A multi-stem cell basis for craniosynostosis and calvarial mineralization.

Craniosynostosis is a group of disorders of premature calvarial suture fusion. The identity of the calvarial stem cells (CSCs) that produce fusion-driving osteoblasts in craniosynostosis remains poorly understood. Here we show that both physiologic calvarial mineralization and pathologic calvarial fusion in craniosynostosis reflect the interaction of two separate stem cell lineages; a previously identified cathepsin K (CTSK) lineage CSC1 (CTSK+ CSC) and a separate discoidin domain-containing receptor 2 (DDR2) lineage stem cell (DDR2+ CSC) that we identified in this study. Deletion of Twist1, a gene associated with craniosynostosis in humans2,3, solely in CTSK+ CSCs is sufficient to drive craniosynostosis in mice, but the sites that are destined to fuse exhibit an unexpected depletion of CTSK+ CSCs and a corresponding expansion of DDR2+ CSCs, with DDR2+ CSC expansion being a direct maladaptive response to CTSK+ CSC depletion. DDR2+ CSCs display full stemness features, and our results establish the presence of two distinct stem cell lineages in the sutures, with both populations contributing to physiologic calvarial mineralization. DDR2+ CSCs mediate a distinct form of endochondral ossification without the typical haematopoietic marrow formation. Implantation of DDR2+ CSCs into suture sites is sufficient to induce fusion, and this phenotype was prevented by co-transplantation of CTSK+ CSCs. Finally, the human counterparts of DDR2+ CSCs and CTSK+ CSCs display conserved functional properties in xenograft assays. The interaction between these two stem cell populations provides a new biologic interface for the modulation of calvarial mineralization and suture patency.

TGFßR1 inhibition drives hepatocellular carcinoma proliferation through induction of toll-like-receptor signalling.

Transforming growth factor (TGF)-ß and toll-like receptors (TLRs) have been shown to independently modulate the proliferation of hepatocellular carcinoma (HCC). Since a direct cross-talk between these two signalling pathways in HCC has not been clearly described before, we aimed here to explore the possibility of such interaction. A human HCC tissue array (n = 20 vs. four control samples), human HCC samples (n = 10) and steatohepatitis-driven murine HCC samples (control, NASH and HCC; n = 6/group) were immunostained for TGFßR1, pSMAD2, TRAF6, IRAK1 and PCNA. The results were confirmed by immunoblotting. Effects of constant activation of the SMAD pathway by constitutive expression of ALK5 or knockdown of mediators of TLR signalling, IRAK1 and MyD88, on HCC proliferation, were investigated in the HCC cell line (HUH-7) after treatment with TGFß1 cytokine or TGFßR1 kinase inhibitor (LY2157299) using PCNA and MTS assay. TGFßR1 expression is decreased in human and murine HCC and associated with downregulated pSMAD2, but increased IRAK1, TRAF6 and PCNA staining. TGFßR1 kinase inhibition abolished the cytostatic effects of TGFß1 and led to the induction of IRAK1, pIRAK1 and elevated mRNA levels of TLR-9. Overexpression of ALK5 and knockdown of MyD88 or IRAK1 augmented the cytostatic effects of TGFß1 on HUH-7. In another epithelial HCC cell line, that is, HepG2, TGFßR1 kinase inhibitor similarly elevated cellular proliferation. There is a balance between the canonical SMAD-driven tumour-suppressing arm and the non-canonical tumour-promoting arm of TGFß signalling. Disruption of this balance, by inhibition of the canonical pathway, induces HCC proliferation through TLR signalling.

The anti-staphylococcal fusidic acid as an efflux pump inhibitor combined with fluconazole against vaginal candidiasis in mouse model.

