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The presented study depicts the synthesis of 11 carborane-thiazole conjugates with anticancer activity, as well as an evaluation of their biological activity as inhibitors of two enzymes: tyrosinase and 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). The overexpression of tyrosinase results in the intracellular accumulation of melanin and can be observed in melanoma. The overexpression of 11β-HSD1 results in an elevation of glucocorticoid levels and has been associated with the aggravation of metabolic disorders such as type II diabetes mellitus and obesity. Recently, as the comorbidity of melanomas and metabolic disorders is being recognized as an important issue, the search for new therapeutic options has intensified. This study demonstrates that carborane-thiazole derivatives inhibit both enzymes, exerting beneficial effects. The antiproliferative action of all newly synthesized compounds was evaluated using three cancer cell lines, namely A172 (human brain glioblastoma), B16F10 (murine melanoma) and MDA-MB-231 (human breast adenocarcinoma), as well as a healthy control cell line of HUVEC (human umbilical vein endothelial cells). The results show that 9 out of 11 newly synthesized compounds demonstrated similar antiproliferative action against the B16F10 cell line to the reference drug, and three of these compounds surpassed it. To the best of our knowledge, this study is the first to demonstrate dual inhibitory action of carborane-thiazole derivatives against both tyrosinase and 11β-HSD1. Therefore, it represents the first step towards the simultaneous treatment of melanoma and comorbid diseases such as type II diabetes mellitus.

The development of surgical techniques, immunosuppressive strategies and new organ preservation methods have meant that transplant centers have to face the problem of an insufficient number of organs for transplantation concerning the constantly growing demand. Therefore, using organs from expanded criteria donors and developing new analytical solutions to find parameters or compounds that would allow a more efficient assessment of organ quality before transplantation are options for meeting this challenge. This study proposed bile metabolomic analysis to evaluate liver metabolism and biliary tract function depending on the organ preservation method and degree of warm ischemia time. The analyses were performed on solid-phase microextraction-prepared bile samples from porcine model donors with mild (heart beating donor [HBD]) and moderate warm ischemia (donation after circulatory death [DCD]) grafts subjected to static cold storage (SCS) or normothermic ex vivo liver perfusion (NEVLP) before transplantation. Bile produced in the SCS-preserved livers was characterized by increased levels of metabolites such as chenodeoxycholic acid, arachidonic acid and 5S-hydroxyeicosatetraeonic acid, as well as saturated and monounsaturated lysophosphatidylcholines (LPC). Such changes may be associated with differences in the bile acid synthesis pathways and organ inflammation. Moreover, it has been shown that NEVLP reduced the negative effect of ischemia on organ function. A linear relationship was observed between levels of lipids from the LPC group and the time of organ ischemia. This study identified metabolites worth considering as potential markers of changes occurring in preserved grafts.

In addition to being the most common primary brain tumor, gliomas are also among the most difficult to diagnose and treat. At present, the "gold standard" in glioma treatment entails the surgical resection of the largest possible portion of the tumor, followed by temozolomide therapy and radiation. However, this approach does not always yield the desired results. Additionally, the ability to cross the blood-brain barrier remains a major challenge for new potential drugs. Thus, researchers continue to search for targeted therapies that can be individualized based on the specific characteristics of each case. Metabolic and lipidomic research may represent two of the best ways to achieve this goal, as they enable detailed insights into the changes in the profile of small molecules in a biological system/specimen. This article reviews the new approaches to glioma therapy based on the analysis of alterations to biochemical pathways, and it provides an overview of the clinical results that may support personalized therapies in the future.

Frailty is a geriatric syndrome causing a reduction in the body's functional reserves. Proper nutrition may be helpful in delaying transitioning older adults from pre-frail to frailty syndrome. The present study evaluates the nutritional status of pre-frail patients who underwent nutritional intervention and metabolomic changes resulting from this intervention. Sixteen pre-frail patients (68.4 ± 5.5 years old; 81.3% women) were enrolled for nutritional intervention, and twenty-nine robust elderly people (69.3 ± 5.3 years old; 82.8% women) were the control group. Pre-frail patients consumed 1.0 g protein/kg BW/day for eight weeks through diet modification and an additional daily intake of a protein powder formula. Taken measurements included: Nutritional anthropometry, assessment of food intake, and blood serum analysis with an untargeted metabolomic assessment. Protein consumption increased by 25.8%; moreover, significant increases in body weight (+1.2 kg; p = 0.023) and muscle mass index (+0.1 kg/m 2 ; p = 0.042) were also observed. The untargeted metabolomic assay showed a significant increase in arachidonic acid ( p = 0.038), and valine ( p = 0.008) among pre-frail patients. Increased protein consumption is reflected in improved anthropometric and biochemical parameters of pre-frail patients. Moreover, metabolomic assay can be a useful tool in determining compliance with dietary recommendations.

