In vitro effect of pentoxifylline and lisofylline on deformability and aggregation of red blood cells from healthy subjects and patients with chronic venous disease

Purpose. The aim of the study was to assess the in vitro potency of pentoxifylline (PTX) and one of its most active metabolites lisofylline (LSF) to improve rheological properties of red blood cells (RBC) from healthy individuals and patients with chronic venous disease (CVD). Additionally, the study aimed to compare the effects of PTX and LSF on RBC deformability and aggregation. Methods. Blood samples were collected from healthy volunteers (antecubital vein) and from CVD patients (varicose and antecubital vein). Deformability and aggregation of RBC were assessed using Laser-assisted Optical Rotational Cell Analyser (LORCA). Results. PTX and LSF increased RBC elongation significantly. Additionally, RBC incubation with PTX resulted in a marked decrease in RBC aggregation. PTX reduced the tendency towards the formation of RBC aggregates and of their stability. The beneficial effect of PTX on RBC aggregation was most apparent for those cells whose aggregation tendency and aggregate stability was the greatest. Conclusions. In vitro addition of PTX or LSF effectively increased deformability of RBC from healthy donors and patients with CVD. Thus, LSF may contribute to the in vivo hemorheological effects of pentoxifylline. On the other hand, there was no significant effect of LSF on aggregation of RBC in vitro. Hence, LSF has no contribution to this particular effect of PTX. Additionally, the present study demonstrated the use of RBC with impaired deformability and aggregation for the evaluation of in vitro rheological activity of xenobiotics

Preliminary safety assessment of new azinesulfonamide analogs of aripiprazole using prokaryotic models

Purpose: Determination of the mutagenic potential of new biologically active compounds is of great concern for preliminary toxicity testing and drug development. Methods: The mutagenic and antimutagenic effects of some quinoline- and isoquinoline-sulfonamide analogs of aripiprazole (1-8), which display potent antidepressant, anxiolytic, and antipsychotic properties, were evaluated using the Vibrio harveyi assay and OSIRIS Property Explorer software. Additionally, the Ames test was used as the reference. Results: In silico prediction showed that compounds 5 (N-(3-(4-(2,3-dichlorophenyl)piperazin-1-yl)propyl)quinoline-7-sulfonamide) and 6 (N-(4-(4-(2,3-Dichlorophenyl)piperazin-1-yl)butyl)quinoline-7-sulfonamide) trigger a mutagenic structural alert. However, this was not confirmed by in vitro assays, as none of the tested compounds displayed mutagenic activity against all tested strains of bacteria. Moreover, compounds 1-8 displayed a protective effect against the mutagenicity induced by a direct acting mutagen NQNO. The most beneficial antimutagenic properties showed compound 5 which exhibited strong antimutagenic properties in all tested V. harveyi strains. High antimutagenic potency of this compound was confirmed in the Ames TA100 assay system. Conclusion: Newly synthesized azinesulfonamide analogs of aripiprazole may be considered as genotoxically safe as they do not display mutagenic activity on the tester strains. Moreover, the tested compounds demonstrated significant antimutagenic properties that can be valuable for prevention of the NQNO genotoxicity. Additionally, it appears that the Vibrio harveyi assay can be applied for primary mutagenicity and antimutagenicity assessment of chemical substances, thus, representing a useful alternative tool for compounds safety evaluation

Evaluation of anticonvulsant and antinociceptive properties of new N-Mannich bases derived from pyrrolidine-2,5-dione and 3-methylpyrrolidine-2,5-dione

The aim of the present experiments was to examine anticonvulsant activity of new pyrrolidine-2,5-dione and 3-methylpyrrolidine-2,5-dione derivatives in animal models of epilepsy. In addition, the possible collateral antinociceptive activity was assessed. Anticonvulsant activity was investigated in the electroconvulsive threshold (MEST) test and the pilocarpine-induced seizure models in mice. Antinociceptive activity was examined in the hot plate and the formalin tests in mice. Considering the drug safety evaluation, the Vibrio harveyi test was used to estimate anti/mutagenic activity. To determine the plausible mechanism of anticonvulsant action, for two chosen compounds (12 and 23), in vitro binding assays were carried out. All of the tested compounds revealed significant anticonvulsant activity in the MEST test. Compounds 12 and 23 displayed anticonvulsant effect also in pilocarpine-induced seizures. Four of the tested compounds (12, 13, 15, and 24) revealed analgesic activity in the hot plate test as well as in the first phase of the formalin test, and all of them were active in the second phase of the formalin test. The possible mechanism of action of compounds 12 and 23 is the influence on the neuronal voltage-sensitive sodium and L-type calcium channels. The obtained results indicate that in the group of pyrrolidine-2,5-diones, new anticonvulsants with collateral analgesic properties can be found

Pan-Phosphodiesterase Inhibitors Attenuate TGF-β-Induced Pro-Fibrotic Phenotype in Alveolar Epithelial Type II Cells by Downregulating Smad-2 Phosphorylation