BACKGROUND: Candida albicans is the most common fungus that causes vaginal candidiasis in immunocompetent women and catastrophic infections in immunocompromised patients. The treatment of such infections is hindered due to the increasing emergence of resistance to azoles in C. albicans. New treatment approaches are needed to combat candidiasis especially in the dwindled supply of new effective and safe antifungals. The resistance to azoles is mainly attributed to export of azoles outside the cells by means of the efflux pump that confers cross resistance to all azoles including fluconazole (FLC). OBJECTIVES: This study aimed to investigate the possible efflux pump inhibiting activity of fusidic acid (FA) in C. albicans resistant isolates and the potential use of Fusidic acid in combination with fluconazole to potentiate the antifungal activity of fluconazole to restore its activity in the resistant C. albicans isolates. METHODS: The resistance of C. albicans isolates was assessed by determination of minimum inhibitory concentration. The effect of Fusidic acid at sub-inhibitory concentration on efflux activity was assayed by rhodamine 6G efflux assay and intracellular accumulation. Mice model studies were conducted to evaluate the anti-efflux activity of Fusidic acid and its synergistic effects in combination with fluconazole. Impact of Fusidic acid on ergosterol biosynthesis was quantified. The synergy of fluconazole when combined with Fusidic acid was investigated by determination of minimum inhibitory concentration. The cytotoxicity of Fusidic acid was tested against erythrocytes. The effect of Fusidic acid on efflux pumps was tested at the molecular level by real-time PCR and in silico study. In vivo vulvovaginitis mice model was used to confirm the activity of the combination in treating vulvovaginal candidiasis. RESULTS: Fusidic acid showed efflux inhibiting activity as it increased the accumulation of rhodamine 6G, a substrate for ABC-efflux transporter, and decreased its efflux in C. albicans cells. The antifungal activity of fluconazole was synergized when combined with Fusidic acid. Fusidic acid exerted only minimal cytotoxicity on human erythrocytes indicating its safety. The FA efflux inhibitory activity could be owed to its ability to interfere with efflux protein transporters as revealed by docking studies and downregulation of the efflux-encoding genes of both ABC transporters and MFS superfamily. Moreover, in vivo mice model showed that using fluconazole-fusidic acid combination by vaginal route enhanced fluconazole antifungal activity as shown by lowered fungal burden and a negligible histopathological change in vaginal tissue. CONCLUSION: The current findings highlight FA's potential as a potential adjuvant to FLC in the treatment of vulvovaginal candidiasis.

Users' experience with health-related content on YouTube: an exploratory study.

BACKGROUND: This study focuses on health-related content (HRC) on YouTube and addresses the issue of misinformation on this platform. While previous research centered on content evaluations by experts, this study takes a user-centered approach and aims to explore users' experiences with and perceptions of HRC videos and to establish links between these perceptions and some socio-demographic characteristics including age, gender, profession, and educational level. METHODS: A quantitative research design was used in the study. 3,000 YouTube users responded to a 35-item anonymous questionnaire to collect information about the content they watch toward decision-making, their perceptions of the usefulness and bias of this content, what they identify as quality indicators for HRC, and what they recommend to improve the quality of such content on YouTube. The data were analyzed using descriptive statistics, frequency, and correlation analyses. RESULTS: The results reveal that 87.6 percent (n=2630) of the participants watch HRC on YouTube, and 84.7 percent (n=2542) make decisions based on what they watch. Exercise and bodybuilding videos are the most popular, with over half of the participants watching them. 40 percent of the users watch YouTube videos to decide whether to consult a doctor or adopt specific health-related practices. In contrast to evaluations by experts in previous studies, most respondents perceive HRC videos on YouTube as useful and do not find connections between video quality and surface features like the number of views and likes. Weak or no correlations were observed between the perceived usefulness of HRC videos and age, gender, profession, or educational level. Participants' recommendations for enhancing HRC quality align with previous research findings. CONCLUSIONS: Users turn to YouTube not only for health information but also as a decision-making tool. Combined with their generally positive attitudes towards content quality on this platform, this can have significant consequences for their health. Follow-up studies are needed to get more insights into decision-making behaviors and how users assess their decisions in retrospect.

Novel Bis(2-cyanoacrylamide) Linked to Sulphamethoxazole: Synthesis, DNA Interaction, Anticancer, ADMET, Molecular Docking, and DFT Studies.

In the light of advancement and potential extensive use of medication design and therapy, new bis(cyanoacrylamides) incorporating sulphamethoxazole derivatives (7 a-7 f) were synthesized and confirmed by different spectral tools. In vitro anticancer activity towards different human cancer cells (HCT116, MDA-MB-231 and A549) was assessed using MTT assay. Among all derivatives, 4C- and 6C-spacer derivatives (7 e and 7 f) had the most potent growth inhibitory activities against HCT116 cells with IC50 values of 39.7 and 28.5 µM, respectively. 7 e and 7 f induced apoptosis and suppressed migration of HCT116 cells. These compounds also induced a significant increase in caspase-3 and CDH1 activities, and a downregulation of Bcl2 using ELISA. pBR322 DNA cleavage activities of cyanoacrylamides were determined using agarose gel electrophoresis. Furthermore, 7 e and 7 f showed good DNA and BSA binding affinities using different spectroscopic techniques. Furthermore, molecular docking for 7 e and 7 f was performed to anticipate their binding capabilities toward various proteins (Bcl2, CDH1 and BSA). The docking results were well correlated with those of experimental results. Additionally, density functional theory and ADMET study were performed to evaluate the molecular and pharmacokinetic features of 7 e and 7 f, respectively. Thus, this work reveals promising antitumor lead compounds that merit future research and activity enhancement.

