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This study investigated the antihypertensive and immunomodulatory effects of defatted corn germ hydrolysates (DCGHs) in vivo and their potential regulatory mechanisms. The systolic blood pressure (SBP) of spontaneously hypertensive rats (SHRs) was significantly reduced (10.30%) by the long-term intragastric administration of DCGHs (high doses). Also, there was drastic inhibition of angiotensin-I-converting enzyme (ACE) activity in the lung, kidney, and heart tissues by 24.53, 22.28, and 12.93%, respectively. It could regulate the blood pressure by adjusting the balance between endothelium-derived vasoconstrictor factors and endothelium-derived relaxing factors. Meanwhile, DCGHs enhanced the phagocytosis of mononuclear macrophages, cellular immunity, and humoral immunity of ICR mice by increasing the phagocytic index of mononuclear macrophages (23.71%), ear swelling degree (44.82%), and antibody levels (52.32%). Moreover, it stimulated the release of immunoactive substances (e.g., lysozyme, interferon-γ, immunoglobulin G, and complement 3). Consequently, DCGHs could suitably be used in the formulation of novel functional foods with antihypertensive and immunomodulatory properties.

Background: Dental implants are considered the gold standard replacement for missing natural teeth. The successful clinical performance of dental implants is due to their ability to osseointegrate with the surrounding bone. Most dental implants are manufactured from Titanium and it alloys. Titanium does however have some shortcomings so alternative materials are frequently being investigated. Effective preclinical studies are essential to transfer the innovations from the benchtop to the patients. Many preclinical studies are carried out in the extra-oral bones of small animal models to assess the osseointegration of the newly developed materials. This does not simulate the oral environment where the dental implants are subjected to several factors that influence osseointegration; therefore, they can have limited clinical value.Aim: This study aimed to develop an appropriate in-vivo model for dental implant research that mimic the clinical setting. The study evaluated the applicability of the new model and investigated the impact of the surgical procedure on animal welfare.Materials and Methods: The model was developed in male New Zealand white rabbits. The implants were inserted in the extraction sockets of the secondary incisors in the maxilla. The model allows a split-mouth comparative analysis. The implants' osseointegration was assessed clinically, radiographically using micro-computed tomography (µ-CT), and histologically. A randomised, controlled split-mouth design was conducted in 6 rabbits. A total of twelve implants were inserted. In each rabbit, two implants; one experimental implant on one side, and one control implant on the other side were applied. Screw-shaped implants were used with a length of 8 mm and a diameter of 2 mm.Results: All the rabbits tolerated the surgical procedure well. The osseointegration was confirmed clinically, histologically and radiographically. Quantitative assessment of bone volume and mineral density was measured in the peri-implant bone tissues. The findings suggest that the new preclinical model is excellent, facilitating a comprehensive evaluation of osseointegration of dental implants in translational research pertaining to the human application.Conclusion: The presented model proved to be safe, reproducible and required basic surgical skills to perform. [ABSTRACT FROM AUTHOR]

Synthetic amorphous silica (SAS) nanomaterial – consisting of aggregates and agglomerates of primary silicon dioxide (SiO2) particles in the nanorange (<100 nm) – is commonly used as excipient in pharmaceuticals, in cosmetics and as food additive (E551). The available data suggest that SAS nanoparticles (NP) after intravenous (IV) exposure persist in liver and spleen; however, insufficient data exist to verify whether SAS may also induce adverse effects. The aim of the present study was to verify the potential long-term effects of SAS NP (NM-203) on spleen and liver as target organs following short-term exposure. Adult male and female Sprague-Dawley rats were treated by IV injection in the tail vein with a single (1-day) dose (SD) and repeated (5-day) doses (RD) of 20 mg/kg bw per day of SAS dispersed in sterile saline solution as vehicle. Histopathological examinations of target organs were performed after 90 days. Tissue biodistribution and full characterization of NM-203, primary particle size 13–45 nm, was performed within the framework of the Nanogenotox project. No mortality or general toxicity occurred; histopathological analysis showed splenomegaly in the RD group accompanied by inflammatory granulomas in both sexes. Granulomas were also present in liver parenchyma in the RD (both sexes) and SD groups (male only). The histopathological results indicated that SAS NP have the potential to persist and induce sex-specific chronic inflammatory lesions in spleen and liver upon short-term treatment. Overall, the data showed that the widespread use of silica in drugs might elicit chronic reactions in spleen and liver prompting to the need of further investigations on the safety of SAS NP. [ABSTRACT FROM AUTHOR]

Background: The leaves of Tasmannia lanceolata mainly contain polygodial that is known to exhibit a range of biological functions including anti‐inflammatory effects. Aims: These studies aimed to assess the effects of Tasmannia lanceolata extract (TLE) on skin and more particularly on stretch marks in women. Patients/Methods: A double‐blind, randomized, placebo‐controlled clinical study was carried out on 29 women, aged from 25 to 60 years, to investigate the effects of TLE on stabilized stretch marks. TLE and placebo products were topically applied daily for 8 weeks. Skin roughness and firmness of stretch marks were assessed by 2D and 3D photograph processing and analyses. Dermal density and thickness were evaluated using ultrasound, while stretch mark conditions (length, color, and depth) were determined by clinical scoring. Matricial proteins (pro‐collagen I and elastin) and pro‐matricial factors, like TGF‐β concentrations, were quantified from cultures of human skin explants presenting stretch marks, treated with TLE or vehicle control. Results: Skin roughness of stretch marks was significantly reduced in the TLE group after 8 weeks of treatment. Skin firmness of stretch marks was significantly increased in the TLE group after 4 weeks of treatment, and this improved effect was maintained until the end of the study. Dermal density and thickness were significantly increased in the TLE group compared to the placebo group. Furthermore, TLE restored the dermal condition of the stretch mark skin, up to normal skin levels. In addition, pro‐collagen I and elastin concentrations were found to be higher in the TLE‐treated stretch mark skin explants compared to the untreated ones, associated with higher quantities of TGF‐β production. Conclusion: These results revealed that TLE could help improve the aspect of stabilized stretch marks in women by restoring the matricial environment. [ABSTRACT FROM AUTHOR]

The present study was conducted to formulate ethosomal thermoreversible in situ gel of apixaban, an anticoagulant drug, for nasal delivery. Ethosomes were formed, of lecithin, cholesterol, and ethanol, by using thin-film hydration method. The prepared ethosomes were characterized by Zetasizer, transmission electron microscope, entrapment efficiency, and in vitro study. The selected ethosomal formula (API-ETHO2) was incorporated in gel using P407 and P188 as thermoreversible agents and carbopol 934 as mucoadhesive agent. Box-Behnken design was used to study the effect of independent variables (concentration of P407, P188, and carbopol 934) on gelation temperature, mucoadhesive strength, and in vitro cumulative percent drug released at 12h (response variables). The optimized formulation was subjected to compatibility study, ex vivo permeation, histopathological examination for the nasal mucosa, and in vivo study. API-ETHO2 was spherical with an average size of 145.1±12.3 nm, zeta potential of –20±4 mV, entrapment efficiency of 67.11%±3.26, and in vitro % release of 79.54%±4.1. All gel formulations exhibited an acceptable pH and drug content. The optimum gel offered 32.3°C, 1226.3 dyne/cm2, and 53.50% for gelation temperature, mucoadhesive strength, and in vitro percent released, respectively. Apixaban ethosomal in situ gel evolved higher ex vivo permeation (1.499±0.11 μg/cm2h) through the nasal mucosa than pure apixaban gel. Histopathological study assured that there is no necrosis or tearing of the nasal mucosa happened by ethosomal gel. The pharmacokinetic parameters in rabbit plasma showed that intranasal administration of optimized API-ethosomal in situ gel achieved higher Cmax and AUC0–∞ than unprocessed API nasal gel, nasal suspension, and oral suspension. The ethosomal thermoreversible nasal gel established its potential to improve nasal permeation and prolong anticoagulant effect of apixaban. [ABSTRACT FROM AUTHOR]

