Dose-dependent Influence Research Articles

Xanthohumol: Anti-Inflammatory Effects in Mechanically Stimulated Periodontal Ligament Stem Cells

Background/Objectives: Initial sterile inflammation is an essential molecular process in the periodontium during orthodontic tooth movement. A better understanding and possible modulations of these processes are of great interest to develop individual therapies for special patient groups. The prenylated plant polyphenol xanthohumol (XN) could have modulating effects as it has shown anti-inflammatory and angiogenesis-inhibiting effects in various cell lines. This study investigated the anti-inflammatory properties of XN in an in vitro model of compressively stimulated human periodontal ligament stem cells (hPDLSCs), which have a different function in the periodontium than the previously used cementoblasts. Methods: The expression of inflammatory markers at the mRNA and protein levels and the regulation of central kinases were investigated. Results: XN showed a dose-dependent influence on cell viability. Low concentrations between 0.2 and 4 µM showed positive effects, while 8 µM caused a significant decrease in viability after 24 h. Mechanical stimulation induced an upregulation of pro-inflammatory gene (IL-6, COX2) and protein (IL-6) expression. Here, XN significantly reduced stimulation-related IL-6 mRNA and gene expression. Furthermore, the phosphorylation of AKT and ERK was upregulated by mechanical stimulation, and XN re-established phosphorylation at a level similar to the control. Conclusions: We demonstrated a selective anti-inflammatory effect of XN in hPDLSCs . These findings provide the basis for further investigation of XN in the modulation of inflammatory responses in orthodontic therapy and the treatment of periodontal inflammation.

Evaluation of Cyto-Genotoxic Effects of Mucuna Bracteata DC. Ex Kurz Leaf Extracts by Allium Cepa

This study was conducted to evaluate the cyto-genotoxicity of leaf decoctions of Mucuna bracteata by Allium cepa bioassay. This kind of study can be used as a baseline monitoring system for plant products before their use. It is an inexpensive, simple, and reliable test to determine the cytotoxic and genotoxic effects of various plant extracts on living organisms. In this experiment, Allium cepa bulbs were placed in five concentrations (0.5 mg/mL, 2.5 mg/mL, 5.0 mg/mL, 7.5 mg/mL, and 10.0 mg/mL) of leaf decoction, with tap water as the negative control and 20.0 µL/L EMS (Ethylmethene sulphonate) as the positive control. Each concentration had five replicates. The cyto-genotoxicity assay exhibited a dose-dependent influence on the mitotic index. The mitotic index of the negative control and the positive control were 16.8 ± 0.37% and 6.86 ± 1.71%, respectively. The lowest dose of the extract, 0.5 mg/mL, had the highest mitotic index (14.2 ± 0.73%), while the highest dose, 10.0 mg/mL, had the lowest (9.6 ± 0.40%), and all indices were significantly higher than the positive control. Except for the 10 mg/mL concentration, the mitotic indices of other concentrations were significantly lower than the negative control. Different types of chromosome disorders, namely, disorderly prophase, sticky chromosomes, chromosome bridges, laggard chromosomes, pole deviation, vagrant chromosomes, nuclear filaments with terminal expansion, c-mitosis, micronuclei, and elongated nuclei, were observed. Various changes in root size, growth, and color were revealed by macroscopic examinations. Tumors were formed in roots at the highest doses but not at lower concentrations. Therefore, M. bracteata leaf extract showed cytotoxic and genotoxic effects on the Allium root meristem. J. Bio-Sci. 32(2): 71-82, 2024

Long-term safety and influence on growth in patients receiving sirolimus: a pooled analysis

