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32 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2019/10/23PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Related Articles The Effect of Temperature on the Stability of In-Use Insulin Pens. Exp Clin Endocrinol Diabetes. 2019 Oct 21;: Authors: Kongmalai T, Preechasuk L, Junnu S, Manocheewa S, Srisawat C, Sriwijitkamol A Abstract BACKGROUND: Improper storage of insulin could decrease its potency. Manufacturers recommend that in-use insulin pens should be kept at between 25-30°C, but room temperature in tropical countries often exceeds this range. This study investigates the effect of temperature on the stability of basal insulin in cartridges 28 days after opening. METHODS: Four different basal insulins were evaluated. Five opened pens of each insulin type were included for each of three storage conditions and 5 unopened insulin pens of each type were stored in the refrigerator as a control. The opened pens were stored for 28 days in either a refrigerator (2-8 °C), at room temperature, or in an incubator (37 °C). Each day insulin pens were mixed 20 times and 2 units were discarded to mimic daily usage. Insulin quantity was evaluated using an ultra-high-performance liquid chromatography assay. RESULTS: The average room temperature during the study period was 29.7 °C. After 28 days, the percentage amount of insulin stored at refrigerator, room temperature or incubator, compared with control was 99.0, 99.7, 101.1% for long-acting insulin; 97.4, 97.2, 99.0% for NPH-1; 101.4, 101.5, 100.7% for NPH-2; and 98.7, 97.8, 98.5% for NPH-3. There were no statistically significant differences. However, we observed a trend toward different stability between clear insulin analog and turbid NPH insulin. CONCLUSIONS: Temperature as high as 37°C and cyclic temperature,had no effect on the stability of in-use insulin pen. PMID: 31634960 [PubMed - as supplied by publisher]

Related Articles Infective juveniles of entomopathogenic nematodes (Steinernema and Heterorhabditis) secrete ascarosides and respond to interspecific dispersal signals. J Invertebr Pathol. 2019 Oct 18;:107257 Authors: Hartley CJ, Lillis PE, Owens RA, Griffin CT Abstract Ascarosides are a modular series of signalling molecules that are widely conserved in nematodes where they function as pheromones with both behavioural and developmental effects. Here we show that the developmentally arrested infective juvenile (IJ) stage of entomopathogenic nematodes (EPN) secrete ascarosides into the surrounding medium. The exometabolome of Steinernema carpocapsae and Heterorhabditis megidis was examined at 0, 1, 7 and 21 days of storage. The concentration of several ascarosides (ascr#11, ascr#9, ascr#12, ascr#1 and ascr#14 for both species, plus ascr#10 for H. megidis) showed a progressive increase over this period, while the concentration of longer chain ascarosides increased up to day 7, with an apparent decline thereafter. Ascr #9 was the main ascaroside produced by both species. Similar ascarosides were found over a 7-day period for Steinernema longicaudum and S. feltiae. Ascaroside blends have previously been shown to promote nematode dispersal. S. carpocapsae and H. megidis IJs were stored for up to 12 weeks and assayed at intervals. IJs where exometabolome was allowed to accumulate showed higher dispersal rates than those where water was changed frequently, indicating that IJ exometabolome maintained high dispersal. Infectivity was not affected. IJ exometabolome accumulated over 7 days promoted dispersal of freshly harvested IJs, both of their own and other EPN species. Similarly, extracts of nematode-infected cadavers promoted dispersal of con- and heterospecific IJs. Thus, IJs are encouraged to disperse from a source cadaver or from other crowded conditions by public information cues, a finding that may have application in enhancing biocontrol. However, the complexity of the ascaroside blend produced by IJs suggests that it may have ecological functions other than dispersal. PMID: 31634473 [PubMed - as supplied by publisher]