[Display omitted] • Chemistry: A series of novel pyrimidine-5-carbonitriles was synthesised. • Biological screening: Compound 7c was the most potent member in our study. The most sensitive cell lines were SNB-75, and OVAR-4. • Compound 7c have dual inhibitory activity against EGFRWT/T790M/PI3K. • Compound 7c block cell cycle at G0-G1 phase. • Compound 7c decrease the expression level of p-AKT protein but increase caspase 3 & 9 & BAX proteins. • Compounds 7c demonstrated less cytotoxicity against normal epithelial colon cells compared to Staurosporine. • Compound 7c showed decrease in tumor weight, and the number of tumor nodules in Mice in which cancer was induced. A new series of 6-(4-fluorophenyl)-2-(methylthio) pyrimidine-5-carbonitrile derivatives were designed and synthesized as EGFR/PI3K dual inhibitors, and potential antiproliferative agents. The new 22 compounds were screened by DTP-NCI against all NCI60 cell lines. Almost all compounds showed cytotoxic activity. Compound 7c showed a promising antitumour activity on CNS cancer (SNB-75), and ovarian cancer (OVAR-4) with IC 50 < 0.01, and 0.64 µM, respectively. Fortunately, 7c exhibited a better safety profile on normal cells (WI-38) than doxorubicin by 2.2-fold. Compound 7c displayed selective inhibitory activity on EGFRt790m over EGFRWT with IC 50 = 0.08, and 0.13 µM, respectively, wherefore it might overcome EGFR-TKIs resistance. In addition to its remarkable inhibitory activity on all PI3K isoforms, specifically PI3K-δ with IC 50 = 0.64 µM Compared with LY294002 IC 50 = 7.6 µM. Compound 7c arrested the cell cycle of SNB-75 & OVAR-4 at the G0-G1 phase coupled with apoptosis induction. The western blotting analysis approved decreasing the expression level of p-AKT coupled with an increase in Casp3, Casp9, and BAX proteins in the SNB-75 & OVAR-4 after being treated with 7c which may support the suggested mechanism of action of 7c as EGFR/PI3K dual inhibitor. Physicochemical parameters were forecasted using SwissADME online tool. MD showed the interaction of 7c with the crucial amino acids of the active domain of both EGFR/PI3K which may explain its potent inhibitory activities. In vivo study disclosed a significant decrease in tumor weight and the number of nodules in the group of mice treated with 7c compared with the control group. [ABSTRACT FROM AUTHOR]

Thimerosal, a preservative commonly used in the pharmaceutical and cosmetic industry, has raised concerns regarding its potentially toxic effects as an organic mercury compound. Within this context, using an NMR-based metabolomics profile and chemometric analysis, zebrafish embryos were used as an in vivo model to study the effects of thimerosal in metabolic profiles after exposure to sublethal concentrations of the mercury compound. The thimerosal concentrations of 40 and 80 nM were employed, corresponding to 40% and 80% of the LC 50 , respectively, for zebrafish embryos. The most significant alterations in the metabolic profile included changes in carbohydrates, amino acids, nucleotides, trimethylamine- N -oxide, ethanolamine, betaine, and ethanol. Furthermore, thimerosal exposure affects various metabolic pathways, impairing the nervous system, disrupting protein metabolism, and potentially causing oxidative damage. Therefore, adopting a metabolomics approach in this investigation provided insights into the potentially implicated metabolic pathways contributing to the deleterious effects of thimerosal in biological systems. [ABSTRACT FROM AUTHOR]

PurposeThe first genomewide association study indicated that variations in the phosphodiesterase 4D (PDE4D) gene confer risk for ischemic stroke. However, inconsistencies among the studies designed to replicate the findings indicated the need for further investigation to elucidate the role of the PDE4 pathway in stroke pathogenesis. Hence, we studied the effect of global inhibition of the PDE4 pathway in two rat experimental stroke models, using the PDE4 inhibitor rolipram. Further, the specific role of the PDE4D isoform in ischemic stroke pathogenesis was studied using PDE4D knockout rats in experimental stroke.MethodsRats were subjected to either the ligation or embolic stroke model and treated with rolipram (3mg/kg; i.p.) prior to the ischemic insult. Similarly, the PDE4D knockout rats were subjected to experimental stroke using the embolic model.ResultsGlobal inhibition of the PDE4 pathway using rolipram produced infarcts that were 225% (p

Abstract Background In colorectal cancer surgery there is a delicate balance between complete removal of the tumor and sparing as much healthy tissue as possible. Especially in rectal cancer, intraoperative tissue recognition could be of great benefit in preventing positive resection margins and sparing as much healthy tissue as possible. To better guide the surgeon, we evaluated the accuracy of diffuse reflectance spectroscopy (DRS) for tissue characterization during colorectal cancer surgery and determined the added value of DRS when compared to clinical judgement. Methods DRS spectra were obtained from fat, healthy colorectal wall and tumor tissue during colorectal cancer surgery and results were compared to histopathology examination of the measurement locations. All spectra were first normalized at 800 nm, thereafter two support vector machines (SVM) were trained using a tenfold cross-validation. With the first SVM fat was separated from healthy colorectal wall and tumor tissue, the second SVM distinguished healthy colorectal wall from tumor tissue. Results Patients were included based on preoperative imaging, indicating advanced local stage colorectal cancer. Based on the measurement results of 32 patients, the classification resulted in a mean accuracy for fat, healthy colorectal wall and tumor of 0.92, 0.89 and 0.95 respectively. If the classification threshold was adjusted such that no false negatives were allowed, the percentage of false positive measurement locations by DRS was 25% compared to 69% by clinical judgement. Conclusion This study shows the potential of DRS for the use of tissue classification during colorectal cancer surgery. Especially the low false positive rate obtained for a false negative rate of zero shows the added value for the surgeons. Trail registration This trail was performed under approval from the internal review board committee (Dutch Trail Register NTR5315), registered on 04/13/2015, https://www.trialregister.nl/trial/5175.

Toxic effects of nanoparticles on human health are considerably increasing their worldwide recognition. Currently silver nanoparticles are being widely used in consumer medical products, due to its uniqueness in biomedical applications. Uptake of these particles via various administration routes can also lead to different toxic effects. In this study, we assessed the toxic effect of 11–75 nm ranged biogenic silver nanoparticles (Bio-AgNPs) on male wistar rats by using two different administration routes namely, intraperitoneal and intravenous routes. The three different concentrations, No Observable Adverse Effect Concentration (NOAEC), Inhibitory concentration (IC50) and Total lethal concentration (TLC) was appraised at the dose range of 97.64 to 132 µg/kg for both i/p and i/v routes. There is no considerable changes in hematological parameters in i/p and i/v routes on 14th and 28th day of observation, but the increase was trivial significant for platelet count at the dose of 97–105 µg/kg (IC50) for i/p route of injection. There is no remarkable adverse impact on liver, spleen and kidney were observed in IC50 and TLC treated group, when determined by biochemical and histopathological analysis both in i/p and i/v routes treated rats. This estimation confirms that, Bio-AgNPs are not going effect the human metabolic system.

Abstract Background Alternative techniques for nasal dorsum augmentation are of paramount importance in reconstructive and plastic surgery. In contrast to autologous cartilage grafts, tissue-engineered grafts can be created de novo and yield low–none donor site morbidity as compared to autologous grafts like rib or ear cartilage. To address this demand, this study investigated the in vivo regenerative potential of polycaprolactone-based implants as an alternative to autologous cartilage grafting during rhinoplasty. Methods Implants were placed at the nasal dorsum in two groups of minipigs and kept in situ for 2 and 6 months, respectively. Subsequently, the implants were harvested and examined by histology (hematoxylin–eosin, alcian blue, and safranin O) and immunostaining (collagen I and collagen II). Further analysis was performed to measure diameter and distance of polycaprolactone struts. Results Histological examination revealed a persistent formation of connective tissue with some spots resembling a cartilaginous-like matrix after 6 months. In such areas, cells of chondrocyte appearance could be identified. There was a significant decrease in strut diameter but a non-significant difference in strut distance. Conclusion Our results indicated that the investigated polycaprolactone-based implants have shown a regenerative and stable nasal dorsum augmentation after 6 months in vivo. Thus, we believe that customized polycaprolactone-based implants could become an alternative technique for nasal dorsum augmentation without the need for autologous cartilage grafts.

