Metabolic network-based identification of plasma markers for non-small cell lung cancer.
Guo Linling,Li Linrui,Xu Zhiyun,Meng Fanchen,Guo Huimin,Liu Peijia,Liu Peifang,Tian Yuan,Xu Fengguo,Zhang Zunjian,Zhang Shuai,Huang Yin
Analytical and bioanalytical chemistry
Metabolic markers, offering sensitive information on biological dysfunction, play important roles in diagnosing and treating cancers. However, the discovery of effective markers is limited by the lack of well-established metabolite selection approaches. Here, we propose a network-based strategy to uncover the metabolic markers with potential clinical availability for non-small cell lung cancer (NSCLC). First, an integrated mass spectrometry-based untargeted metabolomics was used to profile the plasma samples from 43 NSCLC patients and 43 healthy controls. We found that a series of 39 metabolites were altered significantly. Relying on the human metabolic network assembled from Kyoto Encyclopedia of Genes and Genomes (KEGG) database, we mapped these differential metabolites to the network and constructed an NSCLC-related disease module containing 23 putative metabolic markers. By measuring the PageRank centrality of molecules in this module, we computationally evaluated the network-based importance of the 23 metabolites and demonstrated that the metabolism pathways of aromatic amino acids and long-chain fatty acids provided potential molecular targets of NSCLC (i.e., IL4l1 and ACOT2). Combining network-based ranking and support-vector machine modeling, we further found a panel of eight metabolites (i.e., pyruvate, tryptophan, and palmitic acid) that showed a high capability to differentiate patients from controls (accuracy > 97.7%). In summary, we present a meaningful network method for metabolic marker discovery and have identified eight strong candidate metabolites for NSCLC diagnosis.
10.1007/s00216-021-03699-5
Discovering Biomarkers in Peritoneal Metastasis of Gastric Cancer by Metabolomics.
OncoTargets and therapy
BACKGROUND AND OBJECTIVE:Metabolomics has recently been applied in the field of oncology. In this study, we aimed to use metabolomics to explore biomarkers in peritoneal metastasis of gastric cancer. METHODS:Peritoneal lavage fluid (PLF) of 65 gastric cancer patients and related clinical data were collected from the First Hospital of Jilin University. The metabolic components were identified by liquid chromatography-mass spectrometry (LC-MS). Total ion current (TIC) spectra, principal component analysis (PCA), and the Student's -test were used to identify differential metabolites in PLF. A support vector machine (SVM) was used to screen the differential metabolites in PLF with a weight of 100%. Cluster analysis was used to evaluate the similarity between samples. Receiver operating characteristic (ROC) curve analysis was used to assess the diagnostic ability of the metabolites. Univariate and multivariate logistic regression analyses were used to identify potential risk factors for peritoneal metastasis of gastric cancer. RESULTS:We found the differential levels of PLF metabolites by LC-MS, TIC spectra, PCA and the -test. Cluster analysis showed the co-occurrence of metabolites in the peritoneal metastasis group (p<0.05). ROC analysis showed the diagnostic ability of metabolites (p<0.05). Univariate and multivariate logistic regression analyses showed the potential independent risk factors for peritoneal metastasis in gastric cancer patients (p<0.05). CONCLUSION:Through the statistical analysis of metabolomics, we found that TG (54:2), G3P, α-aminobutyric acid, α-CEHC, dodecanol, glutamyl alanine, 3-methylalanine, sulfite, CL (63:4), PE-NMe (40:5), TG (53:4), retinol, 3-hydroxysterol, tetradecanoic acid, MG (21:0/0:0/0:0), tridecanoic acid, myristate glycine and octacosanoic acid may be biomarkers for peritoneal metastasis of gastric cancer.
10.2147/OTT.S245663
Metabolic reprogramming in cervical cancer and metabolomics perspectives.
Li Boning,Sui Long
Nutrition & metabolism
Cumulative studies have shown that metabolic reprogramming is a hallmark of malignant tumors. The emergence of technological advances, such as omics studies, has strongly contributed to the knowledge of cancer metabolism. Cervical cancer is among the most common cancers in women worldwide. Because cervical cancer is a virus-associated cancer and can exist in a precancerous state for years, investigations targeting the metabolic phenotypes of cervical cancer will enhance our understanding of the interference of viruses on host cells and the progression of cervical carcinogenesis. The purpose of this review was to illustrate metabolic perturbations in cervical cancer, the role that human papillomavirus (HPV) plays in remodeling cervical cell metabolism and recent approaches toward application of metabolomics in cervical disease research. Cervical cancer displays typical cancer metabolic profiles, including glycolytic switching, high lactate levels, lipid accumulation and abnormal kynurenine/tryptophan levels. HPV, at least in part, contributes to these alterations. Furthermore, emerging metabolomics data provide global information on the metabolic traits of cervical diseases and may aid in the discovery of biomarkers for diagnosis and therapy.
10.1186/s12986-021-00615-7
Characterization of the Potential Role of NTPCR in Epithelial Ovarian Cancer by Integrating Transcriptomic and Metabolomic Analysis.
Frontiers in genetics
BACKGROUND:Epithelial ovarian carcinoma (EOC) is a malignant tumor with high motility in women. Our previous study found that dysregulated nucleoside-triphosphatase cancer-related (NTPCR) was associated with the prognosis of EOC patients, and thus, this present study attempted to explore the potential roles of NTPCR in disease progression. METHODS:Expressed level of NTPCR was investigated in EOC tissues by RT-qPCR and Western blot analysis. NTPCR shRNA and overexpression vector were generated and transfected into OVCAR-3 or SKOV3 cells to detect the effect of NTPCR on cell proliferation, cell cycle, cell migration, and invasion. Transcriptomic sequencing and metabolite profiling analysis were performed in shNTPCR groups to identify transcriptome or metabolite alteration that might contribute to EOC. Finally, we searched the overlapped signaling pathways correlated with differential metabolites and differentially expressed genes (DEGs) by integrating analysis. RESULTS:Comparing para-cancerous tissues, we found that NTPCR is highly expressed in cancer tissues ( < 0.05). Overexpression of NTPCR inhibited cell proliferation, migration, and invasion and reduced the proportion of S- and G2/M-phase cells, while downregulation of NTPCR showed the opposite results. RNA sequencing analysis demonstrated cohorts of DEGs were identified in shNTPCR samples. Protein-protein interaction networks were constructed for DEGs. STAT1 (degree = 43) and OAS2 (degree = 36) were identified as hub genes in the network. Several miRNAs together with target genes were predicted to be crucial genes related to disease progression, including , , , , , and . We also screened the differential metabolites from shNTPCR samples, including 22 upregulated and 22 downregulated metabolites. By integrating transcriptomics and metabolomics analysis, eight overlapped pathways were correlated with these DEGs and differential metabolites, such as primary bile acid biosynthesis, protein digestion, and absorption, pentose, and glucuronate interconversions. CONCLUSION:NTPCR might serve as a tumor suppressor in EOC progression. Our results demonstrated that DEGs and differential metabolites were mainly related to several signaling pathways, which might be a crucial role in the progression of NTPCR regulation of EOC.
10.3389/fgene.2021.695245
A pilot study for colorectal carcinoma screening by instant metabolomic profiles using conductive polymer spray ionization mass spectrometry.
Li Chao,Li Kexin,Xu Xiaoyu,Qi Wenyuan,Hu Xin,Jin Pengfei
Biochimica et biophysica acta. Molecular basis of disease
BACKGROUND:The rapid and accurate discrimination of colorectal carcinoma (CRC) and polyps at the molecular level enables early intervention of CRC, which can greatly improve the 5-year survival rate of patients. Here we reported the potential of conductive polymer spray ionization mass spectrometry (CPSI-MS) in successfully screening CRC according to the serum metabolic profile. METHODS:Trace intravenous blood (50 μL) was collected from 60 colorectal carcinoma (CRC) and 60 polyp patients, respectively. After centrifugation, serum (2 μL) was loaded onto the tip of conductive polymer to form a dried serum spot. When the 5 μL methanol-water (1:1, v/v) extraction solvent was spiked onto the dried serum spot followed with +4.5 kV high voltage applied on the polymer tip, the extracted components will be ionized and carried into the MS system for direct metabolic profiling. FINDINGS:There were 51 metabolites discovered to be significantly changed in CRC serum compared to polyps. Combining these metabolites as the characteristic panel, the ideal diagnostic performance was achieved by Lasso regression model with the accuracy of 88.3%. INTERPRETATION:This pilot study demonstrated the potential of CPSI-MS as a cost-effective tool in large-scale CRC screening in the high-risk population.
10.1016/j.bbadis.2021.166210
Diagnostic approach to thyroid cancer based on amino acid metabolomics in saliva by ultra-performance liquid chromatography with high resolution mass spectrometry.
Zhang Jing,Wen Xinxin,Li Yuting,Zhang Jing,Li Xian,Qian Cheng,Tian Yonghui,Ling Rui,Duan Yixiang
Talanta
Thyroid cancer is a malignant disease with dramatically low advanced-stage 10-year survival. Meanwhile, the metabolites in saliva are becoming a wealthy source of disease biomarkers. However, there is a lack of non-invasive analytical methods for the identification of biomarkers in saliva for the preoperative diagnosis of thyroid cancer. Therefore, we developed an ultra-high performance liquid chromatography-high resolution mass spectrometry (UPLC-HRMS) method to simultaneously determine the metabolic levels of 10 amino acids in saliva, aiming to study the amino acid metabolism profile to promote early diagnosis of thyroid cancer. We tested unstimulated whole saliva from patients with papillary thyroid carcinoma (PTC; n = 61) and healthy controls (HC; n = 61), and used receiver operating characteristic (ROC) curves to establish the diagnostic value of potential markers. The method validation results showed good precision, linearity (R > 0.99), recovery (92.2 %-110.3 %), intra- and inter-day precision (RSD < 7 % and RSD < 9 %, respectively). The concentration of 10 amino acids was significantly different between PTC and HC in human salivary analysis (P < 0.05), the area under the curve (AUC) values of a single marker for the diagnosis of PTC were ranging from 0.678 to 0.833. A panel of alanine, valine, proline, phenylalanine was selected in combination yielded the AUC of 0.936, which will improve the accuracy of early diagnosis of thyroid cancer (sensitivity: 91.2 %; specificity: 85.2 %). This study proved the possibility of salivary amino acid biomarkers for PTC early diagnosis, providing a simple auxiliary way for the non-invasive diagnosis of thyroid cancer.
10.1016/j.talanta.2021.122729
Metabolomics identified new biomarkers for the precise diagnosis of pancreatic cancer and associated tissue metastasis.
