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Development of Novel ROCK Inhibitors via 3D-QSAR and Molecular Docking Studies: A Framework for Multi-Target Drug Design
No full textBackground/Objectives: Alterations in the actin cytoskeleton correlates to tumor progression and affect critical cellular processes such as adhesion, migration and invasion. Rho-associated coiled-coil-containing protein kinases (ROCK1 and ROCK2), important regulators of the actin cytoskeleton, are frequently overexpressed in various malignancies. The aim of this study was therefore to identify the key structural features of ROCK1/ROCK2 inhibitors using computer-aided drug design (CADD) approaches. In addition, new developed ROCK inhibitors provided a significant framework for the development of multitarget therapeutics—ROCK/HDAC (histone deacetylases) multitarget inhibitors. Methods: 3D-QSAR (Quantitative structure-activity relationship study) and molecular docking study were employed in order to identify key structural features that positively correlate with ROCK inhibition. MDA-MB-231, HCC1937, Panc-1 and Mia PaCa-2 cells were used for evaluation of anticancer properties of synthesized compounds. Results: C-19 showed potent anti-cancer properties, especially enhancement of apoptosis and cell cycle modulation in pancreatic cancer cell lines. In addition, C-19 and C-22 showed potent anti-migratory and anti-invasive effects comparable to the well-known ROCK inhibitor fasudil. Conclusions: In light of the results of this study, we propose a novel multi-target approach focusing on developing dual HDAC/ROCK inhibitors based on the structure of both C-19 and C-22, exploiting the synergistic potential of these two signaling pathways to improve therapeutic efficacy in metastatic tumors. Our results emphasize the potential of multi-target ROCK inhibitors as a basis for future cancer therapies
Harnessing the Potential of Amniotic Membrane Homogenate: A Novel Bioink for 3D Bioprinting in Breast Reconstruction
No full textINTRODUCTION Despite their safety and feasibility for patients, existing breast reconstruction techniques
post mastectomy carry the risk of potential complications, and do not significantly alter the likelihood of disease
recurrence compared to mastectomy alone. The field of tissue engineering has been intensively growing
primarily focusing on crafting diverse scaffolds that act as templates for tissue regeneration. Human amniotic
membrane (hAM) of the placenta has been utilized in skin and cornea regeneration, and numerous studies
have demonstrated its antitumor, antifibrotic, anti-inflammatory, and immunomodulatory properties.
Here we aim to develop the scaffold biomaterial for 3D bioprinting using human AM homogenate (hAM-h)
that will preserve and exhibit its regenerative and antitumor effects over an extended period when applied.
MATERIAL AND METHODS Placentas were collected from healthy donors after the caesarean section
and hAM was separated from the chorion and homogenized according to previously established protocol
[1]. Homogenates were analysed for cytokine composition with flow cytometry, and different rheological
parameters were determined by tensiometer, viscometer and zetasizer. Alginates of different viscosities were
mixed with hAM-h to make a biomaterial for extrusion 3D bioprinting on Cellink BioX bioprinter. Printed
bioscaffolds were crosslinked with CaCl2 and then characterized for their compressive strength and swelling
ability.
RESULTS AND DISCUSSION Results showed that hAM-h samples consisted of high levels of growth factors
such as Angiopoietin-2, EGF, FGF, HGF and other cytokines. As regards physical properties, no significant
difference in density, surface tension and viscosity was noticed among different hAM-h samples.
The average particle size in the samples was 192.1±24.95 nm in diameter, with polydispersity index values >
0.5 meaning the samples had heterogeneous particle size distribution. Regarding zeta potential, all hAM-h
samples possessed a negative surface charge < -30 mV which indicates a solution with moderate stability.
According to the force-strain curves of 3D-printed bioscaffolds, the compression profiles exhibited a trend
with a greater force required to achieve a higher deformation percentage. However, the force required to
compress the highALG-hAM-h bioscaffolds to 70% of original diameter was higher than force needed for
lowALG-hAM-h bioscaffolds under the same deformation conditions. It was noticed also that the weight of
highALG-hAM-h bioscaffolds increased over time unlike that of lowALG-hAM-h which decreased.
