A comprehensive understanding of the molecular details at spatial levels within heterogeneous cardiac tissue in heart failure(HF)is paramount for enhancing our knowledge of the pathophysiology of HF and pinpointing po...A comprehensive understanding of the molecular details at spatial levels within heterogeneous cardiac tissue in heart failure(HF)is paramount for enhancing our knowledge of the pathophysiology of HF and pinpointing potential therapeutic targets.Here,we present an analytical strategy for the deep discovery of heterogeneous metabolism and drug response in the heart tissue of rats with HF using airflow-assisted desorption electrospray ionization mass spectrometry imaging(AFADESI-MSI)coupled with bulk RNAsequencing.Spatial metabolomics illustrated pronounced metabolic heterogeneity between the infarct(I),infarct margin(IM),and non-infarct(NI)areas of heart tissue in HF.Integrated transcriptomics showed that increased mRNA expression of ATP citrate lyase disrupted the tricarboxylic acid(TCA)cycle in the NI area.Impairment of the carnitine shuttle system led to a significant accumulation of carnitines,suggesting potential abnormalities in fatty acid(FA)oxidation.Coupling on-tissue chemical derivatization with AFADESI-MSI enabled us to confirm the occurrence of incomplete oxidation of FAs in the NI area.Additionally,we observed a heterogeneous drug response between the anti-HF medications valsartan and Qishen Yiqi Dripping Pills(QDP).Valsartan exhibited a more pronounced effect on metabolic regulation in the I area,whereas QDP exerted stronger regulatory effects on metabolism in the NI area.Utilizing this method,four potential therapeutic targets were identified in HF:CPT1A,PDHB,ACLY,and BCAT2,which were preliminarily validated by western blotting.Overall,integrating spatial metabolomics with transcriptomics facilitates comprehensive analyses that link differential metabolites and genes,enabling a more precise characterization of metabolic changes in heart injury microareas and providing effective methods for elucidating molecular mechanisms and identifying potential therapeutic targets for HF.展开更多
Objective:In traditional medicine,Asari Radix et Rhizoma(Xi Xin)is used to effectively treat respiratory diseases.However,the therapeutic portion of Xi Xin contains trace quantities of aristolochic acid I(AAI),which r...Objective:In traditional medicine,Asari Radix et Rhizoma(Xi Xin)is used to effectively treat respiratory diseases.However,the therapeutic portion of Xi Xin contains trace quantities of aristolochic acid I(AAI),which raises safety concerns.Furthermore,no compelling laboratory evidence confirms its safety.AAI-induced extensive renal tubular necrosis and inflammatory cell infiltration occurred primarily in the cortex and outer medulla.Accordingly,we examined the changes in metabolites within the aforementioned areas and thoroughly investigated the interactions between these differential metabolites and immune cells.Methods:We mapped the spatial distribution of the differential metabolites L-glutamic acid and glutamine in mouse kidneys and explored the underlying mechanisms using transcriptomics and flow cytometry,further validating these findings through co-culture experiments in vitro.Results:Administering 1 mg/kg AAI daily for 7 days(approximately 200 times the pharmacopeial Xi Xin dose)did not induce detectable levels of carcinogenic 7-(deoxyadenosin-N6-yl)-aristolactam I(dA-ALI)in mouse kidneys.However,dA-ALI was detected on the day after the administration of 10 mg/kg AAI.Mice with lipopolysaccharide-induced pneumonia exhibit increased tolerance to AAI-mediated nephrotoxicity.Based on integrated spatial metabolomics and renal transcriptomic analyses,increased tolerance to AAI-mediated nephrotoxicity may be related to glutamine-mediated oxidative stress regulation mechanisms.During pneumonia,mouse kidneys exhibit both immune and metabolic stress responses.Ly6C^(+)macrophages convert L-glutamic acid into glutamine,thereby reducing reactive oxygen species(ROS)levels in the extracellular matrix.This process,which is regulated by the ITGA5 receptor in renal tubular epithelial cells,modulates the pAkt/pNrf2/NQO1 pathway and reduces AAI-induced kidney damage.Conclusions:Collectively,our findings indicate that Xi Xin is safe at conventional clinical dosages,and its targeted use can further minimize potential risks.展开更多
Evaluating toxicity and decoding the underlying mechanisms of active compounds are crucial for drug development.In this study,we present an innovative,integrated approach that combines air flowassisted desorption elec...Evaluating toxicity and decoding the underlying mechanisms of active compounds are crucial for drug development.In this study,we present an innovative,integrated approach that combines air flowassisted desorption electrospray ionization mass spectrometry imaging(AFADESI-MSI),time-of-flight secondary ion mass spectrometry(ToF-SIMS),and spatial metabolomics to comprehensively investigate the nephrotoxicity and underlying mechanisms of nitidine chloride(NC),a promising anti-tumor drug candidate.Our quantitive AFADESI-MSI analysis unveiled the region specific of accumulation of NC in the kidney,particularly within the inner cortex(IC)region,following single and repeated dose of NC.High spatial resolution ToF-SIMS analysis further allowed us to precisely map the localization of NC within the renal tubule.Employing spatial metabolomics based on AFADESI-MSI,we identified over 70 discriminating endogenous metabolites associated with chronic NC exposure.These findings suggest the renal tubule as the primary target of NC toxicity and implicate renal transporters(organic cation transporters,multidrug and toxin extrusion,and organic cation transporter 2(OCT2)),metabolic enzymes(protein arginine N-methyltransferase(PRMT)and nitric oxide synthase),mitochondria,oxidative stress,and inflammation in NC-induced nephrotoxicity.This study offers novel insights into NC-induced renal damage,representing a crucial step towards devising strategies to mitigate renal damage caused by this compound.展开更多
Eclipta prostrata L.has been used in traditional medicine and known for its liver-protective properties for centuries.Wedelolactone(WEL)and demethylwedelolactone(DWEL)are the major coumarins found in E.prostrata L.How...Eclipta prostrata L.has been used in traditional medicine and known for its liver-protective properties for centuries.Wedelolactone(WEL)and demethylwedelolactone(DWEL)are the major coumarins found in E.prostrata L.However,the comprehensive characterization of these two compounds on non-alcoholic fatty liver disease(NAFLD)still remains to be explored.Utilizing a well-established zebrafish model of thioacetamide(TAA)-induced liver injury,the present study sought to investigate the impacts and mechanisms of WEL and DWEL on NAFLD through integrative spatial metabolomics with liver-specific transcriptomics analysis.Our results showed that WEL and DWEL significantly improved liver function and reduced the accumulation of fat in the liver.The biodistributions and metabolism of these two compounds in whole-body zebrafish were successfully mapped,and the discriminatory endogenous metabolites reversely regulated by WEL and DWEL treatments were also characterized.Based on spatial metabolomics and transcriptomics,we identified that steroid biosynthesis and fatty acid metabolism are mainly involved in the hepatoprotective effects of WEL instead of DWEL.Our study unveils the distinct mechanism of WEL and DWEL in ameliorating NAFLD,and presents a“multi-omics”platform of spatial metabolomics and liver-specific transcriptomics to develop highly effective compounds for further improved therapy.展开更多