BackgroundSirolimus is increasingly utilized in treating diseases associated with mTOR pathway overactivation. Despite its potential, the lack of evidence regarding its long-term safety across all age groups, particularly in pediatric patients, has limited its further application. This study aims to assess the long-term safety of sirolimus, with a specific focus on its impact on growth patterns in pediatric patients.MethodsThis pooled analysis inlcudes two prospective cohort studies spanning 10 years, including 1,738 participants (aged 5 days to 69 years) diagnosed with tuberous sclerosis and/or lymphangioleiomyomatosis. All participants were mTOR inhibitor-naive and received 1 mg/m²/day of sirolimus, with dose adjustments during a two-week titration period to maintain trough blood concentrations between 5 and 10 ng/ml (maximum dose 2 mg). Indicators of physical growth, hematopoietic, liver, renal function, and blood lipid levels were all primary outcomes and were analyzed. The adverse events and related management were also recorded.ResultsSirolimus administration did not lead to deviations from normal growth ranges, but higher doses exhibited a positive association with Z-scores exceeding 2 SD in height, weight, and BMI. Transient elevations in red blood cell and white blood cell counts, along with hyperlipidemia, were primarily observed within the first year of treatment. Other measured parameters remained largely unchanged, displaying only weak correlations with drug use. Stomatitis is the most common adverse event (920/1738, 52.9%). In adult females, menstrual disorders were observed in 48.5% (112/217).ConclusionsSirolimus’s long-term administration is not associated with adverse effects on children’s physical growth pattern, nor significant alterations in hematopoietic, liver, renal function, or lipid levels. A potential dose-dependent influence on growth merits further exploration.Trial registrationPediatric patients: Chinese clinical trial registry, No. ChiCTR-OOB-15,006,535. Adult patients: ClinicalTrials, No. NCT03193892.

Dietary Clostridium autoethanogenum protein has dose-dependent influence on the gut microbiota, immunity, inflammation and disease resistance of abalone Haliotis discus hannai

Clostridium autoethanogenum protein (CAP) is an eco-friendly protein source and has great application potential in aquafeeds. The present study aimed to investigate the effects of dietary CAP inclusion on the anti-oxidation, immunity, inflammation, disease resistance and gut microbiota of abalone Haliotis discus hannai after a 110-day feeding trial. Three isonitrogenous and isolipidic diets were formulated by adding 0 % (control), 4.10 % (CAP4.10) and 16.25 % (CAP16.25) of CAP, respectively. A total of 540 abalones with an initial mean body weight of 22.05 ± 0.19 g were randomly distributed in three groups with three replicates per group and 60 abalones per replicate. Results showed that the activities of superoxide dismutase and glutathione peroxidase in the cell-free hemolymph (CFH) were significantly decreased and the content of malondialdehyde in CFH was significantly increased in the CAP16.25 group. The diet with 4.1 % of CAP significantly increased the activities of lysozyme and acid phosphatase in CFH. The expressions of pro-inflammatory genes such as tumor necrosis factor-α (tnf-α), nuclear factor-κb (nf-κb) and toll-like receptor 4 (tlr4) in digestive gland were downregulated, and the expressions of anti-inflammatory genes such as β-defensin and mytimacin 6 in digestive gland were upregulated in the CAP4.10 group. Dietary CAP inclusion significantly decreased the cumulative mortality of abalone after the challenge test with Vibrio parahaemolyticus for 7 days. Dietary CAP inclusion changed the composition of gut microbiota of abalone. Besides, the balance of the ecological interaction network of bacterial genera in the intestine of abalone was enhanced by dietary CAP. The association analysis showed that two bacterial genera Ruegeria and Bacteroides were closely correlated with the inflammatory genes. In conclusion, the 4.10 % of dietary CAP enhanced the immunity and disease resistance as well as inhibited the inflammation of abalone. The 16.25 % of dietary CAP decreased the anti-oxidative capacity of abalone. The structure of the gut microbiota of abalone changed with dietary CAP levels.

Design and Discovery of Apigenin-based Drugs as a Potential Casein Kinase II Inhibitor for Breast Cancer through Hybrid In-silico Methods

This study investigates the potential of apigenin and derivatives as casein kinase II inhibitors for breast cancer treatment by a hybrid in-silico approach. Drug-drug transcriptomic similarity analysis reveals correlations with 17 drugs, guiding the identification of perturbagens with major transcriptional impressions. Transcriptional impact analysis across cell lines underscores apigenin’s dose-dependent influence on gene expression, particularly in breast cancer cells. Protein pre-preparation and molecular docking, refined by PDB REDO, showcase improved model quality and favorable binding affinities. Notable findings include apigenin’s potency as a CK2 inhibitor and promising compounds like dextromethorphan. Drug-drug transcriptomic similarity rankings identify potential candidates for further investigation. In conclusion, this integrated approach lays the groundwork for targeted therapies in breast cancer.

