LEPR/FOS/JUNB signaling pathway contributes to chronic restraint stress-induced tumor proliferation.

BACKGROUND & AIMS: Psychosocial stress has become an unavoidable part of life, which was reported to promote tumor development. Chronic stress significantly promotes the norepinephrine (NE) secretion and the expression of leptin receptor (LEPR), leading to tumor invasion, metastasis, and proliferation. However, the mechanism of chronic stress-induced tumor proliferation remains unclear. METHODS: To reveal the effect of chronic stress on tumor proliferation, subcutaneous tumor models combined with chronic restraint stress (CRS) were established. Combined with the transcript omics database of liver cancer patients, the target pathways were screened and further verified by in vitro experiments. RESULTS: The results showed that the CRS with subcutaneous tumor transplantation (CRS + tumor) group exhibited significantly larger tumor sizes than the subcutaneous tumor transplantation (tumor) group. Compared with the tumor group, CRS obviously increased the mRNA levels of LEPR, FOS, and JUNB of tumor tissues in the CRS + tumor group. Furthermore, the treatment with norepinephrine (NE) significantly elevated the survival rate of H22 cells and enhanced the expression of LEPR, FOS, and JUNB in vitro. Silencing LEPR significantly reduced the expression of FOS and JUNB, accompanied by a decrease in H22 cell viability. CONCLUSIONS: Our study demonstrated that CRS activates the LEPR-FOS-JUNB signaling pathway by NE, aggravating tumor development. These findings might provide a scientific foundation for investigating the underlying pathological mechanisms of tumors in response to chronic stress.

Design, Synthesis, and Antifungal Activity of Sulfoximine Derivatives Containing Nitroguanidine Moieties.

To discover novel pesticide candidates, a series of sulfoximine derivatives were designed and synthesized via the oxidation coupling reaction of sulfides and N-alkyl nitroguanidines. The compounds were evaluated for their antifungal activity against six phytopathogenic fungi. Most of them exhibited a broad spectrum of fungicidal activity in vitro. Compound 8IV-b displayed good fungicidal activity against Sclerotinia sclerotiorum, Rhizoctonia solani, Botrytis cinerea, Fusarium graminearum, and Phytophthora capsici, with EC50 value of 12.82, 12.50, 17.25, 31.08, and 30.11 mg/L, respectively. In addition, compounds 8III-c and 8IV-e had EC50 values of 22.23 and 20.67 mg/L against P. capsic, which were significantly better than that of the commercial procymidone (118.15 mg/L). Strikingly, 8IV-d exhibited satisfactory fungicidal activity against B. cinerea, which was comparable to control procymidone in terms of their EC50 values (7.42 versus 10.83 mg/L), and the bioassays in vivo further confirmed that 8IV-d possessed potent protective effect against B. cinerea at 200 mg/L (72.2 %). These present findings will facilitate the design and development of novel potent fungicides.

Sex- and Age-Related Metabolic Characteristics of Serum Free Fatty Acids in Healthy Chinese Adults.

Free fatty acids (FFAs), also named nonesterified fatty acids, largely originate from the lipolysis of triacylglycerol stored in adipose tissue. Despite extensive research on sex- and age-dependent effects on lipolysis and lipid mobilization of adipose tissue, the primary differences in the metabolic characteristics of circulating FFAs among normal-weight healthy men and women during aging are still unclear. Here, we measured the concentrations of 45 FFAs in fasting sera of two Chinese community-based studies consisting of 201 metabolically healthy normal-weight adults to ascertain the associations of sex and age with FFA compositions and their upstream and downstream relations. Results showed greater conversions toward n-3 polyunsaturated fatty acids of docosahexaenoic acid and n-6 of docosapentaenoic acid from their precursors in women than in men. Meanwhile, there were significantly positive correlations between the concentrations of a panel of saturated fatty acids with straight chain or branched chain and age in women, whereas no association was found in men. These findings highlight that sex and age should be considered as the potential confounding factors in assessing the risk for metabolic disturbance using FFA biomarkers.

Serum stearic acid/palmitic acid ratio as a potential predictor of diabetes remission after Roux-en-Y gastric bypass in obesity.

