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

Untargeted metabolomics in the aqueous humor reveals the involvement of TAAR pathway in glaucoma

Thu, 20/07/2023 - 12:00
Exp Eye Res. 2023 Jul 18:109592. doi: 10.1016/j.exer.2023.109592. Online ahead of print.ABSTRACTUnderstanding the metabolic dysfunctions and underlying complex pathological mechanisms of neurodegeneration in glaucoma could help discover disease pathways, identify novel biomarkers, and rationalize newer therapeutics. Therefore, we aimed to investigate the local metabolomic alterations in the aqueous humor and plasma of primary glaucomatous patients. This study cohort comprised primary open-angle glaucoma (POAG), primary angle-closure glaucoma (PACG), and cataract control groups. Aqueous humor and plasma samples were collected from patients undergoing trabeculectomy or cataract surgery and subjected to high-resolution mass spectrometry (HRMS) analysis. Spectral information was processed, and the acquired data were subjected to uni-variate as well as multi-variate statistical analyses using MetaboAnalyst ver5.0. To further understand the localized metabolic abnormalities in glaucoma, metabolites affected in aqueous humor were distinguished from metabolites altered in plasma in this study. Nine and twelve metabolites were found to be significantly altered (p < 0.05, variable importance of projection >1 and log2 fold change ≥0.58/≤ -0.58) in the aqueous humor of PACG and POAG patients, respectively. The galactose and amino acid metabolic pathways were locally affected in the PACG and POAG groups, respectively. Based on the observation of the previous findings, gene expression profiles of trace amine-associated receptor-1 (TAAR-1) were studied in rat ocular tissues. The pharmacodynamics of TAAR-1 were explored in rabbits using topical administration of its agonist, β-phenyl-ethylamine (β-PEA). TAAR-1 was expressed in the rat's iris-ciliary body, optic nerve, lens, and cornea. β-PEA elicited a mydriatic response in rabbit eyes without altering intraocular pressure. Targeted analysis of β-PEA levels in the aqueous humor of POAG patients showed an insignificant elevation. This study provides new insights regarding alterations in both localized and systemic metabolites in primary glaucomatous patients. This study also demonstrated the propensity of β-PEA to cause an adrenergic response through the TAAR-1 pathway.PMID:37474016 | DOI:10.1016/j.exer.2023.109592

Application of omics techniques in forensic entomology research

Thu, 20/07/2023 - 12:00
Acta Trop. 2023 Jul 18:106985. doi: 10.1016/j.actatropica.2023.106985. Online ahead of print.ABSTRACTWith the advent of the post-genome era, omics technologies have developed rapidly and are widely used, including in genomics, transcriptomics, proteomics, metabolomics, and microbiome research. These omics techniques are often based on comprehensive and systematic analysis of biological samples using high-throughput analysis methods and bioinformatics, to provide new insights into biological phenomena. Currently, omics techniques are gradually being applied to forensic entomology research and are useful in species identification, phylogenetics, screening for developmentally relevant differentially expressed genes, and the interpretation of behavioral characteristics of forensic-related species at the genetic level. These all provide valuable information for estimating the postmortem interval (PMI). This review mainly discusses the available omics techniques, summarizes the application of omics techniques in forensic entomology, and their future in the field.PMID:37473953 | DOI:10.1016/j.actatropica.2023.106985

The XOR-IDH3α axis controls macrophage polarization in hepatocellular carcinoma

Thu, 20/07/2023 - 12:00
J Hepatol. 2023 Jul 18:S0168-8278(23)04984-X. doi: 10.1016/j.jhep.2023.06.022. Online ahead of print.ABSTRACTBACKGROUND & AIMS: Tumor-associated macrophages (TAMs) are indispensable in the hepatocellular carcinoma (HCC) tumor microenvironment. Xanthine oxidoreductase (XOR), also known as xanthine dehydrogenase (XDH), participates in purine metabolism, uric acid production, and macrophage polarization to a pro-inflammatory phenotype. However, the role of XOR in HCC-associated TAMs is unclear.METHODS: We evaluated the XOR level in macrophages isolated from HCC tissues and paired adjacent tissues. We established DEN/carbon tetrachloride (CCl4)-induced and orthotopically implanted HCC mouse models using mice with Xdh-specific depletion in the myeloid cell lineage (Xdhf/fLyz2cre) or Kupffer cells (Xdhf/fClec4fcre). We determined metabolic differences using specific methodologies, including metabolomics and metabolic flux.RESULTS: We found that XOR expression was downregulated in HCC TAMs and positively correlated with patient survival, which was strongly related to the characteristics of the tumor microenvironment (TME), especially hypoxia. Using HCC-inflicted mice (Xdhf/fLyz2cre and Xdhf/fClec4fcre), we revealed that XOR loss in monocyte-derived TAMs rather than Kupffer cells promoted their M2 polarization and CD8+ T-cell exhaustion, which exacerbated HCC progression. In addition, the tricarboxylic acid cycle was disturbed, and the generation of α-ketoglutarate (α-KG) was enhanced within XOR-depleted macrophages. XOR inhibited α-KG production by interacting with IDH3α catalytic sites (K142 and Q139). The increased IDH3α activity caused increased adenosine and kynurenic acid production in the TAMs, which enhanced the immunosuppressive effects of the TAMs and CD8+ T cells.CONCLUSIONS: The XOR-IDH3α axis mediates TAM polarization and HCC progression and may be a small-molecule therapeutic or immunotherapeutic target against suppressive HCC TAMs.IMPACT AND IMPLICATIONS: HCC is one of the cancers with the highest morbidity in the world, and its 5-year survival rate is low. Currently, lots of immunotherapies have been applied to the treatment of HCC, but the curative effects are not satisfactory. TME of HCC is full of different infiltrating immune cells. TAMs are vital components in TME and involved in HCC progression. Herein, we confirm the downregulation of XOR expression in TAMs isolated from human HCC tissues. The loss of XOR in monocyte-derived macrophages increases IDH3 activity and results in an increase in α-KG production, which can promote M2-like polarization. Additionally, XOR-null TAMs derived from monocytes promote CD8+ T-cell exhaustion via the upregulation of immunosuppressive metabolites, including adenosine and KYNA. Given the prevalence and high rate of incidence of HCC and the need for improved therapeutic options for patients, our findings identify potential therapeutic targets that may be further studied to develop improved therapies.PMID:37473847 | DOI:10.1016/j.jhep.2023.06.022

