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Background: Stem/progenitor cell‐mediated pulpal regeneration could represent a promising therapeutic alternative in the field of clinical endodontics. Aim: The present study aimed to systematically assess and meta‐analyse dental pulpal tissue regeneration, pulpal vitality and apical healing after the transplantation of stem/progenitor cells versus no transplantation. Data sources: MEDLINE, Cochrane CENTRAL and EMBASE were searched up to January 2019 for animal experiments and human trials evaluating the pulpal transplantation of stem/progenitor cells. Cross‐referencing and hand search were additionally performed. Study eligibility criteria, participants and interventions: Based on randomized controlled clinical trials (RCTs) or controlled clinical trials (CCTs), conducted in animals or humans, the effect of the transplantation of stem/progenitor cells compared to no transplantation on pulpal tissue regeneration, pulpal vitality and apical healing was examined. Study appraisal and synthesis methods: The primary outcome was histologically determined pulpal tissue regeneration, whilst pulpal vitality and apical healing were secondary outcomes. The SYstematic Review Centre for Laboratory animal Experimentation (SYRCLE) guidelines and the revised Cochrane risk of bias tool (RoB 2.0) were used for risk‐of‐bias assessment. Pooled standardized differences in means (SDM) and 95% confidence intervals (95% CI) were calculated using random‐effects meta‐analyses. Results: From 2834 identified articles, eight animal experiments (82 animals with 336 experimental pulpal defects) and one human trial (40 humans with 40 pulpal defects) were included. Risk of bias of most animal studies was high, whilst the human trial revealed 'some concerns'. Stem/progenitor cell‐transplanted pulps demonstrated significantly increased pulpal tissue regeneration compared with controls (SDM [95%CI]: 6.29 [3.78–8.80]). Limitations: Data on pulpal vitality and apical healing were sparse and inconsistent. Heterogeneity across studies was substantial, publication bias was present, and mainly indirect, surrogate outcome measures were applied. The overall strength of evidence was very low. Conclusions and implications of key findings: The transplanation of stem/progenitor cells shows promise for pulp regeneration, whilst clinical routine application is still not in reach. Further investigations, employing a comprehensive set of outcomes including those demonstrating functional pulp regeneration relevant for patient‐centred care, are required. [ABSTRACT FROM AUTHOR]

Abstract: Studies of histone deacetylase (HDAC) inhibitors, novel anticancer drugs, in models of autoimmune diseases, asthma, and inflammatory bowel disease suggest that HDAC inhibitors may also have useful anti-inflammatory effects. Accordingly, in vitro studies relevant to asthma and inflammatory bowel disease were conducted using a selection of HDAC inhibitors: suberoylanilide hydroxamic acid (SAHA, Vorinostat™), and a related branched hydroxamic acid, diamide (1), MGCD0103 and two short chain fatty acid derivatives: sodium butyrate (of use in inflammatory bowel disease) and sodium valproate. The ability of those HDAC inhibitors to modulate antigen- or agonist-induced contraction of isolated guinea pig tracheal rings and colon, agonist-induced contraction of rat colon, and histamine release from rat peritoneal mast cells was examined. Pre-incubation (up to 6 h) with 10–40 µM of SAHA, diamide (1), or MGCD0103 caused significant inhibition of the antigen-induced contraction of sensitised guinea pig tracheal rings as well as inhibition of the contraction induced by histamine, 5-hydroxytryptamine and carbachol (G-protein coupled receptor agonists), while sodium butyrate (1 mM) and sodium valproate (100 µM) were weak inhibitors. Contraction of tracheal rings by sodium fluoride (NaF, a non-selective G-protein activator), KCl and a peroxyl radical generator was blocked by MGCD0103. Additionally, MGCD0103 significantly inhibited antigen-induced histamine release from IgE antibody-sensitised rat peritoneal mast cells, and NaF-induced histamine release, as well as inhibiting NaF-induced colon contraction. Those various effects appear to involve modulation of cell signaling, probably involving G-protein coupled pathways, and further support the development of HDAC inhibitors as anti-inflammatory agents. [Copyright &y& Elsevier]

