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Naim Kittana, 1 Mohyeddin Assali, 2 Wolfram-Hubertus Zimmermann, 3, 4 Norman Liaw, 3, 4 Gabriela Leao Santos, 3, 4 Abdul Rehman, 3, 4 Susanne Lutz 3, 4 1Department of Biomedical Sciences, Faculty of Medicine & Health Sciences, An-Najah National University, Nablus, Palestine; 2Department of Pharmacy, Faculty of Medicine & Health Sciences, An-Najah National University, Nablus, Palestine; 3Institute of Pharmacology and Toxicology, University Medical Center Göttingen, Göttingen, Germany; 4DZHK (German Center for Cardiovascular Research) Partner Site Göttingen, Göttingen, GermanyCorrespondence: Naim KittanaDepartment of Biomedical Sciences, Faculty of Medicine and Health Sciences, An Najah National University, Akademia Street, Nablus, PalestineTel +970 (9) 2345113Fax +970 (9) 2345982Email naim.kittana@najah.eduBackground: Under certain conditions, the physiological repair of connective tissues might fail to restore the original structure and function. Optimized engineered connective tissues (ECTs) with biophysical properties adapted to the target tissue could be used as a substitution therapy. This study aimed to investigate the effect of ECT enforcement by a complex of multiwall carbon nanotubes with chitosan (C-MWCNT) to meet in vivo demands.Materials and Methods: ECTs were constructed from human foreskin fibroblasts (HFF-1) in collagen type I and enriched with the three different percentages 0.025, 0.05 and 0.1% of C-MWCNT. Characterization of the physical properties was performed by biomechanical studies using unidirectional strain.Results: Supplementation with 0.025% C-MWCNT moderately increased the tissue stiffness, reflected by Young’s modulus, compared to tissues without C-MWCNT. Supplementation of ECTs with 0.1% C-MWCNT reduced tissue contraction and increased the elasticity and the extensibility, reflected by the yield point and ultimate strain, respectively. Consequently, the ECTs with 0.1% C-MWCNT showed a higher resilience and toughness as control tissues. Fluorescence tissue imaging demonstrated the longitudinal alignment of all cells independent of the condition.Conclusion: Supplementation with C-MWCNT can enhance the biophysical properties of ECTs, which could be advantageous for applications in connective tissue repair.Keywords: engineered connective tissue, multiwall carbon nanotubes, chitosan, mechanical properties, collagen-based tissue scaffold

Elena Romero-Ben,1 Juan José Cid,1 Mohyeddin Assali,1 Elisabeth Fernández-García,2 Ralf Erik Wellinger,2 Noureddine Khiar1 1Asymmetric Synthesis and Functional Nanosystems Group, Institute of Chemical Research-Universidad de Sevilla, Avda. Américo Vespucio, 41092 Seville, Spain; 2Genome Stability Department, Andalusian Center for Molecular Biology and Regenerative Medicine Centre, Universidad de Sevilla-CSIC, Avda. Américo Vespucio, 41092 Seville, Spain Background: Bacterial resistance to antibiotics is one of the biggest challenges facing medicine today. Anti-adhesive therapy, using inhibitors of bacterial adhesion to epithelial cells, one of the first stages of infection, is a promising approximation in this area. The size, shape, number of sugar and their placement are variables that have to be taken into account in order to develop multivalent systems able to inhibit the bacterial adhesion based on sugar-lectin interaction. Materials and methods: In the present work we report a modular approach for the synthesis of water-soluble 1D-carbon nanotube-sugar nanoconstructs, with the necessary flexibility to allow an efficient sugar-lectin interaction. The method is based on the reaction of aryl diazonium salts generated in situ from aniline-substituted mannose and lactose derivatives with single wall carbon nanotubes (SWCNTs) sidewalls. Results: Two hybrid nanosystems, I-II, exposing mannose or lactose and having a tetraethylene glycol spacer between the sugar and the nanotube sidewall were rapidly assembled and adequately characterized. The sweet nano-objects were then tested for their ability to agglutinate and selectively inhibit the growth of uropathogenic Escherichia coli. These studies have shown that nanosystem I, exposing mannose on the nanotube surface is able to agglutinate and to inhibit the bacterial growth unlike nano-objects II exposing lactose.Conclusion: The results reported constitute a proof of principle in using mannose-coated 1D-carbon nanotubes as antiadhesive drugs that compete for FimH binding and prevent the uropathogenic bacteria from adhering to the urothelial surface. Keywords: single-walled carbon nanotubes, carbohydrates, bacterial resistance, antiadhesive therapy, multivalency, aryl diazonium salts chemistry