Brain tumors are neoplasms with one of the highest mortality rates. Therefore, the availability of methods that allow for the quick and effective diagnosis of brain tumors and selection of appropriate treatments is of critical importance for patient outcomes. In this study, coated blade spray-mass spectrometry (CBS-MS), which combines the features of microextraction and fast ionization methods, was applied for the analysis of brain tumors. In this approach, a sword-shaped probe is coated with a sorptive material to enable the extraction of analytes from biological samples. The analytes are then desorbed using only a few microliters of solvent, followed by the insertion of the CBS device into the interface on the mass spectrometer source. The results of this proof-of-concept experiment confirmed that CBS coupled to high-resolution mass spectrometry (HRMS) enables the rapid differentiation of two histologically different lesions: meningiomas and gliomas. Moreover, quantitative CBS-HRMS/MS analysis of carnitine, the endogenous compound, previously identified as a discriminating metabolite, showed good reproducibility with the variation below 10% when using a standard addition calibration strategy and deuterated internal standards for correction. The resultant data show that the proposed CBS-MS technique can be useful for on-site qualitative and quantitative assessments of brain tumor metabolite profiles.

The development of a fast and accurate intraoperative method that enables the differentiation and stratification of cancerous lesions is still a challenging problem in laboratory medicine. Therefore, it is important to find and optimize a simple and effective analytical method of enabling the selection of distinctive metabolites. This study aims to assess the usefulness of solid-phase microextraction (SPME) probes as a sampling method for the lipidomic analysis of brain tumors. To this end, SPME was applied to sample brain tumors immediately after excision, followed by lipidomic analysis via liquid chromatography-high resolution mass spectrometry (LC-HRMS). The results showed that long fibers were a good option for extracting analytes from an entire lesion to obtain an average lipidomic profile. Moreover, significant differences between tumors of different histological origin were observed. In-depth investigation of the glioma samples revealed that malignancy grade and isocitrate dehydrogenase (IDH) mutation status impact the lipidomic composition of the tumor, whereas 1p/19q co-deletion did not appear to alter the lipid profile. This first on-site lipidomic analysis of intact tumors proved that chemical biopsy with SPME is a promising tool for the simple and fast extraction of lipid markers in neurooncology.

In this study, a series of 10 novel 1-methyl-3-octyloxymethylimidazolium derivatives carrying various anionic moieties (4-hydroxybenzenesulfonate, benzenesulfonate, carvacroloxyacetate, chloride, formate, propionate, thymoloxyacetate, vanillinoxyacetate, eugenoloxyacetate and trimethylacetate) were synthesized. Compounds were tested for their antimicrobial activity against six microbe strains (Staph-ylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, Enterococcus faecalis, and Candida albicans), cytotoxic activity against the mouse melanoma cell line (B16 F10), and surface active properties. All synthesized compounds exhibited antimicrobial activity (expressed as minimum inhibitory concentration; in range of 0.10-27.82 mM/L), especially against Gram-positive bacteria and fungi. In addition, all compounds demonstrated cytotoxicity on B16 F10 cells (IC50 values 0.0101-0.0197 mM/L). Surface properties defined as CMC values, ranged from 0.72 to 32.35 mmol L-1. The obtained results provide an insight into the promising activity of a novel group of quaternary imidazolium derivatives having ionic liquid properties. The most potent compounds, containing a thymoloxyacetate and eugenoloxyacetate moiety, could be candidates for new antimicrobial agents or surfactants.

Glioblastoma multiforme is one of the most malignant neoplasms among humans in their third and fourth decades of life, which is evidenced by short patient survival times and rapid tumor-cell proliferation after radiation and chemotherapy. At present, the diagnosis of gliomas and decisions related to therapeutic strategies are based on genetic testing and histological analysis of the tumor, with molecular biomarkers still being sought to complement the diagnostic panel. This work aims to enable the metabolomic characterization of cancer tissue and the discovery of potential biomarkers via high-resolution mass spectrometry coupled to liquid chromatography and a solvent-free sampling protocol that uses a microprobe to extract metabolites directly from intact tumors. The metabolomic analyses were performed independently from genetic and histological testing and at a later time. Despite the small cohort analyzed in this study, the results indicated that the proposed method is able to identify metabolites associated with different malignancy grades of glioma, as well as IDH and 1p19q codeletion mutations. A comparison of the constellation of identified metabolites and the results of standard tests indicated the validity of using the characterization of one comprehensive tumor phenotype as a reflection of all diagnostically meaningful information. Due to its simplicity, the proposed analytical approach was verified as being compatible with a surgical environment and applicable for large-scale studies.

