fam210a MKO reverses the oxidative TCA cycle towards the reductive direction, resulting in acetyl-CoA accumulation and hyperacetylation of cytosolic proteins. Specifically, hyperacetylation of several ribosomal proteins leads to disassembly of ribosomes and translational defects. Transplantation of Fam210a MKO mitochondria into wildtype myoblasts is sufficient to elevate protein acetylation in recipient cells. These findings reveal a novel crosstalk between the mitochondrion and ribosome mediated by FAM210A.PMID:37577696 | PMC:PMC10418219 | DOI:10.1101/2023.08.03.551853

A Taxonomically-informed Mass Spectrometry Search Tool for Microbial Metabolomics Data

Mon, 14/08/2023 - 12:00
Res Sq. 2023 Aug 3:rs.3.rs-3189768. doi: 10.21203/rs.3.rs-3189768/v1. Preprint.ABSTRACTMicrobeMASST, a taxonomically-informed mass spectrometry (MS) search tool, tackles limited microbial metabolite annotation in untargeted metabolomics experiments. Leveraging a curated database of >60,000 microbial monocultures, users can search known and unknown MS/MS spectra and link them to their respective microbial producers via MS/MS fragmentation patterns. Identification of microbial-derived metabolites and relative producers, without a priori knowledge, will vastly enhance the understanding of microorganisms' role in ecology and human health.PMID:37577622 | PMC:PMC10418563 | DOI:10.21203/rs.3.rs-3189768/v1

Mass spectrometry-based multi-omics identifies metabolic signatures of sarcopenia in rhesus monkey skeletal muscle

Mon, 14/08/2023 - 12:00
bioRxiv. 2023 Jul 31:2023.07.31.551315. doi: 10.1101/2023.07.31.551315. Preprint.ABSTRACTSarcopenia is a progressive disorder characterized by age-related loss of skeletal muscle mass and function. Although significant progress has been made over the years to identify the molecular determinants of sarcopenia, the precise mechanisms underlying the age-related loss of contractile function remains unclear. Advances in omics technologies, including mass spectrometry-based proteomic and metabolomic analyses, offer great opportunities to better understand sarcopenia. Herein, we performed mass spectrometry-based analyses of the vastus lateralis from young, middle-aged, and older rhesus monkeys to identify molecular signatures of sarcopenia. In our proteomic analysis, we identified numerous proteins that change with age, including those involved in adenosine triphosphate and adenosine monophosphate metabolism as well as fatty acid beta oxidation. In our untargeted metabolomic analysis, we identified multiple metabolites that changed with age largely related to energy metabolism including fatty acid beta oxidation. Pathway analysis of age-responsive proteins and metabolites revealed changes in muscle structure and contraction as well as lipid, carbohydrate, and purine metabolism. Together, this study discovers new metabolic signatures and offer new insights into the molecular mechanism underlying sarcopenia for the evaluation and monitoring of therapeutic treatment of sarcopenia.PMID:37577600 | PMC:PMC10418093 | DOI:10.1101/2023.07.31.551315

Editorial: Role of starters on the safety of fermented food products

Mon, 14/08/2023 - 12:00
Front Microbiol. 2023 Jul 28;14:1260403. doi: 10.3389/fmicb.2023.1260403. eCollection 2023.NO ABSTRACTPMID:37577433 | PMC:PMC10420064 | DOI:10.3389/fmicb.2023.1260403

Unveiling the spatial distribution and molecular mechanisms of terpenoid biosynthesis in <em>Salvia miltiorrhiza</em> and <em>S. grandifolia</em> using multi-omics and DESI-MSI

Mon, 14/08/2023 - 12:00
Hortic Res. 2023 May 31;10(7):uhad109. doi: 10.1093/hr/uhad109. eCollection 2023 Jul.ABSTRACTSalvia miltiorrhiza and S. grandifolia are rich in diterpenoids and have therapeutic effects on cardiovascular diseases. In this study, the spatial distribution of diterpenoids in both species was analyzed by a combination of metabolomics and mass spectrometry imaging techniques. The results indicated that diterpenoids in S. miltiorrhiza were mainly abietane-type norditerpenoid quinones with a furan or dihydrofuran D-ring and were mainly distributed in the periderm of the roots, e.g. cryptotanshinone and tanshinone IIA. The compounds in S. grandifolia were mainly phenolic abietane-type tricyclic diterpenoids with six- or seven-membered C-rings, and were widely distributed in the periderm, phloem, and xylem of the roots, e.g. 11-hydroxy-sugiol, 11,20-dihydroxy-sugiol, and 11,20-dihydroxy-ferruginol. In addition, the leaves of S. grandifolia were rich in tanshinone biosynthesis precursors, such as 11-hydroxy-sugiol, while those of S. miltiorrhiza were rich in phenolic acids. Genes in the upstream pathway of tanshinone biosynthesis were highly expressed in the root of S. grandifolia, and genes in the downstream pathway were highly expressed in the root of S. miltiorrhiza. Here, we describe the specific tissue distributions and mechanisms of diterpenoids in two Salvia species, which will facilitate further investigations of the biosynthesis of diterpenoids in plant synthetic biology.PMID:37577405 | PMC:PMC10419090 | DOI:10.1093/hr/uhad109

