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Background: One defining feature of various aggressive cancers, including glioblastoma multiforme (GBM), is glycolysis upregulation, making its inhibition a promising therapeutic approach. One promising compound is 2-deoxy-d-glucose (2-DG), a d-glucose analog with high clinical potential due to its ability to inhibit glycolysis. Upon uptake, 2-DG is phosphorylated by hexokinase to 2-DG-6-phosphate, which inhibits hexokinase and downstream glycolytic enzymes. Unfortunately, therapeutic use of 2-DG is limited by poor pharmacokinetics, suppressing its efficacy. Methods: To address these issues, we synthesized novel halogenated 2-DG analogs (2-FG, 2,2-diFG, 2-CG, and 2-BG) and evaluated their glycolytic inhibition in GBM cells. Our in vitro and computational studies suggest that these derivatives modulate hexokinase activity differently. Results: Fluorinated compounds show the most potent cytotoxic effects, indicated by the lowest IC50 values. These effects were more pronounced in hypoxic conditions. 19F NMR experiments and molecular docking confirmed that fluorinated derivatives bind hexokinase comparably to glucose. Enzymatic assays demonstrated that all halogenated derivatives are more effective HKII inhibitors than 2-DG, particularly through their 6-phosphates. By modifying the C-2 position with halogens, these compounds may overcome the poor pharmacokinetics of 2-DG. The modifications seem to enhance the stability and uptake of the compounds, making them effective at lower doses and over prolonged periods. Conclusions: This research has the potential to reshape the treatment landscape for GBM and possibly other cancers by offering a more targeted, effective, and metabolically focused therapeutic approach. The application of halogenated 2-DG analogs represents a promising advancement in cancer metabolism-targeted therapies, with the potential to overcome current treatment limitations.

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults with a poor prognosis. Despite significant progress in drug development, the blood–brain barrier (BBB) continues to limit the use of novel chemotherapeutics. Thus, our attention has been focused on the design, synthesis, and testing of small-molecule anticancer agents that are able to penetrate the BBB. One such compound is the D-glucose analog, 2-deoxy-D-glucose (2-DG), which inhibits glycolysis and induces GBM cell death. 2-DG has already been tested in clinical trials but was not approved as a drug, in part due to inadequate pharmacokinetics. To improve the pharmacokinetic properties of 2-DG, a series of novel derivatives was synthesized. Herein, we report the biological effects of WP1234, a 2-ethylbutyric acid 3,6-diester of 2-DG that can potentially release 2-ethylbutyrate and 2-DG inside the cells when metabolized. Using biochemical assays and examining cell viability, proliferation, protein synthesis, and apoptosis induction, we assessed the cytotoxic potential of WP1234. WP1234 significantly reduced the viability of GBM cells in a dose- and time-dependent manner. The lactate and ATP synthesis assays confirmed the inhibition of glycolysis elicited by released 2-DG. Furthermore, an evaluation of histone deacetylases (HDAC) activity revealed that the 2-ethylbutyrate action resulted in HDAC inhibition. Overall, these results demonstrated that WP1234 is a bifunctional molecule with promising anticancer potential. Further experiments in animal models and toxicology studies are needed to evaluate the efficacy and safety of this new 2-DG derivative.

Over the last decade, we have seen tremendous progress in research on 2-deoxy-D-glucose (2-DG) and its analogs. Clinical trials of 2-DG have demonstrated the challenges of using 2-DG as a monotherapy, due to its poor drug-like characteristics, leading researchers to focus on improving its bioavailability to tissue and organs. Novel 2-DG analogs such as WP1122 and others have revived the old concept of glycolysis inhibition as an effective anticancer strategy. Combined with other potent cytotoxic agents, inhibitors of glycolysis could synergistically eliminate cancer cells. We focused our efforts on the development of new combinations of anticancer agents coupled with 2-DG and its derivatives, targeting glioblastoma, which is in desperate need of novel approaches and therapeutic options and is particularly suited to glycolysis inhibition, due to its reliance on aerobic glycolysis. Herein, we present evidence that a combined treatment of 2-DG analogs and modulation of histone deacetylases (HDAC) activity via HDAC inhibitors (sodium butyrate and sodium valproate) exerts synergistic cytotoxic effects in glioblastoma U-87 and U-251 cells and represents a promising therapeutic strategy.