Endogenous fatty acid metabolism that results in elongation and desaturation lipid products is thought to play a role in the development of type 2 diabetes mellitus (T2DM). In this study, we evaluated the potential of estimated elongase and desaturase activities for use as predictive markers for T2DM remission after Roux-en-Y gastric bypass (RYGB). The results of a targeted metabolomics approach from 2 independent studies were used to calculate 24 serum FA concentration ratios (product/precursor). Gene expression data from an open public data set was also analyzed. In a longitudinal study of 38 obese diabetic patients with RYGB, we found higher baseline stearic acid/palmitic acid (S/P) ratio. This ratio reflects an elovl6-encoded elongase enzyme activity that has been found to be associated with greater possibility for diabetes remission after RYGB [odds ratio, 2.16 (95% CI 1.10-4.26)], after adjustment for age, gender, body mass index, diabetes duration, glycosylated hemoglobin A1c, and fasting C-peptide. Our results were validated by examination of postsurgical elovl6 gene expression in morbidly obese patients. The association of S/P with the metabolic status of obese individuals was further validated in a cross-sectional cohort of 381 participants. In summary, higher baseline S/P was associated with greater probability of diabetes remission after RYGB and may serve as a diagnostic marker in preoperative patient assessment. - Zhao, L., Ni, Y., Yu, H., Zhang, P., Zhao, A., Bao, Y., Liu, J., Chen, T., Xie, G., Panee, J., Chen, W., Rajani, C., Wei, R., Su, M., Jia, W., Jia, W. Serum stearic acid/palmitic acid ratio as a potential predictor of diabetes remission after Roux-en-Y gastric bypass in obesity.

High Throughput and Quantitative Measurement of Microbial Metabolome by Gas Chromatography/Mass Spectrometry Using Automated Alkyl Chloroformate Derivatization.

The ability to identify and quantify small molecule metabolites derived from gut microbial-mammalian cometabolism is essential for the understanding of the distinct metabolic functions of the microbiome. To date, analytical protocols that quantitatively measure a complete panel of microbial metabolites in biological samples have not been established but are urgently needed by the microbiome research community. Here, we report an automated high-throughput quantitative method using a gas chromatography/time-of-flight mass spectrometry (GC/TOFMS) platform to simultaneously measure over one hundred microbial metabolites in human serum, urine, feces, and Escherichia coli cell samples within 15 min per sample. A reference library was developed consisting of 145 methyl and ethyl chloroformate (MCF and ECF) derivatized compounds with their mass spectral and retention index information for metabolite identification. These compounds encompass different chemical classes including fatty acids, amino acids, carboxylic acids, hydroxylic acids, and phenolic acids as well as benzoyl and phenyl derivatives, indoles, etc., that are involved in a number of important metabolic pathways. Within an optimized range of concentrations and sample volumes, most derivatives of both reference standards and endogenous metabolites in biological samples exhibited satisfactory linearity (R2 > 0.99), good intrabatch reproducibility, and acceptable stability within 6 days (RSD < 20%). This method was further validated by examination of the analytical variability of 76 paired human serum, urine, and fecal samples as well as quality control samples. Our method involved using high-throughput sample preparation, measurement with automated derivatization, and rapid GC/TOFMS analysis. Both techniques are well suited for microbiome metabolomics studies.

Global and Targeted Metabolomics Evidence of the Protective Effect of Chinese Patent Medicine Jinkui Shenqi Pill on Adrenal Insufficiency after Acute Glucocorticoid Withdrawal in Rats.

Glucocorticoids are commonly used in anti-inflammatory and immunomodulatory therapies, but glucocorticoid withdrawal can result in life-threatening risk of adrenal insufficiency. Chinese patented pharmaceutical product Jinkui Shenqi pill (JKSQ) has potent efficacy on clinical adrenal insufficiency resulting from glucocorticoid withdrawal. However, the underlying molecular mechanism remains unclear. We used an animal model to study JKSQ-induced metabolic changes under adrenal insufficiency and healthy conditions. Sprague-Dawley rats were treated with hydrocortisone for 7 days with or without 15 days of JKSQ pretreatment. Sera were collected after 72 h hydrocortisone withdrawal and used for global and free fatty acids (FFAs)-targeted metabolomics analyses using gas chromatography/time-of-flight mass spectrometry and ultraperformance liquid chromatography/quadruple time-of-flight mass spectrometry. Rats without hydrocortisone treatment were used as controls. JKSQ pretreatment normalized the significant changes of 13 serum metabolites in hydrocortisone-withdrawal rats, involving carbohydrates, lipids, and amino acids. The most prominent effect of JKSQ was on the changes of FFAs and some [product FFA]/[precursor FFA] ratios, which represent estimated desaturase and elongase activities. The opposite metabolic responses of JKSQ in adrenal insufficiency rats and normal rats highlighted the "Bian Zheng Lun Zhi" (treatment based on ZHENG differentiation) guideline of TCM and suggested that altered fatty acid metabolism was associated with adrenal insufficiency after glucocorticoid withdrawal and the protective effects of JKSQ.