Toxoplasmosis may become a fatal disease in immunodeficient, diabetic patients, pregnant women, and infants. Hence, the diligent search for new effective treatment is among the major concerns worldwide. The well-dispersed multi-walled carbon nanotubes lined with ZnO (ZnO-MWCNT), graphene oxide (GO-NPs), and zinc oxide (ZnO-NPs) were successfully synthesized through rapid and facile hydrothermal arc discharge technique (HTADT). The antiparasitic effects of ZnO-NPs, GO-NPs, and ZnO-MWCNT were investigated in mice infected with Toxoplasma gondii. The percent of tachyzoites reduction were detected. The observed results demonstrated that ZnO-MWCNT revealed a significant reduction in the parasite count reached 61% in brain tissues, followed by liver (52%), then spleen (45%). The assessments of antiparasitic, inflammatory, and anti-inflammatory cytokines confirmed the superior activity of ZnO-MWCNT as antiparasitic agent, which paves the way for the employment of ZnO-MWCNT as a treatment for the acute RH strain of T. gondii infection in vivo.

Galleria mellonella is a well-accepted insect model for the study of pathogen-host interactions and antimicrobial compounds. The main advantages of this model include the low cost of maintenance, the fast life cycle, the possibility of using a large number of caterpillars and the innate immune system, which is evolutionarily conserved relative to mammals. Because of these advantages, different research groups have been working to implement the rearing of G. mellonella in laboratory conditions. This protocol describes our experience in the rearing of G. mellonella caterpillars for experimental infection models and the influence of different artificial diets on developmental and physiological parameters. Here, we suggest a diet composition that benefits the life cycle of G. mellonella by accelerating the larval phase length and increasing the caterpillar weight. This diet also stimulated the immune system of G. mellonella by increasing the hemolymph volume and hemocyte concentration. In addition, our rearing protocol generated caterpillars that are more resistant to infection by Staphylococcus aureus, Escherichia coli and Candida albicans. A standard G. mellonella rearing protocol is fundamental to minimize external influences on the results, and this simple and easy protocol can support researchers starting to rear G. mellonella.

Fluoxetine (FLX) has become the first-line drug in the pharmacotherapy of patients with depression. However, it has a strong unpleasant bitter taste, leading to the failure to complete the therapy. In this study, FLX is formulated into orodispersible tablets (ODTs) characterized by a fast release with an acceptable taste. FLX ODTs were prepared by the complexation of FLX with β-cyclodextrin (β-CD) for taste-masking, using different super disintegrants, namely crospovidone (CP), croscarmellose sodium (Ccs), sodium starch glycolate (SSG), and indion. The FLX powder blend is estimated for pre-and post-compression parameters. The selected tablet formulations based upon drug release at 40 s with acceptable release patterns are investigated for accelerated stability testing and comparative in vivo study with a marketed product. It was found that all FLX-powder blends have good flow properties; all the prepared tablets complied with the pharmacopeial requirements for the unity of content, weight, friability, and hardness. Moreover, all the tablets obtained acceptable taste after complexation with β-CD. The order of release of the drug, regarding super disintegrants used, was as in the following descending order: CP > Ccs > SSG > indion. Accelerated stability study of selected formulation F2 and F6 showed that; there were no considerable changes in physical properties, drug content, and percentage drug release. Furthermore, also the in vivo study proved the effectiveness of FLX ODTs as an antidepressant. The results obtained showed a promising potential of the prepared FLX ODTs for treating depression effectively. [ABSTRACT FROM AUTHOR]

Aim: To compare the clinical performance of composite restorations placed with a universal adhesive, one-step and two-step self-etch adhesives in class I and II posterior cavities. Materials and methods: In this in vivo study, 46 volunteers presenting with at least three carious lesions were included. Each participant received the three restorative systems: universal adhesive/nanofilled composite (Scotchbond Universal/Filtek Z350 XT: SBU/FZXT), one-step selfetch adhesive/microhybrid composite (G-aenial bond/G-aenial Posterior: GB/GP) and the twostep self-etch adhesive/nanohybrid composite (OptiBond XTR/Herculite Ultra: OBX/HU). The adhesives were all placed in self-etch mode. In total, 138 restorations were evaluated at baseline and at 6,12 and 36months using the modified United States Public Health Service criteria. Data were analysed using Kruskal-Wallis, Mann-Whitney U, Friedman and Wilcoxon non-parametric tests (p<.05). Ninety-one restorations were evaluated at 36months. Results: Seven restorations, three SBU/FZXT, three GB/GP and one OBX/HU failed during this study. The reasons for failure were marginal fracture and secondary caries. SBU/FZXT restorations showed significant marginal deterioration in all parameters. Overall success rates were: 93.5% (SBU/FZXT), 96.6% (GB/GP) and 96.8% (OBX/HU). Conclusions: After three years, the three restorative systems have comparable clinical effectiveness and success rates, except for the marginal integrity, that was suboptimal for both the SBU/FZXT and GB/GP restorations in comparison to the OBX/HU restorations. [ABSTRACT FROM AUTHOR]

Purpose: A clinical study to evaluate the intraoral adjustment of crowns fabricated using different scanners. Materials and Methods: A total of 15 patients requiring single ceramic crowns were recruited. Impressions were made according to four protocols: a conventional approach and using three intraoral scanners (IOSs) (CS3600 (Carestream Dental, Atlanta, GA), i500 (Medit, Seoul, Republic of Korea), and EZIS PO (DDS, Seoul, Republic of Korea)). Four crowns per patient were fabricated using lithium disilicate ceramic. An experienced dentist performed the internal adjustment in the oral cavity. Three‐dimensional analysis was conducted using an inspection software program (Geomagic Control X; 3D Systems, Rock Hill, SC). Statistical analysis was conducted using one‐way analysis of variance and Tukey's honest significance difference tests (α = 0.05). Results: A significant difference was observed in the intraoral adjustment among the conventional approach and the three IOSs (F = 213.7, p < 0.001). Crowns fabricated by conventional impressions (20.1 ± 1.4 µm) displayed better three‐dimensional conformity before and after intraoral adjustment than IOS groups (29.6 ± 4.3 µm) (p < 0.001). Conclusions: Crowns fabricated using conventional impressions required fewer intraoral adjustments of the intaglio surface than those fabricated using IOSs. [ABSTRACT FROM AUTHOR]

Background: Biphasic hyaluronic acid (HA) fillers have been used extensively to improve facial skin. However, in some cases, the skin surface is irregular because of the premature loss of HA solution. We propose a new biphasic filler (G-filler) to overcome this problem by using small particles of HA hydrogel instead of HA solution, which can provide a smooth skin surface and good durability. Method: We evaluated the rheologic properties of G-filler and its physiologic effects after subcutaneous injection in a mouse model by histologic analysis. Results: The G-filler showed a similar elastic modulus (G′) and complex viscosity (η*) as the conventional biphasic filler, but had a higher viscous modulus (G″) than the conventional monophasic filler. The highest material elasticity (tan δ) value and the lowest percentage elasticity value indicate the rheologic properties of G-filler are closer to those of liquids. After subcutaneous injection of G-filler, collagen content (~ 2-fold) and elastin fibers (~ 6.5-fold) were significantly increased at 12 weeks compared to those of the saline group. Fibronectin (~ 2.6-fold) and the laminin-immunolabeled cell number (~ 6-fold) were also significantly increased at 12 weeks. Significant increases in the CD31-immunoreactive cell numbers of the G-filler groups were observed at 2, 6, and 12 weeks (~ 3.7-fold) compared to those of the saline groups. There were no significant differences between the G-filler and saline groups in patterns of skin thickness and inflammatory cell numbers around loading sites. Conclusion: These findings demonstrate that the injection of a new biphasic filler with improved rheologic properties can effectively stimulate extracellular matrix production and angiogenesis without safety concerns. No Level Assigned: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors -www.springer.com/00266. [ABSTRACT FROM AUTHOR]

Children with high-risk SHH/TP53-mut and Group 3 medulloblastoma (MB) have a 5-year overall survival of only 40%. Innovative approaches to enhance survival while preventing adverse effects are urgently needed. We investigated an innovative therapy approach combining irradiation (RT), decitabine (DEC), and abacavir (ABC) in a patient-derived orthotopic SHH/TP53-mut and Group 3 MB mouse model. MB-bearing mice were treated with DEC, ABC and RT. Mouse survival, tumor growth (BLI, MRT) tumor histology (H/E), proliferation (Ki-67), and endothelial (CD31) staining were analyzed. Gene expression was examined by microarray and RT-PCR (Ki-67, VEGF, CD31, CD15, CD133, nestin, CD68, IBA). The RT/DEC/ABC therapy inhibited tumor growth and enhanced mouse survival. Ki-67 decreased in SHH/TP53-mut MBs after RT, DEC, RT/ABC, and RT/DEC/ABC therapy. CD31 was higher in SHH/TP53-mut compared to Group 3 MBs and decreased after RT/DEC/ABC. Microarray analyses showed a therapy-induced downregulation of cell cycle genes. By RT-PCR, no therapy-induced effect on stem cell fraction or immune cell invasion/activation could be shown. We showed for the first time that RT/DEC/ABC therapy improves survival of orthotopic SHH/TP53-mut and Group 3 MB-bearing mice without inducing adverse effects suggesting the potential for an adjuvant application of this multimodal therapy approach in the human clinic.

