Efficient Connectivity in Smart Homes: Enhancing Living Comfort through IoT Infrastructure.

Modern homes are experiencing unprecedented levels of convenience because of the proliferation of smart devices. In order to improve communication between smart home devices, this paper presents a novel approach that particularly addresses interference caused by different transmission systems. The core of the suggested framework is an intelligent Internet of Things (IoT) system designed to reduce interference. By using adaptive communication protocols and sophisticated interference management algorithms, the framework minimizes interference caused by overlapping transmissions and guarantees effective data sharing. This can be accomplished by creating an optimization model that takes into account the dynamic nature of the smart home environment and intelligently allocates resources. By maximizing the signal quality at the destination and optimizing the distribution of frequency channels and transmission power levels, the model seeks to minimize interference. A deep learning technique is used to augment the optimization model by adaptively learning and predicting interference patterns from real-time observations and historical data. The experimental results show how effective the suggested hybrid strategy is. While the deep learning model adjusts to shifting interference dynamics, the optimization model efficiently controls resource allocation, leading to better data reception performance at the destination. The system's robustness is assessed in various kinds of situations to demonstrate its flexibility in responding to changing smart home settings. This work not only offers a thorough framework for interference reduction but also clarifies how deep learning and mathematical optimization can work together to improve the dependability of data reception in smart homes.

Hilfer-Katugampola fractional stochastic differential inclusions with Clarke sub-differential.

The objective of this paper is to investigate the existence of mild solutions and optimal controls for a class of stochastic Hilfer-Katugampola fractional differential inclusions (SHKFDIs) with non-instantaneous impulsive (NIIs) that is strengthened by Brownian motion (BM) and the Clarke sub-differential. First, we establish a new set of sufficient conditions for the existence of mild solutions of the aforementioned fractional systems by using stochastic analysis, the Clarke sub-differential's characteristics, and the multi-valued fixed point theorem. Subsequently, by employing Balder's theorem, the existence of optimal control pairs for the considered system is investigated. Eventually, an example is provided to validate the obtained results.

Grey water footprint for evaluating Zefta wastewater treatment plant: a case study.

The numbers of wastewater treatment plants (WWTP) in Egypt are increasing, yet the general level of pollution associated with wastewater discharge after treatment has not been evaluated. Grey water footprint (GWF) was used to assess the effluent discharges from Zefta WWTP. GWF, before and after treatment, was calculated and followed up to determine its impact on the receiving freshwater body. 150 samples were collected and analysed for BOD5 to determine the optimum operating conditions. Averages values were DO = 2.2, SV30 = 500, SVI = 167, SA = 9.3 d, MLVSS = 2392 mg/L, f/m = 0.16, MLSS in RAS = 7922 mg/L, WAS = 140 m3/d and the HRT = 12 h. The removal efficiency of COD and TSS in the primary settling tank reached 39% and 69%, respectively. Average calculations of removal efficiency percentile reached 90-93%. Average freshwater quantities required to reduce pollutants in the receiving body stream were seasonally determined for Zefta WWTP as 5.3 × 107 m3/year. The average influent BOD5 was 376 mg/L, it was reduced to 47 mg/L in the effluent, wherever the Cmin is 6 mg/L and Cnat is 10 mg/L. Statistical analysis has shown a significant direct relation between ΔWFG,mef and WFG,ref reached 0.952 and a significant inverse relation with Cef -0.982. WFG,T has shown a significant direct relation with Cr 0.974. WFG,T- ref has shown a significant direct relation with Cr as 0.971 and WFG,T as 0.803. It can be concluded that ΔWF is effective in evaluating the efficiency of wastewater treatment and its effect on the quality of receiving water bodies.

Enhancing in vitro regeneration via somatic embryogenesis and Fusarium wilt resistance of Egyptian cucumber (Cucumis sativus L.) cultivars.