Abstract: The immunosuppressants cyclosporin A (CsA) and tacrolimus (FK506) inhibit the activation by antigen of T-lymphocytes as well as mast cells. The mechanism of their action on mast cells has yet to be elucidated. We, therefore, assessed their effect on antigen-induced histamine and β-hexosaminidase release, membrane potential changes (bis-oxonol fluorescent probe), 86RB+ (marker for K+)-efflux, the intracellular free calcium concentration ([Ca2+] i in single cells) and 45Ca2+ uptake (CsA only) in RBL-2H3 cells, a mucosal-type mast cell line, passively sensitized with monoclonal mouse IgE antibody. Antigen addition induced depolarization within 1–2 min, followed by slower repolarization, reaching a steady state (∼90% repolarization) after 7–9 min. CsA and FK506 each dose-dependently inhibited antigen-induced histamine and β-hexosaminidase secretion and the membrane repolarization phase, with similar IC50s for both actions, ∼20 nM for CsA and ∼2 nM for FK506. Antigen-induced 86Rb+-efflux was also significantly inhibited. Antigen-evoked increase in [Ca2+] i (area under the curve, AUC) was reduced by 35% and 52% in the presence of CsA or FK506 (1 μM each), respectively. However, 45Ca2+-uptake was not inhibited by CsA. These results suggest that both CsA and FK506 may inhibit mediator release from mast cells via blocking two interrelated processes, which are involved in the secretory process: 1. Membrane repolarization phase, which is essential for optimal mediator secretion and is mediated by a Ca2+-sensitive K+-efflux, yet to be further characterized, and (2) Increase in [Ca2+] i , probably via reduction of Ca+2-release from intracellular stores, [Ca2+]s. [Copyright &y& Elsevier]

Our previous studies on rat basophilic leukaemia (RBL-2H3) cells suggested that IKCa channels similar to those in red blood cells (RBC) may be involved in the antigen-induced β-hexosaminidase release. Since cetiedil blocks these channels in both cell types, we studied the inhibition by a selection of the synthetic analogues of cetiedil (UCL compounds) of antigen-induced β-hexosaminidase release and 86Rb+-efflux from RBL-2H3 cells. We tested the (+)- and (−)-enantiomers of cetiedil (UCL 1348 and UCL 1349), the more lipophilic triphenylacetic acid derivatives (UCL 1495 and UCL 1617) and (9-benzyl-fluoren)-9-yl derivatives (UCL 1608 and UCL 1710). They all inhibited antigen-induced β-hexosaminidase release and 86Rb+-efflux. Their relative potency in inhibiting antigen-induced β-hexosaminidase release was UCL 1608>1710>1617>1348>1349>1495, with IC50 values of 9.6±0.6, 14.4±2.2, 23.4±1.4, 29.8±1.1, 77.5±11.8 and 104.6±14.7 (μM), respectively. These IC50s suggest some dissimilarity between IKCa in RBL-2H3 cells and RBC. Lipophilicity and potency were well correlated in RBC, but not in RBL-2H3 cells. [Copyright &y& Elsevier]

The aggregate–matrix interface plays a leading role in the fracture mechanisms and in the fracture response of concrete. In this work, the influence of the interface on the macroscopic fracture parameters of concrete is investigated. Eleven concrete batches were cast with the same matrix. Different—crushed or rounded—aggregates from the same quarry were used, and several surface treatments were applied to improve or degrade the bond between the matrix and the particles. Fracture tests (three-point bending tests and Brazilian splitting tests) were carried out to determine the fracture energy and other relevant fracture parameters of the concrete batches. The modulus of elasticity and the compressive strength were obtained from uniaxial compression tests. The macroscopic fracture behaviour was modeled by the cohesive crack model with a bilinear softening curve. The results show that concretes with the same matrix and aggregates, and similar behaviour under uniaxial compression, can give very different fracture responses. The work shows how fracture behaviour is governed by the interfacial properties that are also behind the cracking mechanism. [Copyright &y& Elsevier]