Volatile organic compounds (VOCs) have been proposed in the last two decades as biomarkers for disease detection and therapeutic monitoring. Model in vitro experiments with established cell lines are fundamental to clarify whether given VOCs originate from normal human cells or pathogens, including transformed cancer cells. Due to the trace concentrations of target metabolites, adsorptive enrichment is needed before gas chromatography-mass spectrometry (GC-MS) analysis, with solid-phase microextraction (SPME) being perfectly suited for this purpose. Here, a modification of SPME, the thin-film microextraction (TFME) technique, is proposed for analysis of cellular VOCs, which utilizes a planar mesh coated with stationary phase to increase the extraction phase volume and active surface area. In this study, four different adsorbents were compared: carboxen, divinylbenzene, hydrophobic-lipophilic balanced and polydimethylsiloxane. Amongst them, HLB sheets using poly(divinylbenzene-co-N-vinyl-pyrrolidone) skeleton structure proved to be the most versatile, enabling the most sensitive analysis of VOCs with a broad polarity and volatility. For HLB, sampling type (internal static headspace, external bi-directional headspace), extraction temperature and extraction time were also examined. An established method was successfully applied to analyze metabolites produced by A549 cells revealing five volatiles at significantly higher (additionally benzaldehyde at lower) levels in cell culture medium compared to the cell-free reference medium headspace.

Alterations in the carnitine shuttle system may be an indication of the presence of cancer. As such, in-depth analyses of this pathway in different malignant tumors could be important for the detection and treatment of this disease. The current study aims to assess the profiles of carnitine and acylcarnitines in gliomas with respect to their grade, the presence of isocitrate dehydrogenase (IDH) mutations, and 1p/19q co-deletion. Brain tumors obtained from 19 patients were sampled on-site using solid-phase microextraction (SPME) immediately following excision. Analytes were desorbed and then analyzed via liquid chromatography-high-resolution mass spectrometry. The results showed that SPME enabled the extraction of carnitine and 22 acylcarnitines. An analysis of the correlation factor revealed the presence of two separate clusters: short-chain and long-chain carnitine esters. Slightly higher carnitine and acylcarnitine concentrations were observed in the higher-malignancy tumor samples (high vs. low grade) and in those samples with worse projected clinical outcomes (without vs. with IDH mutation; without vs. with 1p/19q co-deletion). Thus, the proposed chemical biopsy approach offers a simple solution for on-site sampling that enables sample preservation, thus supporting comprehensive multi-method analyses.

2-Arylidene-indan-1,3-done derivatives have very different properties, thanks to which they find various applications in science, medicine, and industry. Selected derivatives show antiviral, antibacterial, and anti-inflammatory activity. This paper presents a procedure for the synthesis of a series of indan-1,3-dione derivatives that present antiproliferative activity. The aim of the work was to develop a method of simple synthesis and purification, evaluate the fulfillment of the Lipiński's and Veber's rule, and determine the potential scope of application of the obtained series of compounds. The structure of the synthesized compounds was confirmed, and their lipophilicity was determined using experimental and computational methods. Their antiproliferative activity against selected cell lines was tested in accordance with the MTT protocol; the ability to bind to albumin was tested, and the parameters related to the toxicity of substances in silico were determined. The selected compounds which showed antiproliferative activity were strongly bound to albumin and, in most cases, met the Lipiński's and Veber's rule. Thus, the obtained results suggest that 2-arylidene-indan-1,3-done derivatives appear to be good candidates for drugs with a potential leading structure for further development.

In 2016, the WHO introduced new guidelines for the diagnosis of brain gliomas based on new genomic markers. The addition of these new markers to the pre-existing diagnostic methods provided a new level of precision for the diagnosis of glioma and the prediction of treatment effectiveness. Yet, despite this new classification tool, glioblastoma (GBM), a grade IV glioma, continues to have one of the highest mortality rates among central nervous system tumors. Metabolomics is a particularly promising tool for the analysis of GBM tumors and potential methods of treating them, as it is the only "omics" approach that is capable of providing a metabolic signature of a tumor's phenotype. With careful experimental design, cell cultures can be a useful matrix in GBM metabolomics, as they ensure stable conditions and, under proper conditions, are capable of capturing different tumor phenotypes. This paper reviews in vitro metabolomic profiling studies of high-grade gliomas, with a particular focus on sample-preparation techniques, crucial metabolites identified, cell culture conditions, in vitro-in vivo extrapolation, and pharmacometabolomics. Ultimately, this review aims to elucidate potential future directions for in vitro GBM metabolomics.