Luo Xialin,Liu Jingjing,Wang Huaizhi,Lu Haitao
Pharmacological research
Pancreatic cancer (PC) is one of the most aggressive malignancies with high mortality due to a complex and latent pathogenesis leading to the severe lack of early diagnosis methods. To improve clinical diagnosis and enhance therapeutic outcome, we employed the newly developed precision-targeted metabolomics method to identify and validate metabolite biomarkers from the plasma samples of patients with pancreatic cancer that can sensitively and efficiently diagnose the onsite progression of the disease. Many differential metabolites have the capacity to markedly distinguish patients with pancreatic cancer (n = 60) from healthy controls (n = 60). To further enhance the specificity and selectivity of metabolite biomarkers, a dozen tumor tissues from PC patients and paired normal tissues were used to clinically validate the biomarker performance. We eventually verified five new metabolite biomarkers in plasma (creatine, inosine, beta-sitosterol, sphinganine and glycocholic acid), which can be used to readily diagnose pancreatic cancer in a clinical setting. Excitingly, we proposed a panel biomarker by integrating these five individual metabolites into one pattern, demonstrating much higher accuracy and specificity to precisely diagnose pancreatic cancer than conventional biomarkers (CA125, CA19-9, CA242 and CEA); moreover, this plasma panel biomarker used for PC diagnosis is also quite convenient to implement in clinical practice. Using the same metabolomics method, we characterized succinic acid and gluconic acid as having a great capability to monitor the progression and metastasis of pancreatic cancer at different stages. Taken together, this metabolomics method was used to identify and validate metabolite biomarkers that can precisely and sensitively diagnose the onsite progression and metastasis of pancreatic cancer in a clinical setting. Furthermore, such effort should leave clinicians with the correct time frame to facilitate early and efficient therapeutic interventions, which could largely improve the five-year survival rate of PC patients by significantly lowering clinical mortality.
10.1016/j.phrs.2020.104805
Nuclear Magnetic Resonance-Based Metabolomic Analysis of the Anticancer Effect of Metformin Treatment on Cholangiocarcinoma Cells.
Zhang Jin,Hang Caihua,Jiang Ting,Yi Shenghui,Shao Wei,Li Wengang,Lin Donghai
Frontiers in oncology
Metformin is a widely prescribed anti-diabetes drug with potential utilities for cancer therapies. Several studies have related metformin to the reduced risk of cholangiocarcinoma (CCA), highlighting its potentialities for the treatments of CCA. However, the underlying molecular mechanisms remain elusive. Here, we demonstrated that metformin treatment could inhibit proliferations of the human CCA cell lines Mz-ChA-1 and QBC939 in dose-dependent manners. The NMR-based metabonomic analyses showed distinct discriminations between the metformin-treated (Met) and control (Ctrl) groups of both CCA cells. Characteristic metabolites were identified by a combination of multivariate statistical analysis of 1D H-NMR spectral data and the pair-wise t-test of metabolite levels. We then identified four significantly altered metabolic pathways based on the characteristic metabolites, including glucose metabolism, oxidative stress-related metabolism, energy metabolism, and amino acids metabolism. Comparing CCA cells with normal human umbilical vein endothelial cells (HUVECs), we found that metformin treatment profoundly promoted glycolysis and specifically increased the levels of BCAAs and UDP-GlcNAc, implying the occurrence of autophagy and cell cycle arrest in metformin-treated CAA cells. This work provides a mechanistic understanding of the anticancer effect of metformin treatment on CAA cells, and is beneficial to further developments of metformin as an anticancer drug.
10.3389/fonc.2020.570516
Polyamine: A metabolic compass for T helper cell fate direction.
Shi Hao,Chi Hongbo
Cell
Interplay between metabolic and epigenetic remodeling may be key to cell fate control. In this issue of Cell, Puleston et al. and Wagner et al. use metabolomic, computational, and genetic approaches to uncover that polyamine metabolism directs T helper cell lineage choices, epigenetic state, and pathogenic potential in inflammation.
10.1016/j.cell.2021.07.012
Extraction strategies for tackling complete hair metabolome using LC-HRMS-based analysis.
Chang William Chih-Wei,Wang Pin-Hsuan,Chang Chih-Wei,Chen Yuan-Chih,Liao Pao-Chi
Talanta
Over recent years, metabolomics has been featured as the state-of-the-art technology that successfully opens the paths to understanding biological mechanisms and facilitating biomarker discovery. However, the inherent dynamic and sensitive nature of the metabolome have been challenging the accuracy of capturing the timepoints of interest while using biofluids such as urine and blood. Hair has thus emerged as a valuable analytical specimen for the long-term and retrospective determinations. Unfortunately, notwithstanding the apparent interest on global hair metabolomics, very few studies have engaged in the optimisation of the extraction strategy. In this study, we systemically investigated the extraction procedures for hair metabolome using a single factor experimental design. Three pH values (acidic, neutral, and basic) in aqueous solution, six extraction solvents (methanol, acetonitrile, acetone, phosphate-buffered saline, deionised water, and dichloromethane), different compositions of selected solvent mixtures and their sequential extraction, and a series of extraction times (15, 45, 60, 120, 240, and 480 min) were evaluated. The ideal condition for hair extraction is ultrasonic-assisted extraction with methanol:phosphate-buffered saline 50:50 (v/v) under +55 °C for 240 min. This strategy may secure the true composition of the metabolome, maximise the signal abundance, and guarantee a high coverage of wide-range metabolites in a straightforward approach. The optimised extraction strategy was then coupled with structure annotation tools for hair metabolome profiling. After a single RPLC-HRMS run, hair metabolite identification was achieved as the annotations of 171 probable structures and 853 tentative structures as well as the assignments of 414 unequivocal molecular formulae. In conclusion, we established an efficient extraction strategy for untargeted hair metabolomics, which the method is deliverable to any analytical laboratories and the sample can be directly profiled by means of a conventional RPLC-HRMS gradient.
10.1016/j.talanta.2020.121708
EGFR-HIF1α signaling positively regulates the differentiation of IL-9 producing T helper cells.
Nature communications
Interleukin 9 (IL-9)-producing helper T (Th9) cells are essential for inducing anti-tumor immunity and inflammation in allergic and autoimmune diseases. Although transcription factors that are essential for Th9 cell differentiation have been identified, other signaling pathways that are required for their generation and functions are yet to be explored. Here, we identify that Epidermal Growth Factor Receptor (EGFR) is essential for IL-9 induction in helper T (Th) cells. Moreover, amphiregulin (Areg), an EGFR ligand, is critical for the amplification of Th9 cells induced by TGF-β1 and IL-4. Furthermore, our data show that Areg-EGFR signaling induces HIF1α, which binds and transactivates IL-9 and NOS2 promoters in Th9 cells. Loss of EGFR or HIF1α abrogates Th9 cell differentiation and suppresses their anti-tumor functions. Moreover, in line with its reliance on HIF1α expression, metabolomics profiling of Th9 cells revealed that Succinate, a TCA cycle metabolite, promotes Th9 cell differentiation and Th9 cell-mediated tumor regression.
10.1038/s41467-021-23042-x
Comprehensive metabolomic profiling of osteosarcoma based on UHPLC-HRMS.
Lv Dongming,Zou Yutong,Zeng Ziliang,Yao Hao,Ding Shirong,Bian Yiying,Wen Lili,Xie Xianbiao
Metabolomics : Official journal of the Metabolomic Society
INTRODUCTION:Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents. An increasing number of studies have demonstrated that tumor proliferation and metastasis are closely related to complex metabolic reprogramming. However, there are limited data to provide a comprehensive metabolic picture of osteosarcoma. OBJECTIVES:Our study aims to identify aberrant metabolic pathways and seek potential adjuvant biomarkers for osteosarcoma. METHODS:Serum samples were collected from 65 osteosarcoma patients and 30 healthy controls. Nontargeted metabolomic profiling was performed by liquid chromatography-mass spectrometry (LC-MS) based on univariate and multivariate statistical analyses. RESULTS:The OPLS-DA model analysis identified clear separations among groups. We identified a set of differential metabolites such as higher serum levels of adenosine-5-monophosphate, inosine-5-monophosphate and guanosine monophosphate in primary OS patients compared to healthy controls, and higher serum levels of 5-aminopentanamide, 13(S)-HpOTrE (FA 18:3 + 2O) and methionine sulfoxide in lung metastatic OS patients compared to primary OS patients, revealing aberrant metabolic features during the proliferation and metastasis of osteosarcoma. We found a group of metabolites especially lactic acid and glutamic acid, with AUC values of 0.97 and 0.98, which could serve as potential adjuvant diagnostic biomarkers for primary osteosarcoma, and a panel of 2 metabolites, 5-aminopentanamide and 13(S)-HpOTrE (FA 18:3 + 2O), with an AUC value of 0.92, that had good monitoring ability for lung metastases. CONCLUSIONS:Our study provides new insight into the aberrant metabolic features of osteosarcoma. The potential biomarkers identified here may have translational significance.
10.1007/s11306-020-01745-4
Taurine Attenuates the Hypotaurine-Induced Progression of CRC ERK/RSK Signaling.
Hou Xiaodan,Hu Junwei,Zhao Xinyu,Wei Qing,Zhao Rongping,Li Min,Li Qiong
Frontiers in cell and developmental biology
Colorectal cancer (CRC) is one of the most common malignant tumors, and previous metabolomics work has demonstrated great promise in identifying specific small molecules of tumor phenotype. In the present study, we analyzed the metabolites of resected tissues through gas chromatography-mass spectrometry (GC-MS), and found that the concentration of taurine in CRC tissues diminished whereas the concentration of hypotaurine increased. The results demonstrated that taurine significantly suppressed cellular proliferation, metastasis, and colony formation whereas it induced apoptosis in CRC cells. Furthermore, taurine regulated the expression levels of epithelial mesenchymal transition (EMT)-associated genes in a dose-dependent manner. Taurine also alleviated hypotaurine-induced CRC progression, which was linked to the inhibition of the ERK/RSK-signaling pathway and diminution in intracellular hypotaurine. Taurine additionally attenuated hypotaurine-induced tumor growth and metastasis Patients with CRC exhibited lower levels of serum taurine, suggesting that taurine might be a promising biomarker reflecting a poor prognosis in CRC. Collectively, our results demonstrated that taurine-attenuated, hypotaurine-induced CRC progression provides a potential target for CRC therapy.
10.3389/fcell.2021.631163
Plasma metabolome identifies potential biomarkers of gastric precancerous lesions and gastric cancer risk.