Naim Kittana,1 Mohyeddin Assali,2 Hanood Abu-Rass,1 Susanne Lutz,3,4 Rama Hindawi,2 Lina Ghannam,2 Marah Zakarneh,2 Ahmad Mousa1 1Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus, Palestine; 2Department of Pharmacy, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus, Palestine; 3Institute of Pharmacology and Toxicology, University Medical Center, Göttingen, Germany; 4German Center for Cardiovascular Research e.V., Partner Site, Göttingen, Germany Background: Impaired wound healing is commonly associated with many health problems, including diabetes, bedsores and extensive burns. In such cases, healing often takes a long time, which subjects patients to various complications. This study aims to investigate whether single-wall or multi-wall carbon nanotubes complexed with chitosan hydrogel can improve wound healing. Materials and methods: Initially, the effects of the complexes on the viability and functionality of fibroblasts were investigated in engineered connective tissues. Then, their activity on wound healing was investigated in a mouse model with induced full-thickness wounds, in which the wounds were treated daily with these complexes. Finally, the effect of the complexes on collagen deposition by fibroblasts was investigated in vitro. Results: The engineered connective tissue studies showed that fibroblasts were viable in the presence of the complexes and were still able to effectively organize and contract the extracellular matrix. In vivo data showed that both types of complexes improved the re-epithelialization of the healing wounds; however, they also increased the percentage of wounds with higher fibrosis. In particular, the chitosan-multi-wall carbon nanotube complex significantly enhanced the extensiveness of this fibrosis, which is in line with in vitro data showing a concentration-dependent enhancement of collage deposition by these complexes. These observations were associated with an increase in inflammatory signs in the wound bed. Conclusion: Single-wall and multi-wall carbon nanotubes complexed with chitosan improved the re-epithelialization of wounds, but an increase in fibrosis was detected. Keywords: carbon nanotubes, chitosan, wound healing, re-epithelialization, fibrosis, inflammation

Mohyeddin Assali,1 Abdel Naser Zaid,1 Farah Abdallah,1 Motasem Almasri,2 Rasha Khayyat3 1Department of Pharmacy, Faculty of Medicine and Health Sciences, An Najah National University, Nablus, Palestine; 2Department of Biology and Biotechnology, Faculty of Science, An Najah National University, Nablus, Palestine; 3Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, An Najah National University, Nablus, Palestine Abstract: As infectious diseases continue to be one of the greatest health challenges worldwide, the demand toward alternative agents is continuously increasing. Recent advancement in nanotechnology has expanded our ability to design and construct nanomaterials to treat bacterial infections. Carbon nanotubes are one among these nanomaterials. Herein, we describe the covalent functionalization of the single-walled carbon nanotubes (SWCNTs) with multiple molecules of ciprofloxacin. The prepared nanoantibiotics were characterized using different techniques, including transmission electron microscopy, Raman spectroscopy, and thermogravimetric analysis. The characterization of the nanoantibiotics confirmed the successful covalent functionalization of the SWCNTs with 55% of functionalization as has been observed by thermogravimetric analysis. The release profile revealed that 90% of the loaded ciprofloxacin was released within 2.5 h at pH 7.4 showing a first-order release profile with R2>0.99. Interestingly, the results of the antibacterial activity indicated that the functionalized SWCNTs have significant increase in the antibacterial activity against the three strains of bacteria – by 16-fold for Staphylococcus aureus and Pseudomonas aeruginosa and by 8-fold for Escherichia coli – in comparison to the ciprofloxacin free drug. Moreover, the synthesized nanoantibiotic showed high hemocompatibility and cytocompatibility over a wide concentration range. Keywords: covalent functionalization, hydrophilic/hydrophobic balance, carbon nanotubes, nanoantibiotic