Triclocarban(TCC)is a common antimicrobial agent that has been widely used in medical care.Given the close association between TCC treatment and metabolic disorders,we assessed whether long-term treatment to TCC at a ...Triclocarban(TCC)is a common antimicrobial agent that has been widely used in medical care.Given the close association between TCC treatment and metabolic disorders,we assessed whether long-term treatment to TCC at a human-relevant concentration could induce nephrotoxicity by disrupting the metabolic levels in a mouse model.Matrix-assisted laser desorption/ionization mass spectrometry imaging(MALDI-MSI)was applied to investigate the alterations in the spatial distributions and abundances of TCC,endogenous and exogenous metabolites in the kidney after TCC treatment.The results showed that TCC treatment induced the changes in the organ weight,organ coefficient and histopathology of the mouse kidney.MSI data revealed that TCC accumulated in all regions of the kidney,while its five metabolites mainly distributed in the cortex regions.The abundances of 79 biomolecules associated with pathways of leukotriene E4 metabolism,biosynthesis and degradation of glycerophospholipids and glycerolipids,ceramide-to-sphingomyelin signaling were significantly altered in the kidney after TCC treatment.These biomolecules showed distinctive distributions in the kidney and displayed a favorable spatial correlation with the pathological damage.This work offers new insights into the related mechanisms of TCC-induced nephrotocicity and exhibits the potential of MALDI-MSI-based spatial metabolomics as a promising approach for the risk assessment of agents in medical care.展开更多
The brain's functions are governed by molecular metabolic networks.However,due to the sophisticated spatial organization and diverse activities of the brain,characterizing both the minute and large-scale metabolic...The brain's functions are governed by molecular metabolic networks.However,due to the sophisticated spatial organization and diverse activities of the brain,characterizing both the minute and large-scale metabolic activity across the entire brain and its numerous micro-regions remains incredibly challenging.Here,we offer a high-definition spatially resolved metabolomics technique to better understand the metabolic specialization and interconnection throughout the mouse brain using improved ambient mass spectrometry imaging.This method allows for the simultaneous mapping of thousands of metabolites at a 30 μm spatial resolution across the mouse brain,ranging from structural lipids to functional neurotransmitters.This approach effectively reveals the distribution patterns of delicate microregions and their distinctive metabolic characteristics.Using an integrated database,we annotated 259 metabolites,demonstrating that the metabolome and metabolic pathways are unique to each brain microregion.The distribution of metabolites,closely linked to functionally connected brain regions and their interactions,offers profound insights into the complexity of chemical processes and their roles in brain function.An initial dataset for future metabolomics research might be obtained from the high-definition mouse brain's spatial metabolome atlas.展开更多
Colon cancer is one of the malignant tumors with high morbidity and mortality worldwide[1],and its early diagnosis is crucial for improving patient survival.However,due to the lack of obvious early symptoms of colon c...Colon cancer is one of the malignant tumors with high morbidity and mortality worldwide[1],and its early diagnosis is crucial for improving patient survival.However,due to the lack of obvious early symptoms of colon cancer,many patients are in the middle to late stage when diagnosed and miss the best time for treatment.Therefore,developing an efficient and accurate diagnostic method for colon cancer is of great clinical significance and scientific value.Currently,the current colon cancer biomarkers carcinoembryonic antigen and carbohydrate antigen 19-9[2]have low sensitivity and specificity,the emerging markers circulating tumor DNA(ctDNA)and miRNA face high cost and standardization challenges,and the existing methods lack spatial resolution,prompting the incorporation of spatial metabolomics technologies to enhance diagnostic capabilities.展开更多
Cantharidin (CTD), a natural compound used to treat multiple tumors in the clinic setting, has been limited due to acute kidney injury (AKI). However, the major cause of AKI and its underlying mechanism remain to be e...Cantharidin (CTD), a natural compound used to treat multiple tumors in the clinic setting, has been limited due to acute kidney injury (AKI). However, the major cause of AKI and its underlying mechanism remain to be elucidated. Serum creatinine (SCr) and blood urea nitrogen (BUN) were detected through pathological evaluation after CTD (1.5 mg/kg) oral gavage in mice in 3 days. Kidney lipidomics based on ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used to investigate lipids disorder after CTD exposure in mice. Then, spatial metabolomics based on matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI) was used to detect the kidney spatial distribution of lipids. Integrative analysis was performed to reveal the spatial lipid disorder mechanism and verify key lipids in vitro. The results showed that the levels of SCr and BUN were increased, and tubular necrosis was observed in mouse kidneys, resulting in acute tubular necrosis (ATN) in CTD-induced AKI. Then, lipidomics results revealed that after CTD exposure, 232 differential lipid metabolites and 11 pathways including glycerophospholipid (GP) and sphingolipid (SL) metabolism were disrupted. Spatial metabolomics revealed that 55 spatial differential lipid metabolites and nine metabolic pathways were disturbed. Subsequently, integrative analysis found that GP metabolism was stimulated in the renal cortex and medulla, whereas SL metabolism was inhibited in the renal cortex. Up-regulated lysophosphatidylcholine (LysoPC) (18:2(9Z,12Z)), LysoPC (16:0/0:0), glycerophosphocholine, and down-regulated sphingomyelin (SM) (d18:0/16:0), SM (d18:1/24:0), and SM (d42:1) were key differential lipids. Among them, LysoPC (16:0/0:0) was increased in the CTD group at 1.1196 μg/mL, which aggravated CTD-induced ATN in human kidney-2 (HK-2) cells. LysoPC acyltransferase was inhibited and choline phosphotransferase 1 (CEPT1) was activated after CTD intervention in mice and in HK-2 cells. CTD induces ATN, resulting in AKI, by activating GP metabolism and inhibiting SL metabolism in the renal cortex and medulla, LysoPC (16:0/0:0), LysoPC acyltransferase, and CEPT1 may be the therapeutic targets.展开更多
Background:The response to neoadjuvant chemotherapy(NAC)differs substantially among individual patients with non-small cell lung cancer(NSCLC).Major pathological response(MPR)is a histomorphological read-out used to a...Background:The response to neoadjuvant chemotherapy(NAC)differs substantially among individual patients with non-small cell lung cancer(NSCLC).Major pathological response(MPR)is a histomorphological read-out used to assess treatment response and prognosis in patientsNSCLC afterNAC.Although spatial metabolomics is a promising tool for evaluating metabolic phenotypes,it has not yet been utilized to assess therapy responses in patients with NSCLC.We evaluated the potential application of spatial metabolomics in cancer tissues to assess the response to NAC,using a metabolic classifier that utilizes mass spectrometry imaging combined with machine learning.Methods:Resected NSCLC tissue specimens obtained after NAC(n=88)were subjected to high-resolution mass spectrometry,and these data were used to develop an approach for assessing the response to NAC in patients with NSCLC.The specificities of the generated tumor cell and stroma classifiers were validated by applying this approach to a cohort of biologically matched chemotherapy-naive patients with NSCLC(n=85).Results:The developed tumor cell metabolic classifier stratified patients into different prognostic groups with 81.6%accuracy,whereas the stroma metabolic classifier displayed 78.4%accuracy.By contrast,the accuracies of MPR and TNM staging for stratification were 62.5%and 54.1%,respectively.The combination of metabolic and MPR classifiers showed slightly lower accuracy than either individual metabolic classifier.In multivariate analysis,metabolic classifiers were the only independent prognostic factors identified(tumor:P=0.001,hazards ratio[HR]=3.823,95%confidence interval[CI]=1.716-8.514;stroma:P=0.049,HR=2.180,95%CI=1.004-4.737),whereasMPR(P=0.804;HR=0.913;95%CI=0.445-1.874)and TNM staging(P=0.078;HR=1.223;95%CI=0.977-1.550)were not independent prognostic factors.Using Kaplan-Meier survival analyses,both tumor and stroma metabolic classifiers were able to further stratify patients as NAC responders(P<0.001)and non-responders(P<0.001).Conclusions:Our findings indicate that the metabolic constitutions of both tumor cells and the stroma are valuable additions to the classical histomorphology-based assessment of tumor response.展开更多