Flavonoid profile of Anoectochilus roxburghii (Wall.) Lindl. Under short-term heat stress revealed by integrated metabolome, transcriptome, and biochemical analyses

Thu, 20/07/2023 - 12:00
Plant Physiol Biochem. 2023 Jul 14;201:107896. doi: 10.1016/j.plaphy.2023.107896. Online ahead of print.ABSTRACTGlobal warming severely threatens plant growth, and could lead to yield reduction. Although findings suggest that flavonoids play important roles in biological process in plants, their response to heat stress in Anoectochilus roxburghii (Wall.) Lindl. remains unclear. Here, we aimed to examine the flavonoid profile of A. roxburghii under heat stress and assess the effect of exogenous application of quercetin on heat stress tolerance. Metabolome analysis showed that quercetin, tricetin, isorhamnetin, scutellarein, and 4',7-Isoflavandiol were the main upregulated flavonoids in A. roxburghii, based on variable importance in the projection >1 and with fold change >2. Determination of the concentrations of the flavonoids using a standard curve revealed that quercetin, kaempferol, and isorhamnetin contents increased by 8.24-, 7.55-, and 5.01-fold, respectively, during heat stress, whereas rutin concentration decreased from 83.04 to 80.89 mg/kg (dry weight). Additionally, transcriptome analysis indicated increased expression of several genes in flavonoid biosynthesis pathways, including phenylalanine ammonia-lyase and chalcone synthase. Moreover, exogenous application of quercetin improved the antioxidant capacity and physiological parameters, including photosynthetic rate and chlorophyll content, of A. roxburghii under heat stress. Overall, the flavonoid profile of A. roxburghii under short-term heat stress was characterized based on integrated metabolomic, transcriptomic, and biochemical analyses, providing new insights for improving the biological value of A. roxburghii.PMID:37473674 | DOI:10.1016/j.plaphy.2023.107896

Comparative analysis of different metabolites in semen of Guanzhong dairy goats with different motility rates

Thu, 20/07/2023 - 12:00
Theriogenology. 2023 Jul 14;210:53-61. doi: 10.1016/j.theriogenology.2023.07.009. Online ahead of print.ABSTRACTIn order to explore the different metabolites of buck semen with different motility stored at 4 °C, the semen of bucks was collected by artificial vagina. The collected semen was divided into high motility group and low motility group after treatment, with 6 replicates set for each group. The semen metabolites of high motility group and low motility group were detected by Liquid Chromatography-Mass Spectrometry (LC-MS). The results showed that 101 different metabolites were detected in the high and low motility groups of bucks, of which 48 metabolites were significantly up-regulated (P < 0.05) and 53 metabolites were significantly down regulated (P < 0.05). Most of these metabolites belonged to lipids and lipid-like molecules, organic acids and their derivatives, and organic oxygen compounds, which were mainly related to energy metabolism. According to the functional enrichment analysis of the former differential metabolites in KEGG database, the top 20 most representative metabolic pathways were detected, among which the glycerophospholipid metabolic pathways changed significantly. From the perspective of metabolomics, this study revealed the differences of metabolites and characteristic compounds of semen with different motility of bucks under low temperature preservation, which provided a scientific basis for the preservation and utilization of semen of Guanzhong dairy goats in the future.PMID:37473596 | DOI:10.1016/j.theriogenology.2023.07.009

Lipid metabolic links between serum pyrethroid levels and the risk of incident type 2 diabetes: A mediation study in the prospective design

