Metabolic reprogramming toward aerobic glycolysis unavoidably induces methylglyoxal (MG) formation in cancer cells. MG mediates the glycation of proteins to form advanced glycation end products (AGEs). We have recently demonstrated that MG-induced AGEs are a common feature of breast cancer. Little is known regarding the impact of MG-mediated carbonyl stress on tumor progression. Breast tumors with MG stress presented with high nuclear YAP, a key transcriptional co-activator regulating tumor growth and invasion. Elevated MG levels resulted in sustained YAP nuclear localization/activity that could be reverted using Carnosine, a scavenger for MG. MG treatment affected Hsp90 chaperone activity and decreased its binding to LATS1, a key kinase of the Hippo pathway. Cancer cells with high MG stress showed enhanced growth and metastatic potential in vivo. These findings reinforce the cumulative evidence pointing to hyperglycemia as a risk factor for cancer incidence and bring renewed interest in MG scavengers for cancer treatment.DOI: http://dx.doi.org/10.7554/eLife.19375.001

Gut microbiota may influence blood pressure (BP), namely via end products of carbohydrate fermentation. After informed consent, male volunteers were prospectively categorized into 3 groups upon European Society of Hypertension criteria based on 24-hour ambulatory BP measurements: (1) hypertension, (2) borderline hypertension, and (3) normotension. Stool, urine and serum samples were collected in fasting conditions. Gut microbiota was characterized by 16S amplicon sequencing. Metabolomics, including quantification of short-chain fatty acids, was conducted using nuclear magnetic resonance. Two-way ANOVA combined with Tukey post hoc test, as well as multiple permutation test and Benjamini-Hochberg-Yekutieli false discovery rate procedure, was used. The cohort included 54 males: 38 hypertensive (including 21 under treatment), 7 borderline, and 9 normotensive. No significant difference was observed between groups concerning age, body mass index, smoking habits, and weekly alcohol consumption. The genus Clostridium sensu stricto 1 positively correlated with BP levels in nontreated patients (n=33). This correlation was significant after multiple permutation tests but was not substantiated following false discovery rate adjustment. Short-chain fatty acid levels were significantly different among groups, with higher stool levels of acetate, butyrate, and propionate in hypertensive versus normotensive individuals. No difference was observed in serum and urine metabolomes. Correlation between stool metabolome and 24-hour BP levels was evidenced, with R 2 reaching 0.9. Our pilot study based on 24-hour ambulatory BP measurements, 16S amplicon sequencing, and metabolomics supports an association between gut microbiota and BP homeostasis, with changes in stool abundance of short-chain fatty acids.

Preoperative radiotherapy (RT) is a mainstay in the management of rectal cancer, a tumor characterized by desmoplastic stroma containing cancer-associated fibroblasts (CAF). Although CAFs are abundantly present, the effects of RT to CAF and its impact on cancer cells are unknown. We evaluated the damage responses of CAF to RT and investigated changes in colorectal cancer cell growth, transcriptome, metabolome, and kinome in response to paracrine signals emerging from irradiated CAF. RT to CAF induced DNA damage, p53 activation, cell-cycle arrest, and secretion of paracrine mediators, including insulin-like growth factor-1 (IGF1). Subsequently, RT-activated CAFs promoted survival of colorectal cancer cells, as well as a metabolic switch favoring glutamine consumption through IGF1 receptor (IGF1R) activation. RT followed by IGF1R neutralization in orthotopic colorectal cancer models reduced the number of mice with organ metastases. Activation of the downstream IGF1R mediator mTOR was significantly higher in matched (intrapatient) samples and in unmatched (interpatient) samples from rectal cancer patients after neoadjuvant chemoradiotherapy. Taken together, our data support the notion that paracrine IGF1/IGF1R signaling initiated by RT-activated CAF worsens colorectal cancer progression, establishing a preclinical rationale to target this activation loop to further improve clinical responses and patient survival. These findings reveal that paracrine IGF1/IGF1R signaling promotes colorectal cancer progression, establishing a preclinical rationale to target this activation loop. .