Acute myeloid leukemia(AML)is recognized as an aggressive cancer that is characterized by significant metabolic reprogramming.Here,we applied spatial metabolomics to achieve high-throughput,in situ identification of m...Acute myeloid leukemia(AML)is recognized as an aggressive cancer that is characterized by significant metabolic reprogramming.Here,we applied spatial metabolomics to achieve high-throughput,in situ identification of metabolites within the liver metastases of AML mice.Alterations at metabolite and protein levels were further mapped out and validated by integrating untargeted metabolomics and proteomics.This study showed a downregulation in arginine's contribution to polyamine biosynthesis and urea cycle,coupled with an upregulation of the creatine metabolism.The upregulation of creatine synthetases Gatm and Gamt,as well as the creatine transporter Slc6a8,resulted in a marked accumulation of creatine within tumor foci.This process further enhances oxidative phosphorylation and glycolysis of leukemia cells,thereby boosting ATP production to foster proliferation and infiltration.Importantly,we discovered that inhibiting Slc6a8 can counter these detrimental effects,offering a new strategy for treating AML by targeting metabolic pathways.展开更多
Pulmonary fibrosis (PF) is a chronic progressive end-stage lung disease. However, the mechanisms underlying the progression of this disease remain elusive. Presently, clinically employed drugs are scarce for the treat...Pulmonary fibrosis (PF) is a chronic progressive end-stage lung disease. However, the mechanisms underlying the progression of this disease remain elusive. Presently, clinically employed drugs are scarce for the treatment of PF. Hence, there is an urgent need for developing novel drugs to address such diseases. Our study found for the first time that a natural source of Prismatomeris connata Y. Z. Ruan (Huang Gen, HG) ethyl acetate extract (HG-2) had a significant anti-PF effect by inhibiting the expression of the transforming growth factor beta 1/suppressor of mothers against decapentaplegic (TGF-β1/Smad) pathway. Network pharmacological analysis suggested that HG-2 had effects on tyrosine kinase phosphorylation, cellular response to reactive oxygen species, and extracellular matrix (ECM) disassembly. Moreover, mass spectrometry imaging (MSI) was used to visualize the heterogeneous distribution of endogenous metabolites in lung tissue and reveal the anti-PF metabolic mechanism of HG-2, which was related to arginine biosynthesis and alanine, asparate and glutamate metabolism, the downregulation of arachidonic acid metabolism, and the upregulation of glycerophospholipid metabolism. In conclusion, we elaborated on the relationship between metabolite distribution and the progression of PF, constructed the regulatory metabolic network of HG-2, and discovered the multi-target therapeutic effect of HG-2, which might be conducive to the development of new drugs for PF.展开更多
Against 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...Against 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.展开更多
As for the emerging and cut edge spatially resolved metabolomics,mass spectrometry imaging(MSI)is a powerful tool that can map thousands of metabolites from bio-tissue sections without chemical labels.However,the stab...As for the emerging and cut edge spatially resolved metabolomics,mass spectrometry imaging(MSI)is a powerful tool that can map thousands of metabolites from bio-tissue sections without chemical labels.However,the stability,sensitivity and spatial resolution of MSI are always limited by the performance of its ionization probe.Herein,two types of probes(fine probe(P-100)and large probe(P-200))were designed and characterized to perform air-flow assisted desorption electrospray ionization(AFA-DESI)MSI analysis for spatially resolved metabolomics.It was determined that the spray introduced by P-100 was homogenous and stable under the spray solvent at a flow rate of 5-10μL/min,while P-200 can endure a high flow rate of up to 10-30μL/min.Moreover,the MSI images were acquired by AFA-DESI-MSI with P-100 from rat brain tissue section and with P-200 from whole-body tissue section of mouse,and these results presented unambiguous tissue structure with the distribution information of numerous metabolites.Furthermore,the spatially resolved metabolomic analysis of tumor tissue was successfully realized to discover the tumor associated biomarkers.As the key parts of AFA-DESI-MSI system,it has been demonstrated that the designed probs have excellent performance for spatially resolved metabolomics,and it will further promote its application in life science,and drug research and development.展开更多
Recent studies have highlighted spatially resolved multi-omics technologies,including spatial genomics,transcriptomics,proteomics,and metabolomics,as powerful tools to decipher the spatial heterogeneity of the brain.H...Recent studies have highlighted spatially resolved multi-omics technologies,including spatial genomics,transcriptomics,proteomics,and metabolomics,as powerful tools to decipher the spatial heterogeneity of the brain.Here,we focus on two major approaches in spatial transcriptomics(next-generation sequencing-based technologies and image-based technologies),and mass spectrometry imaging technologies used in spatial proteomics and spatial metabolomics.Furthermore,we discuss their applications in neuroscience,including building the brain atlas,uncovering gene expression patterns of neurons for special behaviors,deciphering the molecular basis of neuronal communication,and providing a more comprehensive explanation of the molecular mechanisms underlying central nervous system disorders.However,further efforts are still needed toward the integrative application of multi-omics technologies,including the real-time spatial multi-omics analysis in living cells,the detailed gene profile in a whole-brain view,and the combination of functional verification.展开更多
Adjuvant chemotherapy improves the survival outlook for patients undergoing operations for lung metastases caused by colorectal cancer (CRC). However, a multidisciplinary approach that evaluates several factors relate...Adjuvant chemotherapy improves the survival outlook for patients undergoing operations for lung metastases caused by colorectal cancer (CRC). However, a multidisciplinary approach that evaluates several factors related to patient and tumor characteristics is necessary for managing chemotherapy treatment in metastatic CRC patients with lung disease, as such factors dictate the timing and drug regimen, which may affect treatment response and prognosis. In this study, we explore the potential of spatial metabolomics for evaluating metabolic phenotypes and therapy outcomes during the local delivery of the anticancer drug, oxaliplatin, to the lung. 12 male Yorkshire pigs underwent a 3 h left lung in vivo lung perfusion (IVLP) with various doses of oxaliplatin (7.5, 10, 20, 40, and 80 mg/L), which were administered to the perfusion circuit reservoir as a bolus. Biocompatible solid-phase microextraction (SPME) microprobes were combined with global metabolite profiling to obtain spatiotemporal information about the activity of the drug, determine toxic doses that exceed therapeutic efficacy, and conduct a mechanistic exploration of associated lung injury. Mild and subclinical lung injury was observed at 40 mg/L of oxaliplatin, and significant compromise of the hemodynamic lung function was found at 80 mg/L. This result was associated with massive alterations in metabolic patterns of lung tissue and perfusate, resulting in a total of 139 discriminant compounds. Uncontrolled inflammatory response, abnormalities in energy metabolism, and mitochondrial dysfunction next to accelerated kynurenine and aldosterone production were recognized as distinct features of dysregulated metabolipidome. Spatial pharmacometabolomics may be a promising tool for identifying pathological responses to chemotherapy.展开更多