Thu, 20/07/2023 - 12:00
J Hazard Mater. 2023 Jul 17;459:132082. doi: 10.1016/j.jhazmat.2023.132082. Online ahead of print.ABSTRACTEmerging evidence revealed that pyrethroids and circulating lipid metabolites are involved in incident type 2 diabetes (T2D). However, the pyrethroid-associated lipid profile and its potential role in the association of pyrethroids with T2D remain unknown. Metabolome-wide association or mediation analyses were performed among 1006 pairs of T2D cases and matched controls nested within the prospective Dongfeng-Tongji cohort. We identified 59 lipid metabolites significantly associated with serum deltamethrin levels, of which eight were also significantly associated with serum fenvalerate (false discovery rate [FDR] < 0.05). Pathway enrichment analysis showed that deltamethrin-associated lipid metabolites were significantly enriched in the glycerophospholipid metabolism pathway (FDR = 0.02). Furthermore, we also found that several deltamethrin-associated lipid metabolites (i.e., phosphatidylcholine [PC] 32:0, PC 34:4, cholesterol ester 20:0, triacylglycerol 52:5 [18:2]), and glycerophosphoethanolamine-enriched latent variable mediated the association between serum deltamethrin levels and T2D risk, with the mediated proportions being 44.81%, 15.92%, 16.85%, 16.66%, and 22.86%, respectively. Serum pyrethroids, particularly deltamethrin, may lead to an altered circulating lipid profile primarily in the glycerophospholipid metabolism pathway represented by PCs and lysophosphatidylcholines, potentially mediating the association between serum deltamethrin and T2D. The study provides a new perspective in elucidating the potential mechanisms through which pyrethroid exposure might induce T2D.PMID:37473566 | DOI:10.1016/j.jhazmat.2023.132082

Effects of (20 R)-Panaxadiol on NAFLD using non‑targeted metabolomics in stool

Thu, 20/07/2023 - 12:00
J Pharm Biomed Anal. 2023 Jul 6;234:115555. doi: 10.1016/j.jpba.2023.115555. Online ahead of print.ABSTRACTNon-alcoholic fatty liver disease (NAFLD) is a clinical syndrome characterized by hepatocyte steatosis and adipose accumulation with the main lesion in the hepatic lobule, but without a history of excessive alcohol consumption. NAFLD ranges from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), and may further accumulate fibrosis leading to cirrhosis. Many studies have found that ginseng can treat NAFLD. (20 R)-Panaxadiol (PD) is a panax ginseng diol type compound, has been proved that can treat the obesity. This study wants to investigate the effect of PD on non-alcoholic liver disease. We used 20 ob/ob mice and 10 C57BL/6 J mice. C57BL/6 J mice as CONTROL group, ob/ob mice were divided into model group and PD group. In PD group, ob/ob mice were treated with PD for eight weeks(10 mg/kg, the CON and OB group was given the same amount of sodium carboxymethyl cellulose), detected the weight, food intake and serum index, observed the HE staining of liver and intestine, performed the 16 S rRNA and untargeted metabolomics analysis used mice feces, and verify the results by detect the expression of TNF-α, MDA and SOD. In vivo results, PD can improve abnormal glucose and lipid metabolism and liver function. In 16 S rRNA result, we found beneficial bacteria Muribaculaceae and Lactobacillus increased; in untargeted metabolomics analysis, inflammatory metabolites prostaglandin (PG) and lipopolysaccharide (LPS) decreased, antioxidant metabolites FAD and lipoic acid increased. Then, we proceeded the association analysis of gut microbiota and metabolites, the result showed gut microbiota have strongly associated with anti-inflammatory and antioxidant metabolites. In addition, PD improves intestinal wall integrity. Meanwhile, the expression of TNF-α、MDA and SOD were detected, it was verified that PD has the effect of antioxidant and anti-inflammation. Our study showed that PD, as an active ingredient of ginseng, can play an anti-inflammatory and antioxidant role by improving intestinal metabolites, thereby preventing and treating non-alcoholic fatty liver disease to a certain extent.PMID:37473506 | DOI:10.1016/j.jpba.2023.115555

Discovery of biomarkers related to abnormal lipid metabolism in liver and serum and intervention mechanism of ginsenoside Rb_1 in hyperlipidemia rats based on non-targeted metabolomics