Muscle relaxant and antipyretic effects of pentacyclic triterpenes isolated from the roots of Diospyros lotus L

The present article describes the muscle relaxant and antipyretic effects of pentacyclic triterpenes, oleanolic acid (OA), ursolic acid (UA) and betulinic acid (BA) isolated from roots of Diospyros lotus in animal models. The muscle relaxant effects of isolated pentacyclic triterpenes were determined by chimney and inclined plane tests. In the chimney test, pretreatment of pentacyclic triterpenes evoked significant dose dependent influence on muscle coordination. When administered intraperitoneally (i.p.) to mice at 10 mg/kg for 90 min, OA, UA, and BA exhibited muscle relaxant effects of 66.72 %, 60.21 %, and 50.77 %, respectively. Similarly, OA, UA, and BA (at 10 mg/kg) illustrated 65.74 %, 59.84 % and 51.40 % muscle relaxant effects in the inclined plane test. In the antipyretic test, significant amelioration was caused by pretreatment of all compounds in dose dependent manner. OA, UA, and BA (at 5 mg/kg) showed 39.32 %, 34.32 % and 29.99 % anti-hyperthermic effects, respectively 4 h post-treatment, while at 10 mg/kg, OA, UA, and BA exhibited 71.59 %, 60.99 % and 52.44 % impact, respectively. The muscle relaxant effect of benzodiazepines is well known for enhancement of GABA receptors. There may exist a similar mechanism for muscle relaxant effect of pentacyclic triterpenes. The in-silico predicted binding pattern of all the compounds reflects good affinity of compounds with GABAA receptor and COX-2. These results indicate that the muscle relaxant and antipyretic activities of these molecules can be further improved by structural optimization.

Methyl β-Cyclodextrin-sperm-mediated gene editing (MBCD-SMGE): a simple and efficient method for targeted mutant mouse production

BackgroundGenerating targeted mutant mice is a crucial technology in biomedical research. This study focuses on optimizing the CRISPR/Cas9 system uptake into sperm cells using the methyl β-cyclodextrin-sperm-mediated gene transfer (MBCD-SMGT) technique to generate targeted mutant blastocysts and mice efficiently. Additionally, the present study elucidates the roles of cholesterol and reactive oxygen species (ROS) in the exogenous DNA uptake by sperm.ResultsIn this study, B6D2F1 mouse sperm were incubated in the c-TYH medium with different concentrations of MBCD (0, 0.75, 1, and 2 mM) in the presence of 20 ng/µl pCAG-eCas9-GFP-U6-gRNA (pgRNA-Cas9) for 30 min. Functional parameters, extracellular ROS, and the copy numbers of internalized plasmid per sperm cell were evaluated. Subsequently, in vitro fertilization (IVF) was performed and fertilization rate, early embryonic development, and transfection rate were assessed. Finally, our study investigated the potential of the MBCD-SMGT technique in combination with the CRISPR-Cas9 system, referred to as MBCD-SMGE (MBCD-sperm-mediated gene editing), for generating targeted mutant blastocysts and mice. Results indicated that cholesterol removal from the sperm membrane using MBCD resulted in a premature acrosomal reaction, an increase in extracellular ROS levels, and a dose-dependent influence on the copy numbers of the internalized plasmids per sperm cell. Moreover, the MBCD-SMGT technique led to a larger population of transfected motile sperm and a higher production rate of GFP-positive blastocysts. Additionally, the current study validated the targeted indel in blastocyst and mouse derived from MBCD-SMGE technique.ConclusionOverall, this study highlights the significant potential of the MBCD-SMGE technique for generating targeted mutant mice. It holds enormous promise for modeling human diseases and improving desirable traits in animals.Graphical