Łódź as a post-industrial city has great potential for post-industrial tourism. An attempt to utilise this has been the creation of the Łódź Industrial Architecture Trail, bringing together buildings related to its industrial past. According to the author, to make the trail a tourist attraction, the first people who should be aware of its value are the city’s inhabitants. The survey confirmed the very important role of social participation in creating the image of a city, and providing the basis for further work on its improvement and promotion. The article does not cover social participation as part of the process of development, but can serve as a contribution to a discussion of the role of a city’s inhabitants in shaping its tourism attractions. At the same time, the article confirms that social participation is an extremely important element of tourism research and forms an introduction to its effective use in practice.

Łódź jako miasto postindustrialne posiada duży potencjał dla turystyki poprzemysłowej. Próbą jego wykorzystania było utworzenie Szlaku Architektury Przemysłowej Łodzi, łączącego obiekty związane z przemysłową przeszłością miasta. W opinii autorki, by szlak mógł pełnić funkcję atrakcji turystycznej pierwszymi osobami świadomymi jego wartości powinni być sami mieszkańcy. Przeprowadzone badania ankietowe potwierdziły niezwykle istotną rolę partycypacji społecznej w kreowaniu wizerunku miasta, stwarzającej podstawę do dalszych działań związanych z udoskonalaniem i promocją szlaku. Artykuł nie wyczerpuje tematu partycypacji społecznej w procesie rozwoju szlaku, ale może posłużyć jako wkład w dyskusję na temat roli mieszkańców w procesie kształtowania atrakcyjności turystycznej miasta. Partycypacja społeczna jest bowiem niezwykle istotnym elementem badań nad turystyką i stanowi wstęp do ich efektywnego wykorzystania w praktyce.

Muscle cachexia is one of the most critical unmet medical needs. Identifying the molecular background of cancer-induced muscle loss revealed a promising possibility of new therapeutic targets and new drug development. In this review, we will define the signal transducer and activator of transcription 3 (STAT3) protein’s role in the tumor formation process and summarize the role of STAT3 in skeletal muscle cachexia. Finally, we will discuss a vast therapeutic potential for the STAT3-inhibiting single-agent treatment innovation that, as the desired outcome, could block tumor growth and generally prevent muscle cachexia.

This review addresses the issue of the numerous roles played by Rap1 GTPase (guanosine triphosphatase) in different cell types, in terms of both physiology and pathology. It is one among a myriad of small G proteins with endogenous GTP-hydrolyzing activity that is considerably stimulated by posttranslational modifications (geranylgeranylation) or guanine nucleotide exchange factors (GEFs), and inhibited by GTPase-activating proteins (GAPs). Rap1 is a ubiquitous protein that plays an essential role in the control of metabolic processes, such as signal transduction from plasma membrane receptors, cytoskeleton rearrangements necessary for cell division, intracellular and substratum adhesion, as well as cell motility, which is needed for extravasation or fusion. We present several examples of how Rap1 affects cells and organs, pointing to possible molecular manipulations that could have application in the therapy of several diseases.

BackgroundTraining-induced muscle, skeletal and joint trauma may result in acute phase response reflected by the changes in the blood concentration of serum amyloid A (SAA) in racehorses. It remains yet unclear if such systemic reaction could be triggered by sport injuries and what is the impact of different types of musculoskeletal trauma on SAA concentrations in racehorses. This study aimed to determine changes in the SAA blood concentration in racehorses with different types of injuries of musculoskeletal system.Materials and methodsThe study involved 28 racehorses diagnosed after the race with bone fractures (n = 7), dorsal metacarpal disease (n = 11), joint trauma (n = 4) or tendon and muscle trauma (n = 6) and 28 healthy control racehorses. Serum samples were collected twice, between 1 and 4 days of the injury or succesful completion of the race. SAA concentration was measured using the commercial ELISA kit. Differences between mean SAA concentration in respective groups were analyzed using ANOVA and Tukey post-hoc test.ResultsMean SAA concentration within the first 4 days of the injury of muscle and tendon was significantly higher than in bone fractures, dorsal metacarpal disease, joint trauma or in the healthy horses (pConclusionsStrain injuries of muscle and tendons can cause a moderate increase in SAA blood concentration in racehorses, reflecting the occurrence of the acute phase response. Similar reaction is not observed in the stress-related bone injuries.