Related Articles Translational Medicine: Exercise Physiology Applied to Metabolic Myopathies. Med Sci Sports Exerc. 2019 Nov;51(11):2183-2192 Authors: Grassi B, Porcelli S, Marzorati M Abstract : The relevance of translational medicine (bringing basic science methods "to the bed of patients") is universally recognized. Too often, however, the tools to be applied translationally are thought to derive only from the "-omics" (genomics, proteomics, transcriptomics, metabolomics, etc.) world. The failures of this "reductionist" approach are widely recognized. In the review, we discuss studies demonstrating that scientifically sound mechanistic insights into diseases, relevant both in terms of basic science and clinically, and very well suited to be utilized within a translational medicine approach, can be obtained from the established field of exercise physiology. Methods originally aimed toward basic physiological mechanisms, and applied for the functional evaluation of athletes and sport performance, can have a valuable translational application in patients with metabolic myopathies; such as myophosphorylase deficiency (McArdle disease) or mitochondrial myopathies, diseases which share the common denominator of an impaired skeletal muscle oxidative metabolism. Several variables can yield pathophysiological insights, can identify and quantify the metabolic impairment and the effects on exercise tolerance (one of the main determinants of the patients' clinical picture and quality of life), and can offer diagnostic clues: the impaired capacity of O2 extraction by skeletal muscle, evaluated by near-infrared spectroscopy; the "exaggerated" cardiovascular response to exercise; the slower speed of adjustment of oxidative metabolism during metabolic transitions; the "slow component" of pulmonary O2 uptake kinetics and the associated reduced efficiency and fatigue; the impaired intramuscular matching between O2 delivery and O2 utilization. The proposed methods are noninvasive, and therefore facilitate repeated or serial evaluations. They provide support for a simple message: physiology and physiological research remain the essential link between genes, molecules, and clinical care. PMID: 31634290 [PubMed - in process]

Related Articles Metabolomics-Based Prospective Studies and Prediction of Type 2 Diabetes Mellitus Risks. Metab Syndr Relat Disord. 2019 Oct 21;: Authors: Satheesh G, Ramachandran S, Jaleel A Abstract The preceding decade has witnessed an intense upsurge in the diabetic population across the world making type 2 diabetes mellitus (T2DM) more of an epidemic than a lifestyle disease. Metabolic disorders are often latent for a while before becoming clinically evident, thus reinforcing the pursuit of early biomarkers of metabolic alterations. A prospective study along with metabolic profiling is the most appropriate way to detect the early pathophysiological changes in metabolic diseases such as T2DM. The aim of this review was to summarize the different potential biomarkers of T2DM identified in prospective studies, which used tools of metabolomics. The review also demonstrates on how metabolomic profiling-based prospective studies can be used to address a concern like population-specific disease mechanism. We performed a literature search on metabolomics-based prospective studies on T2DM using the key words "metabolomics," "Type 2 diabetes," "diabetes mellitus", "metabolite profiling," "prospective study," "metabolism," and "biomarker." Additional articles that were obtained from the reference lists of the articles obtained using the above key words were also examined. Articles on dietary intake, type 1 diabetes mellitus, and gestational diabetes were excluded. The review revealed that many studies showed a direct association of branched-chain amino acids and an inverse association of glycine with T2DM. Majority of the prospective studies conducted were targeted metabolomics-based, with Caucasians as their study cohort. The whole disease risk in populations, including Asians, could therefore not be identified. This review proposes the utility of prospective studies in conjunction with metabolomics platform to unravel the altered metabolic pathways that contribute to the risk of T2DM. PMID: 31634052 [PubMed - as supplied by publisher]

Related Articles The mitochondrial deoxyguanosine kinase is required for cancer cell stemness in lung adenocarcinoma. EMBO Mol Med. 2019 Oct 21;:e10849 Authors: Lin S, Huang C, Sun J, Bollt O, Wang X, Martine E, Kang J, Taylor MD, Fang B, Singh PK, Koomen J, Hao J, Yang S Abstract The mitochondrial deoxynucleotide triphosphate (dNTP) is maintained by the mitochondrial deoxynucleoside salvage pathway and dedicated for the mtDNA homeostasis, and the mitochondrial deoxyguanosine kinase (DGUOK) is a rate-limiting enzyme in this pathway. Here, we investigated the role of the DGUOK in the self-renewal of lung cancer stem-like cells (CSC). Our data support that DGUOK overexpression strongly correlates with cancer progression and patient survival. The depletion of DGUOK robustly inhibited lung adenocarcinoma tumor growth, metastasis, and CSC self-renewal. Mechanistically, DGUOK is required for the biogenesis of respiratory complex I and mitochondrial OXPHOS, which in turn regulates CSC self-renewal through AMPK-YAP1 signaling. The restoration of mitochondrial OXPHOS in DGUOK KO lung cancer cells using NDI1 was able to prevent AMPK-mediated phosphorylation of YAP and to rescue CSC stemness. Genetic targeting of DGUOK using doxycycline-inducible CRISPR/Cas9 was able to markedly induce tumor regression. Our findings reveal a novel role for mitochondrial dNTP metabolism in lung cancer tumor growth and progression, and implicate that the mitochondrial deoxynucleotide salvage pathway could be potentially targeted to prevent CSC-mediated therapy resistance and metastatic recurrence. PMID: 31633874 [PubMed - as supplied by publisher]