Abstract 16495: Cellular Senescence and Mitochondrial Dysfunction in Very Low-Density Lipoprotein-Induced Cardio-Lipotoxicity

Dyslipidemia, the hallmark of the metabolic syndrome, plays an important role in cardiovascular and cardiometabolic diseases. The heart utilizes lipids as major source of ATP and cardiomyocytes expresses abundant receptors for very low-density lipoprotein (VLDL), which is found exhibiting cardio-lipotoxicity in the metabolic syndrome. This study investigates the effects of VLDL in cardiomyocyte senescence and mitochondrial function. VLDL from metabolic syndrome patients was used to treat H9C2 cardiomyocytes for 72 hours. The RNA-sequencing was conducted to find novel senescence-associated signaling pathways in VLDL-induced lipotoxicity. The newly-found targets and regulators were validated using qPCR and Western blot. In addition, the senescence-associated secretory phenotype, the effects of VLDL on mitochondrial ATP production, NAD + /NADH, and mitochondrial membrane potential were also determined. The results showed that VLDL upregulated 97 cardiac hypertrophy-related genes expression. Among them, 84 genes were related to senescence, and 30 genes were apoptosis-related. Besides, 63 autophagy genes were also affected by VLDL treatment. The KEGG analysis showed that VLDL induced multiple senescence-related signaling pathways such as TP53, ERK-FOXO4, and TGF-β-related pathway. VLDL also exhibited dose-dependent influence on intra-mitochondrial Ca 2+ , and associated molecule Hmox1, Htt and Xdh expression. This study revealed novel mechanisms for the VLDL-induced cardio-lipotoxicity, which was shown involving multiple senescence-related signaling pathways and mitochondrial function regulators. The results suggested that the senescence signaling is a potential therapeutic target for cardiometabolic diseases.

Nanosized Silk-Magnesium Complexes for Tissue Regeneration.

Metal ions provide multifunctional signals for cell and tissue functions, including regeneration. Inspired by metal-organic frameworks (MOFs), nanosized silk protein aggregates with a high negative charge density are used to form stable silk-magnesium ion complexes. Magnesium ions (Mg ions) are added directly to silk nanoparticle solutions, inducing gelation through the formation of silk-Mg coordination complexes. The Mg ions are released slowly from the nanoparticles through diffusion, with sustained release via tuning the degradation or dissolution of the nanosized silk aggregates. Studies in vitro reveal a dose-dependent influence of Mg ions on angiogenic and anti-inflammatory functions. Silk-Mg ion complexes in the form of hydrogels also stimulate tissue regeneration with a reduced formation of scar tissue in vivo, suggesting potential utility in tissue regeneration.

Statin Treatment Is Associated with Alterations in the Platelet Lipidome.

Platelets are key players in the pathophysiology of coronary artery disease (CAD) and platelet hyperreactivity leads to increased risk of developing adverse cardiovascular events. Further, significant changes in the platelet lipidome occur in patients with acute coronary syndrome (ACS) and critically regulated lipids lead to platelet hyperresponsiveness. Statin treatment is crucial in the treatment and prevention of patients with CAD by remodeling lipid metabolism. In this study, we investigate the platelet lipidome of CAD patients by untargeted lipidomics, highlighting significant changes between statin-treated and naïve patients. We characterized the platelet lipidome in a CAD cohort (n = 105) by an untargeted lipidomics approach using liquid chromatography coupled to mass spectrometry. Among the annotated lipids, 41 lipids were significantly upregulated in statin-treated patients, whereas 6 lipids were downregulated compared to naïve patients. The most prominent upregulated lipids in statin-treated patients belong to the class of triglycerides, cholesteryl esters, palmitic acid, and oxidized phospholipids, whereas mainly glycerophospholipids were downregulated compared to untreated patients. A more pronounced effect of statin treatment on the platelet lipidome was observed in ACS patients. We further highlight a dose-dependent influence on the platelet lipidome. Our results reveal that the platelet lipidome is altered in CAD patients with statin treatment and upregulated lipids embody mainly characteristic triglycerides, whereas downregulated lipids mostly compromise glycerophospholipids, which may play a role in the pathophysiology of CAD. Results of this study may contribute to the understanding of statin treatment softening the lipid phenotype.

