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1.
Leonurine affected homocysteine-methionine metabolism based on metabolomics and gut microbiota studies of clinical trial samples.
Liao, J, Suguro, R, Zhao, X, Yu, Y, Cui, Y, Zhu, YZ
Clinical and translational medicine. 2021;(10):e535
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2.
Brain on food: The neuroepigenetics of nutrition.
Vaziri, A, Dus, M
Neurochemistry international. 2021;:105099
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Abstract
Humans have known for millennia that nutrition has a profound influence on health and disease, but it is only recently that we have begun mapping the mechanisms via which the dietary environment impacts brain physiology and behavior. Here we review recent evidence on the effects of energy-dense and methionine diets on neural epigenetic marks, gene expression, and behavior in invertebrate and vertebrate model organisms. We also discuss limitations, open questions, and future directions in the emerging field of the neuroepigenetics of nutrition.
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3.
Final Results of the Prospective Biomarker Trial PETra: [11C]-MET-Accumulation in Postoperative PET/MRI Predicts Outcome after Radiochemotherapy in Glioblastoma.
Seidlitz, A, Beuthien-Baumann, B, Löck, S, Jentsch, C, Platzek, I, Zöphel, K, Linge, A, Kotzerke, J, Petr, J, van den Hoff, J, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2021;(5):1351-1360
Abstract
PURPOSE This prospective trial investigates the association of time to recurrence (TTR) in glioblastoma with [11C]methionine (MET) tracer uptake before postoperative radiochemotherapy (RCT) aiming to guide radiotherapy boost regions. EXPERIMENTAL DESIGN Between 2013 and 2016, 102 patients with glioblastoma were recruited. RCT was performed with concurrent and adjuvant temozolomide to a total dose of 60 Gy. Tumor residues in postresection PET and MRI were together defined as gross tumor volumes for radiotherapy treatment planning. [11C]methionine (MET)-PET/MRI was performed before RCT and at each follow-up. RESULTS The primary hypothesis of a longer TTR for patients without increased tracer accumulation in postoperative MET-PET was confirmed in 89 patients. With 18.9 months (95% confidence interval, 9.3-28.5 months), median TTR was significantly (P < 0.001) longer for patients without (n = 29, 32.6%) as compared with 6.3 months (3.6-8.9) for patients with MET accumulation (n = 60, 67.4%) in pre-RCT PET. Although MRI often did not detect all PET-positive regions, an unfavorable impact of residual tumor in postsurgical MRI (n = 38, 42.7%) on TTR was observed [4.6 (4.2-5.1) vs. 15.5 months (6.0-24.9), P < 0.001]. Significant multivariable predictors for TTR were MRI positivity, PET-positive volume, and O6-methylguanine DNA methyltransferase (MGMT) hypermethylation. CONCLUSIONS Postsurgical amino acid PET has prognostic value for TTR after RCT in glioblastoma. Because of the added value of the metabolic beyond the pure structural information, it should complement MRI in radiotherapy planning if available with reasonable effort, at least in the context of maximal therapy. Furthermore, the spatial correlation of regions of recurrence with PET-positive volumes could provide a bioimaging basis for further trials, for example, testing local radiation dose escalation.
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4.
Oral Methioninase for Covid-19 Methionine-restriction Therapy.
Hoffman, RM, Han, Q
In vivo (Athens, Greece). 2020;(3 Suppl):1593-1596
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Abstract
The Covid-19 pandemic is a world-wide crisis without an effective therapy. While most approaches to therapy are using repurposed drugs that were developed for other diseases, it is thought that targeting the biology of the SARS-CoV-2 virus, which causes Covid-19, can result in an effective therapeutic treatment. The coronavirus RNA cap structure is methylated by two viral methyltransferases that transfer methyl groups from S-adenosylmethionine (SAM). The proper methylation of the virus depends on the level of methionine in the host to form SAM. Herein, we propose to restrict methionine availability by treating the patient with oral recombinant methioninase, aiming to treat Covid-19. By restricting methionine we not only interdict viral replication, which depends on the viral RNA cap methyaltion, but also inhibit the proliferation of the infected cells, which have an increased requirement for methionine. Most importantly, the virally-induced T-cell- and macrophage-mediated cytokine storm, which seems to be a significant cause for Covid-19 deaths, can also be inhibited by restricting methionine, since T-cell and macrophrage activation greatly increases the methionine requirement for these cells. The evidence reviewed here suggests that oral recombinant methioninase could be a promising treatment for coronavirus patients.