Tumors are spatially heterogeneous tissues that comprise numerous cell types with intricate structures.By interacting with the microenvironment,tumor cells undergo dynamic changes in gene expression and metabolism,res...Tumors are spatially heterogeneous tissues that comprise numerous cell types with intricate structures.By interacting with the microenvironment,tumor cells undergo dynamic changes in gene expression and metabolism,resulting in spatiotemporal variations in their capacity for proliferation and metastasis.In recent years,the rapid development of histological techniques has enabled efficient and high-throughput biomolecule analysis.By preserving location information while obtaining a large number of gene and molecular data,spatially resolved metabolomics(SRM)and spatially resolved transcriptomics(SRT)approaches can offer new ideas and reliable tools for the in-depth study of tumors.This review provides a comprehensive introduction and summary of the fundamental principles and research methods used for SRM and SRT techniques,as well as a review of their applications in cancer-related fields.展开更多
Polygala tenuifolia,commonly known as Yuanzhi(YZ)in Chinese,has been shown to possess antiinsomnia properties.However,the material basis and the mechanism underlying its sedative-hypnotic effects remain unclear.Herein...Polygala tenuifolia,commonly known as Yuanzhi(YZ)in Chinese,has been shown to possess antiinsomnia properties.However,the material basis and the mechanism underlying its sedative-hypnotic effects remain unclear.Herein,we investigated the active components and neurochemical mechanism of YZ extracts using liquid chromatography tandem mass spectrometry(LC-MS/MS)-based pharmacometabolomics and mass spectrometry imaging(MSI)-based spatial resolved metabolomics.According to the results,17 prototypes out of 101 ingredients in the YZ extract were detected in both the plasma and brain,which might be the major components contributing to the sedative-hypnotic effects.Network pharmacology analysis revealed that these prototypes may exert their effects through neuroactive ligand-receptor interaction,serotonergic synapse,dopaminergic synapse,and dopaminergic synapse,among other pathways.LC-MS/MS-based targeted metabolomics and Western blot(WB)revealed that tryptophan-serotonin-melatonin(Trp-5-HT-Mel)and tyrosine-norepinephrine-adrenaline(Tyr-Ne-Ad)are the key regulated pathways.Dopa decarboxylase(DDC)upregulation and phenylethanolamine Nmethyltransferase(PNMT)downregulation further confirmed these pathways.Furthermore,MSI-based spatially resolved metabolomics revealed notable alterations in 5-HT in the pineal gland(PG),and Ad in the brainstem,including the middle brain(MB),pons(PN),and hypothalamus(HY).In summary,this study illustrates the efficacy of an integrated multidimensional metabolomics approach in unraveling the sedative-hypnotic effects and neurochemical mechanisms of a Chinese herbal medicine,YZ.展开更多
Understanding the specific metabolic changes in multiple regions of the kidney is crucial to revealing the underlying mechanism and developing effective targets for diabetic nephropathy(DN). In this study, integrated ...Understanding the specific metabolic changes in multiple regions of the kidney is crucial to revealing the underlying mechanism and developing effective targets for diabetic nephropathy(DN). In this study, integrated spatially resolved metabolomics and proteomics combined with mass spectrometry imaging(MSI) revealed a multi-scale region profile of the diabetic kidney. Based on anatomic location, spatial metabolomics revealed eight region-specific metabolite biomarkers uniquely localized to kidney segments, which were closely correlated to the clinical parameters of patients with DN. Specifically, treatment with metformin(MET) enriched inosinic acid, adenosine 3′,5′-diphosphate, nicotinamide adenine dinucleotide(NADH), and hydrated NADH(NADHX) levels in the cortex(Cor) and the outer stripe of kidney medulla(OM) anatomical subregions, while in the inner stripe of kidney medulla(IM) segmentation, the p-cresol sulfate level was downregulated. Comparing differently expressed proteins in each region showed that nephrosis 2(Nphs2) was the highest loading feature. A further region-specific analysis of pathway enrichment characteristics indicated that the purine and ether lipid metabolism pathways were enriched in the Cor and OM regions, whereas the pantothenate and coenzyme A(CoA) biosynthesis pathways were mainly enriched in the IM region in response to MET treatment. Taken together, the spatially segregated metabolomics and proteomics studies reveal MET-mediated proteins and function-specific therapeutic pathways related to the anatomical multiregion of diabetic mouse kidneys.展开更多
Plants contain a large number of cell types and exhibit complex regulatory mechanisms.Studies at the single-cell level have gradually become more common in plant science.Single-cell transcriptomics,spatial transcripto...Plants contain a large number of cell types and exhibit complex regulatory mechanisms.Studies at the single-cell level have gradually become more common in plant science.Single-cell transcriptomics,spatial transcriptomics,and spatial metabolomics techniques have been combined to analyze plant development.These techniques have been used to study the transcriptomes and metabolomes of plant tissues at the single-cell level,enabling the systematic investigation of gene expression and metabolism in specific tissues and cell types during defined developmental stages.In this review,we present an overview of significant breakthroughs in spatial multi-omics in plants,and we discuss how these approaches may soon play essential roles in plant research.展开更多
Metabolic dysfunction-associated steatotic liver disease(MASLD)is a metabolic disease that can progress to metabolic dysfunction-associated steatohepatitis(MASH),cirrhosis,and cancer.The zonal distribution of biomolec...Metabolic dysfunction-associated steatotic liver disease(MASLD)is a metabolic disease that can progress to metabolic dysfunction-associated steatohepatitis(MASH),cirrhosis,and cancer.The zonal distribution of biomolecules in the liver is implicated in mediat-ing the disease progression.Recently,G-protein-coupled receptor 35(GPR35)has been highlighted to play a role in MASLD,but the precise mechanism is not fully understood,particularly,in a liver-zonal manner.Here,we aimed to identify spatially distributed specific genes and metabolites in different liver zonation that are regulated by GPR35 in MASLD,by combining lipid metabolomics,spatial transcriptomics(ST),and spatial metabolomics(SM).We found that GPR35 influenced lipid accumulation,inflammatory and metabolism-related factors in specific regions,notably affecting the anti-inflammation factor ELF4(E74 like E-twenty six(ETS)tran-scription factor 4),lipid homeostasis key factor CIDEA(cell death-inducing DNA fragmentation factor alpha(DFFA)-like effector A),and the injury response-related genes SAA1/2/3(serum amyloid A1/2/3),thereby impacting MASLD progression.Furthermore,SM elucidated specific metabolite distributions across different liver regions,such as C10H11N4O7P(3ʹ,5ʹ-cyclic inosine monophosphate(3ʹ,5ʹ-IMP))for the central vein,and this metabolite significantly decreased in the liver zones of GPR35-deficient mice during MASLD progression.Taken together,GPR35 regulates hepatocyte damage repair,controls inflammation,and prevents MASLD progression by influencing phospholipid homeostasis and gene expression in a zonal manner.展开更多
基金supported by the National Natural Science Foundation of China(No.82374158)National Science and Technology Major Project(No.2018ZX09711001-002-004)+1 种基金the Jiangxi University of Chinese Medicine Science and Technology Innovation Team Development Program(No.CXTD22007)the Medical and Health Technology Innovation Project(No.2022-I2M-1-020).