DOSE DEPENDENT INFLUENCE OF OVULATION INHIBITOR, CHLORMADINONE ACETATE OR CETRORELIX ON OOCYTE MATURATION IN NORMAL OVARIAN RESERVE PATIENTS: A RETROSPECTIVE STUDY WITH POISSON REGRESSION ANALYSIS

During controlled ovarian stimulation cycles, ovulation inhibitors play the pivotal role of suppressing a premature LH surge, however their influence on oocyte maturation has remained unclear. We incrementally evaluated the dose-dependent influence of cetrorelix, GnRH antagonist (GnRH-ant) which has been traditionally used, or chlormadinone acetate (CMA), an oral progestin which is used as an alternative to GnRH analog in the progestin-primed ovarian stimulation (PPOS), on oocyte maturation rate in patients with normal ovarian reserve.

Efficacy and safety of oral alpha-lipoic acid supplementation for type 2 diabetes management: a systematic review and dose-response meta-analysis of randomized trials.

ObjectiveTo examine the dose-dependent influence of oral alpha-lipoic acid (ALA) supplementation on cardiometabolic risk factors in patients with type 2 diabetes (T2D).DesignWe followed the instructions outlined in the Cochrane Handbook for Systematic Reviews of Interventions and the Grading of Recommendations, Assessment, Development, and Evaluation Handbook to conduct our systematic review. The protocol of the study was registered in PROSPERO (CRD42021260587).MethodWe searched PubMed, Scopus, and Web of Science to May 2021 for trials of oral ALA supplementation in adults with T2D. The primary outcomes were HbA1c, weight loss, and LDL cholesterol (LDL-C). Secondary outcomes included fasting plasma glucose (FPG), triglyceride (TG), C-reactive protein (CRP), and blood pressure. We conducted a random-effects dose–response meta-analysis to calculate the mean difference (MD) and 95% CI for each 500 mg/day oral ALA supplementation. We performed a nonlinear dose–response meta-analysis using a restricted cubic spline.ResultsWe included 16 trials with 1035 patients. Each 500 mg/day increase in oral ALA supplementation significantly reduced HbA1c, body weight, CRP, FPG, and TG. Dose–response meta-analyses indicated a linear decrement in body weight at ALA supplementation of more than 600 mg/day (MD600 mg/day: −0.30 kg, 95% CI: −0.04, −0.57). A relatively J-shaped effect was seen for HbA1c (MD: −0.32%, 95% CI: −0.45, −0.18). Levels of FPG and LDL-C decreased up to 600 mg/day ALA intake. The point estimates were below minimal clinically important difference thresholds for all outcomes.ConclusionDespite significant improvements, the effects of oral ALA supplementation on cardiometabolic risk factors in patients with T2D were not clinically important.

Dose-dependent influence of red blood cell transfusion volume on adverse outcomes in cardiac surgery.

Red blood cell (RBC) transfusion is associated with adverse outcomes, but there are few studies on the RBC volume. This study aimed to evaluate the relationship between intraoperative RBC volume and postoperative adverse outcomes for on-pump cardiac surgery. Adult patients undergoing on-pump cardiac surgery from 1 January 2017 to 31 December 2018 were included. Those transfused with more than 6 units of RBC were excluded. The clinical characteristics of four groups with various RBC volume were compared. We analyzed the relationship between RBC volume and adverse outcomes through multivariable logistic regression. 12,143 patients were analyzed, of which 3353 (27.6%) were transfused with 1-6U RBC intraoperatively. The incidence of death, overall morbidity, acute kidney injury and prolonged mechanical ventilation were increased stepwise along with incremental RBC volume. After adjusting for possible confounders, patients transfused with 1-2U were associated with a 1.42-fold risk of death (99% CI, 1.21-2.34, p = 0.01) compared with patients without RBC, patients with 3-4U were associated with a 1.57-fold risk (99% CI, 1.32-2.80, p = 0.005) and patients with 5-6U had a 2.26-fold risk of death (99% CI, 1.65-3.88, p < 0.001). Similarly, the incidence of overall morbidity, acute kidney injury and prolonged mechanical ventilation increased several folds as the RBC numbers increased. There was a significant dose-dependent influence of incremental intraoperative RBC volume on increased risk of adverse outcomes for on-pump cardiac surgery patients. Patient blood management practice should aim to reduce not only transfusion rate but also the volume of blood use.