Related Articles Development of a gas chromatography-mass spectrometry method for breast cancer diagnosis based on nucleoside metabolomes 1-methyl adenosine, 1-methylguanosine, and 8-hydroxy-2'-deoxyguanosine. Biomed Chromatogr. 2019 Oct 21;:e4713 Authors: Omran MM, Rashed RE, Darwish H, Belal AA, Mohamed FZ Abstract Metabolomes are small molecule metabolites (<1000 Da) produced by cellular processes. Metabolomes are close counterparts to the genome, transcriptome, and proteome. The aim of this study was to develop a method to detect and quantify candidate nucleoside metabolomes 1-methyl adenosine (1-MA), 1-methylguanosine (1-MG), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) in the urine of patients with breast cancer using gas chromatography-mass spectrometry (GC-MS). The method was applied to urine specimens from patients with breast cancer (n=56) and benign breast tumors (n=22), as well as from healthy females (n=20). The relative standard deviations of precision and repeatability analysis were <10%, and recoveries ranged from 88.5% to 105.6%. Limits of detection were 0.014, 0.012, and 0.018 mg/L for 1-MA, 1-MG, and 8-OHdG, respectively. The lower limits of quantitation were 0.056, 0.048, and 0.072 mg/L, respectively. There were significant differences in concentrations of candidate metabolomes between patients with cancer and the healthy individuals, especially for those in the early stages of the disease (p<0.001). No significant differences were observed between the benign and healthy groups. In conclusion, a reliable GC-MS method for detection and quantification of 1-MA, 1-MG, and 8-OHdG metabolomes in urine has been developed. PMID: 31633807 [PubMed - as supplied by publisher]

Related Articles Dimethylaminomicheliolide (DMAMCL) Suppresses the Proliferation of Glioblastoma Cells via Targeting Pyruvate Kinase 2 (PKM2) and Rewiring Aerobic Glycolysis. Front Oncol. 2019;9:993 Authors: Guo J, Xue Q, Liu K, Ge W, Liu W, Wang J, Zhang M, Li QY, Cai D, Shan C, Zhang C, Liu X, Li J Abstract Glioblastoma (GBM) is the most prevalent malignant tumor in the central nervous system. Aerobic glycolysis, featured with elevated glucose consumption and lactate production, confers selective advantages on GBM by utilizing nutrients to support rapid cell proliferation and tumor growth. Pyruvate kinase 2 (PKM2), the last rate-limiting enzyme of glycolysis, is known to regulate aerobic glycolysis, and considered as a novel cancer therapeutic target. Herein, we aim to describe the cellular functions and mechanisms of a small molecular compound dimethylaminomicheliolide (DMAMCL), which has been used in clinical trials for recurrent GBM in Australia. Our results demonstrate that DMAMCL is effective on the inhibition of GBM cell proliferation and colony formation. MCL, the active metabolic form of DMAMCL, selectively binding to monomeric PKM2 and promoting its tetramerization, was also found to improve the pyruvate kinase activity of PKM2 in GBM cells. In addition, non-targeting metabolomics analysis reveals multiple metabolites involved in glycolysis, including lactate and glucose-6-phosphate, are decreased with DMAMCL treatment. The inhibitory effects of DMAMCL are observed to decrease in GBM cells upon PKM2 depletion, further confirming the importance of PKM2 in DMAMCL sensitivity. In conclusion, the activation of PKM2 by DMAMCL results in the rewiring aerobic glycolysis, which consequently suppresses the proliferation of GBM cells. Hence, DMAMCL represents a potential PKM2-targeted therapeutic agent against GBM. PMID: 31632919 [PubMed]