Nitrogen-containing atoms in their core structures have been exclusive building blocks in drug discovery and development. One of the most significant and well-known heterocycles is the 1,3,4-thidiazole nucleus, which is found in a wide range of natural products and therapeutic agents. In the present work, certain tris-1,3,4-thiadiazole derivatives (6, 7) were synthesized through a multi-step synthesis approach. All synthesized compounds were characterized using different spectroscopic tools. Previously, thiadiazole compounds as anti-Toxoplasma gondii agents have been conducted and reported in vitro. However, this is the first study to test the anti-Toxoplasma gondii activity of manufactured molecular hybrids thiadiazole in an infected mouse model with the acute RH strain of T. gondii. All the observed results demonstrated compound (7)’s powerful activity, with a considerable reduction in the parasite count reaching 82.6% in brain tissues, followed by liver and spleen tissues (65.35 and 64.81%, respectively). Inflammatory and anti-inflammatory cytokines assessments proved that Compound 7 possesses potent antiparasitic effect. Furthermore, docking tests against TgCDPK1 and ROP18 kinase (two major enzymes involved in parasite invasion and egression) demonstrated compound 7’s higher potency compared to compound 6 and megazol. According to the mentioned results, tris-1,3,4-thiadiazole derivatives under test can be employed as potent antiparasitic agents against the acute RH strain of T. gondii.

One of the major concerns for all in vivo experiments is intra- and inter-subject variability, which can be a great source of inaccuracy. The aim of this study is, therefore, to estimate the ability of parallel vs. cross-over design studies in order to describe the relative pharmacokinetic performance of the studied drug formulations. We analyzed the data from a drug development program that examined the performance of innovative abiraterone acetate formulations against the identical reference product in three stages. In stages 1–3, groups A–F were dosed with the reference product once in a parallel manner. Stage 4 was performed to evaluate the intra-individual variability (IIV) by repeated administration of the reference product to the same animals. Although the geometric mean (90% CI) values of abiraterone AUClast in groups A–F were similar to the IIV group (24.36 (23.79–41.00) vs. 26.29 (20.56–47.00) mg/mL·min·g), the results generated in the isolated parallel groups provided imprecise estimates of the true AUClast values ranging from 9.62 to 44.62 mg/mL·min·g due to chance. Notably, in 4 out of 15 possible pair comparisons between the parallel groups, the confidence intervals did not include 100%, which is the true ratio for all comparisons tested after identical formulation administration to all groups. A cross-over design can significantly improve the methodology in short-term comparative pre-clinical pharmacokinetic studies, and can provide more precise and accurate results in comparison to more traditional pre-clinical study designs.

Natural flavonoids, in addition to some of their synthetic derivatives, are recognized for their remarkable medicinal properties. The present study was designed to investigate the in vitro antioxidant and in vivo antistress effect of synthetic flavonoids (flavones and flavonols) in mice, where stress was induced by injecting acetic acid and physically through swimming immobilization. Among the synthesized flavones (F1–F6) and flavonols (OF1–OF6), the mono para substituted methoxy containing F3 and OF3 exhibited maximum scavenging potential against DPPH (2,2-diphenyl-1-picrylhydrazyl) with IC50 of 31.46 ± 1.46 μg/mL and 25.54 ± 1.21 μg/mL, respectively. Minimum antioxidant potential was observed for F6 and OF6 with IC50 values of 174.24 ± 2.71 μg/mL and 122.33 ± 1.98 μg/mL, respectively, in comparison with tocopherol. The ABTS scavenging activity of all the synthesized flavones and flavonols were significantly higher than observed with DPPH assay, indicating their potency as good antioxidants and the effectiveness of ABTS (2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonate) assay in evaluating antioxidant potentials of chemical substances. The flavonoids-treated animals showed a significant (* p < 0.05, ** p < 0.01 and *** p < 0.001, n = 8) reduction in the number of writhes and an increase in swimming endurance time. Stressful conditions changed plasma glucose, cholesterol and triglyceride levels, which were used as markers when evaluating stress in animal models. The level of these markers was nearly brought to normal when pre-treated with flavones and flavonols (10 mg/kg) for fifteen days in experimental animals. These compounds also considerably reduced the levels of lipid peroxidation (TBARS: Thiobarbituric acid reactive substances), which was significant (* p < 0.05, ** p < 0.01 and *** p < 0.001, n = 8) compared to the control group. A significant rise in the level of catalase and SOD (super oxide dismutase) was also observed in the treated groups. Diazepam (2 mg/kg) was used as the standard drug. Additionally, the flavonoids markedly altered the weight of the adrenal glands, spleen and brain in stress-induced mice. The findings of the study suggest that these flavonoids could be used as a remedy for stress and are capable of ameliorating diverse physiological and biochemical alterations associated with stressful conditions. However, further experiments are needed to confirm the observed potentials in other animal models, especially in those with a closer resemblance to humans. Toxicological evaluations are also equally important.

Cyclosporine A (CsA) is an immunosuppressant agent. Two niosomal formulations of CsA, FTS and FSB were formulated. Both formulations were studied in terms of size, polydispersity index (PDI), morphology and entrapment efficacy etc. Niosomal formulations FTS and FSB and plain aqueous dispersion were given to three assemblies of Albino rabbits (n=8 per group). CsA levels in plasma were determined at appropriate time intervals and pharmacokinetic parameters were evaluated. The percentage entrapment efficiencies of FTS and FSB were found to be 77.29 and 89.31% for respectively. Transmission electron microscopy results indicated spherical nature of niosomes. In vivo studies demonstrated that the value of Cmax for the FSB formulation was 1968.419 ng/ml and it was 1498.951 ng/ml and 1073.87 ng/ml for FTS and aqueous dispersion of CsA (control) respectively. It was found that both niosomal formulation FTS & FSB presented significantly high (p<0.05) Cmax, AUC0-t, MRT 0-inf and half-life (t1/2) as associated to plain drug dispersion. However niosomal formulation FSB exhibited better in-vivo performance as compared to FTS. It was established that CsA can be successfully entrapped in niosomes. So niosomes are promising vehicle for CsA oral delivery. [ABSTRACT FROM AUTHOR]

