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The present study explores the synthesis and bio-safety evaluation of gadolinium-doped carbon quantum dots (GCQDs) as a potential dual-contrast agent for diagnostic imaging. GCQDs exhibit both fluorescent and magnetic properties, making them suitable for UV-Vis and magnetic resonance imaging (MRI). The synthesis of GCQDs was achieved via hydrothermal treatment, incorporating gadolinium into the carbon quantum dot matrix. The magnetic properties of GCQDs were analyzed, showing significantly enhanced values compared to gadobutrol, a common MRI contrast agent. However, synthesis constraints limit the gadolinium content achievable in nanodots. To assess the safety of GCQDs, their effects on the embryonic development of zebrafish ( Danio rerio ) were examined. Various concentrations of GCQDs were tested, observing mortality rates, hatchability, malformations, heartbeats, spontaneous movement, and GCQDs uptake. Dialysis studies indicated that gadolinium ions are incorporated into the internal structure of the carbon nanodots. Zebrafish toxicity tests revealed that while survival rates were comparable to control groups, hatchability decreased significantly with higher gadolinium concentrations in GCQDs. Fluorescence microscopy showed no statistical differences in the fluorescence intensity between groups. These findings suggest that GCQDs could serve as an effective dual-contrast agent, combining the optical imaging capabilities of CQDs with the enhanced MRI contrast provided by gadolinium. This study underscores the need for further research on the synthesis methods and biological interactions of GCQDs to ensure their safety and efficacy in medical applications.

In order to find new hypotensive drugs possessing higher activity and better selectivity, a new series of fifteen 5,5-dimethylhydantoin derivatives ( 1 - 15 ) was designed. Three-step syntheses, consisting of N-alkylations using standard procedures as well as microwaves, were carried out. Crystal structures were determined for compounds 7 - 9 . All of the synthesized 5,5-dimethylhydantoins were tested for their affinity to α 1 -adrenergic receptors (α 1 -AR) using both in vitro and in silico methods. Most of them displayed higher affinity (Ki < 127.9 nM) to α 1 -adrenoceptor than urapidil in radioligand binding assay. Docking to two subtypes of adrenergic receptors, α 1A and α 1B , was conducted. Selected compounds were tested for their activity towards two α 1 -AR subtypes. All of them showed intrinsic antagonistic activity. Moreover, for two compounds ( 1 and 5 ), which possess o-methoxyphenylpiperazine fragments, strong activity (IC 50 < 100 nM) was observed. Some representatives ( 3 and 5 ), which contain alkyl linker, proved selectivity towards α 1A -AR, while two compounds with 2-hydroxypropyl linker ( 11 and 13 ) to α 1B -AR. Finally, hypotensive activity was examined in rats. The most active compound ( 5 ) proved not only a lower effective dose than urapidil but also a stronger effect than prazosin.

Noting the worldwide rapid increase in the prevalence of overweight and obesity new effective drugs are now being sought to combat these diseases. Histamine H 3 receptor antagonists may represent an effective therapy as they have been shown to modulate histamine synthesis and release and affect a number of other neurotransmitters (norepinephrine, acetylcholine, γ-aminobutyric acid, serotonin, substance P) thus influencing the food intake. Based on the preliminary studies determining affinity, intrinsic activity, and selected pharmacokinetic parameters, two histamine H 3 receptor ligands were selected. Female rats were fed palatable food for 28 days and simultaneously administered the tested compounds intraperitoneally (i.p.) at a dose of 10 or 1 mg/kg b.w./day. Weight was evaluated daily and calorie intake was evaluated once per week. The plasma levels of cholesterol, triglycerides, leptin, adiponectin, ghrelin, corticosterone, CRP and IL-6 were determined at the end of experiment. The glucose tolerance test was also performed. To exclude false positives, the effect of tested compounds on spontaneous activity was monitored during the treatment, as well as the amount of consumed kaolin clay was studied as a reflection of possible gastrointestinal disturbances comparable to nausea. The histamine H 3 receptor antagonists KSK-59 and KSK-73 administered i.p. at a dose of 10 mg/kg b.w. prevented weight gain in a rat model of excessive eating. They reduced adipose tissue deposits and improved glucose tolerance. Both compounds showed satisfying ability to penetrate through biological membranes determined in in vitro studies. Compound KSK-73 also reduced the caloric intake of the experimental animals what indicates its anorectic effect. These results show the pharmacological properties of histamine H 3 receptor antagonists, (4-pyridyl)piperazine derivatives, as the compounds causing not only slower weight gain but also ameliorating some metabolic disorders in rats having the opportunity to overeat.

