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Targeting extracellular nutrient dependencies of cancer cells.
Garcia-Bermudez, J, Williams, RT, Guarecuco, R, Birsoy, K
Molecular metabolism. 2020;:67-82
Abstract
BACKGROUND Cancer cells rewire their metabolism to meet the energetic and biosynthetic demands of their high proliferation rates and environment. Metabolic reprogramming of cancer cells may result in strong dependencies on nutrients that could be exploited for therapy. While these dependencies may be in part due to the nutrient environment of tumors, mutations or expression changes in metabolic genes also reprogram metabolic pathways and create addictions to extracellular nutrients. SCOPE OF REVIEW This review summarizes the major nutrient dependencies of cancer cells focusing on their discovery and potential mechanisms by which metabolites become limiting for tumor growth. We further detail available therapeutic interventions based on these metabolic features and highlight opportunities for restricting nutrient availability as an anti-cancer strategy. MAJOR CONCLUSIONS Strategies to limit nutrients required for tumor growth using dietary interventions or nutrient degrading enzymes have previously been suggested for cancer therapy. The best clinical example of exploiting cancer nutrient dependencies is the treatment of leukemia with l-asparaginase, a first-line chemotherapeutic that depletes serum asparagine. Despite the success of nutrient starvation in blood cancers, it remains unclear whether this approach could be extended to other solid tumors. Systematic studies to identify nutrient dependencies unique to individual tumor types have the potential to discover targets for therapy.
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Metabolome and proteome of ethylene-treated papayas reveal different pathways to volatile compounds biosynthesis.
Der Agopian, RG, Fabi, JP, Cordenunsi-Lysenko, BR
Food research international (Ottawa, Ont.). 2020;:108975
Abstract
Papayas undergo fast postharvest changes triggered by the plant hormone ethylene. Some important pathways have been analyzed in limited studies (transcriptomics and targeted metabolomics); however, broad use of proteomics or untargeted metabolomics have not yet been used in papayas. In this study, two groups of green papayas (150 days after anthesis-physiological maturity for papayas) were treated with ethylene at different times (6 and 12 h) and their metabolic changes in fruit pulp were evaluated with untargeted metabolomics (general metabolites and volatile compounds) and proteomics. Polar metabolites exhibited distinct patterns, especially with regard to some amino and fatty acids during stimulated ripening. In particular, glutamate increased through a possible gamma aminobutyric acid (GABA) shunt and/or proteases activity. Moreover, the stimulated ripening altered the volatile compounds and the protein profiles. The results suggest that changes in membrane breakdown and the resulting oxidative processes could be responsible for volatile compound production, altering some sensorial qualities of papayas, such as pulp softening and the specific papaya linalool volatile compound increment. Thus, GABA levels could also be a strong biological marker for papaya development and ripening stages. This study applied two "omic" techniques that provided insight into how the plant hormone ethylene could influence papaya postharvest quality.
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Metabolomic signature of the seminal plasma in men with severe oligoasthenospermia.
Boguenet, M, Bocca, C, Bouet, PE, Serri, O, Chupin, S, Tessier, L, Blanchet, O, El Hachem, H, Chao de la Barca, JM, Reynier, P, et al
Andrology. 2020;(6):1859-1866
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Abstract
BACKGROUND Male factor is incriminated in approximately 50% of cases of infertility. The metabolomic approach has recently been used in the assessment of sperm quality and male fertility. MATERIALS AND METHODS We analyzed the metabolomic signatures of the seminal plasma in 20 men with severe oligoasthenospermia (prewash total motile sperm count < 5.106 ) (SOA) and compared it to 20 men with normal semen parameters, with a standardized approach of targeted and quantitative metabolomics using high-performance liquid chromatography, coupled with tandem mass spectrometry, and the Biocrates Absolute IDQ p180 kit. RESULTS Among the 188 metabolites analyzed, 110 were accurately measured in the seminal plasma. A robust model discriminating the two populations (Q2(cum) = 55.2%) was obtained by OPLS-DA (orthogonal partial least-squares discriminant analysis), based on the drop in concentrations of 37 metabolites with a VIP (variable important for projection) greater than 1. Overall, in men with SOA, there was a significant decrease in: 17 phosphatidylcholines and four sphingomyelins; acylcarnitines, with free L-carnitine being the most discriminating metabolite; polyunsaturated fatty acids; six amino acids (glutamate, aspartate, methionine, tryptophan, proline, and alanine); and four biogenic amines (spermine, spermidine, serotonin, and alpha-aminoadipate). DISCUSSION Our signature includes several metabolic changes with different impacts on the sperm quality: a change in phospholipid composition and the saturation of their fatty acids that is potentially linked to the deterioration of sperm membranes; a carnitine deficiency that can negatively impact the energy production via fatty acid oxidation and oxidative phosphorylation; and a decreased level of amino acids and biogenic amines that can lead to dysregulated metabolic and signaling pathways. CONCLUSION We provide a global overview of the metabolic defects contributing to the structural and functional alteration of spermatozoa in severe oligoasthenospermia. These findings offer new insights into the pathophysiology of male factor infertility that could help to develop future specific treatments.