Metabolomics : Official journal of the Metabolomic Society
OBJECTIVES:Currently, metabolic biomarkers with great practicability of gastric cancer (GC) and gastric precancerous lesions (GPL) are scarce. Thus, we are devoted to determining the plasma metabolic profiles of patients with GPL or GC and validate candidate biomarkers for disease diagnosis. METHODS:In this hospital-based case-control study, 68 plasma samples from 27 non-atrophic gastritis (NAG, control), 31 GPL, and 10 GC patients were collected for targeted metabolomics analysis. Univariate and multivariate analyses were used for selecting the differential metabolites. A receiver operating characteristic curve combined with binary logistic regression analysis was performed to test the diagnostic performance of the differential metabolites. Dietary data were obtained using a semiquantitative food frequency questionnaire. RESULTS:Distinct metabolomic profiles were noted for NAG, GPL, and GC. Compared to the NAG patients, the levels of 5 metabolites in the GPL group and 4 metabolites in the GC group were found to significantly elevate. Compared with the model involving 9 traditional risk factors (AUC: 0.89, 95%CI: 0.78-1.00), Trimethylamine N-oxide, the most significant metabolite (P = 2.00 × 10, FDR = 0.003, FC > 2, VIP > 2), showed a good diagnostic performance for the patients with GC (AUC: 0.90, 95%CI: 0.78-1.00), and its diagnostic performance has been further improved with the integration of Rhamnose (AUC: 0.96, 95%CI: 0.89-1.00). CONCLUSION:In our study, 9 defined metabolites might serve as meaningful biomarkers for identifying the high-risk population of GPL and GC, possibly enhancing the prevention and control of GPL and GC.
10.1007/s11306-023-02037-3
GYS1 induces glycogen accumulation and promotes tumor progression via the NF-κB pathway in Clear Cell Renal Carcinoma.
Theranostics
Metabolism reprogramming is a hallmark of many cancer types. We focused on clear cell renal carcinoma (ccRCC) which is characterized by its clear and glycogen-enriched cytoplasm with unknown reasons. The aim of this study was to identify the clinical significance, biological function, and molecular regulation of glycogen synthase 1 (GYS1) in ccRCC glycogen accumulation and tumor progression. We determined the clinical relevance of GYS1 and glycogen in ccRCC by immunohistochemistry and periodic acid-schiff staining in fresh tissue and by tissue micro-array. Metabolic profiling with GYS1 depletion was performed by metabolomics analysis. and xenograft mouse models were used to evaluate the impact of GYS1 on cell proliferation. High-throughput RNA-Seq analyses and co-immunoprecipitation-linked mass spectrometry were used to investigate the downstream targets of GYS1. Flow cytometry and CCK8 assays were performed to determine the effect of GYS1 and sunitinib on cell viability. We observed that GYS1 was significantly overexpressed and glycogen was accumulated in ccRCC tissues. These effects were correlated with unfavorable patient survival. Silencing of GYS1 induced metabolomic perturbation manifested by a carbohydrate metabolism shift. Overexpression of GYS1 promoted tumor growth whereas its silencing suppressed it by activating the canonical NF-κB pathway. The indirect interaction between GYS1 and NF-κB was intermediated by RPS27A, which facilitated the phosphorylation and nuclear import of p65. Moreover, silencing of GYS1 increased the synthetic lethality of ccRCC cells to sunitinib treatment by concomitantly suppressing p65. Our study findings reveal an oncogenic role for GYS1 in cell proliferation and glycogen metabolism in ccRCC. Re-sensitization of ccRCC cells to sunitinib suggests that GYS1 is a useful indicator of unfavorable prognosis as well as a therapeutic target for patients with ccRCC.
10.7150/thno.46825
Evolutionary metabolic landscape from preneoplasia to invasive lung adenocarcinoma.
Nature communications
Metabolic reprogramming evolves during cancer initiation and progression. However, thorough understanding of metabolic evolution from preneoplasia to lung adenocarcinoma (LUAD) is still limited. Here, we perform large-scale targeted metabolomics on resected lesions and plasma obtained from invasive LUAD and its precursors, and decipher the metabolic trajectories from atypical adenomatous hyperplasia (AAH) to adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma (IAC), revealing that perturbed metabolic pathways emerge early in premalignant lesions. Furthermore, three panels of plasma metabolites are identified as non-invasive predictive biomarkers to distinguish IAC and its precursors with benign diseases. Strikingly, metabolomics clustering defines three metabolic subtypes of IAC patients with distinct clinical characteristics. We identify correlation between aberrant bile acid metabolism in subtype III with poor clinical features and demonstrate dysregulated bile acid metabolism promotes migration of LUAD, which could be exploited as potential targetable vulnerability and for stratifying patients. Collectively, the comprehensive landscape of the metabolic evolution along the development of LUAD will improve early detection and provide impactful therapeutic strategies.
10.1038/s41467-021-26685-y
Dose-Dependent Carbon-Dot-Induced ROS Promote Uveal Melanoma Cell Tumorigenicity via Activation of mTOR Signaling and Glutamine Metabolism.
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
Uveal melanoma (UM) is the most common intraocular malignant tumor in adults and has a low survival rate following metastasis; it is derived from melanocytes susceptible to reactive oxygen species (ROS). Carbon dot (Cdot) nanoparticles are a promising tool in cancer detection and therapy due to their unique photophysical properties, low cytotoxicity, and efficient ROS productivity. However, the effects of Cdots on tumor metabolism and growth are not well characterized. Here, the effects of Cdots on UM cell metabolomics, growth, invasiveness, and tumorigenicity are investigated in vitro and in vivo zebrafish and nude mouse xenograft model. Cdots dose-dependently increase ROS levels in UM cells. At Cdots concentrations below 100 µg mL, Cdot-induced ROS promote UM cell growth, invasiveness, and tumorigenicity; at 200 µg mL, UM cells undergo apoptosis. The addition of antioxidants reverses the protumorigenic effects of Cdots. Cdots at 25-100 µg mL activate Akt/mammalian target of rapamycin (mTOR) signaling and enhance glutamine metabolism, generating a cascade that promotes UM cell growth. These results demonstrate that moderate, subapoptotic doses of Cdots can promote UM cell tumorigenicity. This study lays the foundation for the rational application of ROS-producing nanoparticles in tumor imaging and therapy.
10.1002/advs.202002404
Integrative metabolomic characterisation identifies altered portal vein serum metabolome contributing to human hepatocellular carcinoma.
Gut
OBJECTIVE:Altered metabolites are important for the tumourigenicity of hepatocellular carcinoma (HCC). We performed integrative metabolomics analysis of the metabolites changes in portal venous blood and in comparison with the metabolites changes in liver tissues and stool samples of HCC patients and healthy liver donors. DESIGN:Serum (portal and central vein), liver tissue (HCC tumour and adjacent non-tumour, normal liver) and stool samples were collected from 102 subjects (52 HCC patients and 50 healthy controls) in the discovery cohort; and 100 subjects (50 HCC patients and 50 healthy controls) in an independent validation cohort. Untargeted metabolomic profiling was performed using high-performance liquid chromatography-mass spectrometry. The function of candidate metabolites was validated in hepatocyte cell lines. RESULTS:Detailed metabolomic evaluation showed distinct clusters of metabolites in serum, liver tissue and stool samples from patients with HCC and control individuals (p<0.001). HCC patients had significantly higher levels of portal vein serum and HCC tissue metabolites of DL-3-phenyllactic acid, L-tryptophan, glycocholic acid and 1-methylnicotinamide than healthy controls, which were associated with impaired liver function and poor survival. On the other hand, HCC patients had lower levels of linoleic acid and phenol in portal vein and stool samples than healthy controls. Linoleic acid and phenol significantly inhibited HCC proliferation, inferring their anti-HCC function as protective metabolites. CONCLUSIONS:The integrative metabolome analysis of serum, tissue and stool metabolites revealed unreported metabolic alterations in HCC patients. In portal vein, we identified elevated and depleted metabolites signifying that they might play a role in HCC development.
10.1136/gutjnl-2021-325189
Comprehensive metabolomics expands precision medicine for triple-negative breast cancer.
Cell research
Metabolic reprogramming is a hallmark of cancer. However, systematic characterizations of metabolites in triple-negative breast cancer (TNBC) are still lacking. Our study profiled the polar metabolome and lipidome in 330 TNBC samples and 149 paired normal breast tissues to construct a large metabolomic atlas of TNBC. Combining with previously established transcriptomic and genomic data of the same cohort, we conducted a comprehensive analysis linking TNBC metabolome to genomics. Our study classified TNBCs into three distinct metabolomic subgroups: C1, characterized by the enrichment of ceramides and fatty acids; C2, featured with the upregulation of metabolites related to oxidation reaction and glycosyl transfer; and C3, having the lowest level of metabolic dysregulation. Based on this newly developed metabolomic dataset, we refined previous TNBC transcriptomic subtypes and identified some crucial subtype-specific metabolites as potential therapeutic targets. The transcriptomic luminal androgen receptor (LAR) subtype overlapped with metabolomic C1 subtype. Experiments on patient-derived organoid and xenograft models indicate that targeting sphingosine-1-phosphate (S1P), an intermediate of the ceramide pathway, is a promising therapy for LAR tumors. Moreover, the transcriptomic basal-like immune-suppressed (BLIS) subtype contained two prognostic metabolomic subgroups (C2 and C3), which could be distinguished through machine-learning methods. We show that N-acetyl-aspartyl-glutamate is a crucial tumor-promoting metabolite and potential therapeutic target for high-risk BLIS tumors. Together, our study reveals the clinical significance of TNBC metabolomics, which can not only optimize the transcriptomic subtyping system, but also suggest novel therapeutic targets. This metabolomic dataset can serve as a useful public resource to promote precision treatment of TNBC.
10.1038/s41422-022-00614-0
Proteogenomic and metabolomic characterization of human glioblastoma.
Cancer cell
Glioblastoma (GBM) is the most aggressive nervous system cancer. Understanding its molecular pathogenesis is crucial to improving diagnosis and treatment. Integrated analysis of genomic, proteomic, post-translational modification and metabolomic data on 99 treatment-naive GBMs provides insights to GBM biology. We identify key phosphorylation events (e.g., phosphorylated PTPN11 and PLCG1) as potential switches mediating oncogenic pathway activation, as well as potential targets for EGFR-, TP53-, and RB1-altered tumors. Immune subtypes with distinct immune cell types are discovered using bulk omics methodologies, validated by snRNA-seq, and correlated with specific expression and histone acetylation patterns. Histone H2B acetylation in classical-like and immune-low GBM is driven largely by BRDs, CREBBP, and EP300. Integrated metabolomic and proteomic data identify specific lipid distributions across subtypes and distinct global metabolic changes in IDH-mutated tumors. This work highlights biological relationships that could contribute to stratification of GBM patients for more effective treatment.