Background: Quinazoline α 1 -adrenoceptors antagonists have been shown to exert moderately favorable effects on the metabolic profile in hypertensive patients. However, based on AntiHypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) results, they are no longer recommended as a first line therapy of hypertension. Recent studies have shown that quinazoline-based α 1 -adrenoceptors antagonists (prazosin, doxazosin) induce the apoptosis and necrosis, which may be responsible for ALLHAT outcomes; however, these effects were proven to be independent of α 1 -adrenoceptor blockade and were associated with the presence of quinazoline moiety. MH-76 (1-[3-(2,6-dimethylphenoxy)propyl]-4-(2-methoxyphenyl)piperazine hydrochloride)) is a non-quinazoline α 1 -adrenoceptor antagonist which, in fructose-fed rats, exerted antihypertensive effect, and, contrary to prazosin, reduced insulin resistance and abdominal adiposity. In this study we aimed to further investigate and compare the effects of MH-76 and prazosin on inflammation in adipose tissue of fructose-fed rats., Methods: Abdominal adipose tissue was collected from four groups of fructose-fed rats (Control, Fructose, Fructose + MH-76 and Fructose + Prazosin) and subjected to biochemical, histopathological and immunohistochemical studies. Moreover, selected tissue distribution studies were performed., Results: Treatment with MH-76 but not with prazosin improved endothelial integrity, reduced adipose tissue inflammation and infiltration by immune cells, resulting in lowering leptin, MCP-1, IL-6, TNF-α and PAI-1 levels. In adipose tissue from Fructose + MH-76 animals, a higher amount of eosinophils accompanied with higher IL-4 concentration was observed. Treatment with MH-76 but not with prazosin markedly reduced phosphorylation of IRS-1 at Ser307., Conclusion: MH-76 may improve insulin signaling in adipose tissue by reducing the pro-inflammatory cytokine production and inhibiting the inflammatory cells recruitment. In contrast, in adipose tissue from animals treated with prazosin, the inflammatory effect was clearly enhanced.

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., Competing Interests: The authors have declared that no competing interests exist.

Benign prostatic hyperplasia (BPH) is the most common male clinical problem impacting the quality of life of older men. Clinical studies have indicated that the inhibition of α 1A -/α 1D adrenoceptors might offer effective therapy in lower urinary tract symptoms. Herein, a limited series of arylsulfonamide derivatives of (aryloxy)ethyl alicyclic amines was designed, synthesized, and biologically evaluated as potent α₁-adrenoceptor antagonists with uroselective profile. Among them, compound 9 (3-chloro-2-fluoro- N -([1-(2-(2-(2,2,2-trifluoroethoxy)phenoxy]ethyl)piperidin-4-yl)methyl)benzenesulfonamide) behaved as an α 1A -/α 1D -adrenoceptor antagonist ( K i (α₁) = 50 nM, EC 50 (α 1A ) = 0.8 nM, EC 50 (α 1D ) = 1.1 nM), displayed selectivity over α₂-adrenoceptors ( K i (α₂) = 858 nM), and a 5-fold functional preference over the α 1B subtype. Compound 9 showed adequate metabolic stability in rat-liver microsome assay similar to the reference drug tamsulosin (Cl int = 67 and 41 µL/min/mg, respectively). Compound 9 did not decrease systolic and diastolic blood pressure in normotensive anesthetized rats in the dose of 2 mg/kg, i.v . These data support development of uroselective agents in the group of arylsulfonamides of alicyclic amines with potential efficacy in the treatment of lower urinary tract symptoms associated to benign prostatic hyperplasia.

Older and even new antidepressants cause adverse effects, such as orthostatic hypotension, hyper- or hypoglycemia, liver injury or lipid disorders. In our previous experiments we showed significant antidepressant- and anxiolytic-like activities of dual 5-HT1A and 5-HT7 antagonists with α1-adrenolitic properties i.e. 1-[(2,6-dimethylphenoxy)ethoxyethyl]-4-(2-methoxyphenyl)piperazine hydrochloride (HBK-14) and 1-[(2-chloro-6-methylphenoxy)ethoxyethyl]-4-(2-methoxyphenyl)piperazine hydrochloride (HBK-15). Here, we evaluated the influence of chronic administration of HBK-14 and HBK-15 on blood pressure (non-invasive blood pressure measurement system for rodents), lipid profile (total cholesterol, low density lipoproteins-LDL, high density lipoproteins-HDL, triglycerides), glucose level, and liver enzymes activity (aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transferase). We determined potential antihistaminic (isolated guinea pig ileum) and antioxidant properties (ferric reducing ability of plasma-FRAP, non-protein thiols-NPSH, stable free radical diphenylpicrylhydrazyl-DPPH) cytotoxicity. Our experiments revealed that HBK-14 and HBK-15 did not influence blood pressure, lipid profile, glucose level or liver enzymes activity in rats after 2-week treatment. We also showed that none of the compounds possessed antioxidant or cytotoxic properties at antidepressant- and anxiolytic-like doses. HBK-14 and HBK-15 very weakly blocked H1 receptors in guinea pig ileum. Positive results of our preliminary experiments on the safety of HBK-14 and HBK-15 encourage further studies concerning their effectiveness in the treatment of depression and/or anxiety disorders., Competing Interests: The authors have declared that no competing interests exist.