Thu, 20/07/2023 - 12:00
Zhongguo Zhong Yao Za Zhi. 2023 Jul;48(14):3922-3933. doi: 10.19540/j.cnki.cjcmm.20230413.701.ABSTRACTThrough the non-targeted metabolomics study of endogenous substances in the liver and serum of hyperlipidemia rats, the biomarkers related to abnormal lipid metabolism in hyperlipidemia rats were found, and the target of ginsenoside Rb_1 in improving hyperlipidemia was explored and its mechanism was elucidated. The content of serum biochemical indexes of rats in each group was detected by the automatic biochemical analyzer. The metabolite profiles of liver tissues and serum of rats were analyzed by HPLC-MS. Principal component analysis(PCA) and orthogonal partial least squares-discriminant analysis(OPLS-DA) were used to compare and analyze the metabolic data in the normal group, the hyperlipidemia group, and the ginsenoside Rb_1 group, and screen potential biomar-kers. The related metabolic pathways were further constructed by KEGG database analysis. The results showed that hyperlipemia induced dyslipidemia in rats, which was alleviated by ginsenoside Rb_1. The non-targeted metabolomics results showed that there were 297 differential metabolites in the liver tissues of hyperlipidemia rats, 294 differential metabolites in the serum samples, and 560 diffe-rential metabolites in the hyperlipidemia rats treated by ginsenoside Rb_1. Perillic acid and N-ornithyl-L-taurine were common metabolites in the liver and serum samples, which could be used as potential biomarkers for ginsenoside Rb_1 in the improvement of hyperlipidemia. As revealed by pathway enrichment in the liver and serum, ginsenoside Rb_1 could participate in the metabolic pathway of choline in both the liver and serum. In addition, ginsenoside Rb_1 also participated in the ABC transporter, alanine, aspartic acid, and glutamate metabolism, protein digestion and absorption, β-alanine metabolism, taurine and hypotaurine metabolism, caffeine metabolism, valine, leucine, and isoleucine biosynthesis, arachidonic acid metabolism, and methionine and cysteine metabolism to improve dyslipidemia in rats.PMID:37475084 | DOI:10.19540/j.cnki.cjcmm.20230413.701

Core connotation of compatibility of Aconiti Lateralis Radix Praeparata-Glycyrrhizae Radix et Rhizoma herb pair under physiological/ pathological conditions based on metabolomics and network pharmacology

Thu, 20/07/2023 - 12:00
Zhongguo Zhong Yao Za Zhi. 2023 Jul;48(14):3793-3805. doi: 10.19540/j.cnki.cjcmm.20230425.301.ABSTRACTThis study aims to explore the core connotation of the compatibility of Aconiti Lateralis Radix Praeparata(Fuzi)-Glycyrrhizae Radix et Rhizoma(Gancao) herb pair under physiological and pathological conditions. The biochemical indicators of serum/myocardial tissue, pathological changes of the myocardial tissue, and serum metabolic profiles of normal rats and heart failure model rats treated with Fuzi Decoction and Fuzi Gancao Decoction were determined. Network pharmacology and metabolomics were employed to establish the metabolite-target-pathway network for Glycyrrhizae Radix et Rhizoma in enhancing the efficacy and reducing the toxicity of Aconiti Lateralis Radix Praeparata, Western blotting was employed to verify the representative pathways in the network. The results showed that both decoctions lowered the levels of creatine kinase and other indicators and mitigate myocardial pathological injury in model rats. However, they caused the abnormal rises in creatine kinase and other indicators and myocardial pathological injury in normal rats. The results indicated that the compatibility reduced the toxicity in normal rats and enhanced the efficacy in model rats. The results of metabolomics showed that Fuzi Gancao Decoction recovered more metabolites in model rats and had weaker effect on interfe-ring with the metabolites in normal rats than Fuzi Decoction. The association analysis showed that the network of Glycyrrhizae Radix et Rhizoma enhancing the efficacy of Aconiti Lateralis Radix Praeparata involved 112 metabolites, 89 targets, and 15 pathways, including calcium and cAMP signaling pathways. The network of Glycyrrhizae Radix et Rhizoma reducing the cardiotoxicity of Aconiti Lateralis Radix Praeparata involved 36 metabolites, 59 targets, and 11 pathways, including adrenergic signaling and tricarboxylic acid cycle in cardiomyocytes. The experimental results of protein expression verified the reliability of the association analysis. This study demonstrated that the core connotation of the herb pair of Aconiti Lateralis Radix Praeparata-Glycyrrhizae Radix et Rhizoma changed under physio-logical and pathological states, and the compatibility results of enhancing efficacy and reducing toxicity were achieved with different metabolic pathways and biological processes.PMID:37475071 | DOI:10.19540/j.cnki.cjcmm.20230425.301