CONCLUSIONS This research provides valuable findings for preparing printable biomaterial based on
hAM homogenate showing its potential suitability for use in soft tissue engineering applications
ThroLy score and p-selectin predict venous thromboembolism development in patients with diffuse large B-cell lymphoma
No full textBackground: One of the significant complications of lymphoma patients is the development of venous thromboembolic (VTE) events,
which impacts substantially patients’ morbidity and mortality
Aims: The study aimed to determine whether various hemostatic, inflammatory, and clinical biomarkers have an influence on VTE development in patients with diffuse large B-cell lymphoma (DLBCL).The Abstract Book of European Hematology Association’s 29th Annual Congress - EHA2024 Hybrid Congress, June 13-16, Madrid, 202
Omega-3 masne kiseline tokom detinjstva i adolescencije
No full textOmega-3 fatty acids (FA), particularly eicosapentaenoic and docosahexaenoic acids, play a vital role throughout life. These essential molecules are integral to cell membranes and serve as precursors to various bioactive metabolites that can contribute to the prevention of numerous chronic non-communicable diseases. Since our bodies cannot produce omega-3 FA efficiently, these nutrients must primarily be obtained through diet, with seafood being a major source. After birth, newborns receive omega-3 FA through breast milk. Suitable omega-3 FA intake during pregnancy and breastfeeding, often through fish oil supplementation, ensures normal growth and development and reduces the incidence of allergies in infants. Inadequate omega-3 FA intake in children and adolescents is connected to asthma and skin diseases, as well as various neurological and psychiatric disorders. Conversely, higher omega-3 FA consumption improves cognitive function and bone health, and it is linked to better control of depressive and manic symptoms in adolescents with bipolar disorder. Given their extensive health benefits, ensuring adequate omega-3 FA intake through diet or supplementation is crucial for these population groups throughout life
Experimental chemotherapy of reactivated toxoplasmosis: repurposing and de novo synthesis of acridine and acridone derivatives
No full textAbstracts: 14th European Multicolloquium of Parasitology (EMOP), Wrocław, Poland, 26-30.08.2024
An ESIPT active coumarin-diphenyl azine-based AIEgen: Nanomolar Cu2+ ion sensing, Latent Fingerprinting, live-cell imaging, and real sample analysis
No full textDesigning economical and sensitive chemosensors for detecting important metal ions, like Cu2+ ions, is essential and remains a hot topic worldwide. In this investigation, we extended our investigation to design a specific diphenyl-azine-based skeletal system for the selective and sensitive detection of Cu2+ions. We reported a coumarin-diphenyl-azine-based AIEgen (C-1) using an improvised methodology with a large Stoke's shift (∼245 nm) for precisely sensing copper ions in solid, solution, and biological cells. The AIE-ESIPT properties of C-1 were validated using various sophisticated techniques. C-1 was found to be a promising selective and sensitive sensor of Cu2+ ions (nanomolar LOD value ∼10.38 nM) via colorimetric and TURNOFF fluorometric ways. The practical applicability of C-1 was analyzed via real-time estimation of copper ions in water samples (obtained from three varied locations) and in biological samples (urine and serum). The satisfactory recovery with a low RSD value indicates the potential of C-1 in detecting copper ions in actual samples. Estimating copper ions in urine and blood samples demonstrates the usefulness of C-1 in diagnosing disorders like Wilson's disease, which is caused by high concentrations of copper ions in the body. Additionally, we have detected Cu2+ions in live cells (HeLa cells) and carried out Latent Fingerprinting (Level 1 and Level 2) to validate its versatility in physiological and forensic applications. Overall, the proposed C-1 AIEgen is an ultrasensitive Cu2+ions sensor with innumerable applications in the physical world
Elongation index derivative as a potential hemorheological parameter in a diffraction analysis of diabetes mellitus patients’ erythrocytes
No full textComparative analysis of erythrocyte deformability in individuals with Diabetes Mellitus (DM) and healthy individuals (Control) was represented, focusing on the Elongation index (EI) calculation based on diffraction images. While no statistically significant differences in EI values were observed between the groups, we determined specific points along the deformability curve and revealed the first derivative of deformability curve (dEI / dSS) as a potential metric for quantifying erythrocyte response to deformation, where SS represents shear stress in Pa (Pascal). Statistically significant differences in dEI / dSS at the half maximum value of the deformability curve were identified, suggesting a slower erythrocyte response to shear stress in DM patients. Scatter plot analysis demonstrated a linear declining trend in dEI / dSS index with an increase in shear stress, indicating decaying erythrocyte responsiveness to higher shear stress values, particularly pronounced in DM patients. Although pilot, this study suggests that dEI / dSS can provide valuable insights into the hemorheological aspects of DM pathology and contribute to a comprehensive understanding of erythrocyte mechanobiological behavior in response to varying shear stress levels. Correlations between the proposed measure of RBC mechanical properties and established clinical markers of DM and its complications (serum cholesterol, creatinine, and urea level) are obtained to get preliminary insight into dEI / dSS application for better diagnosis and/or patient management
