Potentiation of adipogenesis and insulinomimetic effects of novel vanadium complex (N'-[(E)-(5-bromo-2-oxophenyl)methylidene]-4-methoxybenzohydrazide)oxido(1,10-phenanthroline)vanadium(IV) in 3T3-L1 cells

Recent research on the action of vanadium compounds shows its important effect on adipogenesis processes and adipocyte function. On the basis of previous screening tests in cellular models, the novel vanadium complex (N′-[(E)-(5-bromo-2-oxophenyl)methylidene]4-methoxybenzohydrazide)oxido(1,10-phenanthroline)vanadium(IV) was selected for this study. This complex exhibits potent inhibition of tyrosine phosphatases, and differences in the degree of inhibition were observed particularly for phosphatases. A significant increase in intracellular lipid accumulation and proliferative effect on 3T3-L1 preadipocytes confirmed the ability of this complex to enhance adipogenesis. The insulinomimetic activity of the tested complex was also demonstrated in fully differentiated 3T3-L1 adipocytes, in which glucose utilization was potentiated. The obtained results support the hypothesis that vanadium complexes show promising possibilities for use as new therapeutic strategies for the treatment of type 2 diabetes

Impact of N-alkylamino substituents on serotonin receptor (5-HTR) affinity and phosphodiesterase 10A (PDE10A) inhibition of isoindole-1,3-dione derivatives

In this study, a series of compounds derived from 4-methoxy-1H-isoindole-1,3(2H)-dione, potential ligands of phosphodiesterase 10A and serotonin receptors, were investigated as potential antipsychotics. A library of 4-methoxy-1H-isoindole-1,3(2H)-dione derivatives with various amine moieties was synthesized and examined for their phosphodiesterase 10A (PDE10A)-inhibiting properties and their 5-HT1A and 5-HT7 receptor affinities. Based on in vitro studies, the most potent compound, 18 (2-[4-(1H-benzimidazol-2-yl)butyl]-4-methoxy-1H-isoindole-1,3(2H)-dione), was selected and its safety in vitro was evaluated. In order to explain the binding mode of compound 18 in the active site of the PDE10A enzyme and describe the molecular interactions responsible for its inhibition, computer-aided docking studies were performed. The potential antipsychotic properties of compound 18 in a behavioral model of schizophrenia were also investigated

The incidence of risk factors of type 2 diabetes mellitus in relatives of the patients