Multi-omics in thoracic aortic aneurysm: the complex road to the simplification

Thu, 20/07/2023 - 12:00
Cell Biosci. 2023 Jul 20;13(1):131. doi: 10.1186/s13578-023-01080-w.ABSTRACTBACKGROUND: Thoracic aortic aneurysm (TAA) is a serious condition that affects the aorta, characterized by the dilation of its first segment. The causes of TAA (e.g., age, hypertension, genetic syndromes) are heterogeneous and contribute to the weakening of the aortic wall. This complexity makes treating this life-threatening aortopathy challenging, as there are currently no etiological therapy available, and pharmacological strategies, aimed at avoiding surgical aortic replacement, are merely palliative. Recent studies on novel therapies for TAA have focused on identifying biological targets and etiological mechanisms of the disease by using advanced -omics techniques, including epigenomics, transcriptomics, proteomics, and metabolomics approaches.METHODS: This review presents the latest findings from -omics approaches and underscores the importance of integrating multi-omics data to gain more comprehensive understanding of TAA.RESULTS: Literature suggests that the alterations in TAA mediators frequently involve members of pro-fibrotic process (i.e., TGF-β signaling pathways) or proteins associated with cell/extracellular structures (e.g., aggrecans). Further analyses often reported the importance in TAA of processes as inflammation (PCR, CD3, leukotriene compounds), oxidative stress (chromatin OXPHOS, fatty acids), mitochondrial respiration and glycolysis/gluconeogenesis (e.g., PPARs and HIF1a). Of note, more recent metabolomics studies added novel molecular markers to the list of TAA-specific detrimental mediators (proteoglycans).CONCLUSION: It is increasingly clear that integrating data from different -omics branches, along with clinical data, is essential as well as complicated both to reveal hidden relevant information and to address complex diseases such as TAA. Importantly, recent progresses in metabolomics highlighted novel potential and unprecedented marks in TAA diagnosis and therapy.PMID:37475058 | DOI:10.1186/s13578-023-01080-w

The BinDiscover database: a biology-focused meta-analysis tool for 156,000 GC-TOF MS metabolome samples

Thu, 20/07/2023 - 12:00
J Cheminform. 2023 Jul 20;15(1):66. doi: 10.1186/s13321-023-00734-8.ABSTRACTMetabolomics by gas chromatography/mass spectrometry (GC/MS) provides a standardized and reliable platform for understanding small molecule biology. Since 2005, the West Coast Metabolomics Center at the University of California at Davis has collated GC/MS metabolomics data from over 156,000 samples and 2000 studies into the standardized BinBase database. We believe that the observations from these samples will provide meaningful insight to biologists and that our data treatment and webtool will provide insight to others who seek to standardize disparate metabolomics studies. We here developed an easy-to-use query interface, BinDiscover, to enable intuitive, rapid hypothesis generation for biologists based on these metabolomic samples. BinDiscover creates observation summaries and graphics across a broad range of species, organs, diseases, and compounds. Throughout the components of BinDiscover, we emphasize the use of ontologies to aggregate large groups of samples based on the proximity of their metadata within these ontologies. This adjacency allows for the simultaneous exploration of entire categories such as "rodents", "digestive tract", or "amino acids". The ontologies are particularly relevant for BinDiscover's ontologically grouped differential analysis, which, like other components of BinDiscover, creates clear graphs and summary statistics across compounds and biological metadata. We exemplify BinDiscover's extensive applicability in three showcases across biological domains.PMID:37475020 | DOI:10.1186/s13321-023-00734-8

Integrated models of blood protein and metabolite enhance the diagnostic accuracy for Non-Small Cell Lung Cancer

Thu, 20/07/2023 - 12:00
Biomark Res. 2023 Jul 20;11(1):71. doi: 10.1186/s40364-023-00497-2.ABSTRACTBACKGROUND: For early screening and diagnosis of non-small cell lung cancer (NSCLC), a robust model based on plasma proteomics and metabolomics is required for accurate and accessible non-invasive detection. Here we aim to combine TMT-LC-MS/MS and machine-learning algorithms to establish models with high specificity and sensitivity, and summarize a generalized model building scheme.METHODS: TMT-LC-MS/MS was used to discover the differentially expressed proteins (DEPs) in the plasma of NSCLC patients. Plasma proteomics-guided metabolites were selected for clinical evaluation in 110 NSCLC patients who were going to receive therapies, 108 benign pulmonary diseases (BPD) patients, and 100 healthy controls (HC). The data were randomly split into training set and test set in a ratio of 80:20. Three supervised learning algorithms were applied to the training set for models fitting. The best performance models were evaluated with the test data set.RESULTS: Differential plasma proteomics and metabolic pathways analyses revealed that the majority of DEPs in NSCLC were enriched in the pathways of complement and coagulation cascades, cholesterol and bile acids metabolism. Moreover, 10 DEPs, 14 amino acids, 15 bile acids, as well as 6 classic tumor biomarkers in blood were quantified using clinically validated assays. Finally, we obtained a high-performance screening model using logistic regression algorithm with AUC of 0.96, sensitivity of 92%, and specificity of 89%, and a diagnostic model with AUC of 0.871, sensitivity of 86%, and specificity of 78%. In the test set, the screening model achieved accuracy of 90%, sensitivity of 91%, and specificity of 90%, and the diagnostic model achieved accuracy of 82%, sensitivity of 77%, and specificity of 86%.CONCLUSIONS: Integrated analysis of DEPs, amino acid, and bile acid features based on plasma proteomics-guided metabolite profiling, together with classical tumor biomarkers, provided a much more accurate detection model for screening and differential diagnosis of NSCLC. In addition, this new mathematical modeling based on plasma proteomics-guided metabolite profiling will be used for evaluation of therapeutic efficacy and long-term recurrence prediction of NSCLC.PMID:37475010 | DOI:10.1186/s40364-023-00497-2

