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Invariably, for years, type 2 diabetes has been described as a global, social health problem, affecting approximately 10% of the world's population. A much broader and still growing health problem on a global scale consists in disorders of glucose and lipid metabolism with accompanying insulin resistance, which can lead to symptomatic type 2 diabetes and other serious health consequences. Among these consequences is the nonalcoholic fatty liver disease (NAFLD), which affects about 25% of the population, and it is estimated to become the most common indication for liver transplantation by 2030. Despite the availability of a wide range of antidiabetic drugs, a large proportion of patients struggle to achieve sufficient clinical improvement and reducing the risk of complications associated with T2D. This explains the high number of compounds being evaluated in clinical trials. Currently, there are no approved pharmacotherapies for treating NAFLD or metabolic disorders associated with prediabetic conditions, as pharmacological interventions in this area are not well-established. While vanadium compounds are not considered primary pharmacotherapeutic options for metabolic disorders, their over 100-year history of clinical applications and numerous preclinical evidence suggest their potential in antidiabetic action. Currently, the most promising direction of research i ; s the search for pharmacologically active new vanadium compounds in the form of their complexes, which have several advantages over organic compounds. The aim of the study was to evaluate the pharmacological activity of newly developed and synthesized vanadium complexes by studying their effects on metabolic processes related to various disruptions in glucose and lipid metabolism. This evaluation considered diverse mechanisms and cell models that represent target tissues for antidiabetic effects. The preliminary screening involved the examination of 110 newly synthesized vanadium complexes from various structural groups, which have obtained international patent protection. 93% of the tested complexes showed higher activity in stimulating glucose uptake by C2C12 myocytes compared to bis(maltolato)oxovanadium(IV) (BMOV) and its methyl analogue bis(ethylmaltolato)-oxovanadium(IV) (BEOV), which have demonstrated antidiabetic efficacy in clinical studies. Approximately 50% of the complexes showed better efficiency than BMOV in lipid accumulation by 3T3-L1 adipocytes and insulin secretion by RINm5F pancreatic beta cells. Numerous complexes exhibited greater activity than clinically confirmed antidiabetic compounds such as glibenclamide, rosiglitazone, or metformin, without cytotoxic effects. Vanadium complexes with high pharmacological activity were identified, exhibi ; ting diverse activity profiles across the used cell models. As part of the research, the synthesis and physicochemical characteristics of new vanadium(V) complexes of the ONS type with thioanilide derivatives of amino acids were described for the first time. These complexes were subjected to extensive pharmacological activity studies. The complexes exhibited inhibition of human protein tyrosine phosphatases (PTP1B, LAR, SHP1, and SHP2) in the submicromolar range, as well as inhibition of non-tyrosine phosphatases (CDC25A and PPA2), similar to the BMOV complex. The ONS-type complexes increased the transport of radiolabeled [14C]-deoxy-D-glucose into C2C12 myocytes. Specifically, VC070, one of the ONS complexes, also enhanced this transport in 3T3-L1 adipocytes. These complexes inhibited gluconeogenesis in HepG2 hepatocytes, but none of them reduced lipid accumulation in a non-alcoholic fatty liver disease (NAFLD) model in the same cells. Compared to the simultaneously tested newly synthesized vanadium complexes of the ONO type with 5- bromosalicylaldehyde and substituted benzhydrazides as ligand components of Schiff base type, the ONS complexes exhibited stronger inhibition of protein tyrosine phosphatases. However, the ONO complexes generally showed higher activity in cellular models. Complexes from ONO group inhibited hepatic gluconeogenesis and lipid accumulati ; on in HepG2 hepatocytes in the NAFLD model. Furthermore, most of the active complexes from both groups showed better effects in the used models than the BMOV complex. Complexes from both groups activated AKT and ERK signaling pathways in hepatocytes to a comparable extent. One of the ONO-type complex, VC068, exhibited activity in all the aforementioned models and also increased glucose consumption in C2C12 myocytes. It also reversed the impaired transport of [14C]-deoxy-D-glucose into HepG2 hepatocytes caused by insulin resistance. The selected representative ONO-type complex, VC036, significantly enhanced adipogenesis in 3T3-L1 adipocytes to a greater extent than rosiglitazone. However, this complex did not affect the reduction of intracellular lipid content in fully differentiated adipocytes with high lipid content. In glucose consumption tests conducted on these cells, the VC067 complex showed no activity, unlike the VC048 complex, despite both ONO-type complexes having a high inhibition of PTP1B. Differences in the activity were identified both between the entire groups of ONO and ONS complexes and within each group. Certain structural characteristics were also indicated to be associated with these effects. The observed differences in the effects of ONS and ONO complexes in different models and cellular mechanisms may stem from the specific or selective act ; ions of these complexes, depending on the tissue represented by the cellular model used. However, based on the obtained results, it appears that this diversity may be determined more by the metabolic, structural, or phenotypic state rather than the cell type itself and the interaction of complex structures. The significant number of newly developed and examined vanadium complexes and the diverse experimental models employed in this study have yielded substantial findings that contribute to the current state of knowledge. These research results provide a solid basis for future investigations into the selective or specific actions of new vanadium complexes, which can aid in the development of complexes with improved pharmacological properties for metabolic disorders. This is particularly important given the expanding body of research on vanadium complexes and their potential application in other therapeutic areas.
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Instytucja nadająca tytuł:
Rada Dyscypliny Nauki farmaceutyczne
Promotor:
Papież, Monika ; Jurowska, Anna
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Data ostatniej modyfikacji:
23 maj 2024
Data dodania obiektu:
23 maj 2024
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http://dl.cm-uj.krakow.pl:8080/publication/5116
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| Nazwa wydania | Data |
|---|---|
| ZB-140035 | 23 maj 2024 |
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