Bladder cancer (BC) is a common malignancy of the urinary system and a leading cause of death worldwide. In this work, untargeted metabolomic profiling of biological fluids is presented as a non-invasive tool for bladder cancer biomarker discovery as a first step towards developing superior methods for detection, treatment, and prevention well as to further our current understanding of this disease. In this study, urine samples from 24 healthy volunteers and 24 BC patients were subjected to metabolomic profiling using high throughput solid-phase microextraction (SPME) in thin-film format and reversed-phase high-performance liquid chromatography coupled with a Q Exactive Focus Orbitrap mass spectrometer. The chemometric analysis enabled the selection of metabolites contributing to the observed separation of BC patients from the control group. Relevant differences were demonstrated for phenylalanine metabolism compounds, i.e., benzoic acid, hippuric acid, and 4-hydroxycinnamic acid. Furthermore, compounds involved in the metabolism of histidine, beta-alanine, and glycerophospholipids were also identified. Thin-film SPME can be efficiently used as an alternative approach to other traditional urine sample preparation methods, demonstrating the SPME technique as a simple and efficient tool for urinary metabolomics research. Moreover, this study's results may support a better understanding of bladder cancer development and progression mechanisms.

A new series of hybrid compounds with tropinone and thiazole rings in the structure was designed and synthesized as potential anticancer agents. They were tested against human multiple myeloma (RPMI 8226), lung carcinoma (A549), breast adenocarcinoma (MDA-MB-231), and mouse skin melanoma (B16-F10) cell lines. Toxicity was tested on human normal skin fibroblasts (HSF) and normal colon fibroblasts (CCD-18Co). The growth inhibition mechanism of the most active derivative was analyzed through investigation of its effect on the distribution of cell cycle phases and ability to induce apoptosis and necrosis in RPMI 8226 and A549 cancer cells. The tyrosinase inhibitory potential was assessed, followed by molecular docking studies. Compounds 3a-3h show high anticancer activity against MDA-MB-231 and B16-F10 cell lines with IC 50 values of 1.51-3.03 µM. Moreover, the cytotoxic activity of the investigated compounds against HSF and CCD-18Co cells was 8-70 times lower than against the cancer cells or no toxicity was shown in our tests, with derivative 3a being particularly successful. The mechanism of action of compound 3a in RPMI 8226 cell was shown to be through induction of cell death through apoptosis. The derivatives show ability to inhibit the tyrosinase activity with a mixed mechanism of inhibition. The final molecular docking results showed for IC 50 distinct correlation with experiment.

Given that the extent to which genetics alters the metabolomic profile of tissues is still poorly understood, the current study aimed to characterize and investigate the metabolite profiles of brain, liver, kidney and skeletal muscle of two common mouse inbred strains (BALB/c, C57BL/6) and one outbred stock (CD1) for strain-specific differences. Male mice ( n = 15) at the age of 12 weeks were used: BALB/c ( n = 5), C57BL/6 ( n = 5) and CD1 ( n = 5). Solid phase microextraction (SPME) was applied for the extraction of analytes from the tissues. SPME fibers (approximately 0.2 mm in diameter) coated with a biocompatible sorbent (4 mm length of hydrophilic-lipophilic balanced particles) were inserted into each organ immediately after euthanasia. Samples were analyzed using liquid chromatography coupled to a Q-Exactive Focus Orbitrap mass spectrometer. Distinct interstrain differences in the metabolomic patterns of brain and liver tissue were revealed. The metabolome of kidney and muscle tissue in BALB/c mice differed greatly from C57BL/6 and CD1 strains. The main compounds differentiating all the targeted organs were alpha-amino acids, purine nucleotides and fatty acid esters. The results of the study indicate that the baseline metabolome of organs, as well as different metabolic pathways, vary widely among general-purpose models of laboratory mice commonly used in biomedical research.

Background and Objectives : Recurrence of pericarditis (ROP) is an important complication of the acute pericarditis. The aim of this study was to analyse the influence of aetiology, clinical findings and treatment on the outcome of acute pericarditis. Methods : Data were retrospectively collected from medical records of patients treated from 2011 to 2019 at a tertiary referent heart paediatric center. Results : Our investigation included 56 children with idiopathic and viral pericarditis. Relapse was registered in 8/56 patients, 2/29 (7.41%) treated with nonsteroidal anti-inflammatory drugs (NSAID) and 6/27 (28.57%) treated with corticosteroids (CS) and NSAID. Independent risk factors for ROP were viral pericarditis ( p = 0.01, OR 31.46), lack of myocardial affection ( p = 0.03, OR 29.15), CS use ( p = 0.02, OR 29.02) and ESR ≥ 50 mm/h ( p = 0.03, OR 25.23). In 4/8 patients the first recurrence was treated with NSAID and colchicine, while treatment of 4/8 patients included CS. Children with ROP treated with CS had higher median number of recurrence (5, IQR: 2-15) than those treated with colchicine (0, IQR: 0-0.75). Conclusions : Independent risk factors for recurrence are CS treatment, viral aetiology, pericarditis only and ESR ≥ 50 mm/h. Acute pericarditis should be treated with NSAID. Colchicine and NSAID might be recommended in children with the first ROP.