In vivo investigations are much more complex than trials conducted in a test tube; the results sometimes aren't as illuminating and could raise more questions than answers. Preclinical data projection into clinical truth is a transcriptional science that remains a compelling trial in drug development. Preclinical in vivo and in vitro education is important in novel drug's non-violent or active growth. Pharmacokinetic and metabolic research is necessary to better understand the chemical and biological effects of medicines and their metabolites. Information produced by such a policy can be used to progress Phase I studies, primarily for anticancer medication. Both living and deceased in vitro models are theoretically excellent preclinical tools for calculating the pharmacological action of counterparts from the same family, such as vinca alkaloids. The animal species most closely linked to humans are chosen based on metabolic patterns. The estimation of the duration of drug action, particularly for medicines with varied metabolic clearances (e.g., benzodiazepines); The empathetic or estimate of medicine relations, i.e., those defined for cyclosporin A and macrolide antibiotics; and Sclarification of the metabolic roots of individual inconsistencies in pharmaceutical action., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Due to excellent biocompatibility, bioactivities, and osteoconductivity, hydroxyapatite (HAp) is considered as one of the most suitable biomaterials for numerous biomedical applications. Herein, HAp was fabricated using a bottom-up approach, i.e., a wet chemical method, and its composites with TiC, h-BN, and ZrO 2 were fabricated by a solid-state reaction method with enhanced mechanical and biological performances. Structural, surface morphology, and mechanical behavior of the fabricated composites were characterized using various characterization techniques. Furthermore, transmission electron microscopy study revealed a randomly oriented rod-like morphology, with the length and width of these nanorods ranging from 78 to 122 and from 9 to 13 nm. Moreover, the mechanical characterizations of the composite HZBT4 (80HAp-10TiC-5h-BN-5ZrO 2 ) reveal a very high compressive strength (246 MPa), which is comparable to that of the steel (250 MPa), fracture toughness (14.78 MPa m 1/2 ), and Young's modulus (1.02 GPa). In order to check the biocompatibility of the composites, numerous biological tests were also performed on different body organs of healthy adult Sprague-Dawley rats. This study suggests that the composite HZBT4 could not reveal any significant influence on the hematological, serum biochemical, and histopathological parameters. Hence, the fabricated composite can be used for several biological applications, such as bone implants, bone grafting, and bone regeneration.

Solid oral dosage forms are mostly preferred in pharmaceutical formulation development due to patient convenience, ease of product handling, high throughput, low manufacturing costs, with good physical and chemical stability. However, 70% of drug candidates have poor water solubility leading to compromised bioavailability. This phenomenon occurs because drug molecules are often absorbed after dissolving in gastrointestinal fluid. To address this limitation, delivery systems designed to improve the pharmacokinetics of drug molecules are needed to allow controlled release and target-specific delivery. Among various strategies, amorphous formulations show significantly high potential, particularly for molecules with solubility-limited dissolution rates. The ease of drug molecules to amorphized is known as their glass-forming ability (GFA). Specifically, drug molecules categorized into class III based on the Taylor classification have a low recrystallization tendency and high GFA after cooling, with substantial "glass stability" when heated. In the last decades, the application of mesoporous silica nanoparticles (MSNs) as drug delivery systems (DDS) has gained significant attention in various investigations and the pharmaceutical industry. This is attributed to the unique physicochemical properties of MSNs, including high loading capacity, recrystallization inhibition, excellent biocompatibility, and easy functionalization. Therefore, this study aimed to discuss the current state of good glass former drug loaded mesoporous silica and shows its impact on the pharmaceutical properties including dissolution and physical stability, along with in vivo study. The results show the importance of determining whether mesoporous structures are needed in amorphous formulations to improve the pharmaceutical properties of drug with a favorable GFA., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Budiman et al.)

Introduction: Rheumatoid arthritis (RA) is a chronic autoimmune disease with unknown cause. It mainly affects joints and, without proper treatment, negatively impacts their movement, causes painful deformities, and reduces the patients' quality of life. Current treatment options consist of various types of disease-modifying antirheumatic drugs (DMARDs), however 20-30% of patients are partially resistant to them. Therefore, development of new drugs is necessary. Possible option are compounds exhibiting their action via endocannabinoid system, which plays an important role in pain and inflammation modulation. One such compound - cannabidiol (CBD) has already been shown to attenuate synovitis in animal model of RA in in vivo studies. However, it has low bioavailability due to its low water solubility and lipophilicity. This issue can be addressed by preparation of a lipid containing formulation targeting lymphatic system, another route of absorption in the body. Materials and Methods: CBD-containing emulsion was prepared by high-shear homogenization and its droplet size distribution was analysed by optical microscopy. The relative oral bioavailability compared to oil solution as well as total availability of CBD were assessed in a cross-over study in rats and absorption of CBD via lymphatic system was observed. The effect of CBD on the animal model of RA was determined. Results: Compared to oil solution, the emulsion exhibited higher absolute oral bioavailability. Significant lymphatic transport of CBD was observed in all formulations and the concentrations in lymph were calculated. The therapeutic effect of CBD on RA was confirmed as an improvement in clinical symptoms as well as morphological signs of disease activity were observed during the study. Conclusion: In this work, we prepared a simple stable emulsion formulation, determined the pharmacokinetic parameters of CBD and calculated its absolute bioavailability in rats. Moreover, we successfully tested the pharmaceutical application of such a formulation and demonstrated the positive effect of CBD in an animal model of RA.

The present study was aimed to investigate the in vitro and in vivo studies with H. rigens extracts. The results shows that the, lifespan of H. rigens increases of 103% and 132% from the initial level at dose levels 50 mg/kg body weight. Generally all the extracts exhibited higher levels of dose dependent reducing power, radical scavenging potential and metal chelating ability when compared with the respective standards. The in vivo lipid peroxidation level (TBARS) as well as the activities of certain antioxidative enzymes (SOD, CAT, GSH and GPx) were assessed in male wister albino rats treated with H. rigens extracts. Tumor growth normally affects the haematological picture, resulting in changes in various parameters such as white blood cell count (WBC), red blood cell count (RBC), haemoglobin content (Hb) and lymphocyte, neutrophil and monocyte counts. However, the maximum activity was found in the seed extract (precipitate portion) that was comparable with the standard anti-inflammatory drug diclofenac. The extracts were not imposing any metabolic stress in the treated animals. The overall results indicate the potential of H. rigens in cancer therapy. [ABSTRACT FROM AUTHOR]

The prevailing studies were carried out to formulate and optimize the quetiapine transdermal matrix patch by the usage of Box–Behnken design for ameliorated bioavailability when contrasted with conventional drug delivery. The Box–Behnken design with three-level and three-factor was utilized to explore the intermingle impact of critical attributes on tensile strength, in vitro drug release, and flux. Optimized formulation was characterized for Fourier transform infrared, differential scanning calorimetry, in vivo pharmacokinetics, and skin irritation along with stability studies. The inference of the finalized batch (F14) depicted the flux of 51.81 ± 0.32 µg/h/cm2, TS of 6.46 ± 0.56 MPa, and the % drug release after 20 h of 82.98 ± 1.48% with no remarkable variation even after 6 months stability studies. Correlation between predicted and the observed values of the dependent variables was very closer. Optimized quetiapine transdermal patch did not exert any symptoms of skin irritation. The bioavailability of quetiapine was enhanced almost 4.59 times after topical delivery when contrasted with the conventional dosage form. The outputs of the research work divulged that the developed matrix patch of quetiapine for transdermal drug delivery can be a propitious opportunity that affords effective treatment of schizophrenia. The oral route is not suitable for the drugs having extensive first-pass metabolism which leads to reduced bioavailability. For the parenteral route, invasiveness causes the patient noncompliance while sterility contributes to the cost factor. Moreover, the treatment of schizophrenic patients is a challenging task for caregivers and doctors. Hence, the transdermal patch of quetiapine was developed to bypass the biotransformation of drugs and thereby to enhance the bioavailability as well as to provide sustained drug delivery which ultimately reduces the dosage frequency. [ABSTRACT FROM AUTHOR]

Aim: To assess in vivo the immediate and delayed disinfecting efficacy of erbium, chromium:yttrium scandium gallium garnet (Er,Cr:YSGG) laser against Enterococcus faecalis at the output powers 1, 1.5, and 2 W with a 20 s period of time. Materials and Methods: Study criteria include 45 single-rooted teeth. Patients were randomly divided into three groups (gps) (n = 15/gp) according to the output powers selected in this study. After access opening, first microbiological samples (S1) were collected immediately before Er,Cr:YSGG laser treatment. Second microbiological samples (S2) were taken immediately after instrumentation and laser disinfection at the output powers 1, 1.5, and 2 W with 20 s period of exposure time. Third samples (S3) were collected after 1 week of irradiation. The obtained samples were transferred to an agar plate and incubated for 48 h at 37°C. The colonies of E. faecalis formed were then counted. The collected data were analyzed using one-way analysis of variance (ANOVA) analysis and Duncan multiple range tests at level P =0.05. Results: The result showed no significant difference between number of bacteria before laser treatment and after 1 week of laser application at the output power 1 W. However, significant difference was detected immediately after laser application. At 2 W a significant difference was observed between number of bacteria before laser treatment and after treatment with no difference between number of bacteria immediately after treatment and after 1 week of irradiation. Conclusion: Er,Cr:YSGG laser at high output power (2 W) detected a maximum reduction of E. faecalis in the infected root canals, but bacteria were not eliminated completely. [ABSTRACT FROM AUTHOR]