BACKGROUND: Somatic embryogenesis offers a reliable method for cucumber (Cucumis sativus L.) regeneration and genetic enhancement against Fusarium wilt. This study aimed to establish a tailored somatic embryogenesis system for Egyptian cultivars, fostering genetic improvements and Fusarium wilt-resistance lines. RESULTS: Employing the Optimal Arbitrary Design (OAD) approach, we optimized the induction medium, initiating prolific embryogenic calli (53.3 %) at 1 mg/L 2,4-D. The cotyledonary leaf (CL) was the preferred explant, showing 60 % embryogenic callus development. Bieth Alpha exhibited higher responsiveness, generating âˆ¼ 18 somatic embryos per explant compared to Prince's âˆ¼ 10. Somatic embryogenesis system validation used quantitative RT-PCR, showing Cucumis sativus splicing factor 3B subunit (CUS1) and an embryogenesis marker gene expression exclusively within embryogenic calli and mainly during embryogenesis initiation. Evaluating fungal toxin filtrate concentrations for selecting embryogenic calli, the S2 selection (25 % filtrate, four subculture cycles) was chosen for somatic embryo development. To gauge the ramifications of selection at the genetic stratum, an in-depth analysis was executed. A cluster analysis grounded in ISSR banding patterns revealed a distinct separation between in vivo-cultivated plants of the two cultivars and regenerated plants devoid of pathogen filtrate treatment or those regenerated post-filtrate treatment. This segregation distinctly underscores the discernible genetic impact of the selection process. CONCLUSIONS: The highest embryogenic capacity (53.3%) was achieved in this study by optimizing the induction stage, which demonstrated the optimal concentrations of BA and 2,4-D for induced proembryonic masses. Moreover, consistent gene expression throughout both stages of embryogenesis suggests that our system unequivocally follows the somatic embryogenesis pathway.

Expression profiles of four Nile Tilapia innate immune genes during early stages of Aeromonas veronii infection.

OBJECTIVE: During Egypt's hot summer season, Aeromonas veronii infection causes catastrophic mortality on Nile Tilapia Oreochromis niloticus farms. Egypt is ranked first in aquaculture production in Africa, sixth in aquaculture production worldwide, and third in global tilapia production. This study aimed to investigate, at the molecular level, the early innate immune responses of Nile Tilapia to experimental A. veronii infection. METHODS: The relative gene expression, co-expression clustering, and correlation of four selected immune genes were studied by quantitative real-time polymerase chain reaction in four organs (spleen, liver, gills, and intestine) for up to 72 h after a waterborne A. veronii challenge. The four genes studied were nucleotide-binding oligomerization domain 1 (NOD1), lipopolysaccharide-binding protein (LBP), natural killer-lysin (NKL), and interleukin-1 beta (IL-1ß). RESULT: The four genes showed significant transcriptional upregulation in response to infection. At 72 h postchallenge, the highest NOD1 and IL-1ß expression levels were recorded in the spleen, whereas the highest LBP and NKL expression levels were found in the gills. Pairwise distances of the data points and the hierarchical relationship showed that NOD1 clustered with IL-1ß, whereas LBP clustered with NKL; both genes within each cluster showed a significant positive expression correlation. Tissue clustering indicated that the responses of only the gill and intestine exhibited a significant positive correlation. CONCLUSION: The results suggest that NOD1, LBP, NKL, and IL-1ß genes play pivotal roles in the early innate immune response of Nile Tilapia to A. veronii infection, and the postinfection expression profile trends of these genes imply tissue-/organ-specific responses and synchronized co-regulation.

Quinazoline-chalcone hybrids as HDAC/EGFR dual inhibitors: Design, synthesis, mechanistic, and in-silico studies of potential anticancer activity against multiple myeloma.