Design, synthesis of novel chromene-based scaffolds targeting hepatocellular carcinoma: Cell cycle arrest, cytotoxic effect against resistant cancer cells, apoptosis induction, and c-Src inhibition.

New chromene derivatives were synthesized based on 4-(3,4-dimethoxy)-4H-chromene scaffold. All target compounds exhibited cytotoxic activity against HepG2 cells (IC50 = 2.40-141.22 µM). Chromens 5 and 9 showed superior cytotoxicity over staurosporine (IC50 = 18.27 µM) and vinblastine (IC50 = 5.20 µM). c-Src kinase inhibition assay of compounds 5 and 9 displayed the dominant c-Src inhibitory activity of 5 (IC50 = 0.184 µM) over 9 (IC50 = 0.288 µM). The safety of the most potent compound 5 against normal WI-38 cells was confirmed via its IC50 of 115.75 µM comparable with 5-FU (IC50 = 16.28 µM). Moreover, the promising chromene 5 displayed potent cytotoxicity against resistant HepG2 cells with IC50 of 26.03 µM comparable with 5-FU (IC50 = 42.68 µM). The most active chromene 5 arrested the HepG2 cell cycle at the S phase and induced a 29-fold increase in the total number of apoptotic cells indicating pre-G1 apoptosis. The ability of compound 5 to induce apoptosis was supported via elevation of caspase-3, caspase-7, caspase-9 and proapoptotic Bax protein levels in addition to downregulation of the antiapoptotic Bcl2 protein. Molecular docking studies of compound 5 showed good binding interaction pattern inside c-Src kinase enzyme active site.

The renoprotective activity of amikacin-gamma-amino butyric acid-chitosan nanoparticles: a comparative study.

The development of nanoparticles (NPs) with active components with upgraded stability, and prolonged release helps in enhanced tissue regeneration. In addition, NPs are feasible strategy to boost antibiotic effectiveness and reduce drug side effects. Our study focuses on the use of amikacin (AMK) and gamma amino butyric acid (GABA) unloaded combinations or loaded on chitosan nanoparticles (CSNPs) for kidney protection. The AMK-GABA-CSNPs were prepared with the ionic gelation method, the morphology was studied using transmission electron microscopy (TEM), zetasizer and the Fourier transform-infrared spectroscopy (FT-IR) spectrum of the synthesized NPs was observed. The average size of AMK-GABA-CSNPs was 77.5 ± 16.5 nm. Zeta potential was + 38.94 ± 2.65 mV. AMK-GABA-CSNPs revealed significant in vitro antioxidant, anti-coagulation, non-hemolytic properties and good cell compatibility. To compare the effects of the unloaded AMK-GABA combination and AMK-GABA-CSNPs on the renal tissue, 42 healthy Sprague-Dawley rats were divided into seven groups. G1: normal control (NC), normal saline; G2: low-dose nephrotoxic group (LDN), AMK (20 mg/kg/day; i.p.); G3: unloaded AMK (20 mg/kg/day; i.p.) and GABA (50 mg/kg/day; i.p.); G4: AMK-GABA-CSNPs (20 mg/kg/day; i.p.); G5: high-dose nephrotoxic group (HDN), AMK (30 mg/kg/day; i.p.); G6: unloaded AMK (30 mg/kg/day; i.p.) and GABA (50 mg/kg/day; i.p.) and G7: AMK-GABA-CSNPs (30 mg/kg/day; i.p.). The results showed that AMK-GABA-CSNPs formulation is superior to unloaded AMK-GABA combination as it ameliorated kidney functions, oxidative stress and displayed a significant homeostatic role via suppression of inflammatory cytokines of Th1, Th2 and Th17 types. Hence, AMK-GABA-CSNPs could afford a potential nano-based therapeutic formula for the management of AMK-nephrotoxicity.

Breast self-examination knowledge, attitude, and practice among Jazan women, Kingdom od Saudi Arabia.

