Prostate cancer (PCa), bladder cancer (BCa), and renal cell carcinoma (RCC) are the most common urological cancers, and their incidence has been rising over time. Surgery is the standard treatment ...for these cancers, but this procedure is only effective when the disease is localized. For metastatic disease, PCa is typically treated with androgen deprivation therapy, while BCa is treated with chemotherapy, and RCC is managed primarily with targeted therapies. However, response rates to these therapeutic options remain unsatisfactory due to the development of resistance and treatment-related toxicity. Thus, the discovery of biomarkers with prognostic and predictive value is needed to stratify patients into different risk groups, minimizing overtreatment and the risk of drug resistance development. Pharmacometabolomics, a branch of metabolomics, is an attractive tool to predict drug response in an individual based on its own metabolic signature, which can be collected before, during, and after drug exposure. Hence, this review focuses on the application of pharmacometabolomic approaches to identify the metabolic responses to hormone therapy, targeted therapy, immunotherapy, and chemotherapy for the most prevalent urological cancers.
An untargeted approach, focused in the profile of volatile organic compounds (VOCs), was applied to differentiate natural cork stoppers with different levels of porosity, coded as Group 1 (low ...porosity), Group 2 (intermediate porosity) and Group 3 (high porosity). Statistically significant alterations were found in the levels of several VOCs between cork stoppers of low and intermediate porosity when compared with those of high porosity (Group 1 vs. 3 and Group 2 vs. 3). In addition, the levels of 2-pentylfuran, cyclene, camphene, camphor, limonene and eucalyptol enabled the discrimination of cork stoppers with low porosity (Group 1) into two subgroups, while furfural and 5-methyl-2-furfural enabled the discrimination of subgroups within the intermediate and high porosity stoppers (Group 2 and 3). A headspace solid-phase microextraction coupled to gas chromatography tandem mass spectrometry (HS-SPME-GC-MS/MS) method was developed to quantify the subgroup discriminant compounds, which may provide a proof-of-concept for the development of an efficient method to be applied in cork industry.
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•Lower porosity natural cork stoppers showed higher levels of pleasant flavour compounds.•The volatile profile can be used as a tool for categorization of natural cork stoppers.•A HS-SPME-GC-MS/MS method was validated for quantification of camphor, eucalyptol and furfural.•These compounds were responsible for subgroup classification of natural cork stoppers.
The use of cathinone designer drugs in recreational settings has been associated with severe toxic effects, including liver damage. The precise mechanisms by which cathinones induce hepatotoxicity ...and whether they act by common pathways remain to be elucidated. Herein, we assessed the toxicity of the cathinones methylone, pentedrone, 3,4-methylenedioxypyrovalerone (MDPV) and 4-methylethcathinone (4-MEC) in primary rat hepatocytes (PRH) and HepaRG cells, and compared with that of 3,4-methylenedioxymethamphetamine (MDMA). MDPV and pentedrone were significantly more toxic than MDMA, while methylone was the least cytotoxic compound. Importantly, PRH revealed to be the most sensitive experimental model and was thus used to explore the mechanisms underlying the observed toxicity. All drugs elicited the formation of reactive oxygen and nitrogen species (ROS and RNS), but more markedly for methylone, pentedrone and 4-MEC. GSH depletion was also a common effect at the highest concentration tested, whereas only MDPV and pentedrone caused a significant decrease in ATP levels. The antioxidants ascorbic acid or N-acetyl-L-cysteine partially attenuated the observed cell death. All cathinones triggered significant caspase activation and apoptosis, which was partially reversed by the caspase inhibitor Ac-LETD-CHO. In conclusion, the present data shows that (1) cathinones induce in vitro hepatotoxic effects that vary in magnitude among the different analogues, (2) oxidative stress and mitochondrial dysfunction play a role in cathinones-induced hepatic injury, and (3) apoptosis appears to be an important pathway of cell death elicited by these novel drugs.
Given the high biological impact of classical and emerging toxicants, a sensitive and comprehensive assessment of the hazards and risks of these substances to organisms is urgently needed. In this ...sense, toxicometabolomics emerged as a new and growing field in life sciences, which use metabolomics to provide new sets of susceptibility, exposure, and/or effects biomarkers; and to characterize in detail the metabolic responses and altered biological pathways that various stressful stimuli cause in many organisms. The present review focuses on the analytical platforms and the typical workflow employed in toxicometabolomic studies, and gives an overview of recent exploratory research that applied metabolomics in various areas of toxicology.