WSTĘP. Celem niniejszej pracy była ocena występowania zaburzeń gospodarki węglowodanowej u krewnych I stopnia chorych na cukrzycę typu 2 zależnie od obecności innych czynników ryzyka tej choroby. MATERIAŁ I METODY. Ocenianą grupę tworzyło 42 krewnych I stopnia chorych leczonych w Przyklinicznej Poradni Diabetologicznej Szpitala Uniwersyteckiego w Bydgoszczy. Przeprowadzano badanie podmiotowe, przedmiotowe oraz test doustnego obciążenia 75 g glukozy. WYNIKI. U 13 osób (31%) rozpoznano zaburzenia gospodarki węglowodanowej (grupa ZGW), zaś u 29 ich nie stwierdzono (grupa BZGW). Badani z grupy ZGW byli istotnie statystycznie starsi od osób z grupy BZGW (59,8 &#177; 14,6 vs. 37,8 &#177; 15,5 roku; p < 0,001), cechowały ich znamiennie większe rodzinne obciążenie cukrzycą typu 2 (2,0 &#177; 1,1 vs. 1,1 &#177; 0,4; p < 0,001 - liczba krewnych w rodzinie) i istotnie wyższa liczba czynników ryzyka choroby (2,9 &#177; 1,2 vs. 2,0 &#177; 1,2; p < 0,01). Najczęstsze, istotne statystycznie okazało się występowanie w wywiadzie nieprawidłowego stężenia glukozy we krwi - 61,5% (BZGW - 6,9%). Obie grupy nie różniły się pod względem liczby chorych rodziców, natomiast rodzeństwo chore na cukrzycę miało 92,3% osób z grupy ZGW i tylko 13,8% z grupy BZGW. Przynajmniej jedno dziecko chore na cukrzycę miało 23% osób z grupy ZGW, natomiast nikt z BZGW. Nie wykazano istotnych różnic między grupami odnośnie wskaźnika masy ciała (28,3 &#177; &#177; 4,5 kg/m2 vs. 25,9 &#177; 4,9 kg/m2) oraz wskaźnika talia- biodro (0,86 &#177; 0,08 vs. 0,83 &#177; 0,07, odpowiednio). Cukrzyca ciążowa wystąpiła u 7,7% vs. 6,9% badanych, urodzenie dziecka z masą ciała powyżej 4000 g dotyczyło 7,7% versus 11,9%, a zespół policystycznych jajników stwierdzono u 7,7% versus 3,4%. WNIOSKI. U krewnych I stopnia chorych na cukrzycę typu 2 wystąpienie zaburzeń gospodarki węglowodanowej zależało od: wieku, sumy czynników ryzyka cukrzycy, a zwłaszcza stwierdzenia nieprawidłowych wartości glikemii w wywiadzie, liczby krewnych chorych na cukrzycę typu 2, w szczególności chorego rodzeństwa i dzieci.INTRODUCTION. The aim of the study was the evaluation of glucose metabolism disturbances in I° relatives of the patients with type 2 diabetes, depending on the other present risk factors. MATERIAL AND METHODS. The evaluated group consisted of 42 I° relatives of the patients treated in Outpatient Diabetology Clinic of the University Hospital in Bydgoszcz. A subjective, objective examination and the oral glucose tolerance test were carried out. RESULTS. In 13 patients (31%) glucose metabolism disturbances (ZGW group) were identified, in 29 they were not stated (BZGW group). The examined ZGW group patients were considerably statistically older than the BZGW (59.8 &#177; 14.6 vs. 37.8 &#177; 15.5 years; p < 0.001), had a remarkably greater inherited susceptibility to type 2 diabetes (2.0 &#177; 1.1 vs. 1.1 &#177; &#177; 0.4; p < 0.001 of the number of relatives in the family) and were characterized by a significantly higher number of the diabetes risk factors (2.9 &#177; 1.2 vs. 2.0 &#177; 1.2; p < 0.01). The occurrence of the abnormal glycaemia - 61.5% (BZGW - 6.9%) in the anamnesis turned out to be the most common and statistically important. Both groups did not differ in the number of parents with diabetes, whereas 92.3% patients of the ZGW and only 13.8% of the BZGW had siblings with diabetes. 23% people with ZGW had at least one child with diabetes while no-one thase with BZGW. No significant differences between the groups, regarding BMI were stated: 28.3 &#177; 4.5 kg/m2 versus 25.9 &#177; 4.9 kg/m2 and WHR: 0.86 &#177; 0.08 versus 0.83 &#177; &#177; 0.07 respectively. Gestational diabetes mellitus occurred in 7.7% versus 6.9%, giving birth to a newborn with birth weight above 4000 g: 7.7% versus 11.9%, polycystic ovary syndrome: 7.7% versus 3.4%. CONCLUSIONS. In the I° relatives of the patients with type 2 diabetes the occurrence of glucose metabolism disturbances depended on: age, the amount of diabetes risk factors, especially stating abnormal glycaemia values in the anamnesis, the number of relatives with type 2 diabetes, siblings and children in particular

HBK-17, a 5-HT1A Receptor Ligand With Anxiolytic-Like Activity, Preferentially Activates ß-Arrestin Signaling

Numerous studies have proven that both stimulation and blockade of 5-HT1A and the blockade of 5-HT7 receptors might cause the anxiolytic-like effects. Biased agonists selectively activate specific signaling pathways. Therefore, they might offer novel treatment strategies. In this study, we investigated the anxiolytic-like activity, as well as the possible mechanism of action of 1-[(2,5-dimethylphenoxy)propyl]-4-(2-methoxyphenyl)piperazine hydrochloride (HBK-17). In our previous experiments, HBK-17 showed high affinity for 5-HT1A and 5-HT7 receptors and antidepressant-like properties. We performed the four plate test and the elevated plus maze test to determine anxiolytic-like activity. Toward a better understanding of the pharmacological properties of HBK-17 we used various functional assays to determine its intrinsic activity at 5-HT1A, 5-HT2A, 5-HT7, and D2 receptors and UHPLC-MS/MS method to evaluate its pharmacokinetic profile. We observed the anxiolytic-like activity of HBK-17 in both behavioral tests and the effect was reversed by the pretreatment with WAY-100635, which proves that 5-HT1A receptor activation was essential for the anxiolytic-like effect. Moreover, the compound moderately antagonized D2, weakly 5-HT7 and very weakly 5-HT2A receptors. We demonstrated that HBK-17 preferentially activated ß-arrestin signaling after binding to the 5-HT1A receptor. HBK-17 was rapidly absorbed after intraperitoneal administration and had a half-life of about 150 min. HBK-17 slightly penetrated the peripheral compartment and showed bioavailability of approximately 45%. The unique pharmacological profile of HBK-17 encourages further experiments to understand its mechanism of action fully

Cell-based screening for identification of the novel vanadium complexes with multidirectional activity relative to the cells and the mechanisms associated with metabolic disorders