文摘A comprehensive understanding of the molecular details at spatial levels within heterogeneous cardiac tissue in heart failure(HF)is paramount for enhancing our knowledge of the pathophysiology of HF and pinpointing potential therapeutic targets.Here,we present an analytical strategy for the deep discovery of heterogeneous metabolism and drug response in the heart tissue of rats with HF using airflow-assisted desorption electrospray ionization mass spectrometry imaging(AFADESI-MSI)coupled with bulk RNAsequencing.Spatial metabolomics illustrated pronounced metabolic heterogeneity between the infarct(I),infarct margin(IM),and non-infarct(NI)areas of heart tissue in HF.Integrated transcriptomics showed that increased mRNA expression of ATP citrate lyase disrupted the tricarboxylic acid(TCA)cycle in the NI area.Impairment of the carnitine shuttle system led to a significant accumulation of carnitines,suggesting potential abnormalities in fatty acid(FA)oxidation.Coupling on-tissue chemical derivatization with AFADESI-MSI enabled us to confirm the occurrence of incomplete oxidation of FAs in the NI area.Additionally,we observed a heterogeneous drug response between the anti-HF medications valsartan and Qishen Yiqi Dripping Pills(QDP).Valsartan exhibited a more pronounced effect on metabolic regulation in the I area,whereas QDP exerted stronger regulatory effects on metabolism in the NI area.Utilizing this method,four potential therapeutic targets were identified in HF:CPT1A,PDHB,ACLY,and BCAT2,which were preliminarily validated by western blotting.Overall,integrating spatial metabolomics with transcriptomics facilitates comprehensive analyses that link differential metabolites and genes,enabling a more precise characterization of metabolic changes in heart injury microareas and providing effective methods for elucidating molecular mechanisms and identifying potential therapeutic targets for HF.
基金supported by the Consulting Project Funds of the Chinese Academy of Engineering(2023-XZ-88,China)Key Program of the National Natural Science Foundation of China(81721002 and 82230118,China)Key Program of the National Natural Science Foundation of China Regional Union Fund(U23A20519,China).
文摘Objective:In traditional medicine,Asari Radix et Rhizoma(Xi Xin)is used to effectively treat respiratory diseases.However,the therapeutic portion of Xi Xin contains trace quantities of aristolochic acid I(AAI),which raises safety concerns.Furthermore,no compelling laboratory evidence confirms its safety.AAI-induced extensive renal tubular necrosis and inflammatory cell infiltration occurred primarily in the cortex and outer medulla.Accordingly,we examined the changes in metabolites within the aforementioned areas and thoroughly investigated the interactions between these differential metabolites and immune cells.Methods:We mapped the spatial distribution of the differential metabolites L-glutamic acid and glutamine in mouse kidneys and explored the underlying mechanisms using transcriptomics and flow cytometry,further validating these findings through co-culture experiments in vitro.Results:Administering 1 mg/kg AAI daily for 7 days(approximately 200 times the pharmacopeial Xi Xin dose)did not induce detectable levels of carcinogenic 7-(deoxyadenosin-N6-yl)-aristolactam I(dA-ALI)in mouse kidneys.However,dA-ALI was detected on the day after the administration of 10 mg/kg AAI.Mice with lipopolysaccharide-induced pneumonia exhibit increased tolerance to AAI-mediated nephrotoxicity.Based on integrated spatial metabolomics and renal transcriptomic analyses,increased tolerance to AAI-mediated nephrotoxicity may be related to glutamine-mediated oxidative stress regulation mechanisms.During pneumonia,mouse kidneys exhibit both immune and metabolic stress responses.Ly6C^(+)macrophages convert L-glutamic acid into glutamine,thereby reducing reactive oxygen species(ROS)levels in the extracellular matrix.This process,which is regulated by the ITGA5 receptor in renal tubular epithelial cells,modulates the pAkt/pNrf2/NQO1 pathway and reduces AAI-induced kidney damage.Conclusions:Collectively,our findings indicate that Xi Xin is safe at conventional clinical dosages,and its targeted use can further minimize potential risks.
基金supported by the National Natural Science Foundation of China(Grant No.:21927808)the National Key Research and Development Program of China(Grant No.:2017YFC1704006).
文摘Evaluating toxicity and decoding the underlying mechanisms of active compounds are crucial for drug development.In this study,we present an innovative,integrated approach that combines air flowassisted desorption electrospray ionization mass spectrometry imaging(AFADESI-MSI),time-of-flight secondary ion mass spectrometry(ToF-SIMS),and spatial metabolomics to comprehensively investigate the nephrotoxicity and underlying mechanisms of nitidine chloride(NC),a promising anti-tumor drug candidate.Our quantitive AFADESI-MSI analysis unveiled the region specific of accumulation of NC in the kidney,particularly within the inner cortex(IC)region,following single and repeated dose of NC.High spatial resolution ToF-SIMS analysis further allowed us to precisely map the localization of NC within the renal tubule.Employing spatial metabolomics based on AFADESI-MSI,we identified over 70 discriminating endogenous metabolites associated with chronic NC exposure.These findings suggest the renal tubule as the primary target of NC toxicity and implicate renal transporters(organic cation transporters,multidrug and toxin extrusion,and organic cation transporter 2(OCT2)),metabolic enzymes(protein arginine N-methyltransferase(PRMT)and nitric oxide synthase),mitochondria,oxidative stress,and inflammation in NC-induced nephrotoxicity.This study offers novel insights into NC-induced renal damage,representing a crucial step towards devising strategies to mitigate renal damage caused by this compound.
基金supported by the National Natural Science Foundation of China(Grant No.:82273888)Natural Science Foundation of Shandong Province(Grant Nos.ZR2022QH257,ZR2020YQ60)+2 种基金Shandong Major Technological Innovation Project(Project No.:2021CXGC010508)Taishan Scholars Program of Shandong Province(Program Nos.:tsqn202103096,tsqn202211204)Shandong Province Science and Technology Small and Medium Enterprises Innovation Ability Enhancement Project(Project No.:2022TSGC2210).
文摘Eclipta prostrata L.has been used in traditional medicine and known for its liver-protective properties for centuries.Wedelolactone(WEL)and demethylwedelolactone(DWEL)are the major coumarins found in E.prostrata L.However,the comprehensive characterization of these two compounds on non-alcoholic fatty liver disease(NAFLD)still remains to be explored.Utilizing a well-established zebrafish model of thioacetamide(TAA)-induced liver injury,the present study sought to investigate the impacts and mechanisms of WEL and DWEL on NAFLD through integrative spatial metabolomics with liver-specific transcriptomics analysis.Our results showed that WEL and DWEL significantly improved liver function and reduced the accumulation of fat in the liver.The biodistributions and metabolism of these two compounds in whole-body zebrafish were successfully mapped,and the discriminatory endogenous metabolites reversely regulated by WEL and DWEL treatments were also characterized.Based on spatial metabolomics and transcriptomics,we identified that steroid biosynthesis and fatty acid metabolism are mainly involved in the hepatoprotective effects of WEL instead of DWEL.Our study unveils the distinct mechanism of WEL and DWEL in ameliorating NAFLD,and presents a“multi-omics”platform of spatial metabolomics and liver-specific transcriptomics to develop highly effective compounds for further improved therapy.
基金supported by National Natural Science Foundation of China(Grant Nos.:22036001 and 22276034).
文摘Triclocarban(TCC)is a common antimicrobial agent that has been widely used in medical care.Given the close association between TCC treatment and metabolic disorders,we assessed whether long-term treatment to TCC at a human-relevant concentration could induce nephrotoxicity by disrupting the metabolic levels in a mouse model.Matrix-assisted laser desorption/ionization mass spectrometry imaging(MALDI-MSI)was applied to investigate the alterations in the spatial distributions and abundances of TCC,endogenous and exogenous metabolites in the kidney after TCC treatment.The results showed that TCC treatment induced the changes in the organ weight,organ coefficient and histopathology of the mouse kidney.MSI data revealed that TCC accumulated in all regions of the kidney,while its five metabolites mainly distributed in the cortex regions.The abundances of 79 biomolecules associated with pathways of leukotriene E4 metabolism,biosynthesis and degradation of glycerophospholipids and glycerolipids,ceramide-to-sphingomyelin signaling were significantly altered in the kidney after TCC treatment.These biomolecules showed distinctive distributions in the kidney and displayed a favorable spatial correlation with the pathological damage.This work offers new insights into the related mechanisms of TCC-induced nephrotocicity and exhibits the potential of MALDI-MSI-based spatial metabolomics as a promising approach for the risk assessment of agents in medical care.