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Association of Homocysteine, Methionine, and MTHFR 677C>T Polymorphism With Rate of Cardiovascular Multimorbidity Development in Older Adults in Sweden.
Calderón-Larrañaga, A, Saadeh, M, Hooshmand, B, Refsum, H, Smith, AD, Marengoni, A, Vetrano, DL
JAMA network open. 2020;(5):e205316
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Abstract
IMPORTANCE Strong evidence links high total serum homocysteine (tHcy) and low methionine (Met) levels with higher risk of ischemic disease, but other cardiovascular (CV) diseases may also be associated with their pleiotropic effects. OBJECTIVES To investigate the association of serum concentrations of tHcy and Met with the rate of CV multimorbidity development in older adults and to explore the role of methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism in this association. DESIGN, SETTING, AND PARTICIPANTS The Swedish National Study on Aging and Care in Kungsholmen is a cohort study of randomly selected individuals aged 60 years or older. The present study included data on 1969 individuals with complete information and without CV diseases at baseline, collected from the baseline examination (2001-2004) to the fourth follow-up (2013-2016). Data analysis was conducted from January to May 2019. EXPOSURES Concentrations of tHcy and Met were measured from nonfasting venous blood samples. The Met:tHcy ratio was considered a possible indicator of methylation activity. MTHFR status was dichotomized as any T carriers vs noncarriers. MAIN OUTCOME AND MEASURES The number of CV diseases at each wave was ascertained based on medical interviews and records, laboratory test results, and drug data. Linear mixed models were used to study the association of baseline tHcy and Met levels and the rate of CV multimorbidity development, adjusting for sociodemographic characteristics, CV risk factors, chronic disease burden, and drug use. RESULTS Of 1969 participants, most were women (1261 [64.0%]), with a mean (SD) age of 70.9 (9.8) years; 1703 participants (86.6%) had at least a high school level of education. Baseline measurements of serum tHcy, Met, and the Met:tHcy ratio were associated with the rate of CV disease accumulation (tHcy: β = 0.023 per year; 95% CI, 0.015 to 0.030; P < .001; Met: β = -0.007 per year; 95% CI, -0.013 to -0.001; P = .02; Met:tHcy ratio: β = -0.017 per year; 95% CI, -0.023 to -0.011; P < .001). The association between low Met concentrations and the rate of CV multimorbidity development was restricted to the group with CT/TT alleles of MTHFR (β = 0.023 per year; 95% CI, 0.006 to 0.041; P = .009). Results remained largely significant when individual CV diseases were removed from the total count 1 at a time (eg, ischemic heart disease, tHcy: β = 0.023 per year; 95% CI, 0.013 to 0.027; P < .001; Met: β = -0.006 per year; 95% CI, -0.011 to -0.0003; P = .04; Met:tHcy ratio: β = -0.015 per year; 95% CI, -0.020 to -0.009; P < .001). CONCLUSIONS AND RELEVANCE In this study, high tHcy and low Met levels were associated with faster CV multimorbidity development in older age. The interactive association of Met concentrations and MTHFR polymorphism, together with the association found for the Met:tHcy ratio, point toward the relevance of impaired methylation in the pathogenesis of CV aging.
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Reduction of ureteral stent encrustation by modulating the urine pH and inhibiting the crystal film with a new oral composition: a multicenter, placebo controlled, double blind, randomized clinical trial.