10.1016/j.ccell.2021.01.006
Tumour fatty acid metabolism in the context of therapy resistance and obesity.
Nature reviews. Cancer
Fatty acid metabolism is known to support tumorigenesis and disease progression as well as treatment resistance through enhanced lipid synthesis, storage and catabolism. More recently, the role of membrane fatty acid composition, for example, ratios of saturated, monounsaturated and polyunsaturated fatty acids, in promoting cell survival while limiting lipotoxicity and ferroptosis has been increasingly appreciated. Alongside these insights, it has become clear that tumour cells exhibit plasticity with respect to fatty acid metabolism, responding to extratumoural and systemic metabolic signals, such as obesity and cancer therapeutics, to promote the development of aggressive, treatment-resistant disease. Here, we describe cellular fatty acid metabolic changes that are connected to therapy resistance and contextualize obesity-associated changes in host fatty acid metabolism that likely influence the local tumour microenvironment to further modify cancer cell behaviour while simultaneously creating potential new vulnerabilities.
10.1038/s41568-021-00388-4
CD8 T cell metabolism in infection and cancer.
Nature reviews. Immunology
Cytotoxic CD8 T cells play a key role in the elimination of intracellular infections and malignant cells and can provide long-term protective immunity. In the response to infection, CD8 T cell metabolism is coupled to transcriptional, translational and epigenetic changes that are driven by extracellular metabolites and immunological signals. These programmes facilitate the adaptation of CD8 T cells to the diverse and dynamic metabolic environments encountered in the circulation and in the tissues. In the setting of disease, both cell-intrinsic and cell-extrinsic metabolic cues contribute to CD8 T cell dysfunction. In addition, changes in whole-body metabolism, whether through voluntary or disease-induced dietary alterations, can influence CD8 T cell-mediated immunity. Defining the metabolic adaptations of CD8 T cells in specific tissue environments informs our understanding of how these cells protect against pathogens and tumours and maintain tissue health at barrier sites. Here, we highlight recent findings revealing how metabolic networks enforce specific CD8 T cell programmes and discuss how metabolism is integrated with CD8 T cell differentiation and function and determined by environmental cues.
10.1038/s41577-021-00537-8
GLP-1 improves the supportive ability of astrocytes to neurons by promoting aerobic glycolysis in Alzheimer's disease.
Zheng Jiaping,Xie Yunzhen,Ren Lingjia,Qi Liqin,Wu Li,Pan Xiaodong,Zhou Jianxing,Chen Zhou,Liu Libin
Molecular metabolism
OBJECTIVE:Astrocytes actively participate in energy metabolism in the brain, and astrocytic aerobic glycolysis disorder is associated with the pathology of Alzheimer's disease (AD). GLP-1 has been shown to improve cognition in AD; however, the mechanism remains unclear. The objectives of this study were to assess GLP-1's glycolytic regulation effects in AD and reveal its neuroprotective mechanisms. METHODS:The Morris water maze test was used to evaluate the effects of liraglutide (an analog of GLP-1) on the cognition of 4-month-old 5×FAD mice, and a proteomic analysis and Western blotting were used to assess the proteomic profile changes. We constructed an astrocytic model of AD by treating primary astrocytes with Aβ. The levels of NAD+ and lactate were examined, and the oxidative levels were assessed by a Seahorse examination. Astrocyte-neuron co-culture was performed to evaluate the effects of GLP-1 on astrocytes' neuronal support. RESULTS:GLP-1 improved cognition in 4-month-old 5×FAD mice by enhancing aerobic glycolysis and reducing oxidative phosphorylation (OXPHOS) levels and oxidative stress in the brain. GLP-1 also alleviated Aβ-induced glycolysis declines in astrocytes, which resulted in reduced OXPHOS levels and reactive oxygen species (ROS) production. The mechanism involved the activation of the PI3K/Akt pathway by GLP-1. Elevation in astrocytic glycolysis improved astrocyte cells' support of neurons and promoted neuronal survival and axon growth. CONCLUSIONS:Taken together, we revealed GLP-1's capacity to regulate astrocytic glycolysis, providing mechanistic insight into one of its neuroprotective roles in AD and support for the feasibility of energy regulation treatments for AD.
10.1016/j.molmet.2021.101180
Advances of Mechanisms-Related Metabolomics in Parkinson's Disease.
Frontiers in neuroscience
Parkinson's disease (PD) is a multifactorial disorder characterized by progressively debilitating dopaminergic neurodegeneration in the substantia nigra and the striatum, along with various metabolic dysfunctions and molecular abnormalities. Metabolomics is an emerging study and has been demonstrated to play important roles in describing complex human diseases by integrating endogenous and exogenous sources of alterations. Recently, an increasing amount of research has shown that metabolomics profiling holds great promise in providing unique insights into molecular pathogenesis and could be helpful in identifying candidate biomarkers for clinical detection and therapies of PD. In this review, we briefly summarize recent findings and analyze the application of molecular metabolomics in familial and sporadic PD from genetic mutations, mitochondrial dysfunction, and dysbacteriosis. We also review metabolic biomarkers to assess the functional stage and improve therapeutic strategies to postpone or hinder the disease progression.
10.3389/fnins.2021.614251
Gut Microbiota-Derived Inflammation-Related Serum Metabolites as Potential Biomarkers for Major Depressive Disorder.
Journal of inflammation research
BACKGROUND:Although many works have been conducted to explore the biomarkers for diagnosing major depressive disorder (MDD), the widely accepted biomarkers are still not identified. Thus, the combined application of serum metabolomics and fecal microbial communities was used to identify gut microbiota-derived inflammation-related serum metabolites as potential biomarkers for MDD. METHODS:MDD patients and healthy controls (HCs) were included in this study. Both serum samples and fecal samples were collected. The liquid chromatography mass spectrometry (LC-MS) was used to detect the metabolites in serum samples, and the 16S rRNA gene sequencing was used to analyze the gut microbiota compositions in fecal samples. RESULTS:Totally, 60 MDD patients and 60 HCs were recruited. The 24 differential serum metabolites were identified, and 10 of these were inflammation-related metabolites. Three significantly affected inflammation-related pathways were identified using differential metabolites. The 17 differential genera were identified, and 14 of these genera belonged to phyla Firmicutes. Four significantly affected inflammation-related pathways were identified using differential genera. Five inflammation-related metabolites (LysoPC(16:0), deoxycholic acid, docosahexaenoic acid, taurocholic acid and LysoPC(20:0)) were identified as potential biomarkers. These potential biomarkers had significant correlations with genera belonged to phyla Firmicutes. The panel consisting of these biomarkers could effectively distinguish MDD patients from HCs with an area under the curve (AUC) of 0.95 in training set and 0.92 in testing set. CONCLUSION:These findings suggested that the disturbance of phyla Firmicutes might be involved in the onset of depression by regulating host's inflammatory response, and these potential biomarkers could be useful for future investigating the objective methods for diagnosing MDD.
10.2147/JIR.S324922
A next-generation probiotic: Akkermansia muciniphila ameliorates chronic stress-induced depressive-like behavior in mice by regulating gut microbiota and metabolites.
Ding Yang,Bu Fan,Chen Tuo,Shi Guoping,Yuan Xiaomin,Feng Zeyu,Duan Zhenglan,Wang Rong,Zhang Sumin,Wang Qiong,Zhou Jinyong,Chen Yugen
Applied microbiology and biotechnology
Major depressive disorder (MDD) is a neurasthenic disease, which is the second-largest burden of disease globally. Increasing studies have revealed that depression is associated with abnormalities in gut microbiota and metabolites. Several species of bacteria have been classified as psychobiotics, which confer mental health benefits through interactions with commensal gut microbiota. Therefore, it is essential to identify new psychobiotics and elucidate their mechanisms in the treatment of depression. This study aims to evaluate the antidepressant effect of Akkermansia muciniphila (AKK) in a mouse model of depression induced by chronic restraint stress (CRS). C57BL/6 male mice were divided into three groups: mice subjected to CRS, mice not subjected to CRS, and mice treated with AKK for 3 weeks. Behavioral tests were performed, and hormone, neurotransmitter, and brain-derived neurotrophic factor (BDNF) levels were measured. Cecal microbiota was analyzed using 16S rRNA gene sequencing, and serum metabolites were detected using untargeted metabolomics. In addition, correlations between altered gut microbiota and metabolites with significant variations in serum associated with AKK ameliorating depression were analyzed using Pearson's correlation coefficient. The results revealed that AKK significantly ameliorated depressive-like behavior and restored abnormal variations in depression-related molecular (corticosterone, dopamine, and BDNF). Moreover, AKK altered chronic stress-induced gut microbial abnormalities. Untargeted metabolomics analysis revealed 23 potential biomarkers in serum that could be associated with the mechanisms underlying CRS-induced depression and the therapeutic effects of AKK. Pearson's correlation coefficient analysis revealed that AKK predominantly upregulated β-alanyl-3-methyl-L-histidine and edaravone to relieve depression. Furthermore, β-alanyl-3-methyl-L-histidine and edaravone exhibited the antidepressant phenotype in mice subjected to CRS. In conclusion, the study demonstrated that AKK ameliorates chronic stress-induced depressive symptoms in mice by regulating gut microbiota and metabolites. KEY POINTS: • AKK reduces depressive-like behaviors induced by chronic stress. • AKK regulates the gut microbial structure and metabolomics of serum under the chronic stress. • Antidepressant effect of AKK correlates with the increase of β-alanyl-3-methyl-l-histidine and edaravone.
10.1007/s00253-021-11622-2
Identification and Experimental Validation of Marker Genes between Diabetes and Alzheimer's Disease.