El-Temsah Lake is considered the largest water body in Ismailia governorate, with a total area of 14 km2. A total number of 120 moribund crabs (Callinectes sapidus) were collected from El-Temsah Lake in front of the youth house, Ismailia Governorate, in September 2021. The analyses of water parameters revealed high concentrations of un-ionized ammonia and nitrite. Clinically, moribund C. sapidus showed loss of escape reflex, lethargy, sluggishness, easily catching, and shell lesions on the dorsal cuticle, swimming legs, and walking legs. Several affected C. sapidus showed softening of the cuticle. Internally, the intestine is devoid of food, gills show blackening, and a straw yellow fluid is accumulated around the hepatopancreas. Enterococcus gallinarum was isolated from hemolymph, gills, and shell then identified by traditional bacterial methods, Vitek 2 system, and DNA sequence. C. sapidus was infected with E. gallinarum, withrates of 90% and 83.33%, respectively, in sites 1 (El-Taween club) and 2 (Beach club). E. gallinarum was sensitive for Ciprofloxacin and Rifampicin; whereas, it showed resistance to Vancomycin, Erythromycin, Chloramphenicol, and Tetracycline. It was obvious that the high mortality rate of C. sapidus was associated with deleterious water quality and E. gallinarum infection. [ABSTRACT FROM AUTHOR]

Implantation of tissue-engineered heterotopic cartilage into joint cartilage defects might be an alternative approach to improve articular cartilage repair. Hence, the aim of this study was to characterize and compare the quality of tissue-engineered cartilage produced with heterotopic (auricular, nasoseptal and articular) chondrocytes seeded on polyglycolic acid (PGA) scaffolds in vitro and in vivo using the nude mice xenograft model. PGA scaffolds were seeded with porcine articular, auricular and nasoseptal chondrocytes using a dynamic culturing procedure. Constructs were pre-cultured 3 weeks in vitro before being implanted subcutaneously in nude mice for 1, 6 or 12 weeks, non-seeded scaffolds were implanted as controls. Heterotopic neo-cartilage quality was assessed using vitality assays, macroscopical and histological scoring systems. Neo-cartilage formation could be observed in vitro in all PGA associated heterotopic chondrocytes cultures and extracellular cartilage matrix (ECM) deposition increased in vivo. The 6 weeks in vivo incubation time point leads to more consistent results for all cartilage species, since at 12 weeks in vivo construct size reductions were higher compared with 6 weeks except for auricular chondrocytes PGA cultures. Some regressive histological changes could be observed in all constructs seeded with all chondrocytes subspecies such as cell-free ECM areas. Particularly, but not exclusively in nasoseptal chondrocytes PGA cultures, ossificated ECM areas appeared. Elastic fibers could not be detected within any neo-cartilage. The neo-cartilage quality did not significantly differ between articular and non-articular chondrocytes constructs. Whether tissue-engineered heterotopic neo-cartilage undergoes sufficient transformation, when implanted into joint cartilage defects requires further investigation. [ABSTRACT FROM AUTHOR]

Quinidine and Ba2+, non-selective K+-channel blockers, have previously been shown to inhibit antigen-induced mediator (β-hexosaminidase) release from RBL-2H3 cells, a mucosal-type mast cell line. We therefore used selective blockers of Ca2+-activated and other K+ channels to determine if there was a role for these channels in antigen-induced mediator release. Charybdotoxin and cetiedil dose-dependently inhibited β-hexosaminidase release with IC50 values of 133 nM and 84 μM, respectively. Charybdotoxin also inhibited the repolarization phase of the antigen-induced biphasic change in the membrane potential (IC50 84 nM), antigen-stimulated 86Rb+-efflux and increase in free intracellular calcium, [Ca2+]i. Iberiotoxin, margatoxin, apamin and tetraethylammonium had no effect on β-hexosaminidase release. These results suggest that K+ conductances play a significant role in mediator release from RBL-2H3, that these conductances are of the intermediate conductance Ca2+-activated K+ channel (IKCa) type, and that they are somewhat similar to those which have been described in red blood cells, though they are much less sensitive to clotrimazole. [Copyright &y& Elsevier]