Zuogui Pills and Yougui Pills in differential treatment of diminished ovarian reserve based on metabolomics

Thu, 20/07/2023 - 12:00
Zhongguo Zhong Yao Za Zhi. 2023 Jul;48(13):3664-3677. doi: 10.19540/j.cnki.cjcmm.20230226.502.ABSTRACTBased on the metabolomics, this paper systematically analyzed the metabolic substance basis of Zuogui Pills and Yougui Pills in syndrome differentiation and treatment of diminished ovarian reserve(DOR), so as to provide a scientific basis for the traditional Chinese medicine(TCM) syndrome differentiation and treatment of DOR. Patients with DOR of kidney-Yin deficiency syndrome were collected from outpatient department of hospitals and treated with Zuogui Pills for 12 weeks. And kidney-Yang deficiency syndrome were treated with Yougui Pills for 12 weeks. Based on the non-targeted metabolomic research techniques, the potential biomarkers of Zuogui Pills and Yougui Pills in the treatment of DOR with kidney-Yin deficiency and kidney-Yang deficiency, respectively, were screened out, and metabolic pathways of biomarkers were analyzed. The pregnancy rate, basic serum hormone levels [basal follicle-stimulating hormone(bFSH), basal-luteinizing hormone(bLH), basal-estradiol(bE_2), and anti-Müllerian hormone(AMH)], TCM syndrome type score, and Kupperman score were recorded and statistically analyzed after treatment. The results showed that 23 patients with DOR of kidney-Yin deficiency syndrome and 25 patients of kidney-Yang deficiency syndrome were collected. Twenty-six differential metabolites, including L-carnitine, acetyl-CoA, coenzyme A, and coenzyme Q_(10)(CoQ10), were mapped to 12 metabolic pathways in patients with kidney-Yin deficiency treated with Zuogui Pills. Twenty-two differential metabolites, such as adipoyl-CoA, L-lysine, lysine arginine, and α-tocopherol, were mapped to 11 metabolic pathways in patients with kidney-Yang deficiency. After treatment, bFSH and bLH of patients with DOR were significantly lower than those before treatment(P&lt;0.05). Although the comparison of bE_2 and AMH had no significant differences, there was a improvement trend. The TCM syndrome type score and Kupperman score of patients with DOR after TCM treatment were significantly lower than those before treatment(P&lt;0.05).PMID:37474998 | DOI:10.19540/j.cnki.cjcmm.20230226.502

Bletilla striata polysaccharide improves toxic and side effects induced by 5-FU: an untargeted metabolomics study

Thu, 20/07/2023 - 12:00
Zhongguo Zhong Yao Za Zhi. 2023 Jul;48(13):3612-3622. doi: 10.19540/j.cnki.cjcmm.20230413.705.ABSTRACTThis study aimed to analyze the effect of Bletilla striata polysaccharide(BSP) on endogenous metabolites in serum of tumor-bearing mice treated with 5-fluorouracil(5-FU) by untargeted metabolomics techniques and explore the mechanism of BSP in alleviating the toxic and side effects induced by 5-FU. Male BALB/C mice were randomly divided into a normal group, a model group, a 5-FU group, and a 5-FU + BSP group, with eight mice in each group. Mouse colon cancer cells(CT26) were transplanted into the mice except for those in the normal group to construct the tumor-bearing mouse model by subcutaneous injection, and 5-FU chemotherapy and BSP treatment were carried out from the second day of modeling. The changes in body weight, diarrhea, and white blood cell count in the peripheral blood were recorded. The mice were sacrificed and sampled when the tumor weight of mice in the model group reached approximately 1 g. TUNEL staining was used to detect the cell apoptosis in the small intestine of each group. The proportions of hematopoietic stem cells and myeloid progenitor cells in bone marrow were measured by flow cytometry. Five serum samples were selected randomly from each group for untargeted metabolomics analysis. The results showed that BSP was not effective in inhibiting colon cancer in mice, but diarrhea, leukopenia, and weight loss caused by 5-FU chemotherapy were significantly improved after BSP intervention. In addition, apoptotic cells decreased in the small intestinal tissues and the percentages of hematopoietic stem cells and myeloid progenitor cells in bone marrow were significantly higher after BSP treatment. Metabolomics results showed that the toxic and side effects of 5-FU resulted in significant decrease in 29 metabolites and significant increase in 22 metabolites in mouse serum. Among them, 19 disordered metabolites showed a return to normal levels in the 5-FU+BSP group. The results of pathway enrichment indicated that metabolic pathways mainly involved pyrimidine metabolism, arachidonic acid metabolism, and steroid hormone biosynthesis. Therefore, BSP may ameliorate the toxic and side effects of 5-FU in the intestinal tract and bone marrow presumably by regulating nucleotide synthesis, inflammatory damage, and hormone production.PMID:37474994 | DOI:10.19540/j.cnki.cjcmm.20230413.705