Modeling Electrostatic Charge Shielding Induced by Cationic Drug Carriers in Articular Cartilage Using Donnan Osmotic Theory.

Positively charged drug carriers are rapidly emerging as a viable solution for long-standing challenges in delivery to dense, avascular, negatively charged tissues. These cationic carriers have demonstrated especially strong promise in targeting drugs to articular cartilage for osteoarthritis (OA) treatment. It is critical to evaluate the dose-dependent effects of their high intratissue uptake levels on charge-shielding of anionic matrix constituents, and the resulting changes in tissue osmotic swelling and mechanical integrity. We use the ideal Donnan osmotic theory to derive a model for predicting intracartilage swelling pressures as a function of net charge (z) and equilibrium uptake of short-length, arginine-rich, multivalent, cationic peptide carriers (cationic peptide carriers [CPCs], z varied from +8 to +20) in cartilage samples with varying arthritic severities and fixed charge density (FCD). We use this model to determine the dose-dependent influence of CPCs on both physiological osmotic swelling pressures and compressive electrostatic moduli of cartilage in healthy and arthritic states. Under physiological conditions, the Donnan model predicted carrier-induced reductions in free swelling pressure between 8 and 29 kPa, and diminished compressive modulus by 20-68 kPa, both dependent on the net charge and uptake of CPCs. The magnitudes of deswelling and stiffness reduction increased monotonically with carrier uptake and net charge. Furthermore, predicted levels of deswelling by CPC charge shielding were amplified in tissues with reduced FCD (which model OA). Finally, the Donnan model predicted markedly higher reductions in tissue compressive modulus in hypotonic bathing salinity compared with physiological and hypertonic conditions. This analysis demonstrates the importance of considering charge shielding as a likely adverse effect associated with uptake of cationic drug carriers into negatively charged tissues, especially in the case of damaged tissue. The simple modeling approach and principles described herein can inform the design of cationic drug delivery carriers and their clinical treatment regimens.

A nanoemulsion of Rosmarinus officinalis L. essential oil with allelopathic effect against Lactuca sativa L. seeds / Uma nanoemulsão a partir do óleo essencial de Rosmarinus officinalis L com efeito alelopático em sementes de Lactuca sativa L

Plant's essential oils have a wide range of allelopathic effects with potential uses as bioherbicides. In addition, the application of oils through nanoemulsions represents a promising alternative for agriculture, as it offers better performance and lowers toxic waste generation. Therefore, this study aimed to evaluate the chemical constitution of Rosmarinus officinalis (rosemary) essential oil, as well as its effects on germination, initial growth, Catalase (CAT), Peroxidase (POX), and Superoxide-Dismutase (SOD) enzymes activity of Lactuca sativa seeds. Nanoemulsions were produced at 5% concentration and then diluted with distilled water to 5.0, 7.0, and 10.0 mg/mL. We compared data obtained using variance (ANOVA) analysis, followed by Tukey's test at 5% probability. Rosemary oil showed a wide variety of terpenoid compounds, mainly the 1,8-cineol monoterpene, which accounted for 46% of the sample. The oil showed a dose-dependent negative allelopathic influence on all variables analyzed, causing a drop in germination percentage (%G), germination speed index (GVI), mean germination time (MTG), and leaf and root length. There was no change in CAT and SOD activity. The POX activity showed a reduction starting at the concentration of 7.0 mg/mL. The results showed allelopathic effects of rosemary oil, with potential use as a natural bioherbicide.

