Milk-Derived Carbon Quantum Dots: Study of Biological and Chemical Properties Provides Evidence of Toxicity

Carbon dots (CDs) are carbon-based zero-dimensional nanomaterials that can be prepared from a number of organic precursors. In this research, they are prepared using fat-free UHT cow milk through the hydrothermal method. FTIR analysis shows C=O and C-H bond presence, as well as nitrogen-based bond like C-N, C=N and –NH2 presence in CDs, while the absorption spectra show the absorption band at 280 ± 3 nm. Next, the Biuret test was performed, with the results showing no presence of unreacted proteins in CDs. It can be said that all proteins are converted in CDs. Photo luminance spectra shows the emission of CDs is 420 nm and a toxicity study of CDs was performed. The Presto Blue method was used to test the toxicity of CDs for murine hippocampal cells. CDs at a concentration of 4 mg/mL were hazardous independent of synthesis time, while the toxicity was higher for lower synthesis times of 1 and 2 h. When the concentration is reduced in 1 and 2 h synthesized CDs, the cytotoxic effect also decreases significantly, ensuring a survival rate of 60–80%. However, when the synthesis time of CDs is increased, the cytotoxic effect decreases to a lesser extent. The CDs with the highest synthesis time of 8 h do not show a cytotoxic effect above 60%. The cytotoxicity study shows that CDs may have a concentration and time–dependent cytotoxic effect, reducing the number of viable cells by 40%

A comparison of the anorectic effect and safety of the alpha_{2}-adrenoceptor ligands guanfacine and yohimbine in rats with diet-induced obesity

The search for drugs with anorectic activity, acting within the adrenergic system has attracted the interest of researchers. Partial α2-adrenoceptor agonists might offer the potential for effective and safe treatment of obesity. We compared the effectiveness and safety of α2-adrenoceptor ligands in reducing body mass. We also analyzed if antagonist and partial agonists of α2-adrenoceptor--yohimbine and guanfacine--act similarly, and determined which course of action is connected with anorectic activity. We tested intrinsic activity and effect on the lipolysis of these compounds in cell cultures, evaluated their effect on meal size, body weight in Wistar rats with high-fat diet-induced obesity, and determined their effect on blood pressure, heart rate, lipid profile, spontaneous locomotor activity, core temperature and glucose, as well as glycerol and cortisol levels. Both guanfacine and yohimbine showed anorectic activity. Guanfacine was much more effective than yohimbine. Both significantly reduced the amount of intraperitoneal adipose tissue and had a beneficial effect on lipid profiles. Decreased response of α2A-adrenoceptors and partial stimulation of α2B-receptors seem to be responsible for the anorectic action of guanfacine. The stimulation of α1-adrenoceptors by guanfacine is responsible for cardiovascular side effects but may also be linked with improved anorexic effect. α1-adrenoceptor blockade is connected with the side effects of yohimbine, but it is also associated with the improvement of lipid profiles. Guanfacine has been approved by the Food and Drug Administration (FDA) to treat hypertension and conduct disorder, but as it reduces body weight, it is worth examining its effectiveness and safety in models of obesity

Antidepressant-like activity and safety profile evaluation of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione derivatives as 5-HT1A receptor partial agonists

Current antidepressant therapy has several disadvantages related to the properties of antidepressants. Considering their unfavourable features, the process of searching for new antidepressant drugs with better safety and tolerability requires consistent efforts and many complementary studies. Serotonin 5-HT1A receptor is considered as an interesting target of antidepressant therapy. In the present study, the intrinsic activity at different signaling pathways coupled to serotonin 5-HT1A receptor, antidepressant-like and pharmacokinetic properties, and the safety profile of two novel imidazopurine-2,4-dione derivatives, namely compounds AZ-853 (8-(4-(4-(2-fluorophenyl)piperazin-1-yl)butyl)-1,3-dimethyl-1H- imidazo[2,1-f]purine-2,4(3H,8H)-dione) and AZ-861 (1,3-dimethyl-8-(4-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)butyl)-1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione), were studied in animal models through in vitro and in vivo experiments. We demonstrated that AZ-853 and AZ-861, which structurally differ by one substituent and its placement in the phenyl ring, showed varied functional, pharmacological, and pharmacokinetic properties as well as side effect profiles. AZ-861 exhibited stronger agonistic action in all functional assays. After acute and repeated administration in mice, both compounds showed antidepressant-like activity in the forced swim test, which was partially mediated by 5-HT1A receptor activation. AZ-853 showed a more potent antidepressant-like effect, presumably due to its better penetration into brain structures. Both compounds did not show anticholinergic properties, but after repeated administration, they induced weak sedation and lipid metabolism disturbances without affecting serum glucose level. The stronger α1-adrenolytic effect of AZ-853 is responsible for decreased systolic blood pressure, and in contrast to AZ-861, AZ-853 induced weight gain in mice. The interesting comparative pharmacological profiles of AZ-853 and AZ-861 encourage to conduct further experiments to fully understand their mechanisms and differences in action