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Impact of Crocus Sativus L. on Metabolic Profile in Patients with Diabetes Mellitus or Metabolic Syndrome: A Systematic Review.
Giannoulaki, P, Kotzakioulafi, E, Chourdakis, M, Hatzitolios, A, Didangelos, T
Nutrients. 2020;(5)
Abstract
BACKGROUND Experimental studies demonstrated a positive effect of administration of Crocus sativus L. (saffron) and its bioactive ingredients on metabolic profile through their antioxidant capacity. PURPOSE To determine if the use of saffron in humans is beneficial to patients with diabetes mellitus (DM) or metabolic syndrome (MS). METHODS This systematic review includes 14randomized control trials that investigated the impact of saffron administration and its bioactive ingredient crocin on the metabolic profile of patients with DM, MS, prediabetes, and coronary artery disease. We documented the following clinical outcomes: fasting blood glucose (FBG), glycated haemoglobin (HbA1c), total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, systolic, and diastolic blood pressure. RESULTS Eight studies examined the efficacy of saffron in patients with DM, four with the metabolic syndrome, one with prediabetes and one with coronary artery disease. A favorable effect on FBG was observed. The results regarding blood lipids and blood pressure were inconclusive in the current review. CONCLUSIONS According to the available limited evidence, saffron may have a favorable effect on FBG. Many of the studies in the reviewed literature are of poor quality, and more research is needed in this direction to confirm and establish the above findings.
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A systematic review and meta-analysis: The effects of probiotic supplementation on metabolic profile in patients with neurological disorders.
Tamtaji, OR, Milajerdi, A, Reiner, Ž, Asemi, Z, Dadgostar, E, Heidari-Soureshjani, R, Mamsharifi, P, Amirani, E, Mirzaei, H, Hallajzadeh, J, et al
Complementary therapies in medicine. 2020;:102507
Abstract
BACKGROUND AND OBJECTIVE The objective of meta-analysis of randomized controlled trials (RCTs) was to evaluate the effects of probiotic supplementation on metabolic status in patients with neurological disorders. METHODS The following databases were search up to April 2019: Pubmed, Scopus, Google scholar, Web of Science, and Cochrane Central Register of Controlled Trials. The quality of the relevant extracted data was assessed according to the Cochrane risk of bias tool. Data were pooled by the use of the inverse variance method and expressed as mean difference with 95 % Confidence Intervals (95 % CI). RESULTS Nine studies were included in this meta-analysis. The findings suggested that probiotic supplementation resulted in a significant reduction in C-reactive protein (CRP) [Weighted Mean Difference (WMD): -1.06; 95 % CI: -1.80, -0.32] and malondialdehyde (MDA) levels (WMD: -0.32; 95 % CI: -0.46, -0.18). Supplementation with probiotics also significantly reduced insulin (WMD: -3.02; 95 % CI: -3.88, -2.15) and homeostatic model assessment for insulin resistance (HOMA-IR) (WMD: -0.71; 95 % CI: -0.89, -0.52). Probiotics significantly reduced triglycerides (WMD: -18.38; 95 % CI: -25.50, -11.26) and VLDL-cholesterol (WMD: -3.16; 95 % CI: -4.53, -1.79), while they increased HDL-cholesterol levels (WMD: 1.52; 95 % CI: 0.29, 2.75). CONCLUSION This meta-analysis demonstrated that taking probiotic by patients with neurological disorders had beneficial effects on CRP, MDA, insulin, HOMA-IR, triglycerides, VLDL-cholesterol and HDL-cholesterol levels, but did not affect other metabolic parameters.