Related Articles The aqueous extract of Lycopus lucidus Turcz exerts protective effects on podocytes injury of diabetic nephropathy via inhibiting TGF-β1 signal pathway. Am J Transl Res. 2019;11(9):5689-5702 Authors: Xie S, Ge F, Yao Y, Zhang W, Wang S, Zhang M, Zhong R, Fang L, Qu D Abstract Diabetic nephropathy (DN) is known as a major microvascular complication leading cause of end-stage renal disease, it generally followed by the process of podocyte fragmentation and detachment. Transforming growth factor β1 (TGF-β1) signaling pathway plays a pivotal role in the initiation and progression of DN. In present study, we aim to investigate the effect of lycopus extracts on podocytes injury and TGF-β signaling. In present study, lycopus extracts treatment abolished the gain in blood glucose and body weight in a dose dependent manner and possessed protective effect on the renal damage, which was indicated by the decreased concentration of Scr, BUN and urine creatinine of serum. Histopathological examination also demonstrated lycopus extracts exert protective effect on renal damage. Western blotting and immunohistochemical results revealed lycopus extracts treatment upregulated the expression of nephrin and down-regulated the expression levels of TGF-β1 and Smad4. Moreover, lycopus extracts treatment suppressed TGF-β1-induced phosphorylation of Smad2/3, ERK1/2 and p38 both in vivo and vitro. In conclusion, lycopus extracts is a novel agent that ameliorate podocytes injury by inhibiting TGF-β signaling pathway and possess potential therapeutic effect on renal damage of DN rats. PMID: 31632540 [PubMed]

Related Articles Microfluidics and Metabolomics Reveal Symbiotic Bacterial-Fungal Interactions Between Mortierella elongata and Burkholderia Include Metabolite Exchange. Front Microbiol. 2019;10:2163 Authors: Uehling JK, Entler MR, Meredith HR, Millet LJ, Timm CM, Aufrecht JA, Bonito GM, Engle NL, Labbé JL, Doktycz MJ, Retterer ST, Spatafora JW, Stajich JE, Tschaplinski TJ, Vilgalys RJ Abstract We identified two poplar (Populus sp.)-associated microbes, the fungus, Mortierella elongata strain AG77, and the bacterium, Burkholderia strain BT03, that mutually promote each other's growth. Using culture assays in concert with a novel microfluidic device to generate time-lapse videos, we found growth specific media differing in pH and pre-conditioned by microbial growth led to increased fungal and bacterial growth rates. Coupling microfluidics and comparative metabolomics data results indicated that observed microbial growth stimulation involves metabolic exchange during two ordered events. The first is an emission of fungal metabolites, including organic acids used or modified by bacteria. A second signal of unknown nature is produced by bacteria which increases fungal growth rates. We find this symbiosis is initiated in part by metabolic exchange involving fungal organic acids. PMID: 31632357 [PubMed]

Related Articles Synergistic Combination of Polymyxin B and Enrofloxacin Induced Metabolic Perturbations in Extensive Drug-Resistant Pseudomonas aeruginosa. Front Pharmacol. 2019;10:1146 Authors: Lin YW, Han ML, Zhao J, Zhu Y, Rao G, Forrest A, Song J, Kaye KS, Hertzog P, Purcell A, Creek D, Zhou QT, Velkov T, Li J Abstract Polymyxins are used as a last-resort class of antibiotics against multidrug-resistant (MDR) Gram-negative Pseudomonas aeruginosa. As polymyxin monotherapy is associated with potential development of resistance, combination therapy is highly recommended. This study investigated the mechanism underlying the synergistic killing of polymyxin B and enrofloxacin against extensive drug-resistant (XDR) P. aeruginosa. An XDR isolate P. aeruginosa 12196 was treated with clinically relevant concentrations of polymyxin B (2 mg/L) and enrofloxacin (1 mg/L) alone or in combination. Metabolome profiles were investigated from bacterial samples collected at 1-and 4-h posttreatment using liquid chromatography with tandem mass spectrometry (LC-MS/MS), and data were analyzed using univariate and multivariate statistics. Significantly perturbed metabolites (q < 0.05, fold change ≥ 2) were subjected to pathway analysis. The synergistic killing by polymyxin B-enrofloxacin combination was initially driven by polymyxin B as indicated by the perturbation of lipid metabolites at 1 h in particular. The killing was subsequently driven by enrofloxacin via the inhibition of DNA replication, resulting in the accumulation of nucleotides at 4 h. Furthermore, the combination uniquely altered levels of metabolites in energy metabolism and cell envelope biogenesis. Most importantly, the combination significantly minimized polymyxin resistance via the inhibition of lipid A modification pathway, which was most evident at 4 h. This is the first study to elucidate the synergistic mechanism of polymyxin B-enrofloxacin combination against XDR P. aeruginosa. The metabolomics approach taken in this study highlights its power to elucidate the mechanism of synergistic killing by antibiotic combinations at the systems level. PMID: 31632279 [PubMed]