Torrecilla, C, Fernández-Concha, J, Cansino, JR, Mainez, JA, Amón, JH, Costas, S, Angerri, O, Emiliani, E, Arrabal Martín, MA, Arrabal Polo, MA, et al
BMC urology. 2020;(1):65
Abstract
BACKGROUND Encrustation of ureteral double J stents is a common complication that may affect its removal. The aim of the proposed study is to evaluate the efficacy and safety of a new oral composition to prevent double J stent encrustation in indwelling times up to 8 weeks. METHODS A double-blinded, multicenter, placebo-controlled trial was conducted with 105 patients with indwelling double J stents enrolled across 9 public hospitals in Spain. The patients were randomly assigned (1:1) into intervention (53 patients) or placebo (52 patients) groups for 3 to 8 weeks and both groups self-monitored daily their morning urine pH levels. The primary outcome of analysis was the degree of stent ends encrustation, defined by a 4-point score (0 - none; 3 - global encrustation) using macroscopic and electron microscopy analysis of crystals, after 3 to 8-w indwelling period. Score was exponentially transformed according to calcium levels. Secondary endpoints included urine pH decrease, stent removal, and incidence of adverse events. RESULTS The intervention group benefits from a lower global encrustation rate of stent ends than placebo group (1% vs 8.2%; p < 0.018). Mean encrustation score was 85.12 (274.5) in the placebo group and 18.91 (102.27) in the intervention group (p < 0.025). Considering the secondary end points, treated patients reported greater urine pH decreases (p = 0.002). No differences in the incidence of adverse events were identified between the groups. CONCLUSIONS Our data suggest that the use of this new oral composition is beneficial in the context of ureteral double J indwelling by decreasing mean, as well as global encrustation. TRIAL REGISTRATION This trial was registered at www.clinicaltrials.gov under the name "Combined Use of a Medical Device and a Dietary Complement in Patient Urinary pH Control in Patients With an Implanted Double J Stent" with date 2nd November 2017, code NCT03343275, and URL.
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The diagnostic performance of 99mTc-methionine single-photon emission tomography in grading glioma preoperatively: a comparison with histopathology and Ki-67 indices.
Rani, N, Singh, B, Kumar, N, Singh, P, Hazari, PP, Jaswal, A, Gupta, SK, Chhabra, R, Radotra, BD, Mishra, AK
Nuclear medicine communications. 2020;(9):848-857
Abstract
OBJECTIVE To characterize glioma preoperatively using quantitative 99mTc-methionine SPECT and comparison with MR-perfusion/spectroscopy and histopatholgical/Ki-67 scoring. METHODS Twenty-nine patients (21M: 8F; mean age 42.3 ± 10.5 years) with clinical and radiological suspicion of glioma assessed by 99mTc-MDM/SPECT and ceMRI. Additionally, 12/29 patients underwent dynamic susceptibility contrast-enhanced (DSCE) MRI and magnetic resonance spectroscopy (MRS) examination. Three patients with benign pathologies were recruited as controls. Histopathological tumor analysis was done in all (n = 29) the patients, and the Ki-67 index was evaluated in 20/29 patients. The target-to-nontarget (T/NT) methionine tumor uptake ratios, normalized cerebral blood volume (nCBV) and metabolites [choline/N-acetyl aspartate (Cho/NAA), Cho/creatine (Cr), Cr/NAA and Cr/Cho) ratios were measured in tumor areas. RESULTS On histopathological analysis, 26/29 patients had glioma (G IV-13; G III-04; G II-09). The mean T/NT ratio in G-II was significantly lower (2.46 ± 2.3) than in G-III (7.13 ± 2.2) and G-IV (5.16 ± 1.2). However, the mean ratio was highest (15.9 ± 6.8) in meningioma (n=3). The T/NT cutoff ratio of 3.08 provided 100% sensitivity, 87.5% specificity for discriminating high-grade glioma (HGG) from low-grade glioma (LGG) disease. Likewise, the nCBV cutoff of 2.43 offered 100% sensitivity and 80% specificity. Only the Cho/NAA cutoff value of greater than 3.34 provided reasonable sensitivity and specificity of 85.7% and 80.0% respectively for this differentiation. T/NT ratio correlated significantly with nCBV and Cho/NAA, Cho/Cr ratios but not with Ki-67. CONCLUSION Quantitative 99mTc-MDM -SPECT provided high sensitivity and specificity to differentiate HGG versus LGG preoperatively and demonstrated a potential role for the differential diagnosis of glial versus nonglial tumors.
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Fermentative production of sulfur-containing amino acid with engineering putative l-cystathionine and l-cysteine uptake systems in Escherichia coli.