Airway remodeling is a pathological process that accompanies many chronic lung diseases. One of the important players in this process are epithelial cells, which under the influence of pro-inflammatory and pro-fibrotic factors present in the airway niche, actively participate in the remodeling process by increasing extracellular matrix secretion, acquiring migration properties, and overproducing pro-fibrotic transducers. Here, we investigated the effect of three new 8-arylalkylamino- and 8-alkoxy-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl-N-(5-(tert-butyl)-2-hydroxyphenyl)butanamides (1, 2, and 3), representing prominent pan-phosphodiesterase (pan-PDE) inhibitors on transforming growth factor type β (TGF-β)-induced alveolar epithelial type II cells (A549 cell line) of a pro-fibrotic phenotype. Our results demonstrate for the first time the strong activity of pan-PDE inhibitors in the prevention of TGF-β-induced mesenchymal markers’ expression and A549 cells’ migration. We also showed an increased p-CREB and decreased p-Smad-2 phosphorylation in TGF-β-induced A549 cells treated with 1, 2, and 3 derivatives, thereby confirming a pan-PDE inhibitor mesenchymal phenotype reducing effect in alveolar epithelial type II cells via suppression of the canonical Smad signaling pathway. Our observations confirmed that PDE inhibitors, and especially those active against various isoforms involved in the airway remodeling, constitute an interesting group of compounds modulating the pro-fibrotic response of epithelial cells

Trans-cinnamaldehyde : biological properties and applications in cosmetology.

Trans-cynamoaldehyd (aldehyd cynamonowy, 3-fenyloprop-2-enal) jest związkiem organicznym, nienasyconym aldehydem naturalnie występującym w gatunkach roślin z rodzaju Cinnamomum. Największe jego ilości znajdują się w olejkach eterycznych pozyskiwanych z Cinnamomum zeylanicum oraz Cinnamomum cassia. Ma postać żółtej cieczy o charakterystycznym, intensywnym cynamonowym zapachu. Z powodu interesujących walorów zapachowych oraz wielokierunkowej aktywności biologicznej jest wykorzystywany między innymi jako składnik wielu produktów kosmetycznych. Wykazuje działanie przeciwdrobnoustrojowe, przeciwzapalne, antyoksydacyjne. Ponadto istnieją doniesienia na temat jego działania przeciwnowotworowego, pozytywnego wpływu na pracę serca oraz w leczeniu cukrzycy. Pomimo wielu korzystnych właściwości trans-cynamoaldehydu, w literaturze można znaleźć informacje na temat licznych działań niepożądanych wywołanych przez jego wysokie stężenia. Związek ten jest opisywany jako czynnik uczulający, a jego działanie drażniące skierowane głównie na skórę. Spośród substancji zapachowych wykorzystywanych do produkcji kosmetyków, trans-cynamoaldehyd jest jednym z głównych składników wykazujących działanie alergizujące. Jest agonistą receptora TRPA1 oraz może być przyczyną alergicznego kontaktowego zapalenia skóry i pokrzywki nieimmunologicznej, zaliczanych do chorób z grupy wyprysku kontaktowego. Aldehyd cynamonowy jest również wykorzystywany w testach płatkowych, które stanowią podstawę diagnostyki alergii na składniki kosmetyków.Trans-cinnamaldehyde (cinnamic aldehyde; (2E)-3-phenylprop-2-enal) is an simple organic compound, an unsaturated aldehyde, naturally occurring in plant species of the genus Cinnamomum. The greatest quantities are found in essential oils obtained from Cinnamomum zeylanicum and Cinnamomum cassia. It is a tree of the laurel family (Lauraceae), native to Ceylon. It occurs in the form of a yellow liquid with a characteristic, intense cinnamon scent. In laboratory and industrial conditions, it is obtained using many patented methods. The most common of these is the condensation of benzaldehyde with acetaldehyde. Due to its interesting aromatic qualities and multidirectional biological activity, it is widely used in food products and household chemicals. In the pharmaceutical industry it is used to improve the odor and the taste of drugs, especially those containing bitter substances. However it is also an important ingredient of many cosmetic products. It has antimicrobial, anti-inflammatory and antioxidant properties. In addition, there are reports of its anti-cancer effect, a positive effect on the heart function and in the treatment of diabetes. Trans-cinnamaldehyde is considered as Generally Recognized As Safe (GRAS) by the US Food and Drug Administration (FDA). However, despite the many positive aspects of trans-cinnamaldehyde, in the literature data on numerous side effects caused by its high concentrations can be found. This compound is described as a sensitizing agent and its irritating action is mainly directed at the skin. In cosmetics it is significant allergenic substance. Trans-cinnamaldehyde is an agonist of the TRPA1 receptor and can cause allergic contact dermatitis and non-immune contact urticaria, which are classified as contact eczema. Cinnamaldehyde is also used in patch tests, which are the basis for diagnosing allergies to cosmetic ingredients. Therefore, although it is considered a safe substance, due to its allergenic and irritating effects, its content in cosmetic products is subject to certain restrictions and it should not exceed 0.05%