Propolis Enhances 5-Fluorouracil Mediated Antitumor Efficacy and Reduces Side Effects in Colorectal Cancer: An in Vitro and in Vivo Study

In this study, we investigated the combined treatment of 5-fluorouracil (5-FU) and Anatolian propolis extract (PE) on colorectal cancer (CRC)using in vitro and in vivo studies. We exposed luciferase-transfected (Lovo-Luc CRC) cells and healthy colon cells (CCD-18Co) to varying concentrations of 5-FU and PE to assess their genotoxic, apoptotic, and cytotoxic effects, as well as their intracellular reactive oxygen species (iROS) levels. We also developed a xenograft model in nude mice and evaluated the anti-tumor effects of PE and 5-FU using various methods. Our findings showed that the combination of PE and 5-FU had selectivity against cancer cells, particularly at higher doses, and enhanced the anti-tumor effectiveness of 5-FU against colon CRC. The results suggest that PE can reduce side effects and increase the effectiveness of 5-FU through iROS generation in a dose-dependent manner.     

Design,in Silico Studies and Biological Evaluation of New Chiral Thiourea and 1,3-Thiazolidine-4,5-dione Derivatives

In this study, new chiral thiourea and 1,3-thiazolidine-4,5-dione derivatives were synthesized, it was aimed to evaluate the various biological activities and molecular docking of these compounds. Firstly, the new thioureas ( 1 – 16 ) were obtained by reacting 1-naphthylisothiocyanate with different chiral amines. Then, the chiral thioureas were cyclized with oxalyl chloride to obtain 1,3-thiazolidine-4,5-dione derivatives ( 17 – 32 ). All compounds were evaluated with several in vitro antioxidant and enzyme inhibition activities. Compound 30 was the most active compound against AChE, with a value of IC₅₀=8.09±0.58 μM. On the other hand, all compounds were tested in silico absorption, distribution, metabolism, and excretion (ADME) assays to better understand their bioavailability. These physicochemical properties, pharmacokinetics, and drug-likeness of all compounds were calculated using SwissADME. Furthermore, according to molecular docking analyses compound 30 exhibited significant binding affinities for all enzymes. Based on our overall observations, compound 30 could be recommended as a potential lead for the therapuetic of Alzheimer's.     

Protein Paucimannosylation Is an Enriched N‐Glycosylation Signature of Human Cancers

While aberrant protein glycosylation is a recognized characteristic of human cancers, advances in glycoanalytics continue to discover new associations between glycoproteins and tumorigenesis. This glycomics‐centric study investigates a possible link between protein paucimannosylation, an under‐studied class of human N‐glycosylation [Man_1‐3GlcNAc₂Fuc_0‐1], and cancer. The paucimannosidic glycans (PMGs) of 34 cancer cell lines and 133 tissue samples spanning 11 cancer types and matching non‐cancerous specimens are profiled from 467 published and unpublished PGC‐LC‐MS/MS N‐glycome datasets collected over a decade. PMGs, particularly Man_2‐3GlcNAc₂Fuc₁, are prominent features of 29 cancer cell lines, but the PMG level varies dramatically across and within the cancer types (1.0–50.2%). Analyses of paired (tumor/non‐tumor) and stage‐stratified tissues demonstrate that PMGs are significantly enriched in tumor tissues from several cancer types including liver cancer (p = 0.0033) and colorectal cancer (p = 0.0017) and is elevated as a result of prostate cancer and chronic lymphocytic leukaemia progression (p < 0.05). Surface expression of paucimannosidic epitopes is demonstrated on human glioblastoma cells using immunofluorescence while biosynthetic involvement of N‐acetyl‐β‐hexosaminidase is indicated by quantitative proteomics. This intriguing association between protein paucimannosylation and human cancers warrants further exploration to detail the biosynthesis, cellular location(s), protein carriers, and functions of paucimannosylation in tumorigenesis and metastasis.     

A stereological study of the effects of mercury inhalation on the cerebellum

Mercury in the environment that arises from organic and inorganic sources can cause irreversible damage to the nervous system. Toxicity may be direct or may arise from interactions with other metals in the environment. We evaluated the possible effects of mercury vapor on rat cerebellum. Twelve adult female rats were divided into control and experimental groups. The rats in the experimental group were exposed to mercury vapor for 9 h/day for 45 days. Cerebellar tissue samples were evaluated using stereology and for histopathology. The total number of Purkinje cells was estimated using a physical disector method. We found that in the experimental group, overall volume decreased and the number of Purkinje cells was reduced. We also found cellular damage including pycnotic nuclei, eosinophilic cytoplasm and vacuolization; these features were absent in the control group. We found that chronic exposure to inorganic mercury vapor is toxic to the cerebellum.     

The modified super-ellipsoid yield criterion for human trabecular bone

Despite the importance of multiaxial failure of trabecular bone in many biomechanical applications, to date no complete multiaxial failure criterion for human trabecular bone has been developed. By using experimentally validated nonlinear high-resolution, micromechanical finite-element models as a surrogate for multiaxial loading experiments, we determined the three-dimensional normal strain yield surface and all combinations of the two-dimensional normal-shear strain yield envelope. High-resolution finite-element models of three human femoral neck trabecular bone specimens obtained through microcomputed tomography were used. In total, 889 multiaxial-loading cases were analyzed, requiring over 41,000 CPU hours on parallel supercomputers. Our results indicated that the multiaxial yield behavior of trabecular bone in strain space was homogeneous across the specimens and nearly isotropic. Analysis of stress-strain curves along each axis in the 3-D normal strain space indicated uncoupled yield behavior whereas substantial coupling was seen for normal-shear loading. A modified super-ellipsoid surface with only four parameters fit the normal strain yield data very well with an arithmetic error +/-SD less than -0.04 +/- 5.1%. Furthermore, the principal strains associated with normal-shear loading showed excellent agreement with the yield surface obtained for normal strain loading (arithmetic error +/- SD < 2.5 +/- 6.5%). We conclude that the four-parameter "Modified Super-Ellipsoid" yield surface presented here describes the multiaxial failure behavior of human femoral neck trabecular bone very well.     