Two new series of quinazoline-chalcone hybrids were designed, synthesized as histone deacetylase (HDAC)/epidermal growth factor receptor (EGFR) dual inhibitors, and screened in vitro against the NCI 60 human cancer cell line panel. The most potent derivative, compound 5e bearing a 3,4,5-trimethoxyphenyl chalcone moiety, showed the most effective growth inhibition value against the panel of NCI 60 human cancer cell lines. Thus, it was selected for further investigation for NCI 5 log doses. Interestingly, this trimethoxy-substituted analog inhibited the proliferation of Roswell Park Memorial Institute (RPMI)-8226 cells by 96%, at 10 µM with IC50 = 9.09 ± 0.34 µM and selectivity index = 7.19 against normal blood cells. To confirm the selectivity of this compound, it was evaluated against a panel of tyrosine kinase enzymes. Mechanistically, it successfully and selectively inhibited HDAC6, HDAC8, and EGFR with IC50 = 0.41 ± 0.015, 0.61 ± 0.027, and 0.09 ± 0.004 µM, respectively. Furthermore, the selected derivative induced apoptosis via the mitochondrial apoptotic pathway by raising the Bax/Bcl-2 ratio and activating caspases 3, 7, and 9. Also, the flow cytometry analysis of RPMI-8226 cells showed that the trimethoxy-substituted analog produced cell cycle arrest in the G1 and S phases at 55.82%. Finally, an in silico study was performed to explore the binding interaction of the most active compound within the zinc-containing binding site of HDAC6 and HDAC8.

Benzimidazole-Based Derivatives as Apoptotic Antiproliferative Agents: Design, Synthesis, Docking, and Mechanistic Studies.

A new class of benzimidazole-based derivatives (4a-j, 5, and 6) with potential dual inhibition of EGFR and BRAFV600E has been developed. The newly synthesized compounds were submitted for testing for antiproliferative activity against the NCI-60 cell line. All newly synthesized compounds 4a-j, 5, and 6 were selected for testing against a panel of sixty cancer cell lines at a single concentration of 10 µM. Some compounds tested demonstrated remarkable antiproliferative activity against the cell lines tested. Compounds 4c, 4e, and 4g were chosen for five-dose testing against 60 human tumor cell lines. Compound 4c demonstrated strong selectivity against the leukemia subpanel, with a selectivity ratio of 5.96 at the GI50 level. The most effective in vitro anti-cancer assay derivatives (4c, 4d, 4e, 4g, and 4h) were tested for EGFR and BRAFV600E inhibition as potential targets for antiproliferative action. The results revealed that compounds 4c and 4e have significant antiproliferative activity as dual EGFR/BRAFV600E inhibitors. Compounds 4c and 4e induced apoptosis by increasing caspase-3, caspase-8, and Bax levels while decreasing the anti-apoptotic Bcl2 protein. Moreover, molecular docking studies confirmed the potential of compounds 4c and 4e to act as dual EGFR/BRAFV600E inhibitors.

Pushing the limits of PLA by exploring the power of MWCNTs in enhancing thermal, mechanical properties, and weathering resistance.

The present study focuses on enhancing the mechanical, thermal, and degradation behavior of polylactic acid (PLA) by adding carbon nanotubes (CNTs) with different concentrations of 0.5, 1, 3, and 5%. The CNTs were prepared using catalytic chemical vapor deposition, and the prepared PLA/CNTs nanocomposite films were characterized using techniques such as FT-IR, Raman spectroscopy, TGA, SEM, and XRD. The distinct diffraction patterns of multi-walled carbon nanotubes (MWCNTs) at 2θ angles of 25.7° and 42.7° were no longer observed in the prepared nanocomposites, indicating uniform dispersion of MWCNTs within the PLA matrix. The presence of MWCNTs enhanced the crystallinity of PLA as the CNT loading increased. Mechanical tests demonstrated that incorporating CNTs positively influenced the elongation at the break while decreasing the ultimate tensile strength of PLA. The PLA-3%CNTs composition exhibited the highest elongation at break (51.8%) but the lowest tensile strength (64 MPa). Moreover, thermal gravimetric analysis confirmed that the prepared nanocomposites exhibited greater thermal stability than pure PLA. Among the nanocomposites, PLA-5% CNTs exhibited the highest thermal stability. Furthermore, the nanocomposites demonstrated reduced surface degradation in accelerated weathering tests, with a more pronounced resilience to UV radiation and moisture-induced deterioration observed in PLA-3% CNTs.