Flaxseed Oil Alleviates Trimethyltin-Induced Cell Injury and Inhibits the Pro-Inflammatory Activation of Astrocytes in the Hippocampus of Female Rats
No full textExposure to the neurotoxin trimethyltin (TMT) selectively induces hippocampal neuronal injury and astrocyte activation accompanied with resultant neuroinflammation, which causes severe behavioral, cognitive, and memory impairment. A large body of evidence suggests that flaxseed oil (FSO), as one of the richest sources of essential omega-3 fatty acids, i.e., α-linolenic acids (ALA), displays neuroprotective properties. Here, we report the preventive effects of dietary FSO treatment in a rat model of TMT intoxication. The administration of FSO (1 mL/kg, orally) before and over the course of TMT intoxication (a single dose, 8 mg/kg, i.p.) reduced hippocampal cell death, prevented the activation of astrocytes, and inhibited their polarization toward a pro-inflammatory/neurotoxic phenotype. The underlying protective mechanism was delineated through the selective upregulation of BDNF and PI3K/Akt and the suppression of ERK activation in the hippocampus. Pretreatment with FSO reduced cell death and efficiently suppressed the expression of inflammatory molecules. These beneficial effects were accompanied by an increased intrahippocampal content of n-3 fatty acids. In vitro, ALA pretreatment prevented the TMT-induced polarization of cultured astrocytes towards the pro-inflammatory spectrum. Together, these findings support the beneficial neuroprotective properties of FSO/ALA against TMT-induced neurodegeneration and accompanied inflammation and hint at a promising preventive use of FSO in hippocampal degeneration and dysfunction
Citrus Flavanone Effects on the Nrf2-Keap1/GSK3/NF-κB/NLRP3 Regulation and Corticotroph-Stress Hormone Loop in the Old Pituitary
No full textOxidative stress and inflammation are significant causes of aging. At the same time, citrus flavanones, naringenin (NAR), and hesperetin (HES) are bioactives with proven antioxidant and anti-inflammatory properties. Nevertheless, there are still no data about flavanone’s influence and its potential effects on the healthy aging process and improving pituitary functioning. Thus, using qPCR, immunoblot, histological techniques, and biochemical assays, our study aimed to elucidate how citrus flavanones (15 mg/kg b.m. per os) affect antioxidant defense, inflammation, and stress hormone output in the old rat model. Our results showed that HES restores the redox environment in the pituitary by down-regulating the nuclear factor erythroid 2-related factor 2 (Nrf2) protein while increasing kelch-like ECH-associated protein 1 (Keap1), thioredoxin reductase (TrxR1), and superoxide dismutase 2 (SOD2) protein expression. Immunofluorescent analysis confirmed Nrf2 and Keap1 down- and up-regulation, respectively. Supplementation with NAR increased Keap1, Trxr1, glutathione peroxidase (Gpx), and glutathione reductase (Gr) mRNA expression. Decreased oxidative stress aligned with NLRP3 decrement after both flavanones and glycogen synthase kinase-3 (GSK3) only after HES. The signal intensity of adrenocorticotropic hormone (ACTH) cells did not change, while corticosterone levels in serum decreased after both flavanones. HES showed higher potential than NAR in affecting a redox environment without increasing the inflammatory response, while a decrease in corticosterone level has a solid link to longevity. Our findings suggest that HES could improve and facilitate redox and inflammatory dysregulation in the rat’s old pituitary
Sensory Evaluation of Prototypes of Novel Dishes and Recipes Based on Underutilized Foods
No full textBackground and objectives: Since the beginning of the 20th century, more than 75% of genetic diversity has been lost. As a result of this homogenization, thousands of cultivated and wild food plants are no longer used, although they have high nutritional value. This work aims to develop recipes for new dishes and bring biodiversity to the plate in a way that consumers desire. Methods: Prototypes of new foods were prepared in the experimental kitchen. Each recipe was blind-tasted, evaluated, and ranked according to its organoleptic quality using a systematic approach. Both independent professional taste experts and lay public representatives were involved in the sensory evaluation of dishes. After the initial sensory evaluation (discrimination and hedonic scoring tests) in Serbia, the following recipes were selected for further evaluation in four other countries—Greece, Hungary, France, and Turkey: Dandelion and Tomato Salad; Buckwheat and Grass Pea Stew with Eggplant; Baked Eggplant and Potato à la Papa Alexie; Lentils as a Starter and Buckwheat Pockets Filled with Walnuts and Dried Fruit. The recipes were tested by 132 lay public representatives and 24 professionals. Results and Discussion: Of the five dishes tested, Buckwheat Pockets Filled with Walnuts and Dried Fruit were the most popular, followed by Baked Eggplant and Potato à la Papa Alexie and Dandelion and Tomato Salad. Although cultural differences and individual preferences play a role, none of the dishes was considered unacceptable or undesirable, and most were rated as likable to very likable. In line with the feedback, the optimization of the recipe design was discussed to optimize the sensory perception of the new dishes and to achieve a stimulating and satisfying taste and smell with appropriate texture and mouthfeel. The sensory evaluation showed that the new dishes offered, based on the underutilized foods studied in this project, were highly recognized and well received by consumers. Finally, a recipe book was created that includes a detailed explanation of the preparation methods and a comprehensive presentation of the relevant nutritional information of the new food dishes