Trabecular bone modulus-density relationships depend on anatomic site

One outstanding issue regarding the relationship between elastic modulus and density for trabecular bone is whether the relationship depends on anatomic site. To address this, on-axis elastic moduli and apparent densities were measured for 142 specimens of human trabecular bone from the vertebra (n=61), proximal tibia (n=31), femoral greater trochanter (n=23), and femoral neck (n=27). Specimens were obtained from 61 cadavers (mean+/-SD age=67+/-15 years). Experimental protocols were used that minimized end-artifact errors and controlled for specimen orientation. Tissue moduli were computed for a subset of 18 specimens using high-resolution linear finite element analyses and also using two previously developed theoretical relationships (Bone 25 (1999) 481; J. Elasticity 53 (1999) 125). Resultant power law regressions between modulus and density did depend on anatomic site, as determined via an analysis of covariance. The inter-site differences were among the leading coefficients (p<0.02), but not the exponents (p>0.08), which ranged 1.49-2.18. At a given density, specimens from the tibia had higher moduli than those from the vertebra (p=0.01) and femoral neck (p=0.002); those from the trochanter had higher moduli than the vertebra (p=0.02). These differences could be as large as almost 50%, and errors in predicted values of modulus increased by up to 65% when site-dependence was ignored. These results indicate that there is no universal modulus-density relationship for on-axis loading. Tissue moduli computed using methods that account for inter-site architectural variations did not differ across site (p>0.15), suggesting that the site-specificity in apparent modulus-density relationships may be attributed to differences in architecture.     

Healing-promoting effect of bombesin treatment on chronic gastric ulcer in rats

To evaluate whether bombesin treatment has a facilitatory effect on the healing of chronic gastric ulcer, following the induction of ulcer by serosal application of acetic acid, rats were given bombesin (30 microg/kg/day; subcutaneously) or vehicle three times a day for 7, 14 or 21 days until they were decapitated. Neither food intake nor gastric emptying rate in either vehicle-treated or bombesin-treated groups was not statistically different from control rats. Similarly, ulcer indices and gastric myeloperoxidase (MPO) activities at the first and second weeks of injury were not different among the groups. However, in the 3-week ulcer group, bombesin treatment reduced tissue MPO level significantly back to control levels. Moreover, the analysis of the surface epithelium by scanning electron and light microscopy demonstrated a significant reduction in the severity of ulcers by bombesin treatment. Pretreatment with CCK antagonists (L-364,718 or L365,260; 25 micromol/kg/day) before bombesin treatment showed that neither of the CCK antagonists had a significant effect on the bombesin-mediated healing process, suggesting that CCK receptors are not involved in the action of bombesin. In accordance with the previous studies that show its acute gastroprotective effects, bombesin is also effective in promoting the healing process of chronic gastric ulcer in rats.     

Quantification of mesna and total mesna in kidney tissue by high-performance liquid chromatography with electrochemical detection

A sensitive and selective assay for the determination of mesna and total mesna in tissue was developed and validated. After a simple homogenization, extraction and deproteinization step, mesna could be measured immediately by HPLC with an electrochemical detector provided with a sensitive wall-jet gold electrode. Total mesna (i.e., free mesna and mesna present in mesna disulfides and mixed mesna disulfides) could be measured after pre-column reduction with sodium borohydride to free mesna. The lower limit of quantification of mesna and total mesna was for both compounds 10 nmol/g. The assays for mesna and total mesna in tissue were linear over the ranges of 10-3000 and 10-10000 nmol/g, respectively. The within-day and between-day precisions of both methods were better than 9%. The within-day and between-day accuracy of the mesna assay ranged from 103.7 to 113.6%, whereas the accuracies of the total mesna assay ranged from 97.8 to 106.7%. Mesna in an EDTA containing tissue homogenate or in deproteinized tissue homogenate stored at -80 degrees C was stable for at least 12 weeks. Total mesna was stable under all conditions measured. The developed assays will be applied for the determination of the distribution of mesna and total mesna in tissues of the rat after administration of mesna or BNP7787.     

Does the platelet-activating factor affect the antioxidant defense system?

The platelet-activating factor (PAF) is an inflammatory mediator and it may exert some of its effects by reactive oxygen species (ROS). We investigated the effects of PAF and hyperbaric oxygenation (HBO) on copper (Cu) and zinc (Zn) levels in plasma and the intracellular antioxidant enzyme activities of rats. PAF administration caused a decrease in erythrocyte catalase (CAT) and glutathione peroxidase (GPx) activities and in the plasma zinc level. Following PAF administration, exposure to HBO also caused a decrease in erythrocyte GPx activity. These results support the hypothesis that PAF may produce free oxygen radicals and HBO enhances this effect. The enzyme activities of the antioxidant defense system were found to be affected by these oxidative processes. This is likely to be the result of excessive production of ROS or overutilization and/or inhibition of the antioxidant enzymes.