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

Milk-derived carbon quantum dots : study of biological and chemical properties provides evidence of toxicity

Carbon dots (CDs) are carbon-based zero-dimensional nanomaterials that can be prepared from a number of organic precursors. In this research, they are prepared using fat-free UHT cow milk through the hydrothermal method. FTIR analysis shows C=O and C-H bond presence, as well as nitrogen-based bond like C-N, C=N and –NH(2) presence in CDs, while the absorption spectra show the absorption band at 280 ± 3 nm. Next, the Biuret test was performed, with the results showing no presence of unreacted proteins in CDs. It can be said that all proteins are converted in CDs. Photo luminance spectra shows the emission of CDs is 420 nm and a toxicity study of CDs was performed. The Presto Blue method was used to test the toxicity of CDs for murine hippocampal cells. CDs at a concentration of 4 mg/mL were hazardous independent of synthesis time, while the toxicity was higher for lower synthesis times of 1 and 2 h. When the concentration is reduced in 1 and 2 h synthesized CDs, the cytotoxic effect also decreases significantly, ensuring a survival rate of 60–80%. However, when the synthesis time of CDs is increased, the cytotoxic effect decreases to a lesser extent. The CDs with the highest synthesis time of 8 h do not show a cytotoxic effect above 60%. The cytotoxicity study shows that CDs may have a concentration and time–dependent cytotoxic effect, reducing the number of viable cells by 40%

The selective 5-HT1A receptor biased agonists, F15599 and F13714, show antidepressant-like properties after a single administration in the mouse model of unpredictable chronic mild stress

RATIONALE: The prevalence of depression is ever-increasing throughout the population. However, available treatments are ineffective in around one-third of patients and there is a need for more effective and safer drugs. OBJECTIVES: The antidepressant-like and procognitive effects of the “biased agonists” F15599 (also known as NLX-101) which preferentially targets postsynaptic 5-HT(1A) receptors and F13714, which targets 5-HT(1A) autoreceptors, were investigated in mice. METHODS: Antidepressant-like properties of the compounds and their effect on cognitive functions were assessed using the forced swim test (FST) and the novel object recognition (NOR), respectively. Next, we induced a depressive-like state by an unpredictable chronic mild stress (UCMS) procedure to test the compounds’ activity in the depression model, followed by measures of sucrose preference, FST, and locomotor activity. Levels of phosphorylated cyclic AMP response element-binding protein (p-CREB) and phosphorylated extracellular signal-regulated kinase (p-ERK1/2) were also determined. RESULTS: F15599 reduced immobility time in the FST over a wider dose-range (2 to 16 mg/kg po) than F13714 (2 and 4 mg/kg po), suggesting accentuated antidepressant-like properties in mice. F15599 did not disrupt long-term memory consolidation in the NOR at any dose tested, while F13714 impaired memory formation, notably at higher doses (4–16 mg/kg). In UCMS mice, a single administration of F15599 and F13714 was sufficient to robustly normalize depressive-like behavior in the FST but did not rescue disrupted sucrose preference. Both F15599 and F13714 rescued cortical and hippocampal deficits in p-ERK1/2 levels of UCMS mice but did not influence the p-CREB levels. CONCLUSIONS: Our studies showed that 5-HT(1A) receptor biased agonists such as F13714 and especially F15599, due to its less pronounced side effects, might have potential as fast-acting antidepressants. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00213-021-05849-0