Metabolomics-based search for lung cancer markers among patients with different smoking status.

Tobacco smoking is the main etiological factor of lung cancer (LC), which can also cause metabolome disruption. This study aimed to investigate whether the observed metabolic shift in LC patients was also associated with their smoking status. Untargeted metabolomics profiling was applied for the initial screening of changes in serum metabolic profile between LC and chronic obstructive pulmonary disease (COPD) patients, selected as a non-cancer group. Differences in metabolite profiles between current and former smokers were also tested. Then, targeted metabolomics methods were applied to verify and validate the proposed LC biomarkers. For untargeted metabolomics, a single extraction-dual separation workflow was applied. The samples were analyzed using a liquid chromatograph-high resolution quadrupole time-of-flight mass spectrometer. Next, the selected metabolites were quantified using liquid chromatography-triple-quadrupole mass spectrometry. The acquired data confirmed that patients' stratification based on smoking status impacted the discriminating ability of the identified LC marker candidates. Analyzing a validation set of samples enabled us to determine if the putative LC markers were truly robust. It demonstrated significant differences in the case of four metabolites: allantoin, glutamic acid, succinic acid, and sphingosine-1-phosphate. Our research showed that studying the influence of strong environmental factors, such as tobacco smoking, should be considered in cancer marker research since it reduces the risk of false positives and improves understanding of the metabolite shifts in cancer patients.

Modeling of Intracellular Taurine Levels Associated with Ovarian Cancer Reveals Activation of p53, ERK, mTOR and DNA-Damage-Sensing-Dependent Cell Protection.

Taurine, a non-proteogenic amino acid and commonly used nutritional supplement, can protect various tissues from degeneration associated with the action of the DNA-damaging chemotherapeutic agent cisplatin. Whether and how taurine protects human ovarian cancer (OC) cells from DNA damage caused by cisplatin is not well understood. We found that OC ascites-derived cells contained significantly more intracellular taurine than cell culture-modeled OC. In culture, elevation of intracellular taurine concentration to OC ascites-cell-associated levels suppressed proliferation of various OC cell lines and patient-derived organoids, reduced glycolysis, and induced cell protection from cisplatin. Taurine cell protection was associated with decreased DNA damage in response to cisplatin. A combination of RNA sequencing, reverse-phase protein arrays, live-cell microscopy, flow cytometry, and biochemical validation experiments provided evidence for taurine-mediated induction of mutant or wild-type p53 binding to DNA, activation of p53 effectors involved in negative regulation of the cell cycle (p21), and glycolysis (TIGAR). Paradoxically, taurine's suppression of cell proliferation was associated with activation of pro-mitogenic signal transduction including ERK, mTOR, and increased mRNA expression of major DNA damage-sensing molecules such as DNAPK, ATM and ATR. While inhibition of ERK or p53 did not interfere with taurine's ability to protect cells from cisplatin, suppression of mTOR with Torin2, a clinically relevant inhibitor that also targets DNAPK and ATM/ATR, broke taurine's cell protection. Our studies implicate that elevation of intracellular taurine could suppress cell growth and metabolism, and activate cell protective mechanisms involving mTOR and DNA damage-sensing signal transducti.

Correction: Matysiak et al. Diagnosis of Hymenoptera Venom Allergy: State of the Art, Challenges, and Perspectives. Biomedicines 2022, 10, 2170.

In the original article [...].

Amino Acid Profiling Identifies Disease-Specific Signatures in IgE-Mediated and Non-IgE-Mediated Food Allergy in Pediatric Patients with Atopic Dermatitis.

An IgE-mediated food allergy (FA) in atopic dermatitis (AD) children should be easily differentiated from other immune-mediated adverse effects related to food. Specific IgEs for particular protein components has provided additional diagnostic value. However, component-resolved diagnostics (CRD) has not solved all diagnostic problems either. We analysed the serum profile of 42 amino acids (AAs) in 76 AD children aged 2-60 months with an IgE-mediated FA (n = 36), with a non-IgE-mediated FA (n = 15) and without an FA (n = 25) using high-performance liquid chromatography coupled with mass spectrometry (LC-MS/MS) and an aTRAQ kit. We identified homocitrulline (Hcit), sarcosine (Sar) and L-tyrosine (Tyr) as features that differentiated the studied groups (one-way ANOVA with least significant difference post hoc test). The Hcit concentrations in the non-IgE-mediated FA group were significantly decreased compared with the IgE-mediated FA group (p = 0.018) and the control group (p = 0.008). In AD children with a non-IgE-mediated FA, the Tyr levels were also significantly reduced compared with the controls (p = 0.009). The mean concentration of Sar was the highest in the non-IgE-mediated FA group and the lowest in the IgE-mediated FA group (p = 0.047). Future studies should elucidate the involvement of these AAs in the molecular pathway of IgE- and non-IgE-mediated allergic responses.