Oxidative medicine and cellular longevity
Currently, Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are widely prevalent in the elderly population, and accumulating evidence implies a strong link between them. For example, patients with T2DM have a higher risk of developing neurocognitive disorders, including AD, but the exact mechanisms are still unclear. This time, by combining bioinformatics analysis and in vivo experimental validation, we attempted to find a common biological link between AD and T2DM. We firstly downloaded the gene expression profiling (AD: GSE122063; T2DM: GSE161355) derived from the temporal cortex. To find the associations, differentially expressed genes (DEGs) of the two datasets were filtered and intersected. Based on them, enrichment analysis was carried out, and the least absolute shrinkage and selection operator (LASSO) logistic regression and support vector machine-recursive feature elimination (SVM-RFE) algorithms were used to identify the specific genes. After verifying in the external dataset and in the samples from the AD and type 2 diabetes animals, the shared targets of the two diseases were finally determined. Based on them, the ceRNA networks were constructed. Besides, the logistic regression and single-sample gene set enrichment analysis (ssGSEA) were performed. As a result, 62 DEGs were totally identified between AD and T2DM, and the enrichment analysis indicated that they were much related to the function of synaptic vesicle and MAPK signaling pathway. Based on the evidence from external dataset and RT-qPCR, CARTPT, EPHA5, and SERPINA3 were identified as the marker genes in both diseases, and their clinical significance and biological functions were further analyzed. In conclusion, discovering and exploring the marker genes that are dysregulated in both 2 diseases could help us better comprehend the intrinsic relationship between T2DM and AD, which may inspire us to develop new strategies for facing the dilemmas of clinical or basic research in cognitive dysfunction.
10.1155/2022/8122532
Depression and anxiety in patients with active ulcerative colitis: crosstalk of gut microbiota, metabolomics and proteomics.
Yuan Xiaomin,Chen Biqing,Duan Zhenglan,Xia Ziqian,Ding Yang,Chen Tuo,Liu Huize,Wang Baosheng,Yang Bolin,Wang Xiaoyong,Liu Shijia,Zhou Jin-Yong,Liu Yajun,Wang Qiong,Shen Zhaofeng,Xiao Jun,Shang Hongtao,Liu Weiwei,Shi Guoping,Zhu Lei,Chen Yugen
Gut microbes
Patients with ulcerative colitis (UC) have a high prevalence of mental disorders, such as depression and anxiety. Gut microbiota imbalance and disturbed metabolism have been suggested to play an important role in either UC or mental disorders. However, little is known about their detailed multi-omics characteristics in patients with UC and depression/anxiety. In this prospective observational study, 240 Chinese patients were enrolled, including 129 patients with active UC (69 in Phase 1 and 60 in Phase 2; divided into depression/non-depression or anxiety/non-anxiety groups), 49 patients with depression and anxiety (non-UC), and 62 healthy people. The gut microbiota of all subjects was analyzed using 16S rRNA sequencing. The serum metabolome and proteome of patients with UC in Phase 2 were analyzed using liquid chromatography/mass spectrometry. Associations between multi-omics were evaluated by correlation analysis. The prophylactic effect of candidate metabolites on the depressive-like behavior of mice with colitis was investigated. In total, 58% of patients with active UC had depression, while 50% had anxiety. Compared to patients with UC without depression/anxiety, patients with UC and depression/anxiety had lower fecal microbial community richness and diversity, with more , and but less and . Most metabolites (e.g., glycochenodeoxycholate) were increased in the serum, while few metabolites, including 2'-deoxy-D-ribose and L-pipecolic acid, were decreased, accompanied by a general reduction in immunoglobulin proteins. These related bacteria, metabolites, and proteins were highly connected. A prophylactic administration of 2'-deoxy-D-ribose and L-pipecolic acid significantly reduced the depressive-like behaviors in mice with colitis and alleviated the inflammatory cytokine levels in their colon, blood and brain. This study has identified a comprehensive multi-omics network related to depression and anxiety in active UC. It is composed of a certain set of gut microbiota, metabolites, and proteins, which are potential targets for clinical intervention for patients with UC and depression/anxiety.
10.1080/19490976.2021.1987779
Gut microbial co-metabolite 2-methylbutyrylcarnitine exacerbates thrombosis via binding to and activating integrin α2β1.
Cell metabolism
Thrombosis represents the leading cause of death and disability upon major adverse cardiovascular events (MACEs). Numerous pathological conditions such as COVID-19 and metabolic disorders can lead to a heightened thrombotic risk; however, the underlying mechanisms remain poorly understood. Our study illustrates that 2-methylbutyrylcarnitine (2MBC), a branched-chain acylcarnitine, is accumulated in patients with COVID-19 and in patients with MACEs. 2MBC enhances platelet hyperreactivity and thrombus formation in mice. Mechanistically, 2MBC binds to integrin α2β1 in platelets, potentiating cytosolic phospholipase A2 (cPLA2) activation and platelet hyperresponsiveness. Genetic depletion or pharmacological inhibition of integrin α2β1 largely reverses the pro-thrombotic effects of 2MBC. Notably, 2MBC can be generated in a gut-microbiota-dependent manner, whereas the accumulation of plasma 2MBC and its thrombosis-aggravating effect are largely ameliorated following antibiotic-induced microbial depletion. Our study implicates 2MBC as a metabolite that links gut microbiota dysbiosis to elevated thrombotic risk, providing mechanistic insight and a potential therapeutic strategy for thrombosis.
10.1016/j.cmet.2024.01.014
Effectiveness and safety of selenium supplementation for type 2 diabetes mellitus in adults: a systematic review of randomised controlled trials.
Stróżyk A,Osica Z,Przybylak J D,Kołodziej M,Zalewski B M,Mrozikiewicz-Rakowska B,Szajewska H
Journal of human nutrition and dietetics : the official journal of the British Dietetic Association
BACKGROUND:The role of selenium (Se) in the management of type 2 diabetes mellitus (T2DM) remains unclear. We systematically assessed the effectiveness and safety of Se supplementation in adults with T2DM. METHODS:MEDLINE, EMBASE and the Cochrane Library were searched up to April 2018 for randomised controlled trials (RCTs) evaluating the effectiveness of Se against a comparator on DM-related outcomes. RESULTS:Four RCTs (241 participants) were included. In individual RCTs, Se supplementation significantly reduced fasting insulin levels [mean difference (MD) = -3.6 μIU mL ; 95% confidence interval (CI) = -6.36 to -0.84; MD = -5.8 μIU mL ; 95% CI = -9.23 to -2.37], homeostasis model of assessment-estimated insulin resistance (HOMA-IR) (MD = -1; 95% CI = -1.79 to -0.21; MD = -1.6; 95% CI, -2.58 to -0.62) and homeostasis model of assessment-estimated B cell function (HOMA-B) (MD = -13.6; 95% CI = -23.4 to -3.8; MD = -22.6; 95% CI = -36.39 to -8.81). No effects of Se were noted on most of the other outcomes of interest. None of the RCTs assessed the mortality, diabetes-related complications, non-high-density lipoprotein (non-HDL), blood pressure and health-related quality of life. The impact on HDL and fasting plasma glucose (FPG) was ambiguous. Only one adverse event (nausea) was reported as a reason for discontinuing the intervention; however, among the studies, the reporting was not accurate. Furthermore, only one RCT reported increase in FPG level in the Se group (MD = 36.38 mg dL ; 95% CI = 15.39-57.37). CONCLUSIONS:Currently, there is no evidence to support the effectiveness of Se supplementation in the T2DM population.
10.1111/jhn.12670
Metabolic and Metabo-Clinical Signatures of Type 2 Diabetes, Obesity, Retinopathy, and Dyslipidemia.
Yousri Noha A,Suhre Karsten,Yassin Esraa,Al-Shakaki Alya,Robay Amal,Elshafei Maha,Chidiac Omar,Hunt Steven C,Crystal Ronald G,Fakhro Khalid A
Diabetes
Macro- and microvascular complications of type 2 diabetes (T2D), obesity, and dyslipidemia share common metabolic pathways. In this study, using a total of 1,300 metabolites from 996 Qatari adults (57% with T2D) and 1,159 metabolites from an independent cohort of 2,618 individuals from the Qatar BioBank (11% with T2D), we identified 373 metabolites associated with T2D, obesity, retinopathy, dyslipidemia, and lipoprotein levels, 161 of which were novel. Novel metabolites included phospholipids, sphingolipids, lysolipids, fatty acids, dipeptides, and metabolites of the urea cycle and xanthine, steroid, and glutathione metabolism. The identified metabolites enrich pathways of oxidative stress, lipotoxicity, glucotoxicity, and proteolysis. Second, we identified 15 patterns we defined as "metabo-clinical signatures." These are clusters of patients with T2D who group together based on metabolite levels and reveal the same clustering in two or more clinical variables (obesity, LDL, HDL, triglycerides, and retinopathy). These signatures revealed metabolic pathways associated with different clinical patterns and identified patients with extreme (very high/low) clinical variables associated with extreme metabolite levels in specific pathways. Among our novel findings are the role of N-acetylmethionine in retinopathy in conjunction with dyslipidemia and the possible roles of N-acetylvaline and pyroglutamine in association with high cholesterol levels and kidney function.
10.2337/db21-0490
Metabolomics in Diabetes and Diabetic Complications: Insights from Epidemiological Studies.
Jin Qiao,Ma Ronald Ching Wan
Cells
The increasing prevalence of diabetes and its complications, such as cardiovascular and kidney disease, remains a huge burden globally. Identification of biomarkers for the screening, diagnosis, and prognosis of diabetes and its complications and better understanding of the molecular pathways involved in the development and progression of diabetes can facilitate individualized prevention and treatment. With the advancement of analytical techniques, metabolomics can identify and quantify multiple biomarkers simultaneously in a high-throughput manner. Providing information on underlying metabolic pathways, metabolomics can further identify mechanisms of diabetes and its progression. The application of metabolomics in epidemiological studies have identified novel biomarkers for type 2 diabetes (T2D) and its complications, such as branched-chain amino acids, metabolites of phenylalanine, metabolites involved in energy metabolism, and lipid metabolism. Metabolomics have also been applied to explore the potential pathways modulated by medications. Investigating diabetes using a systems biology approach by integrating metabolomics with other omics data, such as genetics, transcriptomics, proteomics, and clinical data can present a comprehensive metabolic network and facilitate causal inference. In this regard, metabolomics can deepen the molecular understanding, help identify potential therapeutic targets, and improve the prevention and management of T2D and its complications. The current review focused on metabolomic biomarkers for kidney and cardiovascular disease in T2D identified from epidemiological studies, and will also provide a brief overview on metabolomic investigations for T2D.
10.3390/cells10112832
GC-MS-Based Serum Metabolomic Investigations on the Ameliorative Effects of Polysaccharide from in Hyperlipidemia Rats.