Engineered nanoparticles have provided a basis for innovative agricultural applications, specifically in plant disease management. In this interdisciplinary study, by conducting comparison studies using macroscale magnesium oxide (mMgO), we evaluated the fungicidal activity of MgO nanoparticles (nMgO) against soilborne Phytophthora nicotianae and Thielaviopsis basicola for the first time under laboratory and greenhouse conditions. In vitro studies revealed that nMgO could inhibit fungal growth and spore germination and impede sporangium development more efficiently than could macroscale equivalents. Indispensably, direct contact interactions between nanoparticles and fungal cells or nanoparticle adsorption thereof were found, subsequently provoking cell morphological changes by scanning electron microscopy/energy-dispersive spectrometry (SEM/EDS) and transmission electron microscopy (TEM). In addition, the disturbance of the zeta potential and accumulation of various modes of oxidative stress in nMgO-exposed fungal cells accounted for the underlying antifungal mechanism. In the greenhouse, approximately 36.58 and 42.35% decreases in tobacco black shank and black root rot disease, respectively, could testify to the efficiency by which 500 μg/ml of nMgO suppressed fungal invasion through root irrigation (the final control efficiency reached 50.20 and 62.10%, respectively) when compared with that of untreated controls or mMgO. This study will extend our understanding of nanoparticles potentially being adopted as an effective strategy for preventing diversified fungal infections in agricultural fields.

Purpose: The present study was conducted to determine whether biomechanical and histologic parameters would differ between implant surfaces blasted with bioactive ceramic resorbable media (biologic blasting) and blasted with alumina and acid-etched. Materials and Methods: Fourteen beagle dogs were used. Eight animals received two implants of each surface per limb, and each limb provided samples that remained in vivo for 3 and 6 weeks. The other six animals received two implants of each surface in one limb, which remained in vivo for 1 week. After euthanization, half of the implants were subjected to torque-to-interface fracture; the other half of the implants were processed for nondecalcified histology to calculate bone-to-implant contact (BIC) and bone area fraction occupancy (BAFO). Statistical analysis was performed with the Kruskal-Wallis test (95% level of significance). Results: While no significant differences were observed for BIC and BAFO between surfaces at all three times in vivo and for torque levels at 1 and 3 weeks, a significantly higher torque was observed for the biologic blasting group after 6 weeks in vivo. Bone morphology was similar between groups at all times. Conclusion: A significant increase in early biomechanical fixation was observed for implants with the biologic blasting surface. However, no significant differences were observed for BIC and BAFO at any observation point. [ABSTRACT FROM AUTHOR]

Abstract During the present time, anti-microbial features of copper (Cu) and zinc oxide (ZnO) nanoparticles (NPs) are extensively used to combat the growth of pathogenic microbes. CuNPs and ZnONPs are recurrently used in cosmetics, medicine and food additives, and their potential for toxic impacts on human and ecosystem is of high concern. In this study, the fate and toxicity of 16- to 96-nm-ranged biosynthesized copper (Bio-CuNPs) and zinc oxide (Bio-ZnONPs) was assessed in male Wistar rats. In vivo exposures of the two nanoparticles are achieved through two different administration routes namely, intraperitoneal (i/p) and intravenous (i/v) injections. The three different concentrations, no observable adverse effect concentration (NOAEC), inhibitory concentration (IC50) and total lethal concentration (TLC), were appraised at the dose range of 6.1 to 19.82 μg/kg and 11.14 to 30.3 μg/kg for Bio-CuNPs and Bio-ZnONPs respectively, for both i/p and i/v routes on 14th and 28th day of observation. These dose ranges are considered based on the previous study of antibacterial dose on multidrug-resistant pathogenic bacteria. In this study, we investigated the toxic effect of Bio-CuNPs and Bio-ZnONPs on animal behaviour, animal mass, haematologic indices, organ indices and histopathology of liver, spleen, kidney and brain organs. We found that i/v and i/p administration of Bio-ZnONPs in three different doses did not cause mortality and body weight was slightly reduced up to second week of administration compared with the vehicle control group. At the dose ranges of 11–16 μg/kg (i/v) and 24–30 μg/kg (i/p), no significant changes were observed in the serum creatinine level as well as serum ALT, serum AST level and ALP level which were 40.7 mg/dl, 37.9 IU/L and 82.4 IU/L normal as compared to vehicle control on 14th and 28th day of observation. These findings are confirmed in liver, kidney and spleen indices and histopathology studies. Furthermore, liver and kidney injury occurred when the concentrations of Bio-CuNPs were at 9.5 μg/kg (IC50) and 11.7 μg/kg (TLC) for i/v route of administration. Similarly, increase in serum ALT (67.7 mg/dl), AST level (70 IU/L) and ALP (128 IU/L) was also observed. And the body weight was significantly lower than in the control group after 14th day, and there were statistically significant differences observed by this route; interestingly, the toxicity of Bio-CuNPs in serum is prolonged (up to 28th day). Effect of Bio-CuNPs through i/p route was considerably low as compare to the control. Results of the present study revealed that Bio-ZnONPs have no effect on kidney and liver function biomarkers (both i/v and i/p) as compared to Bio-CuNPs.Graphical abstractAs shown in graphical abstract (Fig. 1), our aim is to assess the toxicity of Bio-CuNPs and Bio-ZnONPs through in vivo protocol. According to Kahru and Dubourguier reviews, AgNPs, CuNPs and ZnONPs have been historically used as biocides, for preventing the growth of microorganisms and algae (Kahru and Dubourguier 2010). Therefore, as like pesticides, nanomaterials should be monitored for their toxic response toward non-target species, including humans and animals. To gain a better understanding whether the accidental release of metal-containing NPs may pose a threat to non-target species, assessing of toxic effect is indispensable.The ‘non-target organism’ is an organism which will be exposed to NPs after their incidental release into the environment.

The current study aimed to develop a luteolin gastric floating microsponge for targeting Helicobacter pylori. The microsponge formulations were prepared by a quasi-emulsion method, and then evaluated for various physicochemical variables. The best microsponge was further assessed for drug-polymer interactions, surface morphology, in vivo floating, and in vitro anti H. pylori activity. The formulation which exhibited comparatively good production yield (64.45% ± 0.83), high entrapment efficiency (67.33% ± 3.79), prolonged in vitro floating time (>8 h), and sustained in-vitro drug release was selected as the best microsponge. The SEM study revealed that the best microsponge was spherical in shape and has a porous surface with interconnecting channels. DSC and XRD studies demonstrated the dispersion of luteolin in the polymeric matrix of the microsponge. Ultrasonography confirmed that the best microsponge could in the rat stomach for 4 h. The in vitro MIC results indicate that the anti H. pylori activity of the best microsponge was almost doubled and more sustained compared to pure luteolin. To conclude, it can be said that the developed luteolin gastric floating microsponge could be a better option to effectively eradicate H. pylori infections and the histopathological and pharmacodynamic assessments of our best microsponge can be expected to provide a rewarding outcome.