Mechanism of Gardeniae Fructus in ameliorating rheumatoid arthritis based on metabolomics and intestinal microbiota

Thu, 20/07/2023 - 12:00
Zhongguo Zhong Yao Za Zhi. 2023 Jul;48(13):3602-3611. doi: 10.19540/j.cnki.cjcmm.20230411.401.ABSTRACTRheumatoid arthritis(RA), a chronic autoimmune disease, is featured by persistent joint inflammation. The development of RA is associated with the disturbance of endogenous metabolites and intestinal microbiota. Gardeniae Fructus(GF), one of the commonly used medicinal food in China, is usually prescribed for the prevention and treatment of jaundice, inflammation, ache, fever, and skin ulcers. GF exerts an effect on ameliorating RA, the mechanism of which remains to be studied. In this study, ultra-perfor-mance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS)-based serum non-target metabolomics and 16S rDNA high-throughput sequencing were employed to elucidate the mechanism of GF in ameliorating RA induced by complete Freund's adjuvant in rats. The results showed that GF alleviated the pathological conditions in adjuvant arthritis(AA) rats. The low-and high-dose GF lo-wered the serum levels of interleukin(IL)-6, tumor necrosis factor-α(TNF-α), IL-1β, and prostaglandin E2 in the rats(P&lt;0.05, P&lt;0.01). Pathways involved in metabolomics were mainly α-linolenic acid metabolism and glycerophospholipid metabolism. The results of 16S rDNA sequencing showed that the Streptococcus, Facklamia, Klebsiella, Enterococcus, and Kosakonia were the critical gut microorganisms for GF to treat AA in rats. Spearman correlation analysis showed that the three differential metabolites PE-NMe[18:1(9Z)/20:0], PC[20:1(11Z)/18:3(6Z,9Z,12Z)], and PC[20:0/18:4(6Z,9Z,12Z,15Z)] were correlated with the differential bacteria. In conclusion, GF may ameliorate RA by regulating the composition of intestinal microbiota, α-linolenic acid metabolism, and glycerophospholipid metabolism. The findings provide new ideas and data for elucidating the mechanism of GF in relieving RA.PMID:37474993 | DOI:10.19540/j.cnki.cjcmm.20230411.401

Carbohydrate-based quality consistency evaluation of Saposhnikoviae Radix

Thu, 20/07/2023 - 12:00
Zhongguo Zhong Yao Za Zhi. 2023 Jul;48(13):3535-3545. doi: 10.19540/j.cnki.cjcmm.20230411.203.ABSTRACTThis study aims to evaluate the quality consistency of Saposhnikoviae Radix based on carbohydrates, and explore the potential of carbohydrates as the internal quality control indicators of Saposhnikoviae Radix. The total polysaccharides were quantified by UV-Vis spectrophotometry and the molecular weight range of the polysaccharides was determined by high performance gel-permeation chromatography-evaporative light scattering detection(HPGPC-ELSD). The monosaccharides in polysaccharides and the free monosaccharides were quantified by high performance liquid chromatography-UV detection(HPLC-UV), and the oligosaccharides and fructose were quantified by high performance liquid chromatography-evaporative light scattering detection(HPLC-ELSD). The carbohydrate-based quality of Saposhnikoviae Radix was compared among 45 batches of commercial samples and 13 batches of self-collected samples. The results showed that the molecular weight distribution, monosaccharide composition, oligosaccharide, and free monosaccharide composition were similar in the 58 batches of samples. The average content of total polysaccharides, oligosaccharides, and total free monosaccharides in commercial samples were 39.66, 148.79, and 68.62 mg·g~(-1), respectively. The content showed significant differences among batches, with the highest differences of 3.51, 1.75, and 2.58 times, respectively. The RSD of the relative ratios of monosaccharides in the polysaccharides in commercial samples reached 28%-45%. The average content of total polysaccharides, oligosaccharides, and total free monosaccharides in self-collected samples were 68.07, 145.76, and 42.04 mg·g~(-1), respectively, with the inter-region differences of 2.88, 1.88, and 1.07 times, respectively. The RSD of the relative ratios of monosaccharides in polysaccharides in self-collected samples ranged from 8.2% to 59%. The total polysaccharides and total free monosaccharides in self-collected samples were 1.72 times higher and 1.63 times lower, respectively, than those in commercial samples. The content of oligosaccharides was similar between self-collected samples and commercial samples. To sum up, carbohydrates are one of the material bases for the internal quality consistency of Saposhnikoviae Radix. The qualitative characteristics of polysaccharides and the quantitative characteristics of polysaccharides and oligosaccharides are related to the origin of medicinal materials. Moreover, the quantitative characteristics of polysaccharides and free monosaccharides may be related to the storage conditions. Carbohydrates are potential indicators for the quality control of Saposhnikoviae Radix and deserve attention.PMID:37474987 | DOI:10.19540/j.cnki.cjcmm.20230411.203