Related Articles Closing the Gap Between Therapeutic Use and Mode of Action in Remedial Herbs. Front Pharmacol. 2019;10:1132 Authors: Olivés J, Mestres J Abstract The ancient tradition of taking parts of a plant or preparing plant extracts for treating certain discomforts and maladies has long been lacking a scientific rationale to support its preparation and still widespread use in several parts of the world. In an attempt to address this challenge, we collected and integrated data connecting metabolites, plants, diseases, and proteins. A mechanistic hypothesis is generated when a metabolite is known to be present in a given plant, that plant is known to be used to treat a certain disease, that disease is known to be linked to the function of a given protein, and that protein is finally known or predicted to interact with the original metabolite. The construction of plant-protein networks from mutually connected metabolites and diseases facilitated the identification of plausible mechanisms of action for plants being used to treat analgesia, hypercholesterolemia, diarrhea, catarrh, and cough. Additional concrete examples using both experimentally known and computationally predicted, and subsequently experimentally confirmed, metabolite-protein interactions to close the connection circle between metabolites, plants, diseases, and proteins offered further proof of concept for the validity and scope of the approach to generate mode of action hypotheses for some of the therapeutic uses of remedial herbs. PMID: 31632273 [PubMed]

Related Articles The Immune-Modulator Pidotimod Affects the Metabolic Profile of Exhaled Breath Condensate in Bronchiectatic Patients: A Metabolomics Pilot Study. Front Pharmacol. 2019;10:1115 Authors: D'Amato M, Paris D, Molino A, Cuomo P, Fulgione A, Sorrentino N, Palomba L, Maniscalco M, Motta A Abstract Introduction: Pidotimod, a synthetic dipeptide molecule with biological and immunological activities, is used to reduce the number of exacerbations or pneumonitis in patients with inflammatory diseases. In the present study, we investigated whether Pidotimod modifies the metabolomic pathways measured in the exhaled breath condensate (EBC) of non-cystic fibrosis bronchiectatic patients (NCFB). Materials and Methods: We analyzed 40 adult patients affected by NCFB. They were randomly selected to receive Pidotimod 800 mg b/d for 21 consecutive days (3 weeks) per month for 6 months (20 patients, V1 group) or no drug (20 patients, V0 group), with a 1:1 criterion and then followed as outpatients. Results: EBC samples were collected from all patients at baseline and after 6 months. They were investigated by combined nuclear magnetic resonance (NMR) spectroscopy and multivariate statistical analysis to uncover metabolic differences between EBC from NCFB patients before and after therapy with Pidotimod. Pulmonary function test and pulmonary exacerbations were analyzed at baseline and at the end of Pidotimod therapy. The EBC metabolites were all identified, and through statistical evaluation, we were able to discriminate the two samples' classes, with acetate, acetoin, lactate, and citrate as statistically significant discriminatory metabolites. The model vas validated by using a blind set of 20 NCFB samples, not included in the primary analysis. No differences were observed in PFT after 6 months. At the end of the study, there was a significant decrease of exacerbation rate in V1 group as compared with V0 group, with a substantial reduction of the number of mild or severe exacerbations (p < 0.001). Discussion: Pidotimod modifies the respiratory metabolic phenotype ("metabotype") of NCFB patients and reduces the number of exacerbations. PMID: 31632269 [PubMed]