Inula viscosa is a widely used plant in traditional Mediterranean and Middle Eastern medicine for various illnesses. I. viscosa has been shown to have anticancer effects against various cancers, but its effects against lung cancer have been under limited investigation. At the same time, I. viscosa is rich in terpenoids whose anti-lung cancer effects have been poorly investigated. This study aimed to examine the potential anticancer properties of methanolic and aqueous extracts of stems and leaves of I. viscosa and its terpenoid-rich fraction against human lung cancer A549 cells. Results showed that the methanolic extracts of I. viscosa had significantly higher polyphenol and flavonoid content and radical scavenging capacity than the aqueous extracts. In addition, leaves methanolic extracts (IVLM) caused the highest reduction in viability of A549 cells among all the extracts. IVLM also reduced the viability of human ovarian SK-OV-3, breast MCF-7, liver HepG2, and colorectal HCT116 cancer cells. A terpenoid-rich I. viscosa fraction (IVL DCM), prepared by liquid-liquid separation of IVLM in dichloromethane (DCM), displayed a substantial reduction in the viability of A549 cells (IC 50 = 27.8 ± 1.5 µg/mL at 48 h) and the panel of tested cancerous cell lines but was not cytotoxic to normal human embryonic fibroblasts (HDFn). The assessment of IVL DCM phytochemical constituents using GC-MS analysis revealed 21 metabolites, highlighting an enrichment in terpenoids, such as lupeol and its derivatives, caryophyllene oxide, betulin, and isopulegol, known to exhibit proapoptotic and antimetastatic functions. IVL DCM also showed robust antioxidant capacity and decent polyphenol and flavonoid contents. Furthermore, Western blotting analysis indicated that IVL DCM reduced proliferation (reduction of proliferation marker Ki67 and induction of proliferation inhibitor proteins P21 and P27), contaminant with P38 MAP kinase activation, and induced the intrinsic apoptotic pathway (P53/BCL2/BAX/Caspase3/PARP) in A549 cells. IVL DCM also reduced the migration of A549 cells, potentially by reducing FAK activation. Future identification of anticancer metabolites of IVL DCM, especially terpenoids, is recommended. These data place I. viscosa as a new resource of herbal anticancer agents.

The development of biobased polymeric materials for wastewater purification has become a demand due to the growing need for water free of hazardous metal ions for safe purposes. The organic components of the OLLW including carbohydrates, phenolics, aromatic acids and others are cost-effective and sustainable choices for this application. This work focuses on a method for turning the organic components of liquid waste from the olive industry (OILW) into a foam-based value-added polymer that has several metal ion binding sites. The process of making the target polymers involved reacting the components of the OILW with hexamethylene diisocyante and 1,4-phnyelene diisocynate to create the polymeric materials LHMIDIC and LPDIC that are in foam forms with urethane linkages, respectively. The adsorption competence of the polymeric foams toward Pb(II) was evaluated as a function of various parameters including adsorbent dose, pH, temperature, initial ion concentration and time. The optimum parameters values that led to a quantitative removal of Pb(II) were identified. The obtained thermodynamic parameters showed that the adsorption by the two foams was spontaneous at room temperature. The isothermal and kinetic values showed that the adsorption by synthesized foams follows a second order kinetic and obeys the Langmuir isothermal model. The foams showed a high tendency for removing multi metal ions present in a real sample of wastewater. The original nature of the starting material used in making the foam, cost and the obtained results showed the potential of using the foam in a large-scale plants of wastewater purification., (© 2023. The Author(s).)