基金financial support from the National Natural Science Foundation of China (Nos.82473887 and 21927808)the Scientific and Technological Innovation Program of Shanghai (No.23DZ2202500)the CAMS Innovation Fund for Medical Sciences (No.2021-1-I2M-026)。
文摘The brain's functions are governed by molecular metabolic networks.However,due to the sophisticated spatial organization and diverse activities of the brain,characterizing both the minute and large-scale metabolic activity across the entire brain and its numerous micro-regions remains incredibly challenging.Here,we offer a high-definition spatially resolved metabolomics technique to better understand the metabolic specialization and interconnection throughout the mouse brain using improved ambient mass spectrometry imaging.This method allows for the simultaneous mapping of thousands of metabolites at a 30 μm spatial resolution across the mouse brain,ranging from structural lipids to functional neurotransmitters.This approach effectively reveals the distribution patterns of delicate microregions and their distinctive metabolic characteristics.Using an integrated database,we annotated 259 metabolites,demonstrating that the metabolome and metabolic pathways are unique to each brain microregion.The distribution of metabolites,closely linked to functionally connected brain regions and their interactions,offers profound insights into the complexity of chemical processes and their roles in brain function.An initial dataset for future metabolomics research might be obtained from the high-definition mouse brain's spatial metabolome atlas.
文摘Colon cancer is one of the malignant tumors with high morbidity and mortality worldwide[1],and its early diagnosis is crucial for improving patient survival.However,due to the lack of obvious early symptoms of colon cancer,many patients are in the middle to late stage when diagnosed and miss the best time for treatment.Therefore,developing an efficient and accurate diagnostic method for colon cancer is of great clinical significance and scientific value.Currently,the current colon cancer biomarkers carcinoembryonic antigen and carbohydrate antigen 19-9[2]have low sensitivity and specificity,the emerging markers circulating tumor DNA(ctDNA)and miRNA face high cost and standardization challenges,and the existing methods lack spatial resolution,prompting the incorporation of spatial metabolomics technologies to enhance diagnostic capabilities.
基金supported by the National Natural Science Foundation of China(Grant Nos.:82260812 and 81803838)the Guizhou Provincial Science&Technology Program,China(Project Nos.:YQK[2023]038 and[2020]5007)+1 种基金the Beijing Natural Science Foundation,China(Grant No.:7254489)the Science and Technology Program of Zunyi city of Guizhou province of China(Project Nos.:(2022)420,[2021]-3,[2020]7,and(2022)419).
文摘Cantharidin (CTD), a natural compound used to treat multiple tumors in the clinic setting, has been limited due to acute kidney injury (AKI). However, the major cause of AKI and its underlying mechanism remain to be elucidated. Serum creatinine (SCr) and blood urea nitrogen (BUN) were detected through pathological evaluation after CTD (1.5 mg/kg) oral gavage in mice in 3 days. Kidney lipidomics based on ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used to investigate lipids disorder after CTD exposure in mice. Then, spatial metabolomics based on matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI) was used to detect the kidney spatial distribution of lipids. Integrative analysis was performed to reveal the spatial lipid disorder mechanism and verify key lipids in vitro. The results showed that the levels of SCr and BUN were increased, and tubular necrosis was observed in mouse kidneys, resulting in acute tubular necrosis (ATN) in CTD-induced AKI. Then, lipidomics results revealed that after CTD exposure, 232 differential lipid metabolites and 11 pathways including glycerophospholipid (GP) and sphingolipid (SL) metabolism were disrupted. Spatial metabolomics revealed that 55 spatial differential lipid metabolites and nine metabolic pathways were disturbed. Subsequently, integrative analysis found that GP metabolism was stimulated in the renal cortex and medulla, whereas SL metabolism was inhibited in the renal cortex. Up-regulated lysophosphatidylcholine (LysoPC) (18:2(9Z,12Z)), LysoPC (16:0/0:0), glycerophosphocholine, and down-regulated sphingomyelin (SM) (d18:0/16:0), SM (d18:1/24:0), and SM (d42:1) were key differential lipids. Among them, LysoPC (16:0/0:0) was increased in the CTD group at 1.1196 μg/mL, which aggravated CTD-induced ATN in human kidney-2 (HK-2) cells. LysoPC acyltransferase was inhibited and choline phosphotransferase 1 (CEPT1) was activated after CTD intervention in mice and in HK-2 cells. CTD induces ATN, resulting in AKI, by activating GP metabolism and inhibiting SL metabolism in the renal cortex and medulla, LysoPC (16:0/0:0), LysoPC acyltransferase, and CEPT1 may be the therapeutic targets.
基金Ministry of Education and Research of the Federal Republic of Germany,Grant/Award Numbers:BMBF,01ZX1610B,01KT1615Deutsche Forschungsgmeinschaft,Grant/Award Numbers:SFB 824 C4,CRC/Transregio 205/1+3 种基金Deutsche Krebshilfe,Grant/Award Number:70112617Stiftung zur Krebsbekampfung,Grant/Award Number:SKB425Cancer Research Switzerland,Grant/Award Number:KFS-4694-02-2019Cancer Research Switzerland,Grant/Award Number:MD-PhD-5088-06-2020。
文摘Background:The response to neoadjuvant chemotherapy(NAC)differs substantially among individual patients with non-small cell lung cancer(NSCLC).Major pathological response(MPR)is a histomorphological read-out used to assess treatment response and prognosis in patientsNSCLC afterNAC.Although spatial metabolomics is a promising tool for evaluating metabolic phenotypes,it has not yet been utilized to assess therapy responses in patients with NSCLC.We evaluated the potential application of spatial metabolomics in cancer tissues to assess the response to NAC,using a metabolic classifier that utilizes mass spectrometry imaging combined with machine learning.Methods:Resected NSCLC tissue specimens obtained after NAC(n=88)were subjected to high-resolution mass spectrometry,and these data were used to develop an approach for assessing the response to NAC in patients with NSCLC.The specificities of the generated tumor cell and stroma classifiers were validated by applying this approach to a cohort of biologically matched chemotherapy-naive patients with NSCLC(n=85).Results:The developed tumor cell metabolic classifier stratified patients into different prognostic groups with 81.6%accuracy,whereas the stroma metabolic classifier displayed 78.4%accuracy.By contrast,the accuracies of MPR and TNM staging for stratification were 62.5%and 54.1%,respectively.The combination of metabolic and MPR classifiers showed slightly lower accuracy than either individual metabolic classifier.In multivariate analysis,metabolic classifiers were the only independent prognostic factors identified(tumor:P=0.001,hazards ratio[HR]=3.823,95%confidence interval[CI]=1.716-8.514;stroma:P=0.049,HR=2.180,95%CI=1.004-4.737),whereasMPR(P=0.804;HR=0.913;95%CI=0.445-1.874)and TNM staging(P=0.078;HR=1.223;95%CI=0.977-1.550)were not independent prognostic factors.Using Kaplan-Meier survival analyses,both tumor and stroma metabolic classifiers were able to further stratify patients as NAC responders(P<0.001)and non-responders(P<0.001).Conclusions:Our findings indicate that the metabolic constitutions of both tumor cells and the stroma are valuable additions to the classical histomorphology-based assessment of tumor response.