Exposure of polyunsaturated fatty acid (PUFA)-rich culinary oils (COs) to high temperature frying practices generates high concentrations of cytotoxic and genotoxic lipid oxidation products (LOPs) via oxygen-fueled, recycling peroxidative bursts. These toxins, including aldehydes and epoxy-fatty acids, readily penetrate into fried foods and hence are available for human consumption; therefore, they may pose substantial health hazards. Although previous reports have claimed health benefits offered by the use of PUFA-laden COs for frying purposes, these may be erroneous in view of their failure to consider the negating adverse public health threats presented by food-transferable LOPs therein. When absorbed from the gastrointestinal (GI) system into the systemic circulation, such LOPs may significantly contribute to enhanced risks of chronic non-communicable diseases (NCDs), e.g. , cancer, along with cardiovascular and neurological diseases. Herein, we provide a comprehensive rationale relating to the public health threats posed by the dietary ingestion of LOPs in fried foods. We begin with an introduction to sequential lipid peroxidation processes, describing the noxious effects of LOP toxins generated therefrom. We continue to discuss GI system interactions, the metabolism and biotransformation of primary lipid hydroperoxide LOPs and their secondary products, and the toxicological properties of these agents, prior to providing a narrative on chemically-reactive, secondary aldehydic LOPs available for human ingestion. In view of a range of previous studies focused on their deleterious health effects in animal and cellular model systems, some emphasis is placed on the physiological fate of the more prevalent and toxic α,β-unsaturated aldehydes. We conclude with a description of targeted nutritional and interventional strategies, whilst highlighting the urgent and unmet clinical need for nutritional and epidemiological trials probing relationships between the incidence of NCDs, and the frequency and estimated quantities of dietary LOP intake.

Pancreatic ductal adenocarcinoma (PDAC) remains a deadly malignancy with no efficient therapy available up-to-date. Glycolysis is the main provider of energetic substrates to sustain cancer dissemination of PDAC. Accordingly, altering the glycolytic pathway is foreseen as a sound approach to trigger pancreatic cancer regression. Here, we show for the first time that high transforming growth factor beta-induced (TGFBI) expression in PDAC patients is associated with a poor outcome. We demonstrate that, although usually secreted by stromal cells, PDAC cells synthesize and secrete TGFBI in quantity correlated with their migratory capacity. Mechanistically, we show that TGFBI activates focal adhesion kinase signaling pathway through its binding to integrin αVβ5, leading to a significant enhancement of glycolysis and to the acquisition of an invasive phenotype. Finally, we show that TGFBI silencing significantly inhibits PDAC tumor development in a chick chorioallantoic membrane assay model. Our study highlights TGFBI as an oncogenic extracellular matrix interacting protein that bears the potential to serve as a target for new anti-PDAC therapeutic strategies.

Kidney injury is a common complication of severe disease. Here, we report that injuries of the zebrafish embryonal kidney are rapidly repaired by a migratory response in 2-, but not in 1-day-old embryos. Gene expression profiles between these two developmental stages identify cxcl12a and myca as candidates involved in the repair process. Zebrafish embryos with cxcl12a, cxcr4b, or myca deficiency display repair abnormalities, confirming their role in response to injury. In mice with a kidney-specific knockout, Cxcl12 and Myc gene deletions suppress mitochondrial metabolism and glycolysis, and delay the recovery after ischemia/reperfusion injury. Probing these observations in zebrafish reveal that inhibition of glycolysis slows fast migrating cells and delays the repair after injury, but does not affect the slow cell movements during kidney development. Our findings demonstrate that Cxcl12 and Myc facilitate glycolysis to promote fast migratory responses during development and repair, and potentially also during tumor invasion and metastasis.

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Metabolomics techniques are now applied in numerous fields, with the ability to provide information concerning a large number of metabolites from a single sample in a short timeframe. Although high-frequency (HF) nuclear magnetic resonance (NMR) analysis represents a common method of choice to perform such studies, few investigations employing low-frequency (LF) NMR spectrometers have yet been published. Herein, we apply and contrast LF and HF 1H-NMR metabolomics approaches to the study of urine samples collected from type 2 diabetic patients (T2D), and apply a comparative investigation with healthy controls. Additionally, we explore the capabilities of LF 1H-1H 2D correlation spectroscopy (COSY) experiments regarding the determination of metabolites, their resolution and associated analyses in human urine samples. T2D samples were readily distinguishable from controls, with several metabolites, particularly glucose, being associated with this distinction. Comparable results were obtained with HF and LF spectrometers. Linear correlation analyses were performed to derive relationships between the intensities of 1D and 2D resonances of several metabolites, and R2 values obtained were able to confirm these, an observation attesting to the validity of employing 2D LF experiments for future applications in metabolomics studies. Our data suggest that LF spectrometers may prove to be easy-to-use, compact and inexpensive tools to perform routine metabolomics analyses in laboratories and ‘point-of-care’ sites. Furthermore, the quality of 2D spectra obtained from these instruments in half an hour would broaden the horizon of their potential applications.