Generation of Reactive Oxygen Species by Human Whole Blood Cells Exposed to Iron Oxide Magnetic Nanoparticles Coated with Different Shells.

We compared dose-dependent influence of magnetic nanoparticles (MNP) coated with different shells on ROS generation during incubation with whole human blood. ROS generation was evaluated using luminol dependent chemiluminescence. MNP with polylactide shell in concentrations of 0.2-2.0 mg/ml had no effect on spontaneous chemiluminescence, while MNP with polysaccharide shell induced a dose dependent enhanced spontaneous chemiluminescence that increased during incubation (1-3 h). MNP with albumin shell in concentrations of 0.2 mg/ml gradually enhanced spontaneous chemiluminescence during incubation, but increasing the concentration neutralized this effect.

Quantifying the dose-dependent impact of intracellular amyloid beta in a mathematical model of calcium regulation in xenopus oocyte.

Alzheimer’s disease (AD) is a devastating illness affecting over 40 million people worldwide. Intraneuronal rise of amyloid beta in its oligomeric forms (iAβOs), has been linked to the pathogenesis of AD by disrupting cytosolic Ca2+ homeostasis. However, the specific mechanisms of action are still under debate and intense effort is ongoing to improve our understanding of the crucial steps involved in the mechanisms of AβOs toxicity. We report the development of a mathematical model describing a proposed mechanism by which stimulation of Phospholipase C (PLC) by iAβO, triggers production of IP3 with consequent abnormal release of Ca2+ from the endoplasmic reticulum (ER) through activation of IP3 receptor (IP3R) Ca2+ channels. After validating the model using experimental data, we quantify the effects of intracellular rise in iAβOs on model solutions. Our model validates a dose-dependent influence of iAβOs on IP3-mediated Ca2+ signaling. We investigate Ca2+ signaling patterns for small and large iAβOs doses and study the role of various parameters on Ca2+ signals. Uncertainty quantification and partial rank correlation coefficients are used to better understand how the model behaves under various parameter regimes. Our model predicts that iAβO alter IP3R sensitivity to IP3 for large doses. Our analysis also shows that the upstream production of IP3 can influence Aβ-driven solution patterns in a dose-dependent manner. Model results illustrate and confirm the detrimental impact of iAβOs on IP3 signaling.

Opposite Pathways of Cholinergic Mechanisms of Hypoxic Preconditioning in the Hippocampus: Participation of Nicotinic α7 Receptors and Their Association with the Baseline Level of Startle Prepulse Inhibition.

(1) Background. A one-time moderate hypobaric hypoxia (HBH) has a preconditioning effect whose neuronal mechanisms are not studied well. Previously, we found a stable correlation between the HBH efficiency and acoustic startle prepulse inhibition (PPI). This makes it possible to predict the individual efficiency of HBH in animals and to study its potential adaptive mechanisms. We revealed a bi-directional action of nicotinic α7 receptor agonist PNU-282987 and its solvent dimethyl sulfoxide on HBH efficiency with the level of PPI > or < 40%. (2) The aim of the present study was to estimate cholinergic mechanisms of HBH effects in different brain regions. (3) Methods: in rats pretested for PPI, we evaluated the activity of synaptic membrane-bound and water-soluble choline acetyltransferase (ChAT) in the sub-fractions of ‘light’ and ‘heavy’ synaptosomes of the neocortex, hippocampus and caudal brainstem in the intact brain and after HBH. We tested the dose-dependent influence of PNU-282987 on the HBH efficiency. (4) Results: PPI level and ChAT activity correlated negatively in all brain structures of the intact animals, so that the values of the latter were higher in rats with PPI < 40% compared to those with PPI > 40%. After HBH, this ChAT activity difference was leveled in the neocortex and caudal brainstem, while for membrane-bound ChAT in the ‘light’ synaptosomal fraction of hippocampus, it was reversed to the opposite. In addition, a pharmacological study revealed that PNU-282987 in all used doses and its solvent displayed corresponding opposite effects on HBH efficiency in rats with different levels of PPI. (5) Conclusion: We substantiate that in rats with low and high PPI two opposite hippocampal cholinergic mechanisms are involved in hypoxic preconditioning, and both are implemented by forebrain projections via nicotinic α7 receptors. Possible causes of association between general protective adaptation, HBH, PPI, forebrain cholinergic system and hippocampus are discussed.