Dimethyl fumarate (DMF) is an old drug used for psoriasis treatment that has recently been repurposed to treat relapse–remitting multiple sclerosis, mostly due to its neuro- and immunomodulatory ...actions. However, mining of a pharmacovigilance database recently ranked DMF as the second pharmaceutical most associated with cognitive adverse events. To our best knowledge, the signaling mechanisms underlying its therapeutic and neurotoxic outcomes remain mostly undisclosed. This work thus represents the first-hand assessment of DMF-induced metabolic changes in undifferentiated SH-SY5Y human neuroblastoma cells, through an untargeted metabolomic approach using gas chromatography–mass spectrometry (GC–MS). The endometabolome was analyzed following 24 h and 96 h of exposure to two pharmacologically relevant DMF concentrations (0.1 and 10 μM). None of these conditions significantly reduced metabolic activity (MTT reduction assay). Our data showed that 24 h-exposure to DMF at both concentrations tested mainly affected metabolic pathways involved in mitochondrial activity (e.g., citric acid cycle, de novo triacylglycerol biosynthesis), and the synthesis of catecholamines and serotonin by changing the levels of their respective precursors, namely phenylalanine (0.68-fold decrease for 10 μM DMF vs vehicle), and tryptophan (1.36-fold increase for 0.1 μM DMF vs vehicle). Interestingly, taurine, whose levels can be modulated via Nrf2 signaling (DMF’s primary target), emerged as a key mediator of DMF’s neuronal action, displaying a 3.86-fold increase and 0.27-fold decrease for 10 μM DMF at 24 h and 96 h, respectively. A 96 h-exposure to DMF seemed to mainly trigger pathways associated with glucose production (e.g., gluconeogenesis, glucose-alanine cycle, malate-aspartate shuttle), possibly related to the metabolism of DMF into monomethyl fumarate and its further conversion into glucose via activation of the citric acid cycle. Overall, our data contribute to improving the understanding of the events associated with neuronal exposure to DMF.
Cork stopper granulates from five geographical origins from Portugal and six from Spain were analyzed regarding polyphenol composition by HPLC-DAD/ESI-MS and geographical discrimination studied by ...near-infrared spectroscopy (NIRS). The phenolic composition of the eleven origins ranged from 30 to 52 mg/g cork granulates, with vescavaloninic acid, castalagin, sanguisorbic acid dilactone, vescalagin, castavaloninic acid, dehydrated tergallic-C-Glc, and ellagic acid being the major compounds. NIRS revealed to be a powerful tool to discriminate origins and predict the concentration of polyphenols. However, polyphenols do not fully explain the discrimination of geographical origins. Variability in the polyphenol composition of cork stoppers is not significantly influenced by geographical location but probably may be more related to the plant genetics, tree age, and phytosanitary and edaphoclimatic conditions.
Introduction
Prostate cancer (PCa) is one of the most prevalent cancers in men worldwide. Serum prostate-specific antigen (PSA) remains the most used biomarker in the detection and management of ...patients with PCa, in spite of the problems related with its low specificity, false positive rate and overdiagnosis. Furthermore, PSA is unable to discriminate indolent from aggressive PCa, which can lead to overtreatment. Early diagnosed and treated PCa can have a good prognosis and is potentially curable. Therefore, the discovery of new biomarkers able to detect clinically significant aggressive PCa is urgently needed.
Methods
This revision was based on an electronic literature search, using Pubmed, with Nuclear Magnetic Resonance (NMR), tissue and prostate cancer as keywords. All metabolomic studies performed in PCa tissues by NMR spectroscopy, from 2007 until March 2018, were included in this review.
Results
In the context of cancer, metabolomics allows the analysis of the entire metabolic profile of cancer cells. Several metabolic alterations occur in cancer cells to sustain their abnormal rates of proliferation. NMR proved to be a suitable methodology for the evaluation of these metabolic alterations in PCa tissues, allowing to unveil alterations in citrate, spermine, choline, choline-related compounds, lactate, alanine and glutamate.
Conclusion
The study of the metabolic alterations associated with PCa progression, accomplished by the analysis of PCa tissue by NMR, offers a promising approach for elucidating biochemical pathways affected by PCa and also for discovering new clinical biomarkers. The main metabolomic alterations associated with PCa development and promising biomarker metabolites for diagnosis of PCa were outlined.