Breast cancer is the most common cancer among women worldwide. It is a major cause of cancer death, and its incidence rate has been gradually increasing in the Arab world, Saudi Arabia has a higher proportion of young females getting breast cancer than other countries. This study was conducted to investigate the knowledge, attitude, and practice regarding breast self-examination among females from 20 to 60 years old in Jazan Region, Saudi Arabia. Using A Community-based descriptive cross-sectional approach, data were gathered from 567 Saudi and non-Saudi women using structured interviews and then analyzed using the Statistical Package for Social Sciences (IBM) version 21.0 software program. Where the study indicated that around half of the participants (55.7%) had good total knowledge scores regarding breast self-examination, and most had positive attitudes. However, only 205 (36.2%) respondents practice it regularly. Moreover, the study reveals a significant association between respondents' knowledge and attitudes toward breast self-examination (P = 0.05). These findings indicate moderate knowledge, poor breast self-examination practices, and a significant association between knowledge and attitudes. Therefore, conducting health education programs is necessary to raise awareness about breast self-examination (BSE) among Jazan women.

Le cancer du sein est le cancer le plus répandu chez les femmes dans le monde. Il s'agit d'une cause majeure de décès par cancer et son taux d'incidence augmente progressivement dans le monde arabe. L'Arabie saoudite compte une proportion plus élevée de jeunes femmes atteintes d'un cancer du sein que les autres pays. Cette étude a été menée pour étudier les connaissances, l'attitude et la pratique concernant l'auto-examen des seins chez les femmes de 20 à 60 ans dans la région de Jazan, en Arabie Saoudite. À l'aide d'une approche transversale descriptive communautaire, les données ont été recueillies auprès de 567 femmes saoudiennes et non saoudiennes à l'aide d'entretiens structurés, puis analysées à l'aide du logiciel Statistical Package for Social Sciences (IBM) version 21.0. L'étude a indiqué qu'environ la moitié des participantes (55,7 %) avaient de bons scores totaux de connaissances concernant l'auto-examen des seins et que la plupart avaient des attitudes positives. Cependant, seuls 205 (36,2%) répondants le pratiquent régulièrement. De plus, l'étude révèle une association significative entre les connaissances et les attitudes des répondants à l'égard de l'auto-examen des seins (P = 0,05). Ces résultats indiquent des connaissances modérées, de mauvaises pratiques d'auto-examen des seins et une association significative entre les connaissances et les attitudes. Par conséquent, il est nécessaire de mener des programmes d'éducation sanitaire pour sensibiliser les femmes de Jazan à l'auto-examen des seins (ESB).

Eobania vermiculata whole-body muscle extract-loaded chitosan nanoparticles enhanced skin regeneration and decreased pro-inflammatory cytokines in vivo.

BACKGROUND: Usually, wounds recover in four to six weeks. Wounds that take longer time than this to heal are referred to as chronic wounds. Impaired healing can be caused by several circumstances like hypoxia, microbial colonization, deficiency of blood flow, reperfusion damage, abnormal cellular reaction and deficiencies in collagen production. Treatment of wounds can be enhanced through systemic injection of the antibacterial drugs and/or other topical applications of medications. However, there are a number of disadvantages to these techniques, including the limited or insufficient medication penetration into the underlying skin tissue and the development of bacterial resistance with repeated antibiotic treatment. One of the more recent treatment options may involve using nanotherapeutics in combination with naturally occurring biological components, such as snail extracts (SE). In this investigation, chitosan nanoparticles (CS NPs) were loaded with an Eobania vermiculata whole-body muscle extract. The safety of the synthesized NPs was investigated in vitro to determine if these NPs might be utilized to treat full-skin induced wounds in vivo. RESULTS: SEM and TEM images showed uniformly distributed, spherical, smooth prepared CS NPs and snail extract-loaded chitosan nanoparticles (SE-CS NPs) with size ranges of 76-81 and 91-95 nm, respectively. The zeta potential of the synthesized SE-CS NPs was - 24.5 mV, while that of the CS NPs was 25 mV. SE-CS NPs showed a remarkable, in vitro, antioxidant, anti-inflammatory and antimicrobial activities. Successfully, SE-CS NPs (50 mg/kg) reduced the oxidative stress marker (malondialdehyde), reduced inflammation, increased the levels of the antioxidant enzymes (superoxide dismutase and glutathione), and assisted the healing of induced wounds. SE-CS NPs (50 mg/kg) can be recommended to treat induced wounds safely. SE was composed of a collection of several wound healing bioactive components [fatty acids, amino acids, minerals and vitamins) that were loaded on CS NPs. CONCLUSIONS: The nanostructure enabled bioactive SE components to pass through cell membranes and exhibit their antioxidant and anti-inflammatory actions, accelerating the healing process of wounds. Finally, it is advised to treat rats' wounds with SE-CS NPs.