Effect of Polymer Waste Mix Filler on Polymer Concrete Composites.

The hazards of polymer waste and emitted gas on the environment pose a global challenge. As a trial to control this, the current work aims to reuse the polymer waste mix (PM) as fillers in calcium silicate to prepare new composites of environmentally friendly polymer concrete. PM was first subjected to treatment to obtain treated PM (TPM) and then was filled in new dicalcium silicate cement with different concentrations. The microstructural characterizations declare the successful preparation of the dicalcium silicate base material. After the curing reaction, the precipitated carbonate main product is responsible for the gained properties. The CO2 uptake% in the proposed composites reached 16.6%, referring to the successful storage of CO2 gas during curing. The treatment reaction led to an increase in the flexural and compression strengths due to the strengthening of the polymer waste mix-cement interface; the strengths were increased gradually with more contents of TPM fillers. 7% TPM-cement concentration achieved the highest flexural strength and compression strength of10.2 and 12.7%, respectively, compared with blank cement. The used polymer improved slightly the pull-off force of the prepared cement, and 7 and 5% TPM-cement composites have the maximum values. All the proposed composites passed the impact testing without failure, where the combination between the polymer waste and silicate cement resulted in a stable composite surface. Compared with the blank, the different concentrations of TPM-cement composites show more stability against water absorption. In addition, the proposed composites and blank cement have a very low carbon dioxide emission. The ability to recycle the polymer waste, form new type of low-energy silicate, improve the mechanical and surface properties, uptake CO2 gas, and reduce gas emission makes the proposed polymer waste mix-cement composites as environmentally friendly construction products.

Serum aldosterone in right ventricular failure versus left ventricular failure before and after mineralocorticoid receptor antagonists: case-control clinical trial.

BACKGROUND: Heart failure (HF) is a global growing health threat. This case-control clinical trial aimed to detect the predictive value and difference in aldosterone level between right side heart failure, heart failure with decreased ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF) and compare the efficacy and safety of adding mineralocorticoid receptor antagonist (MRA) for treatment. PATIENTS AND METHODS: We recruited 151 participants, 135 HF patients divided equally into 45 patients in each group:(1) right side HF (2) HFrEF and (3) HFpEF and 16 healthy controls. Serum aldosterone, troponin and echocardiography were evaluated at the beginning of the study, three and six months after administration of MRA. RESULTS: Aldosterone level was significantly greater in HF patients relative to controls. Aldosterone level can detect HF with excellent accuracy. There were significantly lower levels of aldosterone in right side HF compared to left side HF. There was a significant decrease in right ventricle dimensions, pulmonary artery systolic pressure and pulmonary artery size and significant increase in tricuspid annular plane systolic excursion after treatment in patients with right side HF. In the HFrEF group, there was a significant decrease in left ventricular end diastolic dimension and a significant increase in left ventricular EF after treatment. In the HFpEF group, there was a significant decrease in E/A and E/e' after treatment. CONCLUSIONS: Aldosterone may have pathogenic role in HF. Measuring and follow-up of aldosterone levels should be considered in HF patients. MRA treatment gives a significant improvement in right side HF group.

Insights into fourth generation selective inhibitors of (C797S) EGFR mutation combating non-small cell lung cancer resistance: a critical review.

Lung cancer is the second most common cause of morbidity and mortality among cancer types worldwide, with non-small cell lung cancer (NSCLC) representing the majority of most cases. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) are among the most commonly used targeted therapy to treat NSCLC. Recent years have seen the evaluation of many synthetic EGFR TKIs, most of which showed therapeutic activity in pertinent models and were classified as first, second, and third-generation. The latest studies have concluded that their efficacy was also compromised by additional acquired mutations, including C797S. Because second- and third-generation EGFR TKIs are irreversible inhibitors, they are ineffective against C797S containing EGFR triple mutations (Del19/T790M/C797S and L858R/T790M/C797S). Therefore, there is an urgent unmet medical need to develop next-generation EGFR TKIs that selectively inhibit EGFR triple mutations via a non-irreversible mechanism. This review covers the fourth-generation EGFR-TKIs' most recent design with their essential binding interactions, the clinical difficulties, and the potential outcomes of treating patients with EGFR mutation C797S resistant to third-generation EGFR-TKIs was also discussed. Moreover, the utilization of various therapeutic strategies, including multi-targeting drugs and combination therapies, has also been reviewed.