Carbon nanodots, a family of carbon-based nanomaterials, have been synthesized through different methods from various resources, affecting the properties of the resulting product and their application. Herein, carbon nanodots (CNDs) were synthesized with a green and simple hydrothermal method from sage leaves at 200 °C for 6 hours. The obtained CNDs are well dispersed in water with a negative surface charge ( ζ -potential = -11 mV) and an average particle size of 3.6 nm. The synthesized CNDs showed concentration-dependent anticancer activity toward liver cancer (Hep3B) cell lines and decreased the viability of the cancer cells to 23% at the highest used concentration (250 μg ml -1 of CNDs). More interestingly, the cytotoxicity of the CNDs was tested in normal liver cell lines (LX2) revealed that the CNDs at all tested concentrations didn't affect their viability including at the highest concentration showing a viability of 86.7%. The cellular uptake mechanisms of CNDs were investigated and they are thought to be through energy-dependent endocytosis and also through passive diffusion. The main mechanisms of endocytosis were lipid and caveolae-mediated endocytosis. In addition, the CNDs have hindered the formation of 3D spheroids from the Hep3B hepatocellular carcinoma cell line. Hence, it would be concluded that the synthesized CNDs from sage are more highly selective to liver cancer cells than normal ones. The CNDs' cancer-killing ability would be referred to as the production of reactive oxygen species., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Several approaches, including plasmid transfection and viral vectors, were used to deliver genes into cells for therapeutic and experimental purposes. However, due to the limited efficacy and questionable safety issues, researchers are looking for better new approaches. Over the past decade, graphene has attracted tremendous attention in versatile medical applications, including gene delivery, which could be safer than the traditional viral vectors. This work aims to covalently functionalize pristine graphene sheets with a polyamine to allow the loading of plasmid DNA (pDNA) and enhance its delivery into cells. Graphene sheets were successfully covalently functionalized with a derivative of tetraethylene glycol connected to polyamine groups to improve their water dispersibility and capacity to interact with the pDNA. The improved dispersibility of the graphene sheets was demonstrated visually and by transmission electron microscopy. Also, it was shown by thermogravimetric analysis that the degree of functionalization was about 58%. Moreover, the surface charge of the functionalized graphene was +29 mV as confirmed by zeta potential analysis. The complexion of f-graphene with pDNA was achieved at a relatively low mass ratio (10 : 1). The incubation of HeLa cells with f-graphene loaded with pDNA that encodes enhanced green fluorescence protein (eGFP) resulted in the detection of fluorescence signal in the cells within one hour. f-Graphene showed no toxic effect in vitro . Density functional theory (DFT) and quantum theory of atoms in molecules (QTAIM) calculations revealed strong binding with Δ H 298 = 74.9 kJ mol -1 . QTAIM between the f-graphene and a simplified model of pDNA. Taken together, the developed functionalized graphene could be used for the development of a new non-viral gene delivery system., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

In this work, we present a process for converting olive industry solid waste (OISW) into a value-added material with ionic receptors for use in the removal of toxic metal ions from wastewater. This 3D polymer is a promising adsorbent for large-scale application, since it is a low-cost material made from agricultural waste and showed exceptional performance. The synthesis of the network polymer involved the carboxymethylation of OISW and curing of the carboxymethylated OISW at an elevated temperature to promote the formation of ester linkages between OISW's components. FT-IR, atomic force microscopy, and thermal analysis were performed on the crosslinked product. The adsorption efficiency of the crosslinked carboxymethylated OISW toward Pb(II), Cu(II), and other toxic metal ions present in sewage was evaluated as a function of adsorbent dose, temperature, pH, time, and initial metal ion. The percentage removal of about 20 metal ions present in a sewage sample collected from a sewer plant located in the Palestinian Territories was determined. The adsorption efficiency did not drop even after six cycles of use. The kinetic study showed that the adsorption process follows the Langmuir isotherm model and the second-order adsorption rate. The experimental Qe values of 13.91 and 13.71 mg/g were obtained for Pb(II) and Cu(II) removal, respectively. The thermodynamic results confirm the spontaneous metal bonding to the receptor sites of the crosslinked carboxymethylated OISW.