The aim of this study was to evaluate the therapeutic effects of chlorogenic acid (CGA) in rats with advanced alcoholic steatohepatitis. The rats were fed on a high-fat diet and gavaged with ethanol (4 g/kg) for 8 weeks. The livers of ethanol-treated rats showed steatosis; necrosis and mononuclear infiltration; and significant upregulation of the mRNA expression of the prooxidant (Cyp2e1, iNos), lipogenic (Srebp1, Acc), proinflammatory (Tlr4, Nf-κb, TnfA, Il-1B, and Il-6), and profibrogenic (TgfB, Col1, VegfA) genes. Simultaneously, a downregulation of level of Sod and Nrf2 was observed, which was accompanied by increased serum transaminase, TnfA, and serum and liver triglycerides levels. CGA administration (40 and 80 mg/kg, 8 weeks) to ethanol-fed group reduced the liver expression levels of Cyp2e1 and iNos, whereas it markedly enhanced the expression of Sod, Nrf2, and Ho-1. CGA at both doses downregulated the expressions of lipogenic, proinflammatory, and profibrogenic genes, while the expression of Tlr4 was lowered only after the higher dose of CGA. The higher dose of CGA efficiently prevented the progression of alcohol-induced steatosis and reduced inflammation through regulation of the expression of genes encoding the proteins involved in the Tlr4/Nf-κB signaling pathway and fibrosis. The study revealed hepatoprotective and anti-inflammatory effects of CGA through the regulation of expression of genes encoding Cyp2e1/Nrf2 involved in oxidative stress modulation. These results demonstrate CGA as a therapeutic candidate for the prevention and treatment of alcoholic steatohepatitis.

Degradable heart valves based on in situ tissue regeneration have been proposed as potentially durable and non-thrombogenic prosthetic alternatives. We evaluated the acute in vivo function, microstructure, mechanics, and thromboresistance of a stentless biodegradable tissue-engineered heart valve (TEHV) in the tricuspid position. Biomimetic stentless tricuspid valves were fabricated with poly(carbonate urethane)urea (PCUU) by double-component deposition (DCD) processing to mimic native valve mechanics and geometry. Five swine then underwent 24-h TEHV implantation in the tricuspid position. Echocardiography demonstrated good leaflet motion and no prolapse and trace to mild regurgitation in all but one animal. Histology revealed patches of proteinaceous deposits with no cellular uptake. SEM demonstrated retained scaffold microarchitecture with proteinaceous deposits but no platelet aggregation or thrombosis. Explanted PCUU leaflet thickness and mechanical anisotropy were comparable with native tricuspid leaflets. Bioinspired, elastomeric, stentless TEHVs fabricated by DCD were readily implantable and demonstrated good acute function in the tricuspid position. [ABSTRACT FROM AUTHOR]

Wild apple fruit (Malus sylvestris (L.) Mill., Rosaceae) represents a valuable source of biologically active compounds, such as polyphenols and fruit acids. These compounds have been found to have a positive effect on human health and also have a beneficial effect on the skin by improving its overall condition and appearance. In the present study, the efficacy of the application of oil-in-water emulsions containing 12% and 15% of wild apple fruit extract was examined on healthy volunteers. During a 28-day long-term study, biophysical skin parameters (electrical capacitance (EC), transepidermal water loss (TEWL), pH, erythema index (EI), and melanin index (MI)) were monitored. As a result, a significant increase in EC and decrease in EI and MI parameters were observed after both 14 and 28 days of application, where the emulsion containing 15% of the wild apple fruit extract was more efficient than the emulsion containing 12% of the wild apple fruit extract. On the other hand, no significant changes in TEWL and pH values were observed. Given their beneficial effects on the skin (increased skin hydration, reduced skin irritation, good skin lightening potential), the tested emulsions might have potential application in the formulation of cosmetic products for the treatment of dry and irritated skin, as well as products intended to reduce skin hyperpigmentation. [ABSTRACT FROM AUTHOR]

Aim: This work aimed to encapsulate lamivudine in liposomes for targeted delivery to HIV reservoirs and thereby reduce its side effects. Methods: The lamivudine liposomes were prepared by thin film hydration method using 32 factorial design and characterised for vesicle size, % drug entrapment efficiency, polydispersity index etc. Optimisation by graphical and numerical methods was carried out by fixing minimum and maximum limits for each response. In vivo plasma and tissue distribution of plain lamivudine and lamivudine encapsulated optimised liposomes were compared in rats. Results: The optimised liposomes displayed vesicle size 276.20 ± 13.36 nm, percent entrapment 60.20 ± 2.86% and PDI 0.291 ± 0.053. Compared to plain lamivudine, the liposomes were rapidly cleared from the plasma and displayed 10.97 ± 0.72 and 1.38 ± 0.52 fold accumulation in liver and spleen tissues respectively. Conclusions: Lamivudine encapsulated in liposomes remains in the body for a longer period of time with well distribution in tissues. [ABSTRACT FROM AUTHOR]

Biomaterials designed for tissue engineering should be nontoxic and nonimmunogenic and should achieve their intended functions. Treated dentin matrix (TDM), a bioactive extracellular matrix, is promising for tooth regeneration. However, the effect of sterilization on the surface properties of allogenous TDM in the animal model is unclear. The biological characteristics and influences of dental pulp stem cells (DPSCs) with autoclaved TDM (a-TDM) were studied using scanning electron microscopy, immunofluorescence microscopy, immunohistochemistry, and reverse transcription polymerase chain reaction in vitro. In addition, a-TDM was implanted in a mouse model for 6 weeks and was a substrate with DPSCs for tooth reconstruction in a goat animal model in vivo. Allogenous a-TDM induced and supported DPSCs to develop new dentin pulp–like tissues, enamel dental pulp, and cementum periodontal complexes. Immunohistochemistry data showed that the markers dentin sialoprotein, βⅢ-tubulin, dentin matrix protein 1, amelogenin, VIII factors, type I collagen, cementum-derived attachment protein, and scleraxis transcription factor were positive stained in toothlike tissue. Allogenous a-TDM served as an effective scaffold enabling DPSCs to proliferate and differentiate into a broad array of resident cells including odontoblasts, fibroblasts, vascular cells, and neural endings. Allogenous a-TDM with DPSCs can provide an ideal biomaterial for optimizing the regeneration of tooth material. [ABSTRACT FROM AUTHOR]

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The growing applications of nanocelluloses in the fields of advanced nanocomposites, electronics, and medical devices necessitate investigation of their potential adverse effects on human health. The lungs are the primary and the most important route for the entry of nanocelluloses into the human body in occupational settings. However, data on the pulmonary toxicity of cellulose nanofibrils (CNFs) and its molecular mechanism are limited. This study investigated the pulmonary toxicity of CNFs and its genomic expression using the RNA sequencing approach. Female C57BL/6 mice were administered CNFs at 50 μg/mouse by oropharyngeal aspiration. Samples were collected at 3 and 14 days after exposure to CNFs (DAEC). At three DAEC, the microscopic sections of lungs revealed a significant inflammatory response. In terms of gene expression alterations, 94 genes were up-regulated, and 107 genes were down-regulated. Most of these differentially expressed genes were involved in the inflammatory and immune responses, including chemokines, NK cells, killer cell lectin-like receptors, CD antigens, T cell-specific GTPases, immunity-related GTPase family M members, and interferon-induced proteins encoding genes. However, only 9 and 26 genes at 14 DAEC were significantly up- and down-regulated, respectively. The pathological analysis of lung sections and the analysis of sequencing data suggested that the homeostasis of mice lungs was restored at 14 DAEC. The findings of this study provide insights into the pulmonary toxicity, and underlying toxicological mechanisms, caused by exposure to CNFs, and are useful for the assessment of the potential toxicity of nanocelluloses. [ABSTRACT FROM AUTHOR]