Yang Xiao-Lian,Li Li,Zhang Tao-Fu,Deng Jing,Lin Xiu-Lian,Li Ya-Mei,Xia Bo-Hou,Lin Li-Mei
Oxidative medicine and cellular longevity
Hyperlipidemia, a typical metabolic disorder syndrome, can cause various cardiovascular diseases. The polysaccharides were found to have enormous potential in the therapy of hyperlipidemia. This study was aimed at evaluating the ameliorative effects of polysaccharide from (TFP) in rats with hyperlipidemia. A serum metabolomic method based on gas chromatography-mass spectrometry (GC-MS) was used to explore the detailed mechanism of TFP in rats with hyperlipidemia. The oxidative stress indicators, biochemical indexes, and inflammatory factors in serum and histopathological changes in the liver were also evaluated after 10-week oral administration of TFP in rats with high-fat diet-induced hyperlipidemia. TFP significantly relieved oxidative stress, inflammation, and liver histopathology and reduced blood lipid levels. Multivariate statistical approaches such as principal component analysis and orthogonal projection to latent structure square-discriminant analysis revealed clear separations of metabolic profiles among the control, HFD, and HFD+TFP groups, indicating a moderating effect of TFP on the metabolic disorders in rats with hyperlipidemia. Seven metabolites in serum, involved in glycine, serine, and threonine metabolism and aminoacyl-tRNA biosynthesis, were selected as potential biomarkers in rats with hyperlipidemia and regulated by TFP administration. It was concluded that TFP had remarkable potential for treating hyperlipidemia. These findings provided evidence for further understanding of the mechanism of action of TFP on hyperlipidemia.
10.1155/2021/9180635
Dysregulation of autophagy acts as a pathogenic mechanism of non-alcoholic fatty liver disease (NAFLD) induced by common environmental pollutants.
Zhang Yao,Li Kongdong,Kong Anqi,Zhou Yang,Chen Dongfeng,Gu Jie,Shi Haifeng
Ecotoxicology and environmental safety
Non-alcoholic fatty liver disease (NAFLD) has been the most common chronic liver disease in the world, including the developing countries. NAFLD is metabolic disease with significant lipid deposition in the hepatocytes of the liver, which is usually associated with oxidative stress, inflammation and fibrogenesis, and insulin resistance. Progressive NAFLD can develop into non-alcoholic steatohepatitis (NASH) or hepatocellular carcinoma. The current evidence proposes that environmental pollutants promote development and progression of NAFLD, and autophagy plays a vital role but is multifactorial affected in NAFLD. In this review, we analyzed on the regulations of common environmental pollutants on autophagy in NAFLD. To clarify the involved roles of autophagy, we discussed the dysregulation of autophagy by environmental pollutants in adipose tissue and gut, and their interactions with liver, as well as epigenetic regulation on autophagy by environmental pollutants. Furthermore, protective roles of potential therapeutic treatments on the multiple-hits of autophagy in NAFLD were descripted.
10.1016/j.ecoenv.2021.112256
An update on potential biomarkers for diagnosing diabetic foot ulcer at early stage.
Wang Yuqing,Shao Tengteng,Wang Jialin,Huang Xiaoting,Deng Xiaofei,Cao Yemin,Zhou Mingmei,Zhao Cheng
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
As one of major chronic complications of diabetes, diabetic foot ulcer (DFU) is the main cause of disability and death. The clinical diagnosis and prognosis of DFU is inadequate. For clinicians, if the risk stratification of DFU can be obtained earlier in diabetic patients, the hospitalization, disability and mortality rate will be reduced. In addition to the inflammatory biomarkers that have been widely concerned and used, e.g., procalcitonin, pentraxin-3, C-reactive protein (CRP), interleukins (ILs), and tumor necrosis factor-α (TNF-α), etc., a more comprehensive prediction of the risk and severity of DFU is needed to reflect new biomarkers for therapeutic intervention effects. Along with the development of systems biology technology, genomics, proteomics, metabolomics and microbiome have been used in the studies on DFU for better understanding of the disease. In this review, new biomarkers that are expected to assist in the accurate diagnosis and risk stratification of DFU will be discussed and summarized in detail.
10.1016/j.biopha.2020.110991
Recent progress in metabolic reprogramming in gestational diabetes mellitus: a review.
Frontiers in endocrinology
Gestational diabetes mellitus is a prevalent metabolic disease that can impact the normal course of pregnancy and delivery, leading to adverse outcomes for both mother and child. Its pathogenesis is complex and involves various factors, such as insulin resistance and β-cell dysfunction. Metabolic reprogramming, which involves mitochondrial oxidative phosphorylation and glycolysis, is crucial for maintaining human metabolic balance and is involved in the pathogenesis and progression of gestational diabetes mellitus. However, research on the link and metabolic pathways between metabolic reprogramming and gestational diabetes mellitus is limited. Therefore, we reviewed the relationship between metabolic reprogramming and gestational diabetes mellitus to provide new therapeutic strategies for maternal health during pregnancy and reduce the risk of developing gestational diabetes mellitus.
10.3389/fendo.2023.1284160
Potential Therapies Targeting the Metabolic Reprogramming of Diabetes-Associated Breast Cancer.
Journal of personalized medicine
In recent years, diabetes-associated breast cancer has become a significant clinical challenge. Diabetes is not only a risk factor for breast cancer but also worsens its prognosis. Patients with diabetes usually show hyperglycemia and hyperinsulinemia, which are accompanied by different glucose, protein, and lipid metabolism disorders. Metabolic abnormalities observed in diabetes can induce the occurrence and development of breast cancer. The changes in substrate availability and hormone environment not only create a favorable metabolic environment for tumorigenesis but also induce metabolic reprogramming events required for breast cancer cell transformation. Metabolic reprogramming is the basis for the development, swift proliferation, and survival of cancer cells. Metabolism must also be reprogrammed to support the energy requirements of the biosynthetic processes in cancer cells. In addition, metabolic reprogramming is essential to enable cancer cells to overcome apoptosis signals and promote invasion and metastasis. This review aims to describe the major metabolic changes in diabetes and outline how cancer cells can use cellular metabolic changes to drive abnormal growth and proliferation. We will specifically examine the mechanism of metabolic reprogramming by which diabetes may promote the development of breast cancer, focusing on the role of glucose metabolism, amino acid metabolism, and lipid metabolism in this process and potential therapeutic targets. Although diabetes-associated breast cancer has always been a common health problem, research focused on finding treatments suitable for the specific needs of patients with concurrent conditions is still limited. Most studies are still currently in the pre-clinical stage and mainly focus on reprogramming the glucose metabolism. More research targeting the amino acid and lipid metabolism is needed.
10.3390/jpm13010157
Meta-Inflammation and Metabolic Reprogramming of Macrophages in Diabetes and Obesity: The Importance of Metabolites.
Russo Sara,Kwiatkowski Marcel,Govorukhina Natalia,Bischoff Rainer,Melgert Barbro N
Frontiers in immunology
Diabetes mellitus type II and obesity are two important causes of death in modern society. They are characterized by low-grade chronic inflammation and metabolic dysfunction (meta-inflammation), which is observed in all tissues involved in energy homeostasis. A substantial body of evidence has established an important role for macrophages in these tissues during the development of diabetes mellitus type II and obesity. Macrophages can activate into specialized subsets by cues from their microenvironment to handle a variety of tasks. Many different subsets have been described and in diabetes/obesity literature two main classifications are widely used that are also defined by differential metabolic reprogramming taking place to fuel their main functions. Classically activated, pro-inflammatory macrophages (often referred to as M1) favor glycolysis, produce lactate instead of metabolizing pyruvate to acetyl-CoA, and have a tricarboxylic acid cycle that is interrupted at two points. Alternatively activated macrophages (often referred to as M2) mainly use beta-oxidation of fatty acids and oxidative phosphorylation to create energy-rich molecules such as ATP and are involved in tissue repair and downregulation of inflammation. Since diabetes type II and obesity are characterized by metabolic alterations at the organism level, these alterations may also induce changes in macrophage metabolism resulting in unique macrophage activation patterns in diabetes and obesity. This review describes the interactions between metabolic reprogramming of macrophages and conditions of metabolic dysfunction like diabetes and obesity. We also focus on different possibilities of measuring a range of metabolites intra-and extracellularly in a precise and comprehensive manner to better identify the subsets of polarized macrophages that are unique to diabetes and obesity. Advantages and disadvantages of the currently most widely used metabolite analysis approaches are highlighted. We further describe how their combined use may serve to provide a comprehensive overview of the metabolic changes that take place intracellularly during macrophage activation in conditions like diabetes and obesity.
10.3389/fimmu.2021.746151
Pathophysiological communication between hepatocytes and non-parenchymal cells in liver injury from NAFLD to liver fibrosis.
Kumar Santosh,Duan Qihua,Wu Rongxue,Harris Edward N,Su Qiaozhu
Advanced drug delivery reviews
Non-alcoholic fatty liver disease (NAFLD) is a multifactorial disease that encompasses a spectrum of pathological conditions, ranging from simple steatosis (NAFL), nonalcoholic steatohepatitis (NASH), fibrosis/cirrhosis which can further progress to hepatocellular carcinoma and liver failure. The progression of NAFL to NASH and liver fibrosis is closely associated with a series of liver injury resulting from lipotoxicity, oxidative stress, redox imbalance (excessive nitric oxide), ER stress, inflammation and apoptosis that occur sequentially in different liver cells which ultimately leads to the activation of liver regeneration and fibrogenesis, augmenting collagen and extracellular matrix deposition and promoting liver fibrosis and cirrhosis. Type 2 diabetes is a significant risk factor in NAFLD development by accelerating liver damage. Here, we overview recent findings from human study and animal models on the pathophysiological communication among hepatocytes (HCs), Kupffer cells (KCs), hepatic stellate cells (HSCs) and liver sinusoidal endothelial cells (LSECs) during the disease development. The mechanisms of crucial signaling pathways, including Toll-like receptor, TGFβ and hedgehog mediated hepatic injury are also discussed. We further highlight the potentials of precisely targeting hepatic individual cell-type using nanotechnology as therapeutic strategy for the treatment of NASH and liver fibrosis.
10.1016/j.addr.2021.113869
Liver biomarkers, lipid metabolites, and risk of gestational diabetes mellitus in a prospective study among Chinese pregnant women.