Activation of Cdk5/p25 and tau phosphorylation following chronic brain hypoperfusion in rats involves microRNA-195 down-regulation.

Chronic brain hypoperfusion (CBH) is a common clinical feature of Alzheimer's disease and vascular dementia, but the underlying molecular mechanism is unclear. Our previous study reported that the down-regulation of microRNA-195 (miR-195) promotes amyloidogenesis via regulation of amyloid precursor protein and ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) expression at the post-transcriptional level in CBH rats with bilateral common carotid artery occlusion (2VO). CBH owing to unilateral common carotid artery occlusion (UCCAO) increases tau phosphorylation levels at multiple phosphorylation sites in the brain, but the molecular mechanism is poorly understood. The purpose of this study was to investigate whether miR-195 could both deregulate amyloid metabolism and indirectly deregulate tau phosphorylation in CBH. We observed that 2VO leads to tau hyperphosphorylation at Ser202/Thr205, Ser262, Thr231, and Ser422 and to the conversion from cyclin-dependent kinase 5 (Cdk5)/p35 to Cdk5/p25 in rat hippocampi. Endogenous miR-195 was knocked down using over-expression of its antisense molecule (pre-AMO-miR-195) via a lentivirus (lenti-pre-AMO-miR-195); this knockdown increased the tau phosphorylation at Ser202/Thr205, Ser262, Thr231, Ser422, and the Cdk5/p25 activation, but over-expression of miR-195 using lenti-pre-miR-195 decreased the tau phosphorylation and Cdk5/p25 activation. Further in vitro studies demonstrated that miR-195 over-expression prevented tau hyperphosphorylation and Cdk5/p35 activity, which were increased by miR-195 inhibition. A dual luciferase reporter assay showed that miR-195 bound to the Cdk5r1 gene, which encodes p35 protein, in the 3'UTR and inhibited p35 expression. We concluded that tau hyperphosphorylation involves the down-regulation of miR-195, which is mediated by Cdk5/p25 activation in 2VO rats. Our findings demonstrated that down-regulation of miR-195 led to increased vulnerability via the regulation of multiple targets. Schematic diagram of miR-195 mediated Aß aggregation and tau hyperphosphorylation in chronic brain hypoperfusion (CBH). First, CBH results in the elevation of nuclear factor-κB (NF-κB), which binds with the promoter sequences of miR-195 and negatively regulates the expression of miR-195. Second, down-regulated miR-195 induces up-regulation of APP and BACE1 and leads to an increase in Aß levels. Third, some of the elevated Aß then enter the intracellular space and activate calpain, which promotes the conversion of Cdk5/p35 to Cdk5/p25 and catalyzes the degradation of IκB; IκB is an inhibitor of NF-κB, which activates NF-κB. Cdk5/p25 directly phosphorylates Tau. Fourth, down-regulated miR-195 induces an up-regulation of p35, which provides the active substrates of p25. Our findings demonstrated that the down-regulation of miR-195 plays a key role in the increased vulnerability to dementia via the regulation of multiple targets following CBH.

Crystal structure of 4-chloro-2-[(5-eth-oxy-1,3,4-thia-diazol-2-yl)meth-yl]-5-(piperidin-1-yl)pyridazin-3(2H)-one.

In the title mol-ecule, C14H18ClN5O2S, the six atoms of the 1,6-di-hydro-pyridazine ring are essentially coplanar (r.m.s. deviation = 0.008 Å), and the dihedral angle between this and the 1,3,4-thia-diazole ring is 62.06 (10)°. In the crystal, centrosymmetrically related mol-ecules are linked by inter-molecular C-H-O hydrogen bonding to form a supra-molecular dimer. The terminal ethyl group is statistically disordered over two positions.