Dopamine alleviates cadmium stress in apple trees by recruiting beneficial microorganisms to enhance the physiological resilience revealed by high-throughput sequencing and soil metabolomics

Mon, 14/08/2023 - 12:00
Hortic Res. 2023 May 22;10(7):uhad112. doi: 10.1093/hr/uhad112. eCollection 2023 Jul.ABSTRACTDopamine has demonstrated promise as a stress-relief substance. However, the function of dopamine in Cd tolerance and its mechanism remains largely unknown. The current study was performed to investigate the mechanism of dopamine on alleviating apple Cd stress through regular application of CdCl2 and dopamine solution to potting soil. The results indicated that dopamine significantly reduced reactive oxygen species (ROS) and Cd accumulation and alleviated the inhibitory effect of Cd stress on the growth of apple plants through activation of the antioxidant system, enhancement of photosynthetic capacity, and regulation of gene expression related to Cd absorption and detoxification. The richness of the rhizosphere microbial community increased, and community composition and assembly were affected by dopamine treatment. Network analysis of microbial communities showed that the numbers of nodes and total links increased significantly after dopamine treatment, while the keystone species shifted. Linear discriminant analysis effect size indicated that some biomarkers were significantly enriched after dopamine treatment, suggesting that dopamine induced plants to recruit potentially beneficial microorganisms (Pseudoxanthomonas, Aeromicrobium, Bradyrhizobium, Frankia, Saccharimonadales, Novosphingobium, and Streptomyces) to resist Cd stress. The co-occurrence network showed several metabolites that were positively correlated with relative growth rate and negatively correlated with Cd accumulation, suggesting that potentially beneficial microorganisms may be attracted by several metabolites (L-threonic acid, profenamine, juniperic acid and (3β,5ξ,9ξ)-3,6,19-trihydroxyurs-12-en-28-oic acid). Our results demonstrate that dopamine alleviates Cd stress in apple trees by recruiting beneficial microorganisms to enhance the physiological resilience revealed. This study provides an effective means to reduce the harm to agricultural production caused by heavy metals.PMID:37577402 | PMC:PMC10419553 | DOI:10.1093/hr/uhad112

Discovering metabolic vulnerability using spatially resolved metabolomics for antitumor small molecule-drug conjugates development as a precise cancer therapy strategy

Mon, 14/08/2023 - 12:00
J Pharm Anal. 2023 Jul;13(7):776-787. doi: 10.1016/j.jpha.2023.02.010. Epub 2023 Feb 28.ABSTRACTAgainst tumor-dependent metabolic vulnerability is an attractive strategy for tumor-targeted therapy. However, metabolic inhibitors are limited by the drug resistance of cancerous cells due to their metabolic plasticity and heterogeneity. Herein, choline metabolism was discovered by spatially resolved metabolomics analysis as metabolic vulnerability which is highly active in different cancer types, and a choline-modified strategy for small molecule-drug conjugates (SMDCs) design was developed to fool tumor cells into indiscriminately taking in choline-modified chemotherapy drugs for targeted cancer therapy, instead of directly inhibiting choline metabolism. As a proof-of-concept, choline-modified SMDCs were designed, screened, and investigated for their druggability in vitro and in vivo. This strategy improved tumor targeting, preserved tumor inhibition and reduced toxicity of paclitaxel, through targeted drug delivery to tumor by highly expressed choline transporters, and site-specific release by carboxylesterase. This study expands the strategy of targeting metabolic vulnerability and provides new ideas of developing SMDCs for precise cancer therapy.PMID:37577390 | PMC:PMC10422108 | DOI:10.1016/j.jpha.2023.02.010

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