New pyrazolyl-thiazolidinone/thiazole derivatives as celecoxib/dasatinib analogues with selective COX-2, HER-2 and EGFR inhibitory effects: design, synthesis, anti-inflammatory/anti-proliferative activities, apoptosis, molecular modelling and ADME studies.

Two new series of pyrazolyl-thiazolidinone/thiazole derivatives 16a-b and 18a-j were synthesised, merging the scaffolds of celecoxib and dasatinib. Compounds 16a, 16b and 18f inhibit COX-2 with S.I. 134.6, 26.08 and 42.13 respectively (celecoxib S.I. = 24.09). Compounds 16a, 16b, 18c, 18d and 18f inhibit MCF-7 with IC50 = 0.73-6.25 µM (dasatinib IC50 = 7.99 µM) and (doxorubicin IC50 = 3.1 µM) and inhibit A549 with IC50 = 1.64-14.3 µM (dasatinib IC50 = 11.8 µM and doxorubicin IC50 = 2.42 µM) with S.I. (F180/MCF7) of 33.15, 7.13, 18.72, 13.25 and 8.28 respectively higher than dasatinib (4.03) and doxorubicin (3.02) and S.I. (F180/A549) of 14.75, 12.96, 4.16, 7.07 and 18.88 respectively higher than that of dasatinib (S.I. = 2.72) and doxorubicin (S.I = 3.88). Derivatives 16a, 18c, 18d, 18f inhibit EGFR and HER-2 IC50 for EGFR of 0.043, 0.226, 0.388, 0.19 µM respectively and for HER-2 of 0.032, 0.144, 0.195, 0.201 µM respectively.

New 1,2,3-triazole/1,2,4-triazole hybrids linked to oxime moiety as nitric oxide donor selective COX-2, aromatase, B-RAFV600E and EGFR inhibitors celecoxib analogs: design, synthesis, anti-inflammatory/anti-proliferative activities, apoptosis and molecular modeling study.

A new series of bis-triazole 19a-l was synthesised for the purpose of being hybrid molecules with both anti-inflammatory and anti-cancer activities and assessed for cell cycle arrest, NO release. Compounds 19c, 19f, 19h, 19 l exhibited COX-2 selectivity indexes in the range of 18.48 to 49.38 compared to celecoxib S.I. = 21.10), inhibit MCF-7 with IC50 = 9-16 µM compared to tamoxifen (IC50 = 27.9 µM). and showed good inhibitory activity against HEP-3B with IC50 = 4.5-14 µM compared to sorafenib (IC50 = 3.5 µM) (HEP-3B). Moreover, derivatives 19e, 19j, 19k, 19 l inhibit HCT-116 with IC50 = 5.3-13.7 µM compared to 5-FU with IC50 = 4.8 µM (HCT-116). Compounds 19c, 19f, 19h, 19 l showed excellent inhibitory activity against A549 with IC50 = 3-4.5 µM compared to 5-FU with IC50 = 6 µM (A549). Compounds 19c, 19f, 19h, 19 l inhibit aromatase (IC50 of 22.40, 23.20, 22.70, 30.30 µM), EGFR (IC50 of 0.112, 0.205, 0.169 and 0.066 µM) and B-RAFV600E (IC50 of 0.09, 0.06, 0.07 and 0.05 µM).

Toxicity bioassay and sub-lethal effects of profenofos-based insecticide on behavior, biochemical, hematological, and histopathological responses in Grass carp (Ctenopharyngodon idella).