Novel Sulfoximine Derivatives Containing Cyanoguanidine and Nitroguanidine Moieties: Design, Synthesis, and Bioactivities.

A total of 32 novel sulfoximines bearing cyanoguanidine and nitroguanidine moieties were designed and synthesized by a rational molecule design strategy. The bioactivities of the title compounds were evaluated and the results revealed that some of the target compounds possessed excellent antifungal activities against six agricultural fungi, including Sclerotinia sclerotiorum, Fusarium graminearum, Phytophthora capsici, Botrytis cinerea, Rhizoctonia solani, and Pyricularia grisea. Among them, compounds 8e1 and 8e4 exhibited significant efficacy against P. grisea with EC50 values of 2.72 and 2.98 µg/mL, respectively, which were much higher than that of commercial fungicides boscalid (47.95 µg/mL). Interestingly, in vivo assays determined compound 8e1 possessed outstanding activity against S. sclerotiorum with protective and curative effectiveness of 98 and 95.6% at 50 µg/mL, which were comparable to those of boscalid (93.2, 91.9%). The further preliminary mechanism investigation disclosed that compound 8e1 could damage the structure of the cell membrane of S. sclerotiorum, increase its permeability, and suppress its growth. Overall, the findings enhanced that these novel sulfoximine derivatives could be potential lead compounds for the development of new fungicides.

Metabonomics identifies serum metabolite markers of colorectal cancer.

Recent studies suggest that biofluid-based metabonomics may identify metabolite markers promising for colorectal cancer (CRC) diagnosis. We report here a follow-up replication study, after a previous CRC metabonomics study, aiming to identify a distinct serum metabolic signature of CRC with diagnostic potential. Serum metabolites from newly diagnosed CRC patients (N = 101) and healthy subjects (N = 102) were profiled using gas chromatography time-of-flight mass spectrometry (GC-TOFMS) and ultraperformance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-QTOFMS). Differential metabolites were identified with statistical tests of orthogonal partial least-squares-discriminant analysis (VIP > 1) and the Mann-Whitney U test (p < 0.05). With a total of 249 annotated serum metabolites, we were able to differentiate CRC patients from the healthy controls using an orthogonal partial least-squares-discriminant analysis (OPLS-DA) in a learning sample set of 62 CRC patients and 62 matched healthy controls. This established model was able to correctly assign the rest of the samples to the CRC or control groups in a validation set of 39 CRC patients and 40 healthy controls. Consistent with our findings from the previous study, we observed a distinct metabolic signature in CRC patients including tricarboxylic acid (TCA) cycle, urea cycle, glutamine, fatty acids, and gut flora metabolism. Our results demonstrated that a panel of serum metabolite markers is of great potential as a noninvasive diagnostic method for the detection of CRC.

Design, synthesis, and antifungal activities of novel sulfoximine derivatives for plant protection.

BACKGROUND: Fungicides play a significant role in the integrated management of plant pathogens. However, the irrational application of fungicides with similar structures has led to development of cross-resistance, therefore there is a need to seek novel fungicides with new structures. RESULTS: Twenty-eight novel sulfoximine derivatives incorporating nitroguanidine moieties were designed, synthesized, and evaluated as antifungal agents. The bioassay results indicated that most of the synthesized compounds displayed excellent fungicidal activities against Sclerotinia sclerotiorum, Rhizoctonia solani, Fusarium graminearum, and Pyricularia grisea. Among these, compounds 6c4 , 6c5 , and 6c6 exhibited remarkable fungicidal activities against P. grisea, with EC50 values of 1.28, 1.17, and 1.68 µg mL-1 , respectively. In addition, compound 6c2 displayed the most potent activity against S. sclerotiorum (EC50  = 3.64 µg mL-1 ). Further in vivo fungicidal activity screening against S. sclerotiorum demonstrated that the protective and curative effects of compound 6c2 were 98.1% and 91.3% at 25 µg mL-1 , respectively, comparable to that of boscalid (94.4%, 89.6%). The preliminary mechanism study found that the hyphae of S. sclerotiorum treated with compound 6c2 was abnormal with mycelial collapse and membrane permeability increase. The present findings can help to develop new fungicides for crop protection. CONCLUSION: Novel sulfoximine derivatives containing nitroguanidine possess potential antifungal activity, and the unique structure may offer an alternative option for fungicide development in the future. © 2022 Society of Chemical Industry.