Yamazaki, S, Ziyatdinov, MK, Nonaka, G
Journal of bioscience and bioengineering. 2020;(1):14-19
Abstract
Here, proteins involved in sulfur-containing amino acid uptake in Escherichia coli strains were investigated with the aim of applying the findings in fermentative amino acid production. A search of genes in an l-methionine auxotrophic strain library suggested YecSC as the putative transporter of l-cystathionine. l-Methionine production increased by 15% after amplification of yecSC in producer strains. A candidate protein responsible for l-cysteine uptake was also found by experimentation with multicopy suppressor E. coli strains that recovered from growth defects caused by l-cysteine auxotrophy. Based on the results of an uptake assay, growth using l-cysteine as a sole sulfur source, and sensitivity to l-cysteine toxicity, we proposed that YeaN is an l-cysteine transporter. l-Cysteine production increased by 50% as a result of disrupting yeaN in producer strain. The study of amino acid transporters is valuable to industrialized amino acid production and also sheds light on the role of these transporters in sulfur assimilation.
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Catechol-O-methyltransferase gene Val158Met polymorphism and obsessive compulsive disorder susceptibility: a meta-analysis.
Kumar, P, Rai, V
Metabolic brain disease. 2020;(2):241-251
Abstract
Obsessive-compulsive disorder (OCD) is a common psychiatric disorder that affects approximately 1-3% of the general population. It is characterized by disabling obsessions (intrusive unwanted thoughts) and/or compulsions (ritualized repetitive behaviors). Catechol-O-methyltransferase (COMT) enzyme has an important role in inactivation of dopamine and higher dopamine levels may be implicated in OCD, hence COMT gene is a suitable candidate for OCD. Several case-control studies have evaluated the role of COMT Val 158Met (rs4680;472G- > A) polymorphism as a risk factor for OCD but the results remained inconclusive, hence present meta-analysis was designed to find out correct assessment. All studies that investigated the association of COMT gene Val158Met polymorphism with OCD risk, were considered in the present meta-analysis. Statistical analysis was performed with the software program MetaAnalyst. In the current meta-analysis, 14 case-control studies with 1435 OCD cases and 2753 healthy controls were included. The results indicated significant association between COMT Val158Met polymorphism and OCD risk using allele contrast, homozygote and dominant models (ORA vs G = 1.14; 95% CI = 1.02-1.27; p = 0.01; ORAAvs.GG = 1.33; 95% CI = 1.09-1.62, p = 0.004; ORAA + AGvs.GG = 1.14; 95% CI = 1.0-1.32; p = 0.04). In subgroup analysis based on case gender, meta-analysis of male cases showed significant association using all five genetic models (ORAAvsGG = 1.99; 95%CI = 1.42-2.59; p = <0.001; ORAA + AGvs.GG = 1.59; 95% CI = 1.20-2.10; p = 0.001), but did not show any association between COMT Val 158Met polymorphism and OCD risk in females. In conclusion, results of present meta-analysis supports that the COMT Val158Met polymorphism is a risk factor for OCD especially for males.
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Vitamin B Supplementation and Nutritional Intake of Methyl Donors in Patients with Chronic Kidney Disease: A Critical Review of the Impact on Epigenetic Machinery.
Cappuccilli, M, Bergamini, C, Giacomelli, FA, Cianciolo, G, Donati, G, Conte, D, Natali, T, La Manna, G, Capelli, I
Nutrients. 2020;(5)
Abstract
Cardiovascular morbidity and mortality are several-fold higher in patients with advanced chronic kidney disease (CKD) and end-stage renal disease (ESRD) than in the general population. Hyperhomocysteinemia has undoubtedly a central role in such a prominent cardiovascular burden. The levels of homocysteine are regulated by methyl donors (folate, methionine, choline, betaine), and cofactors (vitamin B6, vitamin B12,). Uremia-induced hyperhomocysteinemia has as its main targets DNA methyltransferases, and this leads to an altered epigenetic control of genes regulated through methylation. In renal patients, the epigenetic landscape is strictly correlated with the uremic phenotype and dependent on dietary intake of micronutrients, inflammation, gut microbiome, inflammatory status, oxidative stress, and lifestyle habits. All these factors are key contributors in methylome maintenance and in the modulation of gene transcription through DNA hypo- or hypermethylation in CKD. This is an overview of the epigenetic changes related to DNA methylation in patients with advanced CKD and ESRD. We explored the currently available data on the molecular dysregulations resulting from altered gene expression in uremia. Special attention was paid to the efficacy of B-vitamins supplementation and dietary intake of methyl donors on homocysteine lowering and cardiovascular protection.