Environmentally Friendly Polymer Concrete: Polymer Treatment, Processing, and Investigating Carbon Footprint with Climate Change.

Climate change is being currently faced globally; controlling the plastic waste and gas emission is aimed to reduce their hazardous effects. In this work, polyethylene terephthalate (PET) and polyvinyl chloride (PVC) polymer wastes are used as fillers to calcium silicate. Chemical treatment was performed to get the best efficiency of the binder material with the treated PET (TPET) and treated PVC (TPVC). The used silicate, new nonhydraulic dicalcium silicate, was synthesized by sintering. A new environmentally friendly polymer concrete, based on different concentrations of PET-/TPET-/PVC-/TPVC-dicalcium silicate composites, was prepared and cured by carbonation. FTIR analysis confirms that the treatment gave functional groups on the polymer surface; also, the hydrophilicity was increased after treatment. SEM photos show that the treated polymers have a rougher surface, which led to improved attachment with cement. The structures of the prepared and cured cement materials are proved by XRD, FTIR analysis, and SEM, through the change of calcium silicate to carbonate. Carbon footprint is used to analyze the environmental implications of the prepared composites. After the treatment reaction, the TPET-cement and TPVC-cement composites showed improved compression and flexural properties and more stability against water absorption. The novelty arises from recycling this plastic waste in the proposed low-energy dicalcium silicate cement, for the first time, to give improved environmentally friendly composites after converting CO2 gas to carbonates, with the reduced carbon footprint.

Dietary Effects of Nanopowder Eggshells on Mineral Contents, Bone Turnover Biomarkers, and Regulators of Bone Resorption in Healthy Rats and Ovariectomy-Induced Osteoporosis Rat Model.

Postmenopausal osteoporosis is a critical issue for female health worldwide. This current study was designed to evaluate the role of nanopowder eggshell (NPES) in healthy and ovariectomy-induced osteoporosis rats. Fifty-six female rats were divided into healthy rats (35) and ovariectomized rats (21). The healthy rats were subdivided into five groups (G1-G5) and received one of the following treatments: saline, 20 or 40 mg/kg of calcium carbonate, and 20 or 40 mg/kg of NPES. The 21 ovariectomized rats were divided into three groups (G6-G8) and received either saline, 40 mg/kg of calcium carbonate, or 40 mg/kg of NPES. Biochemical and histopathological assessments of bone formation and resorption were performed. Biomarkers of bone formation (calcium and osteocalcin (OCN)) and calcium content in left femur ashes were significantly higher in healthy rats given 40-mg/kg NPES than in healthy control rats and healthy rats given 40-mg/kg calcium carbonate. The ovariectomized groups had significantly lower levels of vitamin D3, OCN, and osteoprotegerin (OPG) than the healthy control. Alanine transaminase (ALT), alkaline phosphatase (ALP), and receptor activator of nuclear factor-κB ligand (RANKL) were significantly increased in the ovariectomized group than in the healthy control group. Treatment with NPES and calcium carbonate reduced liver enzymes in ovariectomized rats. NPES treatment significantly increased Vit D3, OCN, OPG, and bone ash mineral content (calcium, magnesium, zinc, and phosphorus) in ovariectomized rats. NPES also increased femur cortical thickness, osteoblast number, and collagen fiber. The current study suggests that NPES can modulate bone turnover biomarkers and increase bone trace elements. Moreover, NPES alleviates bone resorption in ovariectomy-induced osteoporosis.

Spanlastics gel-A novel drug carrier for transdermal delivery of glimepiride.