The nutritional supplement taurine activates p53-dependent and independent tumor suppressor mechanisms in various cellular models of ovarian cancer.

Loss of treatment-induced ovarian carcinoma (OC) growth suppression poses a major clinical challenge because it leads to disease recurrence. Therefore, there is a compelling need for well- -tolerated approaches that can support tumor growth-suppression after therapy is stopped. We have profiled ascites as OC tumor microenvironments to search for potential non-toxic soluble components that would activate tumor suppressor pathways in OC cells. Our investigations revealed that low levels of taurine, a non-proteogenic sulfonic amino acid, were present within OC ascites. Taurine supplementation, beyond levels found in ascites, induced growth suppression without causing cytotoxicity in various OC cells, including chemotherapy-resistant cell clones and patient-derived organoids representing primary or chemotherapy recovered disease. Inhibition of proliferation by taurine was linked to increased mutant or wild-type p53 proteins binding to DNA, induction of p21, and independently of p53, TIGAR expression. Taurine-induced activation of p21 and TIGAR was associated with suppression of cell-cycle progression, glycolysis, and mitochondrial respiration. Expression of p21 or TIGAR in OC cells mimicked taurine-induced growth suppression. Our studies support the potential therapeutic value of taurine supplementation in OC.

Diagnosis of Hymenoptera Venom Allergy: State of the Art, Challenges, and Perspectives.

Hymenoptera venom allergy is the most common cause of anaphylaxis in adults and the second-most frequent in children. The proper diagnosis of this life-threatening allergy remains a challenge. This review focuses on the current knowledge regarding diagnostics of Hymenoptera venom allergy. The paper includes a brief description of the representatives of Hymenoptera order and the composition of their venoms. Then, diagnostic tests for allergy to Hymenoptera venom are described. Common diagnostic problems, especially double positivity in tests for IgE antibodies specific to honeybee and wasp venom, are also discussed. Special attention is paid to the search for new diagnostic capabilities using modern methodologies. Multidimensional molecular analysis offers an opportunity to characterize changes in body fluids associated with Hymenoptera venom allergy and yields a unique insight into the cell status. Despite recent developments in the diagnostics of Hymenoptera venom allergy, new testing methodologies are still needed to answer questions and doubts we have.

The Metabolomic Approach Reveals the Alteration in Human Serum and Cerebrospinal Fluid Composition in Parkinson's Disease Patients.

Parkinson's disease (PD) is a major public health problem. Since currently there are no reliable diagnostic tools to reveal the early steps of PD, new methods should be developed, including those searching the variations in human metabolome. Alterations in human metabolites could help to establish an earlier and more accurate diagnosis. The presented research shows a targeted metabolomics study of both of the serum and CSF from PD patients, atypical parkinsonian disorders (APDs) patients, and the control. The use of the LC-MS/MS system enabled to quantitate 144 analytes in the serum and 51 in the CSF. This information about the concentration enabled for selection of the metabolites useful for differentiation between the studied group of patients, which should be further evaluated as candidates for markers of screening and differential diagnosis of PD and APDs. Among them, the four compounds observed to be altered in both the serum and CSF seem to be the most important: tyrosine, putrescine, trans-4-hydroxyproline, and total dimethylarginine. Furthermore, we indicated the metabolic pathways potentially related to neurodegeneration processes. Our studies present evidence that the proline metabolism might be related to neurodegeneration processes underlying PD and APDs. Further studies on the proposed metabolites and founded metabolic pathways may significantly contribute to understanding the molecular background of PD and improving the diagnostics and treatment in the future.

Free Amino Acid Alterations in Patients with Gynecological and Breast Cancer: A Review.

Gynecological and breast cancers still remain a significant health problem worldwide. Diagnostic methods are not sensitive and specific enough to detect the disease at an early stage. During carcinogenesis and tumor progression, the cellular need for DNA and protein synthesis increases leading to changes in the levels of amino acids. An important role of amino acids in many biological pathways, including biosynthesis of proteins, nucleic acids, enzymes, etc., which serve as an energy source and maintain redox balance, has been highlighted in many research articles. The aim of this review is a detailed analysis of the literature on metabolomic studies of gynecology and breast cancers with particular emphasis on alterations in free amino acid profiles. The work includes a brief overview of the metabolomic methodology and types of biological samples used in the studies. Special attention was paid to the possible role of selected amino acids in the carcinogenesis, especially proline and amino acids related to its metabolism. There is a clear need for further research and multiple external validation studies to establish the role of amino acid profiling in diagnosing gynecological and breast cancers.