Oral mesenchymal stem/progenitor cells (MSCs) are renowned in the field of tissue engineering/regeneration for their multilineage differentiation potential and easy acquisition. These cells encompass the periodontal ligament stem/progenitor cells (PDLSCs), the dental pulp stem/progenitor cells (DPSCs), the stem/progenitor cells from human exfoliated deciduous teeth (SHED), the gingival mesenchymal stem/progenitor cells (GMSCs), the stem/progenitor cells from the apical papilla (SCAP), the dental follicle stem/progenitor cells (DFSCs), the bone marrow mesenchymal stem/progenitor cells (BM-MSCs) from the alveolar bone proper, and the human periapical cyst-mesenchymal stem cells (hPCy-MSCs). Apart from their remarkable regenerative potential, oral MSCs possess the capacity to interact with an inflammatory microenvironment. Although inflammation might affect the properties of oral MSCs, they could inversely exert a multitude of immunological actions to the local inflammatory microenvironment. The present review discusses the current understanding about the immunomodulatory role of oral MSCs both in periodontitis and systemic diseases, their "double-edged sword" uniqueness in inflammatory regulation, their affection of the immune system, and the underlying mechanisms, involving oral MSC-derived extracellular vesicles. [ABSTRACT FROM AUTHOR]

Background. In the field of periodontal guided tissue regeneration, microperforated membranes have recently proved to be very promising periodontal regenerative tissue engineering tools. Regenerative periodontal approaches, employing gingival mesenchymal stem/progenitor cells in combination with these novel membranes, would occur mostly in inflamed microenvironmental conditions intraorally. This in turn entails the investigation into how inflammation would affect the proliferation as well as the migration dynamics of gingival mesenchymal stem/progenitor cells. Materials and Methods. Clones of human gingival mesenchymal stem/progenitor cells (GMSCs) from inflamed gingival tissues were characterized for stem/progenitor cells' characteristics and compared to clones of healthy human GMSCs (n = 3), to be subsequently seeded on perforated collagen-coated poly-tetra-floro-ethylene (PTFE) membranes with a pore size 0.4 and 3 microns and polycarbonic acid membranes of 8 microns pore size in Transwell systems. The population doubling time and the MTT test of both populations were determined. Fetal bovine serum (FBS) was used as a chemoattractant in the culturing systems, and both groups were compared to their negative controls without FBS. Following 24 hours of incubation period, migrating cells were determined on the undersurface of microperforated membranes and the membrane-seeded cells were examined by scanning electron microscopy. Results. GMSCs demonstrated all predefined stem/progenitor cell characteristics. GMSCs from inflamed gingival tissues showed significantly shorter population doubling times. GMSCs of inflamed and healthy tissues did not show significant differences in their migration abilities towards the chemoattractant, with no cellular migration observed in the absence of FBS. GMSCs from healthy gingival tissue migrated significantly better through larger micropores (8 microns). Scanning electron microscopic images proved the migratory activity of the cells through the membrane pores. Conclusions. Inflammation appears to boost the proliferative abilities of GMSCs. In terms of migration through membrane pores, GMSCs from healthy as well as inflamed gingival tissues do not demonstrate a difference in their migration abilities through smaller pore sizes, whereas GMSCs from healthy gingival tissues appear to migrate significantly better through larger micropores. [ABSTRACT FROM AUTHOR]

(1 S ,2 E ,4 R ,6 R ,-7 E ,11 E )-2,7,11-cembratriene-4,6-diol (4R) is a precursor to key flavor ingredients in leaves of Nicotiana species. The present study shows 4R decreased brain damage in rodent ischemic stroke models. The 4R-pretreated mice had lower infarct volumes (26.2 ± 9.7 mm 3 ) than those in control groups (untreated: 63.4 ± 4.2 mm 3 , DMSO: 60.2 ± 14.2 mm 3 ). The 4R-posttreated rats also had less infarct volumes (120 ± 65 mm 3 ) than those in the rats of the DMSO group (291 ± 95 mm 3 ). The results from in vitro experiments indicate that 4R decreased neuro2a cell (neuroblastoma cells) apoptosis induced by oxygen–glucose deprivation (OGD), and improved the population spikes’ (PSs) recovery in rat acute hippocampal slices under OGD; a phosphatidylinositol 3-kinase (PI3K) inhibitor, wortmannin, abolished the effect of 4R on PSs recovery. Furthermore, 4R also inhibited monocyte adhesion to murine brain-derived endothelial (bEND5) cells and upregulation of intercellular adhesion molecule-1(ICAM-1) induced by OGD/reoxygenation (OGD/R), and restored the p-Akt level to pre-OGD/R values in bEND5 cells. In conclusion, the present study indicates that 4R has a protective effect in rodent ischemic stroke models. Inhibition of ICAM-1 expression and restoration of Akt phosphorylation are the possible mechanisms involved in cellular protection by 4R. [ABSTRACT FROM AUTHOR]