Biodegradable nanomaterials for diagnosis and therapy of tumors.

Although degradable nanomaterials have been widely designed and applied for cancer bioimaging and various cancer treatments, few reviews of biodegradable nanomaterials have been reported. Herein, we have summarized the representative research advances of biodegradable nanomaterials with respect to the mechanism of degradation and their application in tumor imaging and therapy. First, four kinds of tumor microenvironment (TME) responsive degradation are presented, including pH, glutathione (GSH), hypoxia and matrix metalloproteinase (MMP) responsive degradation. Second, external stimulation degradation is summarized briefly. Next, we have outlined the applications of nanomaterials in bioimaging. Finally, we have focused on some typical examples of biodegradable nanomaterials in radiotherapy (RT), photothermal therapy (PTT), starvation therapy, photodynamic therapy (PDT), chemotherapy, chemodynamic therapy (CDT), sonodynamic therapy (SDT), gene therapy, immunotherapy and combination therapy.

Cordyceps militaris polysaccharide alleviates diabetic symptoms by regulating gut microbiota against TLR4/NF-κB pathway.

The relationship between gut microbiota and type 2 diabetes mellitus (T2DM) has attracted increasing attention. In our work, one purified fraction a (AEPSa) was obtained from Cordyceps militaris polysaccharides, and its hypoglycemic activity and underlying mechanisms were investigated in high-fat diet (HFD)- and streptozotocin (STZ)-induced T2DM mice. The results revealed that AEPSa reshaped gut microbiota by increasing Allobaculum, Alistipes, Lachnospiraceae_NK4A136_group and norank_f_Muribaculaceae and decreasing Enterococcus and Ruminococcus_torques_group to inhibit the colonic toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) pathway and upregulate intestinal tight junction protein expression, thereby improving glucose and serum lipid metabolism, hormone secretion and complications. Fecal microbiota transplantation (FMT) also confirmed these findings. These results indicated that symptomatic relief of T2DM might be related to AEPSa regulating the gut microbiota against the TLR4/NF-κB pathway to protect the intestinal barrier. Therefore, AEPSa might be developed as a prebiotic agent against T2DM by regulating gut microbiota.

Menthone Exerts its Antimicrobial Activity Against Methicillin Resistant Staphylococcus aureus by Affecting Cell Membrane Properties and Lipid Profile.

Objective: The characteristic constituents of essential oils from aromatic plants have been widely applied as antimicrobial agents in the last decades. However, their mechanisms of action remain obscure, especially from the metabolic perspective. The aim of the study was to explore the antimicrobial effect and mechanism of menthone, a main component of peppermint oil, against methicillin resistant Staphylococcus aureus (MRSA). Methods: An integrated approach including the microbiology and the high-coverage lipidomics was applied. The changes of membrane properties were studies by the fluorescence and electron microscopical observations. The lipid profile was analyzed by ultra-high performance liquid chromatography coupled with quadruple Exactive mass spectrometry (UHPLC-QE-MS). The lipid-related key targets which were associated with the inhibitory effect of menthone against MRSA, were studied by network analysis and molecular docking. Results: Menthone exhibited antibacterial activities against MRSA, with minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) of 3,540 and 7,080 µg/mL, respectively. The membrane potential and membrane integrity upon menthone treatment were observed to change strikingly. Further, lipids fingerprinting identified 136 significantly differential lipid species in MRSA cells exposed to menthone at subinhibitory level of 0.1× MIC. These metabolites span 30 important lipid classes belonging to glycerophospholipids, glycolipids, and sphingolipids. Lastly, the correlations of these altered lipids, as well as the potential metabolic pathways and targets associated with menthone treatment were deciphered preliminarily. Conclusion: Menthone had potent antibacterial effect on MRSA, and the mechanism of action involved the alteration of membrane structural components and corresponding properties. The interactions of identified key lipid species and their biological functions need to be further determined and verified, for the development of novel antimicrobial strategies against MRSA.

A pH-responsive ZC-QPP hydrogel for synergistic antibacterial and antioxidant treatment to enhance wound healing.