Self-assembled nanoparticles present unique properties that have potential applications in the development of a successful drug delivery system. Doxorubicin (DOX) is an important anti-neoplastic anthracycline chemotherapeutic drug widely described. However, it suffers from serious dose-dependent cardiotoxicity. d-Limonene is a major constituent of numerous citrus oils that is considered a specific monoterpene against free radicals producing antioxidant activity. Herein, we aimed to design three types of self-assembled nanodelivery systems (nanoemulsion, niosomes, and polylactide nanoparticles) for loading both DOX and d-limonene to enhance the solubilization of d-limonene and provide antioxidant activity with excellent anticancer activity. As confirmed by dynamic light scattering and transmission electron microscopy, the nanoparticles were prepared successfully with diameter sizes of 52, 180, and 257 nm for the DOX-loaded nanoemulsion, niosomes, and polylactide nanoparticles, respectively. The zeta potential values were above -30 mV in all cases, which confirms the formation of stable nanoparticles. The loading efficiency of DOX was the highest in the case of the DOX-loaded nanoemulsion (75.8%), followed by niosomes (62.8%), and the least was in the case of polylactide nanoparticles with a percentage of 50.2%. The in vitro release study of the DOX-loaded nanoparticles showed a sustained release profile of doxorubicin with the highest release in the case of DOX-loaded PDLLA nanoparticles. The kinetic release model for all developed nanoparticles was the Peppas-Sahlin model, demonstrating DOX release through Fickian diffusion phenomena. Moreover, all developed nanoparticles maintain the antioxidant activity of d-limonene. The cytotoxicity study of the DOX-loaded nanoparticles showed concentration-dependent anticancer activity with excellent anticancer activity in the case of the DOX-loaded nanoemulsion and polylactide nanoparticles. These nanoparticles will be further studied in vivo to prove the cardioprotective effect of d-limonene in combination with DOX., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

The rate constant for the self-reaction of the acetonyl peroxy radicals, CH 3 C(O)CH 2 O 2 , has been determined using laser photolysis/continuous wave cavity ring down spectroscopy (cw-CRDS). CH 3 C(O)CH 2 O 2 radicals have been generated from the reaction of Cl atoms with CH 3 C(O)CH 3 , and the concentration time profiles of four radicals (HO 2 , CH 3 O 2 , CH 3 C(O)O 2 , and CH 3 C(O)CH 2 O 2 ) have been determined by cw-CRDS in the near-infrared. The rate constant for the self-reaction was found to be k = (5.4 ± 1.4) × 10 -12 cm 3 s -1 , in good agreement with a recently published value (Zuraski, K., et al. J. Phys. Chem. A 2020 , 124 , 8128); however, the branching ratio for the radical path was found to be ϕ 1b = (0.6 ± 0.1), which is well above the recently published value (0.33 ± 0.13). The influence of a fast reaction of Cl atoms with the CH 3 C(O)CH 2 O 2 radical became evident under some conditions; therefore, this reaction has been investigated in separate experiments. Through the simultaneous fitting of all four radical profiles to a complex mechanism, a very fast rate constant of k = (1.35 ± 0.8) × 10 -10 cm 3 s -1 was found, and experimental results could be reproduced only if Cl atoms would partially react through H-atom abstraction to form the Criegee intermediate with a branching fraction of ϕ Criegee = (0.55 ± 0.1). Modeling the HO 2 concentration-time profiles was possible only if a subsequent reaction of the Criegee intermediate with CH 3 C(O)CH 3 was included in the mechanism leading to HO 2 formation with a rate constant of k = (4.5 ± 2.0) × 10 -14 cm 3 s -1 .