In this study, 110 newly synthesized vanadium complexes from different structural groups were screened in three cell-based models representing the main target tissues for anti-diabetic drugs. In glucose utilization in C2C12 myocyte experiments, 93% of vanadium complexes were shown to have equal or greater activity than bis(maltolato)oxovanadium(IV) (BMOV), the methyl analog of bis(ethylmaltolato)oxovanadium(IV) (BEOV) which has been tested in clinical trials. Moreover, 49% and 50% of these complexes were shown to have equal or greater activity than BMOV in lipid accumulation in 3T3-L1 adipocytes and insulin secretion in RINm5F beta cell experiments, respectively. These results were the basis for the selection of compounds for the subsequent steps in the characterization of anti-diabetic properties. This study provides strong support for the application of screening cell-based assays with a phenotypic approach for the discovery of novel anti-diabetic drugs from the vanadium complex class. This is especially desirable due to the multiple and not fully defined mechanisms of action vanadium compounds

Novel Multimodal Salicylamide Derivative with Antidepressant-like, Anxiolytic-like, Antipsychotic-like, and Anti-Amnesic Activity in Mice

Depression, anxiety, and schizophrenia may coexist in psychiatric patients. Moreover, these disorders are very often associated with cognitive impairments. However, pharmacotherapy of these conditions remains challenging due to limited drug effectiveness or numerous side effects. Therefore, there is an urgent need to develop novel multimodal compounds that can be used to treat depression, anxiety, and schizophrenia, as well as memory deficits. Thus, this study aimed to evaluate the potential antidepressant-like, anxiolytic-like, antipsychotic-like effects, and anti-amnesic properties, of the novel arylpiperazine derivative of salicylamide, JJGW07, with an affinity towards serotonin 5-HT1A, 5-HT2A, and 5-HT7 and dopamine D2 receptors. Firstly, we investigated the compound&rsquo;s affinity for 5-HT6 receptors and its functional activity by using in vitro assays. JJGW07 did not bind to 5-HT6 receptors and showed antagonistic properties for 5-HT1A, 5-HT2A, 5-HT7, and D2 receptors. Based on the receptor profile, we performed behavioral studies in mice to evaluate the antidepressant-like, anxiolytic-like, and antipsychotic-like activity of the tested compound using forced swim and tail suspension tests; four-plate, marble-burying, and elevated plus maze tests; and MK-801- and amphetamine-induced hyperlocomotion tests, respectively. JJGW07 revealed antidepressant-like properties in the tail suspension test, anxiolytic-like effects in the four-plate and marble-burying tests, and antipsychotic-like activity in the MK-801-induced hyperlocomotion test. Importantly, the tested compound did not induce catalepsy and motor impairments or influence locomotor activity in rodents. Finally, to assess the potential procognitive and anti-amnesic properties of JJGW07, we used passive avoidance and object recognition tests in mice. JJGW07 demonstrated positive effects on long-term emotional memory and also ameliorated MK-801-induced emotional memory impairments in mice, but showed no procognitive properties in the case of recognition memory. Our results encourage the search for new compounds among salicylamide derivatives, which could be model structures with multitarget mechanisms of action that could be used in psychiatric disorder therapy

Vanadium Complexes with Thioanilide Derivatives of Amino Acids: Inhibition of Human Phosphatases and Specificity in Various Cell Models of Metabolic Disturbances

In the text, the synthesis and characteristics of the novel ONS-type vanadium (V) complexes with thioanilide derivatives of amino acids are described. They showed the inhibition of human protein tyrosine phosphatases (PTP1B, LAR, SHP1, and SHP2) in the submicromolar range, as well as the inhibition of non-tyrosine phosphatases (CDC25A and PPA2) similar to bis(maltolato)oxidovanadium(IV) (BMOV). The ONS complexes increased [14C]-deoxy-D-glucose transport into C2C12 myocytes, and one of them, VC070, also enhanced this transport in 3T3-L1 adipocytes. These complexes inhibited gluconeogenesis in hepatocytes HepG2, but none of them decreased lipid accumulation in the non-alcoholic fatty liver disease model using the same cells. Compared to the tested ONO-type vanadium complexes with 5-bromosalicylaldehyde and substituted benzhydrazides as Schiff base ligand components, the ONS complexes revealed stronger inhibition of protein tyrosine phosphatases, but the ONO complexes showed greater activity in the cell models in general. Moreover, the majority of the active complexes from both groups showed better effects than VOSO4 and BMOV. Complexes from both groups activated AKT and ERK signaling pathways in hepatocytes to a comparable extent. One of the ONO complexes, VC068, showed activity in all of the above models, including also glucose utilizatiand ONO Complexes are Inhibitors ofon in the myocytes and glucose transport in insulin-resistant hepatocytes. The discussion section explicates the results within the wider scope of the knowledge about vanadium complexes