Related Articles Amino Acid-Based Metabolic Indexes Identify Patients With Chronic Obstructive Pulmonary Disease And Further Discriminates Patients In Advanced BODE Stages. Int J Chron Obstruct Pulmon Dis. 2019;14:2257-2266 Authors: Kuo WK, Liu YC, Chu CM, Hua CC, Huang CY, Liu MH, Wang CH Abstract Background: The BODE index is a multidimensional grading system for predicting the prognoses of patients with chronic obstructive pulmonary disease (COPD). This study investigated whether an amino acids-based metabolic profile developed for heart failure patients (including histidine, ornithine, phenylalanine, and leucine) could identify COPD patients and further discriminates COPD patients in advanced BODE stages. Methods: Ultra-performance liquid chromatography was performed on 119 participants, including 75 COPD patients at different BODE stages and 44 normal controls. Albumin, pre-albumin, transferrin, high sensitivity C-reactive protein, and hand grip strength were also measured. Receiver operating characteristic curves and area under curves were used for estimation. Results: The BODE points in our patients were 3.29 [95% confidence interval (CI) = 2.74-3.85]. Compared to normal controls, COPD patients had lower leucine but higher ornithine levels. A COPD score, developed based on leucine and ornithine, significantly discriminated COPD from normal controls [odds ratio (OR) = 2.71, 95% CI = 1.83-4.04, p <0.001]. A COPD score of ≥ 3.00 had an OR of 15.58 (95% CI = 5.96-40.73, p <0.001). In COPD patients from BODE 1 to BODE 4, the levels of histidine, ornithine and phenylalanine increased significantly. In multivariable analysis, histidine and phenylalanine were independently able to distinguish BODE stages 3 and 4 from BODE 1 and were adopted to develop a metabolic score. Metabolic scores identified patients at BODE 3 and 4 (OR = 2.74, 95% CI =1.41-5.29, p = 0.003) better than hand grip strength, high sensitive C-reactive protein, albumin, pre-albumin, and transferrin value. A metabolic score of ≥9.53 significantly discriminated BODE 3 and 4 from BODE 1 and 2 (OR = 8.56, 95% CI = 2.77-26.39, p <0.001). Conclusion: Amino acid-based COPD score and metabolic score discriminate COPD patients from normal controls, and identify patients in advanced stages of COPD. PMID: 31631995 [PubMed - in process]

Related Articles Amino acids signatures of distance-related surgical margins of oral squamous cell carcinoma. EBioMedicine. 2019 Oct 17;: Authors: Yang XH, Zhang XX, Jing Y, Ding L, Fu Y, Wang S, Hu SQ, Zhang L, Huang XF, Ni YH, Hu QG Abstract BACKGROUND: Histological assessment of resected margins has some drawbacks. We therefore aimed to identify a panel of metabolic markers for evaluating the surgical margins of oral squamous cell carcinoma during surgery. METHODS: A total of 28 case of OSCC samples were enrolled in the study. Gas chromatography-mass spectrometry based untargeted metabolic analysis was employed to acquire the metabolic perturbation of the distance-related surgical margins in the development group. The acquired MS data were then subjected to univariate and multivariate analysis by MetaboAnalyst. Ultra-high performance liquid chromatography-tandem mass spectrometerbased targeted metabolomics for quantitative analysis of the validation group was performed to verify the results of the development group. Another 60 OSCC patients with dysplastic surgical margins were used to further validate the results of the development group by immunohistochemical examination of key enzyme expression, and correlate them with clinicopathological parameters and clinical outcomes. FINDINGS: We finally identified 4 amino acids as negative margin markers, and 6 amino acids as dysplastic margin markers. IHC analysis showed that asparagine synthetase positive expression in dysplastic surgical margins and its higher expression was correlated with tumor recurrence and local relapse-free survival. INTERPRETATIONS: We developed a panel of metabolic molecular markers to supplement the evaluation of negative and dysplastic margins. FUND: This study was supported by Nanjing Municipal Key Medical Laboratory Constructional Project Funding (Since 2012); Center of Nanjing Clinical Medicine Tumor (Since 2014). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. PMID: 31631041 [PubMed - as supplied by publisher]