基金supported by the National Natural Science Foundation of China(No.81770124)the Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support(RC20210190,China)。
文摘Acute myeloid leukemia(AML)is recognized as an aggressive cancer that is characterized by significant metabolic reprogramming.Here,we applied spatial metabolomics to achieve high-throughput,in situ identification of metabolites within the liver metastases of AML mice.Alterations at metabolite and protein levels were further mapped out and validated by integrating untargeted metabolomics and proteomics.This study showed a downregulation in arginine's contribution to polyamine biosynthesis and urea cycle,coupled with an upregulation of the creatine metabolism.The upregulation of creatine synthetases Gatm and Gamt,as well as the creatine transporter Slc6a8,resulted in a marked accumulation of creatine within tumor foci.This process further enhances oxidative phosphorylation and glycolysis of leukemia cells,thereby boosting ATP production to foster proliferation and infiltration.Importantly,we discovered that inhibiting Slc6a8 can counter these detrimental effects,offering a new strategy for treating AML by targeting metabolic pathways.
基金supported by the National Natural Science Foundation of China(Grant No.:82074104)the Research Project of Clinical Toxicology Transformation from the Chinese Society of Toxicology,China(Grant No.:CST2021CT101)the Chinese Academy of Medical Science Innovation Fund for Medical Sciences,China(Grant Nos.:2017-I2M-1-011 and 2022-I2M-2-002).
文摘Pulmonary fibrosis (PF) is a chronic progressive end-stage lung disease. However, the mechanisms underlying the progression of this disease remain elusive. Presently, clinically employed drugs are scarce for the treatment of PF. Hence, there is an urgent need for developing novel drugs to address such diseases. Our study found for the first time that a natural source of Prismatomeris connata Y. Z. Ruan (Huang Gen, HG) ethyl acetate extract (HG-2) had a significant anti-PF effect by inhibiting the expression of the transforming growth factor beta 1/suppressor of mothers against decapentaplegic (TGF-β1/Smad) pathway. Network pharmacological analysis suggested that HG-2 had effects on tyrosine kinase phosphorylation, cellular response to reactive oxygen species, and extracellular matrix (ECM) disassembly. Moreover, mass spectrometry imaging (MSI) was used to visualize the heterogeneous distribution of endogenous metabolites in lung tissue and reveal the anti-PF metabolic mechanism of HG-2, which was related to arginine biosynthesis and alanine, asparate and glutamate metabolism, the downregulation of arachidonic acid metabolism, and the upregulation of glycerophospholipid metabolism. In conclusion, we elaborated on the relationship between metabolite distribution and the progression of PF, constructed the regulatory metabolic network of HG-2, and discovered the multi-target therapeutic effect of HG-2, which might be conducive to the development of new drugs for PF.
基金supported by the National Natural Science Foundation of China(Grant Nos.:81974500,81773678)the CAMS Innovation Fund for Medical Sciences(Grant No.:2022-I2M-2-001).
文摘Against 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.
基金financial support from the National Natural Science Foundation of China(Nos.81974500 and 81773678)the CAMS Innovation Fund for Medical Sciences(No.2022-I2M-2-001)。
文摘As for the emerging and cut edge spatially resolved metabolomics,mass spectrometry imaging(MSI)is a powerful tool that can map thousands of metabolites from bio-tissue sections without chemical labels.However,the stability,sensitivity and spatial resolution of MSI are always limited by the performance of its ionization probe.Herein,two types of probes(fine probe(P-100)and large probe(P-200))were designed and characterized to perform air-flow assisted desorption electrospray ionization(AFA-DESI)MSI analysis for spatially resolved metabolomics.It was determined that the spray introduced by P-100 was homogenous and stable under the spray solvent at a flow rate of 5-10μL/min,while P-200 can endure a high flow rate of up to 10-30μL/min.Moreover,the MSI images were acquired by AFA-DESI-MSI with P-100 from rat brain tissue section and with P-200 from whole-body tissue section of mouse,and these results presented unambiguous tissue structure with the distribution information of numerous metabolites.Furthermore,the spatially resolved metabolomic analysis of tumor tissue was successfully realized to discover the tumor associated biomarkers.As the key parts of AFA-DESI-MSI system,it has been demonstrated that the designed probs have excellent performance for spatially resolved metabolomics,and it will further promote its application in life science,and drug research and development.
基金supported by the National Natural Science Foundation of China(Grant Nos.:U21A20418,82003727,82273903)l Zhejiang Provincial Natural Science Foundation,China(Grant No.:LQ21H310002).
文摘Recent studies have highlighted spatially resolved multi-omics technologies,including spatial genomics,transcriptomics,proteomics,and metabolomics,as powerful tools to decipher the spatial heterogeneity of the brain.Here,we focus on two major approaches in spatial transcriptomics(next-generation sequencing-based technologies and image-based technologies),and mass spectrometry imaging technologies used in spatial proteomics and spatial metabolomics.Furthermore,we discuss their applications in neuroscience,including building the brain atlas,uncovering gene expression patterns of neurons for special behaviors,deciphering the molecular basis of neuronal communication,and providing a more comprehensive explanation of the molecular mechanisms underlying central nervous system disorders.However,further efforts are still needed toward the integrative application of multi-omics technologies,including the real-time spatial multi-omics analysis in living cells,the detailed gene profile in a whole-brain view,and the combination of functional verification.
基金supported by the Canadian Institute of Health Research(CIHR)-Natural Sciences and Engineering Research Council(NSERC)of Canada Collaborative Health Research Projects program(Grant No.:355935)as well as by NSERC through the Industrial Research Chair(IRC)program(Program No.:#IRCPJ 184412e15).
文摘Adjuvant chemotherapy improves the survival outlook for patients undergoing operations for lung metastases caused by colorectal cancer (CRC). However, a multidisciplinary approach that evaluates several factors related to patient and tumor characteristics is necessary for managing chemotherapy treatment in metastatic CRC patients with lung disease, as such factors dictate the timing and drug regimen, which may affect treatment response and prognosis. In this study, we explore the potential of spatial metabolomics for evaluating metabolic phenotypes and therapy outcomes during the local delivery of the anticancer drug, oxaliplatin, to the lung. 12 male Yorkshire pigs underwent a 3 h left lung in vivo lung perfusion (IVLP) with various doses of oxaliplatin (7.5, 10, 20, 40, and 80 mg/L), which were administered to the perfusion circuit reservoir as a bolus. Biocompatible solid-phase microextraction (SPME) microprobes were combined with global metabolite profiling to obtain spatiotemporal information about the activity of the drug, determine toxic doses that exceed therapeutic efficacy, and conduct a mechanistic exploration of associated lung injury. Mild and subclinical lung injury was observed at 40 mg/L of oxaliplatin, and significant compromise of the hemodynamic lung function was found at 80 mg/L. This result was associated with massive alterations in metabolic patterns of lung tissue and perfusate, resulting in a total of 139 discriminant compounds. Uncontrolled inflammatory response, abnormalities in energy metabolism, and mitochondrial dysfunction next to accelerated kynurenine and aldosterone production were recognized as distinct features of dysregulated metabolipidome. Spatial pharmacometabolomics may be a promising tool for identifying pathological responses to chemotherapy.