Introduction and Objectives: The failure of targeted chemotherapy especially in triple negative breast cancer (TNBC) patients has been correlated with the overexpression of the mesenchymalepithelial transition factor (c-Met) receptor. Thus, the hepatocyte growth factor (HGF)/c-Met signaling axis has gained considerable attention as a valid molecular target for breast cancer therapy. No reports addressed the potential anticancer action of Ziziphus lotus, an edible typical Tunisian plant known by locals for its numerous therapeutic virtues. In the present study, we investigated for the first time the anti-tumor activity of Z. lotus leaf extract against human breast cancer cell lines. Material and Methods: Bioguided fractionation of leaves ethanolic extract was performed using different chromatographic techniques and MTT assay. The structures of three compounds were elucidated by NMR spectroscopy analysis and high-resolution mass spectrometry. The cell free Z'-LYTE kinase assay and in vitro biological screening on human breast cancer cells using cell viability, adhesion, migration, western blotting and in silico docking experiments were carried out to investigate the anti-tumoral activity of the purified lead compound and its mechanism of action. Tumor growth was evaluated in vivo using nude mice breast cancer xenograft model. Results: This study reports the discovery of three purified photosensitizers as the potent antiproliferative compounds against the human breast cancer cells MDA-MB-231 and MCF-7. Compound 3 exerted the most light-independent antitumor effect against the metastatic human MDA-MB-231 cells. In silico, this compound showed excellent binding mode and score at the kinase domain of multiple c-Met crystal structures. It potently inhibited the kinase domain phosphorylation of wild and mutant c-Met. Compound (3) inhibited HGF-induced downstream c-Met-dependent cell proliferation, survival, adhesion and migration through RAF/MEK/ERK and PI3K/PTEN/AKT signaling pathways modulation, ROS generation and activation of JNK and p38 pathways. Interestingly, this compound impaired the ability of MDA-MB-231 cells to adhere at different extracellular matrix proteins by reducing the HGF-induced expression of integrins av, ß3, a2 and ß1. Moreover, compound (3) exhibited potent anti-migratory properties through impacting the expression levels of E-cadherin, vimentin, -catenin, FAK, Brk, Rac, and Src proteins. Importantly, treatment with this compound significantly inhibited the MDA-MB-231 tumor growth in orthotopic athymic mouse xenograft model. Conclusion: Compound (3) is a novel c-Met inhibitory lead with promise to control c-Met/HGFdependent breast malignancies. [ABSTRACT FROM AUTHOR]

To report the rapid (5 min) and simple detection of a nuclear matrix protein (NMP) in the urine of patients with bladder cancer, using a newly developed office-based dot-enzyme-linked immunosorbent assay (ELISA). Western blot and specific immunoglobulin-G antibody were used to identify the urinary NMP marker. Urine samples from 149 patients with bladder cancer and 72 controls were evaluated using the developed dot-ELISA. The initial responses of 43 patients treated by irradiation were followed using the assay. The NMP marker was identified in the urine of patients with bladder cancer at 52 kDa (NMP-52) by Western blot. The dot-ELISA detected the urinary NMP-52 marker in 92% of patients with squamous cell carcinoma, 98% with transitional cell carcinoma, and all six of those with adenocarcinoma of the bladder, with a specificity of 94%. The positive and negative predictive values (97% and 94%, respectively) and efficiency (96%) of the dot-ELISA were high. In addition, the NMP-52 tumour marker was not detected in the urine of patients who showed a response after radiotherapy. Detecting the urinary NMP-52 marker using dot-ELISA would be helpful in the rapid diagnosis and follow-up of patients with bladder cancer. [ABSTRACT FROM AUTHOR]