Glimepiride (3rd-generation sulfonylurea) is used for treatment of type 2 diabetes, but its oral administration has been associated with severe gastric disturbances such as nausea, vomiting, heartburn, anorexia, haemolytic anaemia. Accordingly, the transdermal route may represent a potentially suitable alternative. This work investigates the usefulness of a novel drug carrier system for transdermal application. The system investigated were called spanlastics gels and constituted span 60 with edge activator (tween 60 or tween 80). Spanlastics gel has been introduced as a stable form alternative to the liquid formulations of spanlastics. Spanlastics gels were prepared by coacervation phase separation method. Entrapment efficiency and size of spanlastics vesicles produced from the hydration of spanlastics gels were characterised. In vitro release and skin permeation of glimepiride from various spanlastics gel formulations were investigated across mixed cellulose membrane and excised rabbit skin. The obtained results indicated that the maximum entrapment efficiency was 65.36% when the tween 60 content was 30%. The drug release and permeation were increase as the concentration of edge activator increased. Spanlastics gel prepared with Tween 80 at concentration 50% showed higher permeability and flux value (248.69 µg/cm2and 8.31 µg/cm2.h, respectively) through rabbit skin.

Design, Synthesis, Molecular Modeling, and Anticancer Evaluation of New VEGFR-2 Inhibitors Based on the Indolin-2-One Scaffold.

A new series of indoline-2-one derivatives was designed and synthesized based on the essential pharmacophoric features of VEGFR-2 inhibitors. Anti-proliferative activities were assessed for all derivatives against breast (MCF-7) and liver (HepG2) cancer cell lines, using sunitinib as a reference agent. The most potent anti-proliferative derivatives were evaluated for their VEGFR-2 inhibition activity. The effects of the most potent inhibitor, 17a, on cell cycle, apoptosis, and expression of apoptotic markers (caspase-3&-9, BAX, and Bcl-2) were studied. Molecular modeling studies, such as docking simulations, physicochemical properties prediction, and pharmacokinetic profiling were performed. The results revealed that derivatives 5b, 10e, 10g, 15a, and 17a exhibited potent anticancer activities with IC50 values from 0.74-4.62 µM against MCF-7 cell line (sunitinib IC50 = 4.77 µM) and from 1.13-8.81 µM against HepG2 cell line (sunitinib IC50 = 2.23 µM). Furthermore, these compounds displayed potent VEGFR-2 inhibitory activities with IC50 values of 0.160, 0.358, 0.087, 0.180, and 0.078 µM, respectively (sunitinib IC50 = 0.139 µM). Cell cycle analysis demonstrated the ability of 17a to induce a cell cycle arrest of the HepG2 cells at the S phase and increase the total apoptosis by 3.5-fold. Moreover, 17a upregulated the expression levels of apoptotic markers caspase-3 and -9 by 6.9-fold and 3.7-fold, respectively. In addition, 17a increased the expression level of BAX by 2.7-fold while decreasing the expression level of Bcl-2 by 1.9-fold. The molecular docking simulations displayed enhanced binding interactions and similar placement as sunitinib inside the active pocket of VEGFR-2. The molecular modeling calculations showed that all the test compounds were in accordance with Lipinski and Veber rules for oral bioavailability and had promising drug-likeness behavior.

Novel 1,3-diaryl pyrazole derivatives bearing methylsulfonyl moiety: Design, synthesis, molecular docking and dynamics, with dual activities as anti-inflammatory and anticancer agents through selectively targeting COX-2.