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Analysis of immune, microbiota and metabolome maturation in infants in a clinical trial of Lactobacillus paracasei CBA L74-fermented formula.
Roggero, P, Liotto, N, Pozzi, C, Braga, D, Troisi, J, Menis, C, Giannì, ML, Berni Canani, R, Paparo, L, Nocerino, R, et al
Nature communications. 2020;(1):2703
Abstract
Mother's milk is the best choice for infants nutrition, however when it is not available or insufficient to satisfy the needs of the infant, formula is proposed as an effective substitute. Here, we report the results of a randomized controlled clinical trial (NCT03637894) designed to evaluate the effects of two different dietary regimens (standard formula and Lactobacillus paracasei CBA L74-fermented formula) versus breastfeeding (reference group) on immune defense mechanisms (primary endpoint: secretory IgA, antimicrobial peptides), the microbiota and its metabolome (secondary outcomes), in healthy full term infants according to the type of delivery (n = 13/group). We show that the fermented formula, safe and well tolerated, induces an increase in secretory IgA (but not in antimicrobial peptides) and reduces the diversity of the microbiota, similarly, but not as much as, breastmilk. Metabolome analysis allowed us to distinguish subjects based on their dietary regimen and mode of delivery. Together, these results suggest that a fermented formula favors the maturation of the immune system, microbiota and metabolome.
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Adiposity, metabolites, and colorectal cancer risk: Mendelian randomization study.
Bull, CJ, Bell, JA, Murphy, N, Sanderson, E, Davey Smith, G, Timpson, NJ, Banbury, BL, Albanes, D, Berndt, SI, Bézieau, S, et al
BMC medicine. 2020;(1):396
Abstract
BACKGROUND Higher adiposity increases the risk of colorectal cancer (CRC), but whether this relationship varies by anatomical sub-site or by sex is unclear. Further, the metabolic alterations mediating the effects of adiposity on CRC are not fully understood. METHODS We examined sex- and site-specific associations of adiposity with CRC risk and whether adiposity-associated metabolites explain the associations of adiposity with CRC. Genetic variants from genome-wide association studies of body mass index (BMI) and waist-to-hip ratio (WHR, unadjusted for BMI; N = 806,810), and 123 metabolites from targeted nuclear magnetic resonance metabolomics (N = 24,925), were used as instruments. Sex-combined and sex-specific Mendelian randomization (MR) was conducted for BMI and WHR with CRC risk (58,221 cases and 67,694 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry). Sex-combined MR was conducted for BMI and WHR with metabolites, for metabolites with CRC, and for BMI and WHR with CRC adjusted for metabolite classes in multivariable models. RESULTS In sex-specific MR analyses, higher BMI (per 4.2 kg/m2) was associated with 1.23 (95% confidence interval (CI) = 1.08, 1.38) times higher CRC odds among men (inverse-variance-weighted (IVW) model); among women, higher BMI (per 5.2 kg/m2) was associated with 1.09 (95% CI = 0.97, 1.22) times higher CRC odds. WHR (per 0.07 higher) was more strongly associated with CRC risk among women (IVW OR = 1.25, 95% CI = 1.08, 1.43) than men (IVW OR = 1.05, 95% CI = 0.81, 1.36). BMI or WHR was associated with 104/123 metabolites at false discovery rate-corrected P ≤ 0.05; several metabolites were associated with CRC, but not in directions that were consistent with the mediation of positive adiposity-CRC relations. In multivariable MR analyses, associations of BMI and WHR with CRC were not attenuated following adjustment for representative metabolite classes, e.g., the univariable IVW OR for BMI with CRC was 1.12 (95% CI = 1.00, 1.26), and this became 1.11 (95% CI = 0.99, 1.26) when adjusting for cholesterol in low-density lipoprotein particles. CONCLUSIONS Our results suggest that higher BMI more greatly raises CRC risk among men, whereas higher WHR more greatly raises CRC risk among women. Adiposity was associated with numerous metabolic alterations, but none of these explained associations between adiposity and CRC. More detailed metabolomic measures are likely needed to clarify the mechanistic pathways.
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The effects of wheat germ supplementation on metabolic profile in patients with type 2 diabetes mellitus: A randomized, double-blind, placebo-controlled trial.