基金supported by the National Natural Science Foundation of China(Grant No.:81974500)the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences,China(Grant No.:2022-I2M-2-001).
文摘Tumors are spatially heterogeneous tissues that comprise numerous cell types with intricate structures.By interacting with the microenvironment,tumor cells undergo dynamic changes in gene expression and metabolism,resulting in spatiotemporal variations in their capacity for proliferation and metastasis.In recent years,the rapid development of histological techniques has enabled efficient and high-throughput biomolecule analysis.By preserving location information while obtaining a large number of gene and molecular data,spatially resolved metabolomics(SRM)and spatially resolved transcriptomics(SRT)approaches can offer new ideas and reliable tools for the in-depth study of tumors.This review provides a comprehensive introduction and summary of the fundamental principles and research methods used for SRM and SRT techniques,as well as a review of their applications in cancer-related fields.
基金support from the National Key R&D Program of China(Grant No:2022YFC3401003)the National Natural Science Foundation of China(Grant No:21927808)+2 种基金the National Natural Science Foundation of China(Grant No:22104160)the National Key Research and Development Program of China(Grant No:2017YFC1704006)the Innovation Team of Ethnomedicine of National Ethnic Affairs Commission,China.We thank all the research staff who contributed to the study.
文摘Polygala tenuifolia,commonly known as Yuanzhi(YZ)in Chinese,has been shown to possess antiinsomnia properties.However,the material basis and the mechanism underlying its sedative-hypnotic effects remain unclear.Herein,we investigated the active components and neurochemical mechanism of YZ extracts using liquid chromatography tandem mass spectrometry(LC-MS/MS)-based pharmacometabolomics and mass spectrometry imaging(MSI)-based spatial resolved metabolomics.According to the results,17 prototypes out of 101 ingredients in the YZ extract were detected in both the plasma and brain,which might be the major components contributing to the sedative-hypnotic effects.Network pharmacology analysis revealed that these prototypes may exert their effects through neuroactive ligand-receptor interaction,serotonergic synapse,dopaminergic synapse,and dopaminergic synapse,among other pathways.LC-MS/MS-based targeted metabolomics and Western blot(WB)revealed that tryptophan-serotonin-melatonin(Trp-5-HT-Mel)and tyrosine-norepinephrine-adrenaline(Tyr-Ne-Ad)are the key regulated pathways.Dopa decarboxylase(DDC)upregulation and phenylethanolamine Nmethyltransferase(PNMT)downregulation further confirmed these pathways.Furthermore,MSI-based spatially resolved metabolomics revealed notable alterations in 5-HT in the pineal gland(PG),and Ad in the brainstem,including the middle brain(MB),pons(PN),and hypothalamus(HY).In summary,this study illustrates the efficacy of an integrated multidimensional metabolomics approach in unraveling the sedative-hypnotic effects and neurochemical mechanisms of a Chinese herbal medicine,YZ.
基金support from the Program of Natural Science Foundation of State (Grant Nos.81973745 and 82104733)the Hainan Province "Nanhai New Star" Science and Technology Innovation Talent Platform Project by Hainan Provincial Department of Science and Technology (NHXXRCXM202317)the Natural Science Foundation of Heilongjiang Province (YQ2019H030)。
文摘Understanding the specific metabolic changes in multiple regions of the kidney is crucial to revealing the underlying mechanism and developing effective targets for diabetic nephropathy(DN). In this study, integrated spatially resolved metabolomics and proteomics combined with mass spectrometry imaging(MSI) revealed a multi-scale region profile of the diabetic kidney. Based on anatomic location, spatial metabolomics revealed eight region-specific metabolite biomarkers uniquely localized to kidney segments, which were closely correlated to the clinical parameters of patients with DN. Specifically, treatment with metformin(MET) enriched inosinic acid, adenosine 3′,5′-diphosphate, nicotinamide adenine dinucleotide(NADH), and hydrated NADH(NADHX) levels in the cortex(Cor) and the outer stripe of kidney medulla(OM) anatomical subregions, while in the inner stripe of kidney medulla(IM) segmentation, the p-cresol sulfate level was downregulated. Comparing differently expressed proteins in each region showed that nephrosis 2(Nphs2) was the highest loading feature. A further region-specific analysis of pathway enrichment characteristics indicated that the purine and ether lipid metabolism pathways were enriched in the Cor and OM regions, whereas the pantothenate and coenzyme A(CoA) biosynthesis pathways were mainly enriched in the IM region in response to MET treatment. Taken together, the spatially segregated metabolomics and proteomics studies reveal MET-mediated proteins and function-specific therapeutic pathways related to the anatomical multiregion of diabetic mouse kidneys.
基金supported by the National Key Research and Development Program of China(no.2022YFD120030)the National Natural Science Foundation of China(31670233).
文摘Plants contain a large number of cell types and exhibit complex regulatory mechanisms.Studies at the single-cell level have gradually become more common in plant science.Single-cell transcriptomics,spatial transcriptomics,and spatial metabolomics techniques have been combined to analyze plant development.These techniques have been used to study the transcriptomes and metabolomes of plant tissues at the single-cell level,enabling the systematic investigation of gene expression and metabolism in specific tissues and cell types during defined developmental stages.In this review,we present an overview of significant breakthroughs in spatial multi-omics in plants,and we discuss how these approaches may soon play essential roles in plant research.
基金supported by the National Key Research and Development Program of China(2022YFA0806503)the National Natural Science Foundation of China(81972625 and 32201217)+3 种基金Liaoning Revitalization Talents Program(XLYC2002035)Liaoning Science and Technology Innovation Funding(20230101-JH2/1013)the Innovation Program of Science and Research from Dalian Institute of Chemical Physics,Chinese Academy of Sciences(DICP I202129 and DICP I202209)the Science and Technology Innovation Fund(Youth Science and Technology Star)of Dalian(2021RQ009 and 2023RQ040).
文摘Metabolic dysfunction-associated steatotic liver disease(MASLD)is a metabolic disease that can progress to metabolic dysfunction-associated steatohepatitis(MASH),cirrhosis,and cancer.The zonal distribution of biomolecules in the liver is implicated in mediat-ing the disease progression.Recently,G-protein-coupled receptor 35(GPR35)has been highlighted to play a role in MASLD,but the precise mechanism is not fully understood,particularly,in a liver-zonal manner.Here,we aimed to identify spatially distributed specific genes and metabolites in different liver zonation that are regulated by GPR35 in MASLD,by combining lipid metabolomics,spatial transcriptomics(ST),and spatial metabolomics(SM).We found that GPR35 influenced lipid accumulation,inflammatory and metabolism-related factors in specific regions,notably affecting the anti-inflammation factor ELF4(E74 like E-twenty six(ETS)tran-scription factor 4),lipid homeostasis key factor CIDEA(cell death-inducing DNA fragmentation factor alpha(DFFA)-like effector A),and the injury response-related genes SAA1/2/3(serum amyloid A1/2/3),thereby impacting MASLD progression.Furthermore,SM elucidated specific metabolite distributions across different liver regions,such as C10H11N4O7P(3ʹ,5ʹ-cyclic inosine monophosphate(3ʹ,5ʹ-IMP))for the central vein,and this metabolite significantly decreased in the liver zones of GPR35-deficient mice during MASLD progression.Taken together,GPR35 regulates hepatocyte damage repair,controls inflammation,and prevents MASLD progression by influencing phospholipid homeostasis and gene expression in a zonal manner.