Metabolomics, an emerging field of “omics” sciences, has caught wide scientific attention in the area of biomarker research for cancers in which early diagnostic biomarkers have the potential to ...greatly improve patient outcome, such as renal cell carcinoma (RCC). Metabolomic approaches have been successfully applied to various human RCC model systems, mostly ex vivo neoplastic renal tissues and biofluids (urine and serum) from patients with RCC. Importantly, in contrast to other cancers, only a few studies have addressed the RCC metabolome using cancer cell culture–based in vitro models. Herein, we first carried out a comprehensive review of current metabolomic data in RCC, with emphasis on metabolite disturbances and dysregulated metabolic pathways identified in each of these experimental models. We then critically analyzed the consistency of evidence in this field and whether metabolites found altered in tumor cell and tissue microenvironment are reflected in biofluids, which constitute the rationale underlying the translation of discovered metabolic biomarkers into noninvasive diagnostic tools. Finally, dominant metabolic pathways and promising metabolites as biomarkers for diagnosis and prognosis of RCC are outlined.
An automated headspace solid-phase microextraction (HS-SPME) combined with gas chromatography-ion trap/mass spectrometry (GC-IT/MS) was developed in order to quantify a large number of volatile ...compounds in wines such as alcohols, ester, norisoprenoids and terpenes. The procedures were optimized for SPME fiber selection, pre-incubation temperature and time, extraction temperature and time, and salt addition. A central composite experimental design was used in the optimization of the extraction conditions. The volatile compounds showed optimal extraction using a DVB/CAR/PDMS fiber, incubation of 5ml of wine with 2g NaCl at 45°C during 5min, and subsequent extraction of 30min at the same temperature. The method allowed the identification of 64 volatile compounds. Afterwards, the method was validated successfully for the most significant compounds and was applied to study the volatile composition of different white wines.
► An automated headspace solid-phase microextraction (HS-SPME) combined with gas chromatography-ion trap/mass spectrometry (GC-IT/MS) allowed the quantification of the most important volatiles in wines (simultaneously: alcohols, ester, norisoprenoids, terpenes, sequiterpens, carbonyl compounds and sulfur compounds). ► The optimal extraction of volatile compounds (optimized using Central Composite Design) occurs using a DVB/CAR/PDMS fiber, 5ml of wine+2g NaCl at an extraction temperature of 45°C during 30min. ► The method allowed the identification of a large range of volatiles compounds (64). ► The developed method can be applied to study the volatile composition of wines.
Synthetic cathinones have emerged in recreational drug markets as legal alternatives for classical amphetamines. Though currently banned in several countries, 3,4-methylenedioxypyrovalerone (MDPV) is ...one of the most commonly abused cathinone derivatives worldwide. We have recently reported the potential of MDPV to induce hepatocellular damage, but the underlying mechanisms responsible for such toxicity remain to be elucidated. Similar to amphetamines, a prominent toxic effect of acute intoxications by MDPV is hyperthermia. Therefore, the present in vitro study aimed to provide insights into cellular mechanisms involved in MDPV-induced hepatotoxicity and also evaluate the contribution of hyperthermia to the observed toxic effects. Primary cultures of rat hepatocytes were exposed to 0.2–1.6 mM MDPV for 48 h, at 37 or 40.5 °C, simulating the rise in body temperature that follows MDPV intake. Cell viability was measured through the MTT reduction and LDH leakage assays. Oxidative stress endpoints and cell death pathways were evaluated, namely the production of reactive oxygen and nitrogen species (ROS and RNS), intracellular levels of reduced (GSH) and oxidized (GSSG) glutathione, adenosine triphosphate (ATP) and free calcium (Ca
2+
), as well as the activities of caspases 3, 8 and 9, and nuclear morphological changes with Hoechst 33342/PI double staining. At 37 °C, MDPV induced a concentration-dependent loss of cell viability that was accompanied by GSH depletion, as one of the first signs of toxicity, observed already at low concentrations of MDPV, with negligible changes on GSSG levels, followed by accumulation of ROS and RNS, depletion of ATP contents and increases in intracellular Ca
2+
concentrations. Additionally, activation of caspases 3, 8, and 9 and apoptotic nuclear morphological changes were found in primary rat hepatocytes exposed to MDPV, indicating that this cathinone derivative activates both intrinsic and extrinsic apoptotic death pathways. The cytotoxic potential of MDPV and all the studied endpoints were markedly aggravated under hyperthermic conditions (40.5 °C). In conclusion, these data suggest that MDPV toxicity in primary rat hepatocytes is mediated by oxidative stress, subsequent to GSH depletion and increased ROS and RNS accumulation, mitochondrial dysfunction, and impairment of Ca
2+
homeostasis. Furthermore, the rise in body temperature subsequent to MDPV abuse greatly exacerbates its hepatotoxic potential.
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