Three series of novel 1-aryl-3-(4-methylsulfonylphenyl) pyrazole derivatives were synthesized, characterized by several spectroscopic techniques, and investigated as potential anti-inflammatory and anticancer agents. The biological evaluation showed that almost all the synthesized compounds have significant potency and selectivity for the COX-2 enzyme over COX-1 with noticeable anti-inflammatory activity compared to celecoxib and indomethacin. Accordingly, compounds 8a, 8b, 8e, 8j, 8l, 9a, 9b, 9c, and 10b showed the best COX-2 inhibition (IC50 ranged from 0.059 to 0.079 µM) with good anti-inflammatory activity (% of edema inhibition ranged from 87.9 to 67.5). Moreover, compound 8b possessed the highest selectivity index regarding COX-2 isozyme (SI = 211) in comparison to celecoxib (SI = 312) with good in vivo anti-inflammatory activity (% edema inhibition = 77.70 after 5 h). Also, compounds 8a, 8b, 8j, 8l, and 9a showed ulcerogenic liability and histopathological changes close to celecoxib. Molecular docking and dynamics simulations were also conducted to illustrate the binding modes inside the COX-2 active site. Furthermore, all compounds were screened against three cancer cell line panels to determine their antiproliferative properties by MTT assay. Compounds 8a, 8b, and 8e along with their cyclized forms 9a, 9b, and 9c exhibited a considerable antiproliferative effect on liver (IC50: 6.81-19.71 µM), colon (IC50: 7.64-15.34 µM), and breast (IC50: 6.77-18.41 µM) cancer cell lines. More importantly, compounds 8a, 8e, 9a, and 9b were found to be safe on normal HEK-293T kidney cells in comparison to cancer. cells, especially compound 8e with IC50 value of 66.45 µM. Mechanistic studies demonstrated the apoptotic activity of the most active compounds 8a, 8e, 9a, and 9b on MCF-7 cancer cells by inducing a strong S phase cell cycle arrest suggesting that the mechanism of its antiproliferative activity may be through COX-2 inhibition. Finally, the hit compounds 8a, 8b and 9a were discovered to have selective COX-2 inhibitory activity and good anti-inflammatory activity with minimal ulcerogenic effect as well as potent anticancer activity.

Design and synthesis of novel benzimidazole derivatives as potential Pseudomonas aeruginosa anti-biofilm agents inhibiting LasR: Evidence from comprehensive molecular dynamics simulation and in vitro investigation.

Quorum sensing (QS) inhibition is one of the potential methods to target bacterial infection. In this study, comprehensive molecular dynamics simulation (MDS) experiments were conducted on the LasR structure to understand its structural dynamic behavior either in its ligand-free form or in its ligand-bound form (i.e. agonist or antagonist). The results revealed that LasR structure is significantly unstable in its ligand-free and antagonist-bound forms and such structural instability led eventually to complete dissociation of the functioning LasR dimeric form. Accordingly, twenty-eight benzimidazole derivatives were designed, synthesized as potential LasR antagonists, and characterized in vitro as QS inhibitors. Compounds 3d and 7f disclosed the highest percentage inhibition in biofilm formation, pyocyanin, and rhamnolipids production in Pseudomonas aeruginosa (71.70%, 68.70%, 54.00%) and (68.90%, 68.00%, 51.80%), respectively. MDS experiments revealed that these compounds as inhibitors, particularly, 3d, 7f, 8a, and 9g induce LasR structure instability and complete dissociation of its functioning dimeric form similarly to the previously reported inhibitor bromophenethyl-2-nitrobenzamide (BPNB). Furthermore, gene expression assays as another mechanism targeting quorum sensing genes to prove the inhibitory activity of these compounds on virulence factors, revealed that a number of the synthesized compounds were able to downregulate lasR (e.g. 3d and 7f by 61.70% and 26.00%, respectively) and rhlR (e.g. 7f by 16.30%) expressions. The results presented here provide a functional model for LasR that could guide future design of LasR inhibitors.

Design, synthesis and mechanistic studies of novel imidazo[1,2-a]pyridines as anticancer agents.