Crosstalk between RNA m<sup>6</sup>A and DNA methylation regulates transposable element chromatin activation and cell fate in human pluripotent stem cells

Thu, 20/07/2023 - 12:00
Nat Genet. 2023 Jul 20. doi: 10.1038/s41588-023-01452-5. Online ahead of print.ABSTRACTTransposable elements (TEs) are parasitic DNA sequences accounting for over half of the human genome. Tight control of the repression and activation states of TEs is critical for genome integrity, development, immunity and diseases, including cancer. However, precisely how this regulation is achieved remains unclear. Here we develop a targeted proteomic proximity labeling approach to capture TE-associated proteins in human embryonic stem cells (hESCs). We find that the RNA N6-methyladenosine (m6A) reader, YTHDC2, occupies genomic loci of the primate-specific TE, LTR7/HERV-H, specifically through its interaction with m6A-modified HERV-H RNAs. Unexpectedly, YTHDC2 recruits the DNA 5-methylcytosine (5mC)-demethylase, TET1, to remove 5mC from LTR7/HERV-H and prevent epigenetic silencing. Functionally, the YTHDC2/LTR7 axis inhibits neural differentiation of hESCs. Our results reveal both an underappreciated crosstalk between RNA m6A and DNA 5mC, the most abundant regulatory modifications of RNA and DNA in eukaryotes, and the fact that in hESCs this interplay controls TE activity and cell fate.PMID:37474847 | DOI:10.1038/s41588-023-01452-5

Oncolytic viruses engineered to enforce cholesterol efflux restore tumor-associated macrophage phagocytosis and anti-tumor immunity in glioblastoma

Thu, 20/07/2023 - 12:00
Nat Commun. 2023 Jul 20;14(1):4367. doi: 10.1038/s41467-023-39683-z.ABSTRACTThe codependency of cholesterol metabolism sustains the malignant progression of glioblastoma (GBM) and effective therapeutics remain scarce. In orthotopic GBM models in male mice, we identify that codependent cholesterol metabolism in tumors induces phagocytic dysfunction in monocyte-derived tumor-associated macrophages (TAMs), resulting in disease progression. Manipulating cholesterol efflux with apolipoprotein A1 (ApoA1), a cholesterol reverse transporter, restores TAM phagocytosis and reactivates TAM-T cell antitumor immunity. Cholesterol metabolomics analysis of in vivo-sorted TAMs further reveals that ApoA1 mediates lipid-related metabolic remodeling and lowers 7-ketocholesterol levels, which directly inhibits tumor necrosis factor signaling in TAMs through mitochondrial translation inhibition. An ApoA1-armed oncolytic adenovirus is also developed, which restores antitumor immunity and elicits long-term tumor-specific immune surveillance. Our findings provide insight into the mechanisms by which cholesterol metabolism impairs antitumor immunity in GBM and offer an immunometabolic approach to target cholesterol disturbances in GBM.PMID:37474548 | DOI:10.1038/s41467-023-39683-z

Enhanced belowground sink activity in Populus: 'Spray and pray' meets high throughput transcriptomics and metabolomics

Thu, 20/07/2023 - 12:00
Tree Physiol. 2023 Jul 20:tpad090. doi: 10.1093/treephys/tpad090. Online ahead of print.NO ABSTRACTPMID:37471649 | DOI:10.1093/treephys/tpad090

Uncovering the Carboxylated Metabolome in Gut Microbiota-Host Co-metabolism: A Chemical Derivatization-Molecular Networking Approach

Thu, 20/07/2023 - 12:00
Anal Chem. 2023 Jul 20. doi: 10.1021/acs.analchem.3c02353. Online ahead of print.ABSTRACTGut microbiota-host co-metabolites serve as essential mediators of communication between the host and gut microbiota. They provide nutrient sources for host cells and regulate gut microenvironment, which are associated with a variety of diseases. Analysis of gut microbiota-host co-metabolites is of great significance to explore the host-gut microbiota interaction. In this study, we integrated chemical derivatization, liquid chromatography-mass spectrometry, and molecular networking (MN) to establish a novel CD-MN strategy for the analysis of carboxylated metabolites in gut microbial-host co-metabolism. Using this strategy, 261 carboxylated metabolites from mouse feces were detected, which grouped to various classes including fatty acids, bile acids, N-acyl amino acids, benzoheterocyclic acids, aromatic acids, and other unknown small-scale molecular clusters in MN. Based on the interpretation of the bile acid cluster, a novel type of phenylacetylated conjugates of host bile acids was identified, which were mediated by gut microbiota and exhibited a strong binding ability to Farnesoid X receptor and Takeda G protein-coupled receptor 5. Our proposed strategy offers a promising platform for uncovering carboxylated metabolites in gut microbial-host co-metabolism.PMID:37471289 | DOI:10.1021/acs.analchem.3c02353

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