BMC medicine
BACKGROUND:Liver plays an important role in maintaining glucose homeostasis. We aimed to examine the associations of liver enzymes and hepatic steatosis index (HSI, a reliable biomarker for non-alcoholic fatty liver disease) in early pregnancy with subsequent GDM risk, as well as the potential mediation effects of lipid metabolites on the association between HSI and GDM. METHODS:In a birth cohort, liver enzymes were measured in early pregnancy (6-15 gestational weeks, mean 10) among 6,860 Chinese women. Multivariable logistic regression was performed to examine the association between liver biomarkers and risk of GDM. Pearson partial correlation and least absolute shrinkage and selection operator (LASSO) regression were conducted to identify lipid metabolites that were significantly associated with HSI in a subset of 948 women. Mediation analyses were performed to estimate the mediating roles of lipid metabolites on the association of HSI with GDM. RESULTS:Liver enzymes and HSI were associated with higher risks of GDM after adjustment for potential confounders, with ORs ranging from 1.42 to 2.24 for extreme-quartile comparisons (false discovery rate-adjusted P-trend ≤0.005). On the natural log scale, each SD increment of alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, alkaline phosphatase, and HSI was associated with a 1.15-fold (95% CI: 1.05, 1.26), 1.10-fold (1.01, 1.20), 1.21-fold (1.10, 1.32), 1.15-fold (1.04, 1.27), and 1.33-fold (1.18, 1.51) increased risk of GDM, respectively. Pearson partial correlation and LASSO regression identified 15 specific lipid metabolites in relation to HSI. Up to 52.6% of the association between HSI and GDM risk was attributed to the indirect effect of the HSI-related lipid score composed of lipid metabolites predominantly from phospholipids (e.g., lysophosphatidylcholine and ceramides) and triacylglycerol. CONCLUSIONS:Elevated liver enzymes and HSI in early pregnancy, even within a normal range, were associated with higher risks of GDM among Chinese pregnant women. The association of HSI with GDM was largely mediated by altered lipid metabolism.
10.1186/s12916-023-02818-6
The role of the gut microbiome and its metabolites in metabolic diseases.
Wu Jiayu,Wang Kai,Wang Xuemei,Pang Yanli,Jiang Changtao
Protein & cell
It is well known that an unhealthy lifestyle is a major risk factor for metabolic diseases, while in recent years, accumulating evidence has demonstrated that the gut microbiome and its metabolites also play a crucial role in the onset and development of many metabolic diseases, including obesity, type 2 diabetes, nonalcoholic fatty liver disease, cardiovascular disease and so on. Numerous microorganisms dwell in the gastrointestinal tract, which is a key interface for energy acquisition and can metabolize dietary nutrients into many bioactive substances, thus acting as a link between the gut microbiome and its host. The gut microbiome is shaped by host genetics, immune responses and dietary factors. The metabolic and immune potential of the gut microbiome determines its significance in host health and diseases. Therefore, targeting the gut microbiome and relevant metabolic pathways would be effective therapeutic treatments for many metabolic diseases in the near future. This review will summarize information about the role of the gut microbiome in organism metabolism and the relationship between gut microbiome-derived metabolites and the pathogenesis of many metabolic diseases. Furthermore, recent advances in improving metabolic diseases by regulating the gut microbiome will be discussed.
10.1007/s13238-020-00814-7
Molecular biomarkers for gestational diabetes mellitus and postpartum diabetes.
Chinese medical journal
ABSTRACT:Gestational diabetes mellitus (GDM) is a growing public health problem worldwide that threatens both maternal and fetal health. Identifying individuals at high risk for GDM and diabetes after GDM is particularly useful for early intervention and prevention of disease progression. In the last decades, a number of studies have used metabolomics, genomics, and proteomic approaches to investigate associations between biomolecules and GDM progression. These studies clearly demonstrate that various biomarkers reflect pathological changes in GDM. The established markers have potential use as screening and diagnostic tools in GDM and in postpartum diabetes research. In the present review, we summarize recent studies of metabolites, single-nucleotide polymorphisms, microRNAs, and proteins associated with GDM and its transition to postpartum diabetes, with a focus on their predictive value in screening and diagnosis.
10.1097/CM9.0000000000002160
Skeletal muscle energy metabolism in obesity.
Mengeste Abel M,Rustan Arild C,Lund Jenny
Obesity (Silver Spring, Md.)
Comparing energy metabolism in human skeletal muscle and primary skeletal muscle cells in obesity, while focusing on glucose and fatty acid metabolism, shows many common changes. Insulin-mediated glucose uptake in skeletal muscle and primary myotubes is decreased by obesity, whereas differences in basal glucose metabolism are inconsistent among studies. With respect to fatty acid metabolism, there is an increased uptake and storage of fatty acids and a reduced complete lipolysis, suggesting alterations in lipid turnover. In addition, fatty acid oxidation is decreased, probably at the level of complete oxidation, as -oxidation may be enhanced in obesity, which indicates mitochondrial dysfunction. Metabolic changes in skeletal muscle with obesity promote metabolic inflexibility, ectopic lipid accumulation, and formation of toxic lipid intermediates. Skeletal muscle also acts as an endocrine organ, secreting myokines that participate in interorgan cross talk. This review highlights interventions and some possible targets for treatment through action on skeletal muscle energy metabolism. Effects of exercise in vivo on obesity have been compared with simulation of endurance exercise in vitro on myotubes (electrical pulse stimulation). Possible pharmaceutical targets, including signaling pathways and drug candidates that could modify lipid storage and turnover or increase mitochondrial function or cellular energy expenditure through adaptive thermogenic mechanisms, are discussed.
10.1002/oby.23227
Identification of biomarkers associated with immune scores in diabetic retinopathy.
Frontiers in endocrinology
Background:Diabetic retinopathy (DR) causes irreversible visual impairment in diabetes mellitus (DM) patients. Immunity played a crucial role in DR. Nevertheless, the triggering mechanism of DR was not yet thorough enough. Herein, we aim to identify the immune-associated genes as biomarkers associated with immune scores that can distinguish early DR from DM without DR. Methods:In this study, total RNA of peripheral blood mononuclear cell (PBMC) samples from 15 non-proliferative DR patients and 15 DM patients without DR were collected and the transcriptome sequencing data were extracted. Firstly, the target genes were obtained by intersecting the differentially expressed genes (DEGs), which were screened by "limma", and the module genes (related to immune scores), which were screened by "WGCNA". In order to screen for the crucial genes, three machine learning algorithms were implemented, and a receiver operating characteristic (ROC) curve was used to obtain the diagnostic genes. Moreover, the gene set enrichment analysis (GSEA) was performed to understand the function of diagnostic genes, and analysis of the proportions of immune cells and their association with diagnostic genes was performed to analyze the pathogenesis of DR. Furthermore, the regulatory network of TF-mRNA-miRNA was built to reveal the possible regulation of diagnostic genes. Finally, the quantitative real-time polymerase chain reaction (qRT-PCR) was performed to verify the mRNA level of diagnostic genes. Results:A total of three immune-associated diagnostic genes, namely, , , and , were obtained, and their expression was increased in PBMC samples of DR, and qRT-PCR results confirmed these results. Moreover, the functions of these genes were associated with immune response. The expression of and was significantly negatively associated with naive B cells, and the expression of was significantly negatively associated with immature dendritic cells. Moreover, could regulate both and . Conclusion:This study identified three immune-associated diagnostic genes, , , and , as biomarkers associated with immune scores in DR for the first time. This finding might proffer a novel perspective of the triggering mechanism of DR, and help to understand the role of immune-associated genes in the molecular mechanism of DR more deeply.
10.3389/fendo.2023.1228843
Metabolomics of various samples advancing biomarker discovery and pathogenesis elucidation for diabetic retinopathy.
Frontiers in endocrinology
Diabetic retinopathy (DR) is a universal microvascular complication of diabetes mellitus (DM), which is the main reason for global sight damage/loss in middle-aged and/or older people. Current clinical analyses, like hemoglobin A1c, possess some importance as prognostic indicators for DR severity, but no effective circulating biomarkers are used for DR in the clinic currently, and studies on the latent pathophysiology remain lacking. Recent developments in omics, especially metabolomics, continue to disclose novel potential biomarkers in several fields, including but not limited to DR. Therefore, based on the overview of metabolomics, we reviewed progress in analytical technology of metabolomics, the prominent roles and the current status of biomarkers in DR, and the update of potential biomarkers in various DR-related samples metabolomics, including tear as well as vitreous humor, aqueous humor, retina, plasma, serum, cerebrospinal fluid, urine, and feces. In this review, we underscored the in-depth analysis and elucidation of the common biomarkers in different biological samples based on integrated results, namely, alanine, lactate, and glutamine. Alanine may participate in and regulate glucose metabolism through stimulating N-methyl-D-aspartate receptors and subsequently suppressing insulin secretion, which is the potential pathogenesis of DR. Abnormal lactate could cause extensive oxidative stress and neuroinflammation, eventually leading to retinal hypoxia and metabolic dysfunction; on the other hand, high-level lactate may damage the structure and function of the retinal endothelial cell barrier the G protein-coupled receptor 81. Abnormal glutamine indicates a disturbance of glutamate recycling, which may affect the activation of Müller cells and proliferation the PPP1CA-YAP-GS-Gln-mTORC1 pathway.
10.3389/fendo.2022.1037164
Biomarkers in Diabetic Retinopathy.
Jenkins Alicia J,Joglekar Mugdha V,Hardikar Anandwardhan A,Keech Anthony C,O'Neal David N,Januszewski Andrzej S
The review of diabetic studies : RDS
There is a global diabetes epidemic correlating with an increase in obesity. This coincidence may lead to a rise in the prevalence of type 2 diabetes. There is also an as yet unexplained increase in the incidence of type 1 diabetes, which is not related to adiposity. Whilst improved diabetes care has substantially improved diabetes outcomes, the disease remains a common cause of working age adult-onset blindness. Diabetic retinopathy is the most frequently occurring complication of diabetes; it is greatly feared by many diabetes patients. There are multiple risk factors and markers for the onset and progression of diabetic retinopathy, yet residual risk remains. Screening for diabetic retinopathy is recommended to facilitate early detection and treatment. Common biomarkers of diabetic retinopathy and its risk in clinical practice today relate to the visualization of the retinal vasculature and measures of glycemia, lipids, blood pressure, body weight, smoking, and pregnancy status. Greater knowledge of novel biomarkers and mediators of diabetic retinopathy, such as those related to inflammation and angiogenesis, has contributed to the development of additional therapeutics, in particular for late-stage retinopathy, including intra-ocular corticosteroids and intravitreal vascular endothelial growth factor inhibitors ('anti-VEGFs') agents. Unfortunately, in spite of a range of treatments (including laser photocoagulation, intraocular steroids, and anti-VEGF agents, and more recently oral fenofibrate, a PPAR-alpha agonist lipid-lowering drug), many patients with diabetic retinopathy do not respond well to current therapeutics. Therefore, more effective treatments for diabetic retinopathy are necessary. New analytical techniques, in particular those related to molecular markers, are accelerating progress in diabetic retinopathy research. Given the increasing incidence and prevalence of diabetes, and the limited capacity of healthcare systems to screen and treat diabetic retinopathy, there is need to reliably identify and triage people with diabetes. Biomarkers may facilitate a better understanding of diabetic retinopathy, and contribute to the development of novel treatments and new clinical strategies to prevent vision loss in people with diabetes. This article reviews key aspects related to biomarker research, and focuses on some specific biomarkers relevant to diabetic retinopathy.