Profenofos (organophosphate) is among the major toxicant polluting freshwater bodies, exerting a significant effect on fish health. The LC50 value of Profenofos (PRO) was resolved in Grass carp (Ctenopharyngodon idella) with average body weight (55.82 ± 5.42 g) and determined the 96 h LC50 value as 7.2 µg/L for the assay. Twenty-one-day exposures to 1.8 µg/ L and 3.6 µg/ L doses were conducted to evaluate the sub-lethal effects, and various toxicological endpoints were assessed on the 1st, 7th, 15th and 21st days of exposure. Acute toxic stress was observed with fish displaying behavioral toxicity. The most hematological change was extreme microcytic hypochromic anemia. Leucocyte count increased in experimented fish. Moderate neutrophilia, monocytosis and lymphocytosis were observed. Serum total protein, albumin, and globulin concentrations were significantly diminished. Overall, increments over control were recognized in serum urea, creatinine and acid phosphatase. However, serum glucose, total lipid, cholesterol, serum ALT and AST activity showed a significant decrease in fish exposed to both concentrations of PRO. Serum IgM concentrations insignificantly changed in treated fish except for on the 21st day of exposure to 3.6 µg/ L of PRO, while serum lysozyme significantly decreased. Furthermore, total protein, lipid and glycogen concentrations in muscles and the liver exhibited a decreasing trend at all concentrations. Moreover, histopathological alterations in the liver, kidney, and muscles occurred exclusively after treatment. From the obtained results, it is assumed that profenofos induced general toxic impacts under field conditions and might disturb ecologically relevant processes.

Effect of an educational program on pediatric nurses' knowledge, practice, and self-confidence about level of consciousness scales.

BACKGROUND: Nurses of pediatric acute critical care units routinely assess the Level of Consciousness (LOC). The precise, exact, and restriction-free evaluation tool aids pediatric nurses in LOC assessment and clinical decision-making. This study aimed to examine the effect of an educational program on pediatric nurses' knowledge, practice, and self-confidence about level of consciousness scales. METHODS: This pretest-post, single-group, quasi-experimental, double-site study included 49 pediatric nurses. The Glasgow Coma Scale (GCS)/Pediatric Glasgow Coma Scale (PGCS) and Pediatric Full Outline of UnResponsiveness Score Scale (PFSS) knowledge questionnaire and pediatric nurse practice checklist were developed and adopted. Self-reflection confidence statements were rated 1-5 (not confident-confident). RESULTS: The results of the study indicate that there were significant increases in knowledge, practice, and self-confidence after the intervention. The paired samples tests revealed that knowledge scores significantly increased from the pretest to the posttest for both GCS/PGCS (pretest mean:7.91, posttest mean:9.95) and PFSS (pretest mean:2.1, posttest mean:6.79). Practice scores also showed significant improvement for both GCS/PGCS (pretest mean: 4.12, post-test mean: 6.22) and PFSS (pretest mean: 2.46, post-test mean: 5.79). Furthermore, self-confidence significantly improved for GCS/PGCS (pretest mean:16.08, posttest mean:18.79) and PFSS (pretest mean:10.32, posttest mean:17.81). The statistical analyses supported the significance of these improvements (p < 0.001 for all except self-confidence in GCS/PGCS with p < 0.005). CONCLUSION: The educational program improved pediatric nurses' GCS/PGCS and PFSS knowledge, practice, and self-confidence. IMPLICATIONS TO PRACTICE: Effective teaching of pediatric nurses is required to address gaps in care practices and improve the use of the Consciousness Level Assessment Scales.

Between a rock and a hard place: Regulation of mineralization in the periodontium.

The periodontium supports and attaches teeth via mineralized and nonmineralized tissues. It consists of two, unique mineralized tissues, cementum and alveolar bone. In between these tissues, lies an unmineralized, fibrous periodontal ligament (PDL), which distributes occlusal forces, nourishes and invests teeth, and harbors progenitor cells for dentoalveolar repair. Many unanswered questions remain regarding periodontal biology. This review will focus on recent research providing insights into one enduring mystery: the precise regulation of the hard-soft tissue borders in the periodontium which define the interfaces of the cementum-PDL-alveolar bone structure. We will focus on advances in understanding the molecular mechanisms that maintain the unmineralized PDL "between a rock and a hard place" by regulating the mineralization of cementum and alveolar bone.

Characterization of novel heterocyclic compounds based on 4-aryl-4H-chromene scaffold as anticancer agents: Design, synthesis, antiprofilerative activity against resistant cancer cells, dual ß-tubulin/c-Src inhibition, cell cycle arrest and apoptosis induction.