The problems of bacterial resistance and high oxidation level severely limit wound healing. Therefore, we constructed a multifunctional platform of chitosan quaternary ammonium salts (QCS)/polyvinyl alcohol (PVA)/polyethylene glycol (PEG) hydrogels (QPP) loaded with ZnO@CeO2 (ZC-QPP). Firstly, the hydrogel was co-cross-linked by hydrogen and borate ester bonds, which allows easy adherence to a tissue surface for offering a protective barrier and moist environment for wounds. The chitosan quaternary ammonium salts due to their amino groups have inherent antibacterial properties to induce bacterial death. In response to the acidic conditions of the bacterial infection microenvironment, the borate ester bonds in the QPP hydrogel break and the ZC NCs dispersed in the hydrogel are released. The gradual dissociation of Zn2+ under acidic conditions can directly damage bacterial membranes. The wound site of bacterial infection always causes overexpression of reactive oxygen species (ROS) levels, often leading to inflammation and preventing rapid wound repair. CeO2 can eliminate excess ROS to reduce the inflammatory response. From in vitro and in vivo results, the high biosafety of the ZC-QPP hydrogel has demonstrated excellent antibacterial and antioxidant performance to enhance wound healing. Therefore, the ZC-QPP hydrogel opens a method to develop multifunctional synergistic therapeutic platforms combining enzyme-like nanomaterials with hydrogels for synergistic antibacterial and antioxidant treatment to promote wound healing.

Transcriptomic and metabonomic profiling reveal synergistic effects of quercetin and resveratrol supplementation in high fat diet fed mice.

Dietary quercetin and resveratrol have been frequently used in treating various diseases, but the underlying mechanisms are not entirely clear. Here, we report combined transcriptomic and metabonomic profiling that showed that the combined supplementation with quercetin and resveratrol produced synergistic effects on a high-fat diet-induced metabolic phenotype in mice. Histological and phenotypic improvements in serum and hepatic total cholesterol, insulin, fasting blood glucose, and HbA1c were also observed in mice receiving combined quercetin and resveratrol supplementation. This combined quercetin and resveratrol supplementation resulted in significant restoration of gene sets in functional pathways of glucose/lipid metabolism, liver function, cardiovascular system, and inflammation/immunity, which were altered by high fat diet feeding. The integration of transcriptomic and metabonomic data indicated quercetin and resveratrol supplementation enhanced processes of glycolysis and fatty acid oxidation, as well as suppressed gluconeogenesis. These alterations discovered at both the transcriptional and metabolic levels highlight the significance of combined "omics" platforms for elucidating mechanistic pathways altered by dietary polyphenols, such as quercetin and resveratrol, in a synergistic manner.

Metabolic fate of tea polyphenols in humans.

Polyphenols, a ubiquitous group of secondary plant metabolites sharing at least one aromatic ring structure with one or more hydroxyl groups, represent a large group of natural antioxidants abundant in fruits, vegetables, and beverages, such as grape juice, wine, and tea, and are widely considered to contribute to health benefits in humans. However, little is yet known concerning their bioactive forms in vivo and the mechanisms by which they may alter our metabolome, which ultimately contribute toward disease prevention. Here we report a study to determine the metabolic fate of polyphenolic components in a Chinese tea (Pu-erh) in human subjects using a metabonomic profiling approach coupled with multivariate and univariate statistical analysis. Urine samples were collected at 0 h, 1 h, 3 h, 6 h, 9 h, 12 h, and 24 h within the first 24 h and once a day during a 6 week period including a 2 week baseline phase, a 2 week daily Pu-erh tea ingestion phase, and a 2 week "wash-out" phase, and they were analyzed by gas chromatography mass spectrometry and liquid chromatography mass spectrometry. The dynamic concentration profile of bioavailable plant molecules (due to in vivo absorption and the hepatic and gut bacterial metabolism) and the human metabolic response profile were measured and correlated with each other. This study demonstrates that the metabonomic strategy will enable us to integrate the overwhelming amount of metabolic end points as a systems' response to the absorption, metabolism, and disposition of a multicomponent botanical intervention system, leading to a direct elucidation of their mechanisms of action.

Distinct urinary metabolic profile of human colorectal cancer.