Mohammadi, H, Karimifar, M, Heidari, Z, Zare, M, Amani, R
Phytotherapy research : PTR. 2020;(4):879-885
Abstract
The aim of the present trial was to examine the effects of wheat germ (WG) consumption on metabolic control and oxidative stress status of type 2 diabetes mellitus (T2DM) patients. Eighty participants with T2DM were randomly allocated to receive 20-g WG (n = 40) or placebo (n = 40) in a randomized double-blind clinical trial for 12 weeks. Serum lipid profiles, glycaemic indices, total antioxidant capacity, and malondialdhyde (MDA) were assessed. A total of 75 subjects completed the trial. Compared with the placebo, WG consumption led to significant reduction in total cholesterol (TC) concentrations (p = .04). There was a trend regarding TC to high density lipoprotein ratio (p = .08) following 12 weeks WG consumption, although they were not statistically significant after correcting for multiple testing. In addition, within-group comparison revealed a significant rise in total antioxidant capacity concentration (p = .001) in WG group. We observed no significant effects of WG intake on glycaemic status, blood pressure, MDA, triglyceride, and low density lipoprotein levels. WG consumption for 12 weeks could decrease serum TC levels and had no significant effects on other metabolic variables and MDA in patients with T2DM. Though observed health benefit effects were small, it might lead to a major impact on wider public health.
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Microbial Contribution to the Human Metabolome: Implications for Health and Disease.
Van Treuren, W, Dodd, D
Annual review of pathology. 2020;:345-369
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The human gastrointestinal tract is home to an incredibly dense population of microbes. These microbes employ unique strategies to capture energy in this largely anaerobic environment. In the process of breaking down dietary- and host-derived substrates, the gut microbiota produce a broad range of metabolic products that accumulate to high levels in the gut. Increasingly, studies are revealing that these chemicals impact host biology, either by acting on cells within the gastrointestinal tract or entering circulation and exerting their effects at distal sites within the body. Given the high level of functional diversity in the gut microbiome and the varied diets that we consume, the repertoire of microbiota-derived molecules within our bodies varies dramatically across individuals. Thus, the microbes in our gut and the metabolic end products they produce represent a phenotypic lever that we can potentially control to develop new therapeutics for personalized medicine. Here, we review current understanding of how microbes in the gastrointestinal tract contribute to the molecules within our gut and those that circulate within our bodies. We also highlight examples of how these molecules affect host physiology and discuss potential strategies for controlling their production to promote human health and to treat disease.
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Metabolomics Analysis of Aspirin's Effects in Human Colon Tissue and Associations with Adenoma Risk.
Barry, EL, Fedirko, V, Uppal, K, Ma, C, Liu, K, Mott, LA, Peacock, JL, Passarelli, MN, Baron, JA, Jones, DP
Cancer prevention research (Philadelphia, Pa.). 2020;(10):863-876
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Abstract
Although substantial evidence supports aspirin's efficacy in colorectal cancer chemoprevention, key molecular mechanisms are uncertain. An untargeted metabolomics approach with high-resolution mass spectrometry was used to elucidate metabolic effects of aspirin treatment in human colon tissue. We measured 10,269 metabolic features in normal mucosal biopsies collected at colonoscopy after approximately 3 years of randomized treatment with placebo, 81 or 325 mg/day aspirin from 325 participants in the Aspirin/Folate Polyp Prevention Study. Linear regression was used to identify aspirin-associated metabolic features and network analysis was used to identify pathways and predict metabolite identities. Poisson regression was used to examine metabolic features associations with colorectal adenoma risk. We detected 471 aspirin-associated metabolic features. Aside from the carnitine shuttle, aspirin-associated metabolic pathways were largely distinct for 81 mg aspirin (e.g., pyrimidine metabolism) and 325 mg (e.g., arachidonic acid metabolism). Among aspirin-associated metabolic features, we discovered three that were associated with adenoma risk and could contribute to the chemopreventive effect of aspirin treatment, and which have also previously been associated with colorectal cancer: creatinine, glycerol 3-phosphate, and linoleate. The last two of these are in the glycerophospholipid metabolism pathway, which was associated with 81 mg aspirin treatment and provides precursors for the synthesis of eicosanoids from arachidonic acid upstream of cyclooxygenase inhibition by aspirin. Conversely, carnitine shuttle metabolites were increased with aspirin treatment and associated with increased adenoma risk. Thus, our untargeted metabolomics approach has identified novel metabolites and pathways that may underlie the effects of aspirin during early colorectal carcinogenesis.