Herein, the design, synthesis and mechanistic study of five series of imidazo[1,2-a]pyridines 8a-d, 9a-f, 11a-c, 12a-d and 14a-d as anticancer agents were discussed. The cytotoxicity of imidazo[1,2-a]pyridine derivatives was screened against NCI 60 cancer cell lines. The cytotoxicity of compounds 8b, 8c, 9e and 9f was then evaluated against leukemia K-562 cancer cell line and normal lung fibroblasts (WI38). The hydrazone derivatives 8b and 8c exhibited significant cytotoxic activities against the leukemia K-562 cancer cell line with good safety margins (IC50 = 2.91 µM, SI = 8.32 and IC50 = 1.09 µM, SI = 10.54, respectively). In addition, compounds 8b, 8c, 9e and 9f were tested for their EGFR and COX-2 inhibitory activities. The hydrazone derivatives 8b and 8c were the most active EGFR inhibitors with IC50 values of 0.123 and 0.072 µM, respectively. Compound 8c selectively inhibited COX-2 (IC50 = 1.09 µM, SI = 13.78). Moreover, the potential of compound 8c to induce apoptosis in leukemia K-562 cell line was determined. Compound 8c showed a pre-G1 apoptosis and a growth arrest of leukemia K-562 cell line at G1 phase of cell cycle. Also, compound 8c was able to induce caspase-3 overexpression (6.98 folds), if compared to control. Finally, molecular docking studies and physicochemical properties calculation of compounds 8b, 8c, 9e and 9f were carried out to explain the biological data and to predict bioavailability of the most active compounds.

Diagnostic value of salivary gland ultrasonography for secondary Sjögren syndrome in patients with systemic lupus erythematosus.

BACKGROUND: Salivary gland ultrasound (SGUS) is a reliable technique for assessing the salivary glands in patients with primary Sjögren's syndrome (SS); however, the role of SGUS for diagnosis of secondary SS (sSS) in patients with systemic lupus erythematosus (SLE) was not examined. OBJECTIVE: To assess the diagnostic value of SGUS for sSS in patients with SLE, and to investigate the relationship between SGUS findings with clinical and laboratory characteristics of patients with SLE. PATIENTS AND METHODS: This cross-sectional study included 49 patients with SLE. The diagnosis of sSS was confirmed according to the 2016 ACR/EULAR criteria. Salivary gland US was performed for all patients and graded using a validated Hocevar scoring system. A complete clinical and laboratory workup for SLE was assessed. Schirmer's test and the ocular staining were performed. RESULTS: Of the 49 patients with a mean age of 30.2 ± 9.6 years, 98% were female. 19 (38.8%) had sSS. SGUS changes consistent with sSS (≥17) were found in 29 (59.2%) of the patients. Patients with higher SGUS score had more sicca findings as well as positive anti-Ro, anti-La antibodies, and poorer psychological stress (p < 0.05). The SGUS (≥17) showed a sensitivity of 84.2% and a specificity of 56.7% for sSS diagnosis, with an area under the curve of 0.77 (95% CI: 0.63, 0.91). CONCLUSION: We propose salivary gland ultrasound as a non-invasive method in the diagnostic workup for sSS in patients with SLE. Further studies to confirm the diagnostic value of SGUS in a larger sample of patients with sSS will be necessary.

Design, synthesis, biological assessment, and in-Silico studies of 1,2,4-triazolo[1,5-a]pyrimidine derivatives as tubulin polymerization inhibitors.

A series of 1,2,4-triazolo[1,5-a]pyrimidine derivatives have been designed and synthesized as combretastatin CA-4 analogs. They were screened for anticancer and tubulin polymerization inhibition activities. The trimethoxyphenyl 1,2,4-triazolo[1,5-a]pyrimidine derivative 4c showed significant antiproliferative activity in which it exhibited IC50 = 0.53 µM against HCT-116 cancer cell line. It was further tested as a tubulin polymerization inhibitor showing an IC50 = 3.84 µM if compared to combretastatin IC50 = 1.10 µM. Further mechanism studies revealed that compound 4c could obviously inhibit the proliferation of HCT-116 cancer cells by inducing apoptosis and arresting the cell cycle at the G2/M phase. Furthermore, docking studies showed that compound 4c illustrated good fitting to the colchicine binding site of tubulin. Thus, it is considered an anticancer lead compound worthy of further development as a tubulin polymerization inhibitor.