In this study, three novel sets of 4-aryl-4H-chromene derivatives 4a-c, 6a-d and 7a-c were synthesized and evaluated for anticancer activity. Characterization of new compounds was established on basis of elemental analyses and spectral data. All new compounds were investigated for their antiproliferative activity against HCT-116, HepG-2 and MCF-7 cell lines using vinblastine and staurosporine as positive controls. Compounds 4b, 4c and 6d showed superior cytotoxicity against HCT-116, HepG-2 and MCF-7 cell lines, respectively with IC50 ranged from 3.31 to 4.95 µM. Additionally, compound 4b showed excellent cytotoxic activity (IC50 = 39.83 µM) against resistant HCT-116 better than doxorubicin (IC50 = 164.60 µM), while compounds 4c and 6d exhibited moderate cytotoxic activity against resistant HepG-2 and resistant MCF-7 cell lines. The most potent compounds inhibited both ß-tubulin polymerization (IC50 = 8.78 - 16.47 µM) and c-Src kinase (IC50 = 0.07 - 0.18 µM) enzymes. Compounds 4b, 4c and 6d activated caspase-3, caspase-7, and caspase-9 proteins relative to untreated cells, revealing apoptosis induction. Apoptosis was also confirmed through up-regulation of Bax and down-regulation of Bcl-2 protein expression levels. Cell cycle analysis of compound 6d showed accumulation of cells in pre-G1 phase and cell cycle arrest at S phase in MCF-7 treated cells. As well 6d caused 7- and 63- fold increase in apoptotic cell population at early and late apoptosis stages. Finally, molecular modeling study was performed to predict the binding pattern of the target compounds inside c-Src kinase receptor.

Design, synthesis, and biological evaluation of novel pyrido-dipyrimidines as dual topoisomerase II/FLT3 inhibitors in leukemia cells.

Dual inhibition of topoisomerase (topo) II and FLT3 kinase, as in the case of C-1311, was shown to overcome the shortcomings of using topo II inhibitors solely. In the present study, we designed and synthesized two series of pyrido-dipyrimidine- and pseudo-pyrido-acridone-containing compounds. The two series were evaluated against topo II and FLT3 as well as the HL-60 promyelocytic leukemia cell line in vitro. Compounds 6, 7, and 20 showed higher potency against topo II than the standard amsacrine (AMSA), whereas compounds 19 and 20 were stronger FLT3 inhibitors than the standard DACA. Compounds 19 and 20 showed to be dual inhibitors of both enzymes. Compounds 6, 7, 19, and 20 were more potent inhibitors of the HL-60 cell line than the standard AMSA. The results of the in vitro DNA flow cytometry analysis assay and Annexin V-FITC apoptosis analysis showed that 19 and 20 induced cell cycle arrest at the G2/M phase, significantly higher total percentage of apoptosis, and late-stage apoptosis in HL-60 cell lines than AMSA. Furthermore, 19 and 20 upregulated several apoptosis biomarkers such as p53, TNFα, caspase 3/7 and increased the Bax/Bcl-2 ratio. These results showed that 19 and 20 deserve further evaluation of their antiproliferative activities, particularly in leukemia. Molecular docking studies were performed for selected compounds against topo II and FLT3 enzymes to investigate their binding patterns. Compound 19 exerted dual fitting inside the active site of both enzymes.

Optimization and SAR investigation of novel 2,3-dihydropyrazino[1,2-a]indole-1,4-dione derivatives as EGFR and BRAFV600E dual inhibitors with potent antiproliferative and antioxidant activities.

Using a single drug to treat cancer with dual-targeting is an unusual approach when compared to other drug combinations. Dual-targeting agents were developed as a result of insufficient efficacy and drug resistance when single-targeting agents were used. As a result, the 2,3-dihydropyrazino[1,2-a]indole-1,4-dione derivatives 13-22 have been developed as dual EGFR and BRAFV600E inhibitors. The target compounds were synthesized and tested in vitro against four cancer cell lines, with compounds 15, and 19-22 demonstrating potent antiproliferative activity. In vitro studies revealed that these compounds have dual inhibitory effect on EGFR and BRAFV600E. Compounds 15, and 19-22 exhibited inhibitions of EGFR with IC50 ranging from 32 nM to 63 nM which were superior to erlotinib (IC50 = 80 ± 10 nM). Compounds 20, 21 and 22 showed promising inhibitory activity of BRAFV600E (IC50 = 55, 45 and 51 nM, respectively) and were found to be potent inhibitors of cancer cell proliferation (GI50 = 51, 35 and 44 nM, respectively). Compounds 20, 21 and 22 showed good antioxidant activity comparable to the reference Trolox. Lastly, the best active dual inhibitors were docked inside EGFR and BRAFV600E active sites to clarify their binding modes.

Inhibition of TLR7 and TLR9 Reduces Human Cholangiocarcinoma Cell Proliferation and Tumor Development.