Modifications of structural and optical properties of nanophase BaWO4 phosphors: Dose dependent effect of high energy electron beam irradiation

The present work reports dose dependent influence of 8 MeV electron beam irradiation on the structural and optical properties of BaWO4 nanoparticles fabricated by chemical precipitation route. The synthesized materials were calcined at 400 °C for 3 h to get well defined nanocrystalline particles. The calcined materials were irradiated by 8 MeV electron beams of different doses and studied the influence of irradiation on the structural and optical properties of BaWO4 nanoparticles using various characterization tools. The structural studies revealed modifications of lattice parameters a and c, unit cell volume, d spacing, crystallite size, micro-strain, and peak shift for major peaks of X-ray diffraction patterns of the electron irradiated samples. The electron irradiation also results some defects in the crystal lattice of BaWO4 nanocrystals upon electron beam irradiation. Scanning electron microscopic images demonstrated mesoporous behaviour of the BaWO4 materials. The optical studies established that optical bandgap and intensity of photoluminescence emission can be modified by using electron irradiation technique for potential applications in electronics. Photoluminescence emission properties of BaWO4 phosphors suggest that they are useful for the construction of near ultraviolet light excited blue light emitting diodes. Results explored from the present work constitute the first report for the dose-dependent influence of electron beam irradiation on the structure, optical absorption and photoluminescence properties of BaWO4 nanoparticles.

Dietary supplementation with magnesium citrate may improve pancreatic metabolic indices in an alloxan-induced diabetes rat model

The purpose of the current study was to evaluate the protective properties of dietary magnesium supplementation on pancreatic tissue of rats with alloxan-induced diabetes mellitus. Twenty-five male Wistar rats were split into five groups (control, diabetes, diabetes with 100 mg Mg daily, diabetes with 250 mg Mg daily, diabetes with 500 mg Mg daily) with feeding supplementation starting on day 1, diabetes induction on day 21, and animal sacrifice on day 30. Fasting glucose in blood serum was measured on days 21, 25, 27, and day 30. Glucose metabolism enzymes, namely, lactate dehydrogenase and glucose-6-phosphate dehydrogenase, were measured in pancreatic tissue upon the sacrifice, as well as lipid peroxidation, antioxidant system protective enzymes (catalase and superoxide dismutase), and glutathione system components (glutathione reductase, glutathione peroxidase, and glutathione reduced). Pearson correlation coefficients showed strong negative correlation between serum glucose (control and diabetic animals) and glucose metabolism enzymes, catalase, superoxide dismutase, glutathione peroxidase in pancreatic tissue (r &gt;-0.9, p &lt;0.05), moderate negative correlation with reduced glutathione (r = -0.79, p &lt;0.05), moderate positive correlation with lipid peroxidation index (r = +0.67, p &lt;0.05), weak correlation with glutathione reductase (r = -0.57, p &lt;0.05). Magnesium supplementation slowed down diabetes onset considering fasting glucose levels in rats (p &lt;0.05), as well as partially restored investigated dehydrogenase levels in the pancreas of rats comparing to diabetes group (p &lt;0.05). The lipid peroxidation index varied between treatments showing the dose-dependent influence of Mg2+. Magnesium supplementation partially restored catalase and superoxide dismutase activities in pancreatic tissue, as well as glutathione peroxidase and reduced glutathione levels (p &lt;0.05), while glutathione reductase levels remained unaffected (p &gt;0.05). The obtained results suggested a model, where magnesium ions may have a possible protective effect on pancreatic tissue against the negative influence of alloxan inside β cells of the pancreas.