10.1900/RDS.2015.12.159
Intermittent Fasting Confers Protection in CNS Autoimmunity by Altering the Gut Microbiota.
Cell metabolism
Multiple sclerosis (MS) is more common in western countries with diet being a potential contributing factor. Here we show that intermittent fasting (IF) ameliorated clinical course and pathology of the MS model, experimental autoimmune encephalomyelitis (EAE). IF led to increased gut bacteria richness, enrichment of the Lactobacillaceae, Bacteroidaceae, and Prevotellaceae families and enhanced antioxidative microbial metabolic pathways. IF altered T cells in the gut with a reduction of IL-17 producing T cells and an increase in regulatory T cells. Fecal microbiome transplantation from mice on IF ameliorated EAE in immunized recipient mice on a normal diet, suggesting that IF effects are at least partially mediated by the gut flora. In a pilot clinical trial in MS patients, intermittent energy restriction altered blood adipokines and the gut flora resembling protective changes observed in mice. In conclusion, IF has potent immunomodulatory effects that are at least partially mediated by the gut microbiome.
10.1016/j.cmet.2018.05.006
Gut microbiota mediates intermittent-fasting alleviation of diabetes-induced cognitive impairment.
Nature communications
Cognitive decline is one of the complications of type 2 diabetes (T2D). Intermittent fasting (IF) is a promising dietary intervention for alleviating T2D symptoms, but its protective effect on diabetes-driven cognitive dysfunction remains elusive. Here, we find that a 28-day IF regimen for diabetic mice improves behavioral impairment via a microbiota-metabolites-brain axis: IF enhances mitochondrial biogenesis and energy metabolism gene expression in hippocampus, re-structures the gut microbiota, and improves microbial metabolites that are related to cognitive function. Moreover, strong connections are observed between IF affected genes, microbiota and metabolites, as assessed by integrative modelling. Removing gut microbiota with antibiotics partly abolishes the neuroprotective effects of IF. Administration of 3-indolepropionic acid, serotonin, short chain fatty acids or tauroursodeoxycholic acid shows a similar effect to IF in terms of improving cognitive function. Together, our study purports the microbiota-metabolites-brain axis as a mechanism that can enable therapeutic strategies against metabolism-implicated cognitive pathophysiologies.
10.1038/s41467-020-14676-4
Metabolic Effects of Intermittent Fasting.
Patterson Ruth E,Sears Dorothy D
Annual review of nutrition
The objective of this review is to provide an overview of intermittent fasting regimens, summarize the evidence on the health benefits of intermittent fasting, and discuss physiological mechanisms by which intermittent fasting might lead to improved health outcomes. A MEDLINE search was performed using PubMed and the terms "intermittent fasting," "fasting," "time-restricted feeding," and "food timing." Modified fasting regimens appear to promote weight loss and may improve metabolic health. Several lines of evidence also support the hypothesis that eating patterns that reduce or eliminate nighttime eating and prolong nightly fasting intervals may result in sustained improvements in human health. Intermittent fasting regimens are hypothesized to influence metabolic regulation via effects on (a) circadian biology, (b) the gut microbiome, and (c) modifiable lifestyle behaviors, such as sleep. If proven to be efficacious, these eating regimens offer promising nonpharmacological approaches to improving health at the population level, with multiple public health benefits.
10.1146/annurev-nutr-071816-064634
Research progress in the relationship between type 2 diabetes mellitus and intestinal flora.
Ma Quantao,Li Yaqi,Li Pengfei,Wang Min,Wang Jingkang,Tang Ziyan,Wang Ting,Luo Linglong,Wang Chunguo,Wang Ting,Zhao Baosheng
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
Type 2 diabetes mellitus (T2DM) is a common clinical chronic disease, while its pathogenesis is still inconclusive. Intestinal flora, the largest micro-ecological system in the human body, is involved in, meanwhile has a major impact on the body's material and energy metabolism. Recent studies have shown that in addition to obesity, genetics, and islet dysfunction, the disturbance of intestinal flora may partly give rise to diabetes. In this paper, we summarized the current research on the correlation between T2DM and intestinal flora, and concluded the pathological mechanisms of intestinal flora involved in T2DM. Moreover, the ideas and methods of prevention and treatment of T2DM based on intestinal flora were proposed, providing theoretical basis and literature reference for the treatment of T2DM and its complications based on the regulation of intestinal flora.
10.1016/j.biopha.2019.109138
An early response transcription factor, Egr-1, enhances insulin resistance in type 2 diabetes with chronic hyperinsulinism.
Shen Ning,Yu Xiao,Pan Fei-Yan,Gao Xiang,Xue Bin,Li Chao-Jun
The Journal of biological chemistry
One of the most important characteristics of type 2 diabetes is insulin resistance, during which the patients normally experienced hyperinsulinism stress that would alter insulin signal transduction in insulin target tissues. We have previously found that early growth responsive gene-1 (Egr-1), a zinc finger transcription factor, is highly expressed in db/db mice and in the fat tissue of individuals with type 2 diabetes. In this report, we found that chronic exposure to hyperinsulinism caused persistent Erk/MAPK activity in adipocytes and enhanced insulin resistance in an Egr-1-dependent manner. An elevation in Egr-1 augmented Erk1/2 activation via geranylgeranyl diphosphate synthase (GGPPS). Egr-1-promoted GGPPS transcription increased Ras prenylation and caused Erk1/2 activation. The sustained activation of Erk1/2 resulted in the phosphorylation of insulin receptor substrate-1 at Serine 612. Phosphorylation at this site impaired insulin signaling in adipocytes and reduced glucose uptake. The loss of Egr-1 function, knockdown of GGPPS, or inhibition of Erk1/2 activity in insulin-resistant adipocytes restored insulin receptor substrate-1 tyrosine phosphorylation and increased insulin sensitivity. Our results suggest a new mechanism by which the Egr-1/GGPPS/Erk1/2 pathway is responsible for insulin resistance during hyperinsulinism. This pathway provides a new therapeutic target for increasing insulin sensitivity: inhibiting the function of Egr-1.
10.1074/jbc.M110.190165
Lytic cell death in metabolic liver disease.
Journal of hepatology
Regulated cell death is intrinsically associated with inflammatory liver disease and is pivotal in governing outcomes of metabolic liver disease. Different types of cell death may coexist as metabolic liver disease progresses to inflammation, fibrosis, and ultimately cirrhosis. In addition to apoptosis, lytic forms of hepatocellular death, such as necroptosis, pyroptosis and ferroptosis elicit strong inflammatory responses due to cell membrane permeabilisation and release of cellular components, contributing to the recruitment of immune cells and activation of hepatic stellate cells. The control of liver cell death is of fundamental importance and presents novel opportunities for potential therapeutic intervention. This review summarises the underlying mechanism of distinct lytic cell death modes and their commonalities, discusses their relevance to metabolic liver diseases of different aetiologies, and acknowledges the limitations of current knowledge in the field. We focus on the role of hepatocyte necroptosis, pyroptosis and ferroptosis in non-alcoholic fatty liver disease, alcohol-associated liver disease and other metabolic liver disorders, as well as potential therapeutic implications.
10.1016/j.jhep.2020.04.001
Low-dose metformin targets the lysosomal AMPK pathway through PEN2.
Nature
Metformin, the most prescribed antidiabetic medicine, has shown other benefits such as anti-ageing and anticancer effects. For clinical doses of metformin, AMP-activated protein kinase (AMPK) has a major role in its mechanism of action; however, the direct molecular target of metformin remains unknown. Here we show that clinically relevant concentrations of metformin inhibit the lysosomal proton pump v-ATPase, which is a central node for AMPK activation following glucose starvation. We synthesize a photoactive metformin probe and identify PEN2, a subunit of γ-secretase, as a binding partner of metformin with a dissociation constant at micromolar levels. Metformin-bound PEN2 forms a complex with ATP6AP1, a subunit of the v-ATPase, which leads to the inhibition of v-ATPase and the activation of AMPK without effects on cellular AMP levels. Knockout of PEN2 or re-introduction of a PEN2 mutant that does not bind ATP6AP1 blunts AMPK activation. In vivo, liver-specific knockout of Pen2 abolishes metformin-mediated reduction of hepatic fat content, whereas intestine-specific knockout of Pen2 impairs its glucose-lowering effects. Furthermore, knockdown of pen-2 in Caenorhabditis elegans abrogates metformin-induced extension of lifespan. Together, these findings reveal that metformin binds PEN2 and initiates a signalling route that intersects, through ATP6AP1, the lysosomal glucose-sensing pathway for AMPK activation. This ensures that metformin exerts its therapeutic benefits in patients without substantial adverse effects.
10.1038/s41586-022-04431-8
Gestational diabetes mellitus.
McIntyre H David,Catalano Patrick,Zhang Cuilin,Desoye Gernot,Mathiesen Elisabeth R,Damm Peter
Nature reviews. Disease primers
Hyperglycaemia that develops during pregnancy and resolves after birth has been recognized for over 50 years, but uniform worldwide consensus is lacking about threshold hyperglycaemic levels that merit a diagnosis of 'gestational diabetes mellitus' (GDM) and thus treatment during pregnancy. GDM is currently the most common medical complication of pregnancy, and prevalence of undiagnosed hyperglycaemia and even overt diabetes in young women is increasing. Maternal overweight and obesity, later age at childbearing, previous history of GDM, family history of type 2 diabetes mellitus and ethnicity are major GDM risk factors. Diagnosis is usually performed using an oral glucose tolerance test (OGTT), although a non-fasting, glucose challenge test (GCT) is used in some parts of the world to screen women for those requiring a full OGTT. Dietary modification and increased physical activity are the primary treatments for GDM, but pharmacotherapy, usually insulin, is used when normoglycaemia is not achieved. Oral hypoglycaemic agents, principally metformin and glibenclamide (glyburide), are also used in some countries. Treatment improves immediate pregnancy outcomes, reducing excess fetal growth and adiposity and pregnancy-related hypertensive disorders. GDM increases the risk of long-term complications, including obesity, impaired glucose metabolism and cardiovascular disease, in both the mother and infant. Optimal management of mother and infant during long-term follow-up remains challenging, with very limited implementation of preventive strategies in most parts of the world.
10.1038/s41572-019-0098-8