A full spectrum of metabolic aberrations that are directly linked to colorectal cancer (CRC) at early curable stages is critical for developing and deploying molecular diagnostic and therapeutic approaches that will significantly improve patient survival. We have recently reported a urinary metabonomic profiling study on CRC subjects (n = 60) and health controls (n = 63), in which a panel of urinary metabolite markers was identified. Here, we report a second urinary metabonomic study on a larger cohort of CRC (n = 101) and healthy subjects (n = 103), using gas chromatography time-of-flight mass spectrometry and ultra performance liquid chromatography quadrupole time-of-flight mass spectrometry. Consistent with our previous findings, we observed a number of dysregulated metabolic pathways, such as glycolysis, TCA cycle, urea cycle, pyrimidine metabolism, tryptophan metabolism, polyamine metabolism, as well as gut microbial-host co-metabolism in CRC subjects. Our findings confirm distinct urinary metabolic footprints of CRC patients characterized by altered levels of metabolites derived from gut microbial-host co-metabolism. A panel of metabolite markers composed of citrate, hippurate, p-cresol, 2-aminobutyrate, myristate, putrescine, and kynurenate was selected, which was able to discriminate CRC subjects from their healthy counterparts. A receiver operating characteristic curve (ROC) analysis of these markers resulted in an area under the receiver operating characteristic curve (AUC) of 0.993 and 0.998 for the training set and the testing set, respectively. These potential metabolite markers provide a novel and promising molecular diagnostic approach for the early detection of CRC.

Integrated Analysis of Gut Microbiome and Lipid Metabolism in Mice Infected with Carbapenem-Resistant Enterobacteriaceae.

The disturbance in gut microbiota composition and metabolism has been implicated in the process of pathogenic bacteria infection. However, the characteristics of the microbiota and the metabolic interaction of commensals−host during pathogen invasion remain more than vague. In this study, the potential associations of gut microbes with disturbed lipid metabolism in mice upon carbapenem-resistant Escherichia coli (CRE) infection were explored by the biochemical and multi-omics approaches including metagenomics, metabolomics and lipidomics, and then the key metabolites−reaction−enzyme−gene interaction network was constructed. Results showed that intestinal Erysipelotrichaceae family was strongly associated with the hepatic total cholesterol and HDL-cholesterol, as well as a few sera and fecal metabolites involved in lipid metabolism such as 24, 25-dihydrolanosterol. A high-coverage lipidomic analysis further demonstrated that a total of 529 lipid molecules was significantly enriched and 520 were depleted in the liver of mice infected with CRE. Among them, 35 lipid species showed high correlations (|r| > 0.8 and p < 0.05) with the Erysipelotrichaceae family, including phosphatidylglycerol (42:2), phosphatidylglycerol (42:3), phosphatidylglycerol (38:5), phosphatidylcholine (42:4), ceramide (d17:1/16:0), ceramide (d18:1/16:0) and diacylglycerol (20:2), with correlation coefficients higher than 0.9. In conclusion, the systematic multi-omics study improved the understanding of the complicated connection between the microbiota and the host during pathogen invasion, which thereby is expected to lead to the future discovery and establishment of novel control strategies for CRE infection.

Association between gut microbiome and metabolome in mice suffering from acute carbapenem-resistant Escherichia coli infection.

Increasing evidence highlighted the metabolic associations between host and gut microbiota during infection. However, how host-gut microbiota metabolic partnership response to carbapenem-resistant Escherichia coli (CRE) infection has yet to be elucidated. In this study, we subjected the mice to a single intraperitoneal injection of CRE and studied the alterations of the small molecule metabolites derived from host-microbial co-metabolism, as well as the gut microbiome in mice, at 24 h after infection by a two-level strategy. A panel of metabolites in feces and serum, were found to alter significantly in the CRE group, including 26 joint metabolites between them. Meanwhile, the relative abundance of 14 OTUs in Firmicutes (10 OTU), Bacteroidetes (2 OTU), Actinomycetes (1 OTU), and Proteobacteria (1 OTU) were observed to change after infection. Association analyses demonstrated that 9 OTUs including six in the Firmicutes phylum, two in the Bacteroidetes phylum, and one in the Actinomycetes phylum, were associated with the changes of 49 fecal metabolites and 42 serum metabolites. The study of gut microbiota-host metabolic interactions in the early stage of the infection is expected to provide novel diagnostic methods and therapeutic strategies for CRE infection, bring innovative solutions to resolve the current challenge.