BACKGROUND: Toll-like receptors (TLRs) are key players in innate immunity and modulation of TLR signaling has been demonstrated to profoundly affect proliferation and growth in different types of cancer. However, the role of TLRs in human intrahepatic cholangiocarcinoma (ICC) pathogenesis remains largely unexplored. AIMS: We set out to determine if TLRs play any role in ICCs which could potentially make them useful treatment targets. METHODS: Tissue microarrays containing samples from 9 human ICCs and normal livers were examined immunohistochemically for TLR4, TLR7, and TLR9 expression. Proliferation of human ICC cell line HuCCT1 was measured by MTS assay following treatment with CpG-ODN (TLR9 agonist), imiquimod (TLR7 agonist), chloroquine (TLR7 and TLR9 inhibitor) and IRS-954 (TLR7 and TLR9 antagonist). The in vivo effects of CQ and IRS-954 on tumor development were also examined in a NOD-SCID mouse xenograft model of human ICC. RESULTS: TLR4 was expressed in all normal human bile duct epithelium but absent in the majority (60%) of ICCs. TLR7 and TLR9 were expressed in 80% of human ICCs. However, TLR7 was absent in all cases of normal human bile duct epithelium and only one was TLR9 positive. HuCCT1 cell proliferation in vitro significantly increased following IMQ or CpG-ODN treatment (P < 0.03 and P < 0.002, respectively) but decreased with CQ (P < 0.02). In the mouse xenograft model there was significant reduction in size of tumors from CQ and IRS-954 treated mice compared to untreated controls. CONCLUSION: TLR7 and TLR9 should be further explored for their potential as actionable targets in the treatment of ICC.

Is YouTube a reliable source of health-related information? A systematic review.

BACKGROUND: YouTube is a valuable source of health-related educational material which can have a profound impact on people's behaviors and decisions. However, YouTube contains a wide variety of unverified content that may promote unhealthy behaviors and activities. We aim in this systematic review to provide insight into the published literature concerning the quality of health information and educational videos found on YouTube. METHODS: We searched Google Scholar, Medline (through PubMed), EMBASE, Scopus, Direct Science, Web of Science, and ProQuest databases to find all papers on the analysis of medical and health-related content published in English up to August 2020. Based on eligibility criteria, 202 papers were included in our study. We reviewed every article and extracted relevant data such as the number of videos and assessors, the number and type of quality categories, and the recommendations made by the authors. The extracted data from the papers were aggregated using different methods to compile the results. RESULTS: The total number of videos assessed in the selected articles is 22,300 (median = 94, interquartile range = 50.5-133). The videos were evaluated by one or multiple assessors (median = 2, interquartile range = 1-3). The video quality was assessed by scoring, categorization, or based on creators' bias. Researchers commonly employed scoring systems that are either standardized (e.g., GQS, DISCERN, and JAMA) or based upon the guidelines and recommendations of professional associations. Results from the aggregation of scoring or categorization data indicate that health-related content on YouTube is of average to below-average quality. The compiled results from bias-based classification show that only 32% of the videos appear neutral toward the health content. Furthermore, the majority of the studies confirmed either negative or no correlation between the quality and popularity of the assessed videos. CONCLUSIONS: YouTube is not a reliable source of medical and health-related information. YouTube's popularity-driven metrics such as the number of views and likes should not be considered quality indicators. YouTube should improve its ranking and recommender system to promote higher-quality content. One way is to consider expert reviews of medical and health-related videos and to include their assessment data in the ranking algorithm.

Design, synthesis, and biological evaluation of novel EGFR inhibitors containing 5-chloro-3-hydroxymethyl-indole-2-carboxamide scaffold with apoptotic antiproliferative activity.

New EGFR inhibitor series of fifteen 5-chloro-3-hydroxymethyl-indole-2-carboxamide derivatives has been designed, synthesized, and tested for antiproliferative activity against a panel of cancer cell lines. The results showed that p-substituted phenethyl derivatives 10, 11, 13, 15 and 17-19 showed superior antiproliferative activity compared to their m-substituted counterparts 12, 14, 16 and 20. Compounds 15, 16, 19 and 20 displayed promising EGFR inhibitory activity as well as an increase in caspase 3 levels. Compounds 15 and 19 increased caspase-8 and 9 levels, as well as inducing Bax and decreasing Bcl-2 protein levels. Compound 19 demonstrated cell cycle arrest at pre-G1 and G2/M phases. The results of the docking study into the active site of EGFR revealed strong fitting of the new compounds with higher binding affinities compared to erlotinib.