Related Articles Monitoring glycation levels of a bispecific monoclonal antibody at subunit level by ultrahigh resolution MALDI FT-ICR mass spectrometry. MAbs. 2019 Oct 21;: Authors: Gstöttner C, Reusch D, Haberger M, Dragan I, van Veelen P, Kilgour DPA, Tsybin YO, van der Burgt YEM, Wuhrer M, Nicolardi S Abstract Bispecific monoclonal antibodies (BsAbs) are engineered proteins with multiple functionalities and properties. The "bi-specificity" of these complex biopharmaceuticals is a key characteristic for the development of novel and more effective therapeutic strategies. The high structural complexity of BsAbs poses a challenge to the analytical methods needed for their characterization. Modifications of the BsAb structure, resulting from enzymatic and non-enzymatic processes, further complicate the analysis. An important example of the latter type of modification is glycation, which can occur in the manufacturing process, during storage in formulation or in vivo after application of the drug. Glycation affects the structure, function and stability of monoclonal antibodies, and consequently, detailed analysis of glycation levels is required. Mass spectrometry (MS) plays a key role in the structural characterization of monoclonal antibodies and top-down, middle-up and middle-down MS approaches are increasingly used for the analysis of modifications. Here, we apply a novel middle-up strategy, based on IdeS digestion and matrix-assisted laser desorption ionization (MALDI) Fourier transform ion cyclotron resonance (FT-ICR) MS, to analyze all six different BsAb subunits in a single high-resolution mass spectrum, namely two light chains, two half fragment crystallizable regions and two Fd' regions, thus avoiding upfront chromatography. This method was used to monitor glycation changes during a 168h forced-glycation experiment. In addition, hot spot glycation sites were localized using top-down and middle-down MALDI-in-source decay FT-ICR MS, which provided complementary information compared to standard bottom-up MS. PMID: 31630606 [PubMed - as supplied by publisher]

Related Articles Therapeutic potential of natural products in glioblastoma treatment: targeting key glioblastoma signaling pathways and epigenetic alterations. Clin Transl Oncol. 2019 Oct 19;: Authors: Abbas MN, Kausar S, Cui H Abstract Glioma is the most common primary tumor of the nervous system, and approximately 50% of patients exhibit the most aggressive form of the cancer, glioblastoma. Currently, considerable research in glioblastoma therapeutics is aimed at developing vaccines or drugs to target key molecules for combating this disease. Studies on plant natural products from spices, vegetables, fruits, teas, and traditional medicinal herbs display that these plant-derived natural products can act as effective antioxidant and anti-tumor agents. The advancements in metabolomics and in genomics have enabled researchers to better evaluate the potential use of immunomodulatory natural plant products for treatment of different cancerous diseases. The glioblastoma protective activities of the different natural plant products lie in their effects on cellular defenses such as antioxidant enzyme systems, detoxification and the stimulation of anti-inflammatory, anti-metastasis responses and by modifying epigenetic alterations, often through targeting specific key transcription factors such as activator protein, nuclear factor kappa B, signal transducers and activators of transcription and so on. Here, we review recent knowledge on the molecular mechanisms by which different inflammatory activities are linked to progression of glioblastoma and the particular immunomodulatory plant products that may reduce inflammation and the associated progression and metastasis of glioblastoma both in vitro and in vivo. Furthermore, their impact on the epigenetic alterations will also be discussed. PMID: 31630356 [PubMed - as supplied by publisher]

Related Articles Gas Chromatography-Mass Spectrometry Analysis of Urinary Steroid Metabolomics for Detection of Early Signs of Adrenal Neoplasm Malignancy in Patients with Cushing's Syndrome. Bull Exp Biol Med. 2019 Oct 19;: Authors: Velikanova LI, Shafigullina ZR, Vorokhobina NV, Malevanaya EV Abstract The metabolomics of urinary steroids was studied by gas chromatography-mass spectrometry in 25 patients with Cushing's syndrome without malignant potential and in 12 patients with malignant potential of adrenal neoplasms (Weiss score 1-3). Patients with adrenocortical adenoma (N=24) constituted the control group. In patients with Cushing's syndrome and malignant potential, increased urinary excretion of 16-oxo-androstendiol, tetrahydro-11-deoxycortisol, and 16-hydroxypregnendiol, which had 100% specificity and sensitivity >90% for the diagnosis of malignant potential. Additionally, non-classical 5-ene-pregnenes (16-OHpregnenolone, 21-OH-pregnenolone, 3β,16,20-pregnentriol, and 3β,17,20-pregnentriol) were identified. The revealed changes in the metabolomics of steroids can be early signs of malignant potential in patients with Cushing's syndrome. In patients with malignant potential, three signs of reduced activity of 11β-hydroxysteroid dehydrogenase type 2 were detected and in patients without malignant potential, one sign was found. In patients with and without malignant potential, three signs increased activity of 5β-reductase were found. PMID: 31630306 [PubMed - as supplied by publisher]