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.

The oxidation of cyanide (CN-) to a much less toxic thiocyanate (SCN-) is the main in vivo biochemical pathway for CN- detoxification. SCN- is excreted mainly in urine. This study was performed to investigate the effect of lipoic acid (LA) on the urinary excretion of thiocyanate (SCN-; rhodanate) in rats. Groups of the animals were treated intraperitoneally (i.p.) as follows: group 1: potassium cyanide (KCN) (1 mg/kg); group 2: KCN (1 mg/kg) + LA (100 mg/kg). Urine was collected for 24 h and the pooled samples were examined for SCN- levels. The obtained results indicated that the treatment of animals with potassium cyanide and LA in combination significantly increased the urinary excretion of SCN- in comparison with the respective values in the KCN-alone-treated group. It indicates that LA increased the rate of CN- detoxification in rats.

This work aimed to investigate the effect of lipoic acid (LA) on sulfane sulfur (S*) level, infiltration of neutrophils and vascular permeability in a model of zymosan-induced peritonitis. The study showed that lipoic acid increased the sulfane sulfur level. Also, it decreased count of neutrophils and inhibition of intensity of early vascular permeability compared to the control group. These studies indicated that LA exhibits antiinflammatory activity. LA serves as a sulfane sulfur acceptor and releases sulfane sulfur in the form of hydrogen sulfide (H2S), which is probably responsible for its anti-inflammatory activity.

Background: Nanoparticles (a part of matter which size is less than 100 nm) have numerous potential applications in biomedicine, due to their unique surface, electronic and optical properties. The goal of the present study was to examine the distribution of gold nanoparticles (GNPs) in mice after single intravenous administration., Methods: Spherical GNPs were synthesized by chemical reduction of tetrachloroauric acid with ascorbic acid as a reductant. GNPs were stabilized using polyvinyl alcohol (PVA, m.w. = 67000Da) a substance approved for use in the pharmaceutical industry. The size of colloidal gold particles (diameter equals 25 ± 8 nm) was determined using HR SEM and DLS techniques; ζ potential of GNPs was determined using Malvern Zetasizer Nano ZS and it equals -5.2 ± 5.4 mV. An aqueous dispersion of GNPs was administered to mice in a dose of about 10 cm(3)/kg and 24 h later the amount of gold in different organs was determined using the inductively coupled plasma mass spectrometer (ICP MS). Initial concentration of GNPs equals 29.55 mg/l., Results: GNPs after single intravenous administration preferentially accumulated in the liver (12.7% of the applied dose), while the other organs accumulated around 0.1% or less., Conclusion: Colloidal GNPs of the used size (about 25 ± 8 nm) provide new potential route for direct delivery system to the liver, which may be important e.g., in liver cancer diagnosis.

Background: Lipoic acid (LA) was shown to possess anti-inflammatory properties. In this study, we present evidence supporting the hypothesis that the anti-inflammatory properties of LA are associated with the formation of hydrogen sulfide (H2S)., Methods: The study was conducted on male albino Swiss mice. The animals were treated with carrageenan by subcutaneous (sc) injection into the right hind paw to induce acute inflammation. Animals were treated intraperitoneally (ip) with LA (30, 50 and 100 mg/kg) or indomethacin (20 mg/kg) 30 min before carrageenan administration. The control group was given ip the vehicle (1% Tween 80) 30 min before carrageenan administration. Additional experiment involved ip combined treatment of mice with glibenclamide (10 mg/kg) or glibenclamide (10 mg/kg) and LA(100 mg/kg) 30 min before carrageenan administration. LA, indomethacin and glibenclamide were suspended in 1% Tween 80. At 1, 2 and 3 h after treatment with carrageenan the degree of the paw edema was evaluated by the measurement of the paw volume using aqueous plethysmometer., Results: Injection of carrageenan into the mouse hind paw increased paw volume. The increase in paw edema was completely suppressed by pretreatment with LA. The reduction of paw edema by LA was abolished by pretreatment with the K(ATP) channel antagonist, glibenclamide., Conclusion: Our findings demonstrate for the first time in vivo that the anti-inflammatory activity of LA might be connected with the formation of H2S.