Porphyridium cruentum, known as red microalga, is able to produce extra-cellular polysaccharides (EPs) that have beneficial health effects. In this study, the effect of P. cruentum biomass and EPs with various doses was studied in streptozotocin (STZ)-induced diabetic rats to determine their antihyperglycemic activity and its potential mechanism. The doses of biomass were 600, 1200 and 1800 mg/kg body weight (BW) while the doses of EPs were 150, 300 and 450 mg/kg BW. P. cruentum biomass and EPs could slightly reduce food intake in STZ-diabetic rats as compared with diabetic group. After a 14-day treatment, P. cruentum EPs could decrease blood glucose levels of STZ-induced diabetic rats while P. cruentum biomass at all doses could not. P. cruentum EPs was as effective as glibenclamide in lowering blood glucose levels of diabetic rats. In addition, P. cruentum EPs could significantly increase (p < 0.05) Langerhans islets areas, the number of β-cells and the height of intestinal villi. Treatment with 450 mg/kg BW of EPs resulted in the most effective antihyperglycemic activity. Thus, P. cruentum has the potential to resolve hyperglycemic and diabetic problems. • Porphyridium cruentum was cultured using Guillard medium. • Porphyridium cruentum biomass and extra-cellular polysaccharides were obtained using sedimentation and ethanol precipitation method, respectively. • The antihyperglycemic effect of Porphyridium cruentum biomass and extra-cellular polysaccharides was studied in streptozotocin-induced diabetic rats. • Porphyridium cruentum extra-polysaccharides could significantly reduce blood glucose levels, increase Langerhans islets areas, the number of β-cells and the height of intestinal villi. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the function of circ_0005576 in colorectal cancer (CRC) progression. Patients and Methods: Circ_0005576 expression in CRC patients was detected by quantitative real-time polymerase chain reaction (qRT-PCR) and in situ hybridization (ISH). CRC cells were transfected using Lipofectamine 2000 reagent. CRC cell proliferation was researched by Cell Counting Kit-8 (CCK-8) assay and 5-ethynyl-2-deoxy-uridine (EdU) incorporation experiment. Cell cycle and apoptosis were determined by flow cytometry analysis. Luciferase reporter assay was used to explore the relationship between circ_0005576 and miR-874 or between miR-874 and CDK8. qRT-PCR and Western blot were used to detect circ_0005576, miR-874, and CDK8 expression. In vivo experiments were performed using nude mice. CDK8 and Ki67 expression in xenograft tumors was investigated by immunohistochemistry. Tunel assay was conducted to analyze the apoptosis of xenograft tumors. Results: Circ_0005576 expression was up-regulated in CRC, which was associated with tumor progression (P < 0.05 or P < 0.01). Circ_0005576 knockdown in CRC cells reduced proliferation, induced apoptosis, increased cells in the G1 phase, and decreased cells in the S phase (P < 0.01 or P < 0.001). Circ_0005576 promoted CDK8 expression via sponging miR-874. miR-874 knockdown and CDK8 overexpression significantly reversed the inhibitory effect of circ_0005576 knockdown on CRC cells malignant phenotype (P < 0.05 or P < 0.01). Circ_0005576 knockdown inhibited tumor growth in vivo (P < 0.01). Circ_0005576 knockdown reduced CDK8, Ki67 expression, and enhanced apoptosis in xenograft tumors. Conclusion: Circ_0005576 promoted malignant progression through the miR-874/CDK8 axis in CRC. [ABSTRACT FROM AUTHOR]

The study focuses on the in vitro and in vivo evaluation of the developed gentamicin sulphate (GS)-loaded poly lactic-co-glycolic acid (PLGA) nanoparticle (PNP)-based pullulan film (PNP-F). Sterilization being an essential pre-requisite for the dosage form was carried out using ethylene oxide. Post-sterilization, PNP-F was evaluated for mechanical properties, percentage drug loading, antimicrobial effectiveness study, test for sterility and in vitro dissolution study using Strat-M® membrane. In vitro dissolution study revealed that GS gradually released from PNP-F and the highest cumulative percentage drug release was found to be 86.76 ± 0.03% at 192 h. Wound healing assay was performed to study the effect of PNP-F over migratory potential of dermal fibroblast cells (NIH-3T3) in the presence of micro-organisms, Pseudomonas aeruginosa (PA) and Staphylococcus aureus (SA). PNP-F inhibited the growth of PA and SA, allowing the growth of fibroblast cells indicating its suitability for application. In vivo study of surgical site was performed by superficial incision model in Wistar rats. Measurement of in vivo incision healing confirmed faster wound healing in the incision which received PNP-F compared to marketed cream containing GS. [ABSTRACT FROM AUTHOR]

The purpose of this study was to describe the distinct regional distribution patterns of expression of the α7 and α4 subunits of nicotinic acetylcholine receptors (nAChRs) and their left‐right lateralisation in the rat hippocampus during the first 2 weeks of postnatal (P) development. Eighteen male pups were randomly divided into three groups: P0, P7, and P14. After removing the newborn brains, real‐time polymerase chain reaction, western blot, and immunohistochemistry techniques were used to evaluate expression of the receptors. Results indicated that the expression profile of these receptors were time‐ and spatially dependent. A significant increase was observed in the distribution of α7 and α4 nAChR subunits in the developing rat hippocampus from P0 to P7 (p <.001); however, there was a significant decrease from P7 to P14 (p <.05). As a spatial effect, the highest optical density (OD) was observed in the CA3 and CA2 regions of the hippocampus, while the lowest OD was in the dentate gyrus. Moreover, the distribution of α7 and α4 nAChR subunits in the left hippocampus was significantly higher than their counterparts in the right (p <.05). From these data, the expression patterns of α7 and α4 nAChR subunits exhibited left‐right asymmetry in the developing rat hippocampus. [ABSTRACT FROM AUTHOR]

Aim: The aim of this in vivo study was to evaluate the utility of bone graft gel containing hydroxyapatite nanoparticles in promoting bone regeneration in a mouse model of vertical bone augmentation. Materials and Methods: Gel implants with high and low viscosity were compared for their bone regenerating ability. Bone formation at 12 weeks and material reactions were observed radiographically and histologically. Results: Radiological analysis showed that most bone augmentation area in the graft material occurred in the fourth week after surgery regardless of the viscosity of the gel, and then gradually decreased. The volume of bone augmentation area was greater in the high-viscosity implant group than in the low-viscosity implant group at all time points, the difference was statistically significant at 8 and 12 weeks. Histological evaluation indicated that the new bone area was significantly smaller in the high-viscosity implant group. Conclusion: Gelatinous graft materials containing hydroxyapatite nanoparticles were confirmed to be useful in vertical bone augmentation. [ABSTRACT FROM AUTHOR]

Sesquiterpene lactones, a vast range of terpenoids isolated from Asteraceae species, exhibit a broad spectrum of biological effects and several of them are already commercially available, such as artemisinin. Here the most recent and impactful results of in vivo, preclinical and clinical studies involving a selection of ten sesquiterpene lactones (alantolactone, arglabin, costunolide, cynaropicrin, helenalin, inuviscolide, lactucin, parthenolide, thapsigargin and tomentosin) are presented and discussed, along with some of their derivatives. In the authors' opinion, these compounds have been neglected compared to others, although they could be of great use in developing important new pharmaceutical products. The selected sesquiterpenes show promising anticancer and anti-inflammatory effects, acting on various targets. Moreover, they exhibit antifungal, anxiolytic, analgesic, and antitrypanosomal activities. Several studies discussed here clearly show the potential that some of them have in combination therapy, as sensitizing agents to facilitate and enhance the action of drugs in clinical use. The derivatives show greater pharmacological value since they have better pharmacokinetics, stability, potency, and/or selectivity. All these natural terpenoids and their derivatives exhibit properties that invite further research by the scientific community. [ABSTRACT FROM AUTHOR]

Engineered nanoparticles have provided a basis for innovative agricultural applications, specifically in plant disease management. In this interdisciplinary study, by conducting comparison studies using macroscale magnesium oxide (mMgO), we evaluated the fungicidal activity of MgO nanoparticles (nMgO) against soilborne Phytophthora nicotianae and Thielaviopsis basicola for the first time under laboratory and greenhouse conditions. In vitro studies revealed that nMgO could inhibit fungal growth and spore germination and impede sporangium development more efficiently than could macroscale equivalents. Indispensably, direct contact interactions between nanoparticles and fungal cells or nanoparticle adsorption thereof were found, subsequently provoking cell morphological changes by scanning electron microscopy/energy-dispersive spectrometry (SEM/EDS) and transmission electron microscopy (TEM). In addition, the disturbance of the zeta potential and accumulation of various modes of oxidative stress in nMgO-exposed fungal cells accounted for the underlying antifungal mechanism. In the greenhouse, approximately 36.58 and 42.35% decreases in tobacco black shank and black root rot disease, respectively, could testify to the efficiency by which 500 μg/ml of nMgO suppressed fungal invasion through root irrigation (the final control efficiency reached 50.20 and 62.10%, respectively) when compared with that of untreated controls or mMgO. This study will extend our understanding of nanoparticles potentially being adopted as an effective strategy for preventing diversified fungal infections in agricultural fields. [ABSTRACT FROM AUTHOR]