Related Articles Phenotyping reproductive stage chilling and frost tolerance in wheat using targeted metabolome and lipidome profiling. Metabolomics. 2019 Oct 20;15(11):144 Authors: Cheong BE, Ho WWH, Biddulph B, Wallace X, Rathjen T, Rupasinghe TWT, Roessner U, Dolferus R Abstract INTRODUCTION: Frost events lead to A$360 million of yield losses annually to the Australian wheat industry, making improvement of chilling and frost tolerance an important trait for breeding. OBJECTIVES: This study aimed to use metabolomics and lipidomics to explore genetic variation in acclimation potential to chilling and to identify metabolite markers for chilling tolerance in wheat. METHODS: We established a controlled environment screening assay that is able to reproduce field rankings of wheat germplasm for chilling and frost tolerance. This assay, together with targeted metabolomics and lipidomics approaches, were used to compare metabolite and lipid levels in flag leaves of two wheat varieties with contrasting chilling tolerance. RESULTS: The sensitive variety Wyalkatchem showed a strong reduction in amino acids after the first cold night, followed by accumulation of osmolytes such as fructose, glucose, putrescine and shikimate over a 4-day period. Accumulation of osmolytes is indicative of acclimation to water stress in Wyalkatchem. This response was not observed for tolerant variety Young. The two varieties also displayed significant differences in lipid accumulation. Variation in two lipid clusters, resulted in a higher unsaturated to saturated lipid ratio in Young after 4 days cold treatment and the lipids PC(34:0), PC(34:1), PC(35:1), PC(38:3), and PI(36:4) were the main contributors to the unsaturated to saturated ratio change. This indicates that Young may have superior ability to maintain membrane fluidity following cold exposure, thereby avoiding membrane damage and water stress observed for Wyalkatchem. CONCLUSION: Our study suggests that metabolomics and lipidomics markers could be used as an alternative phenotyping method to discriminate wheat varieties with differences in cold acclimation. PMID: 31630279 [PubMed - in process]

Related Articles Metabolomic identification of novel diagnostic biomarkers in ectopic pregnancy. Metabolomics. 2019 Oct 19;15(11):143 Authors: Turkoglu O, Citil A, Katar C, Mert I, Kumar P, Yilmaz A, Uygur DS, Erkaya S, Graham SF, Bahado-Singh RO Abstract INTRODUCTION: Ectopic pregnancy (EP) is a potentially life-threatening condition and early diagnosis still remains a challenge, causing a delay in management leading to tubal rupture. OBJECTIVES: To identify putative plasma biomarkers for the detection of tubal EP and elucidate altered biochemical pathways in EP compared to intrauterine pregnancies. METHODS: This case-control study included prospective recruitment of 39 tubal EP cases and 89 early intrauterine pregnancy controls. Plasma samples were biochemically profiled using proton nuclear magnetic resonance spectroscopy (1H NMR). To avoid over-fitting, datasets were randomly divided into a discovery group (26 cases vs 60 controls) and a test group (13 cases and 29 controls). Logistic regression models were developed in the discovery group and validated in the independent test group. Area under the receiver operating characteristics curve (AUC), 95% confidence interval (CI), sensitivity, and specificity values were calculated. RESULTS: In total 13 of 43 (30.3%) metabolite concentrations were significantly altered in EP plasma (p < 0.05). Metabolomic profiling yielded significant separation between EP and controls (p < 0.05). Independent validation of a two-metabolite model consisting of lactate and acetate, achieved an AUC (95% CI) = 0.935 (0.843-1.000) with a sensitivity of 92.3% and specificity of 96.6%. The second metabolite model (D-glucose, pyruvate, acetoacetate) performed well with an AUC (95% CI) = 0.822 (0.657-0.988) and a sensitivity of 84.6% and specificity of 86.2%. CONCLUSION: We report novel metabolomic biomarkers with a high accuracy for the detection of EP. Accurate biomarkers could potentially result in improved early diagnosis of tubal EP cases. PMID: 31630278 [PubMed - in process]