Tissue engineering is one of the hot topics in recent research that needs special requirements. It depends on the development of scaffolds that allow tissue formation with certain characteristics, carbon nanotubes (CNTs)-collagen composite attracted the attention of the researchers with this respect. However, CNTs suffer from low water dispersibility, which hampered their utilization. Therefore, we aim to functionalize CNTs non-covalently with pyrene moiety using an appropriate hydrophilic linker derivatized from polyethylene glycol (PEG) terminated with hydroxyl or carboxyl group to disperse them in water. The functionalization of the CNTs is successfully confirmed by TEM, absorption spectroscopy, TGA, and zeta potential analysis. 3T3 cells-based engineered connective tissues (ECTs) are generated with different concentrations of the functionalized CNTs (f-CNTs). These tissues show a significant enhancement in electrical conductivity at a concentration of 0.025%, however, the cell viability is reduced by about 10 to 20%. All ECTs containing f-CNTs show a significant reduction in tissue fibrosis and matrix porosity relative to the control tissues. Taken together, the developed constructs show great potential for further in vivo studies as engineered tissue., (© 2022. The Author(s).)

Carbon nanodots (CNDs) have many fascinating properties, such as optical properties (UV-Visible absorption and fluorescence emission), which make them good candidates in many applications, such as photocatalysts for the degradation of several organic pollutants. This study aims to synthesize CNDs from olive solid wastes at different carbonization temperatures from 300 to 900 °C and study the effect on the optical properties of the CNDs, such UV-Vis, fluorescence, quantum yield, and energy bandgap, in addition to the influence on the photoactivity of the CNDs as photocatalysts for the degradation of methylene blue (MB). CNDs were prepared from olive solid wastes (OSWs) by pyrolysis at different temperatures (300-900 °C) for conversion to carbonized material, and then oxidized chemically in the presence of hydrogen peroxide (H 2 O 2 ). It was found that an increase in the carbonization temperature of the OSWs leads to an increase in the product yield with a maximum value at 500 °C, and it then decreased dramatically. On the other hand, a decrease in fluorescence due to the diminishment of oxygen groups and the destruction of the surface of the CNDs was observed. The higher quantum yield (5.17%) and bandgap (2.77 eV) were achieved for CNDs prepared from OSWs that carbonized at 300 °C. The rate and degradation efficiency of MB were studied with the different synthesized CNDs, and it was found that an increase in the carbonization temperature leads to a decrease in the rate and degradation efficiency of MB, with the highest degradation rate of 0.0575 min -1 and degradation efficiency of 100% after 120 minutes of light irradiation being realized for the sample carbonized at 300 °C., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Cosmeceuticals are a branch of cosmetic products that forms a bridge between cosmetic and drug products. It is a fast-growing branch of the cosmetic industry, especially after the introduction of novel formulation and manufacturing techniques such as lipid nanoparticles (LNPs). These LNPs-based cosmeceutical products offer several advantages such as enhanced bioavailability of cosmeceutical active ingredients (CAIs), improved aesthetic appeal, and stability of the final products. However, the use of these LNPs may raise some concerns about possible side effects of these LNPs and potential hazards to the customer's health. Accordingly, an update that focuses on the use of this important branch of nanoparticles is necessary since most review papers are dealing with all types of nanocarriers in the same review with little focus on LNPs. Therefore, in the current review, a detailed analysis of the advantages and disadvantages of LNPs in this field was highlighted, to emphasize the LNPs-based cosmeceuticals on the market, as well as the potential risk posed by LNPs on exposure and recently introduced regulatory guidelines to address them. In addition, if these products can be a candidate as products that meet the sustainable development goals raised by the UN are discussed., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 Published by Elsevier B.V. on behalf of King Saud University.)

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely prescribed for the treatment of various types of inflammatory conditions. Diclofenac is a very common NSAID that is utilized to relieve pain and reduce fever and, most importantly, inflammation. However, it suffers from low water solubility and a low dissolution profile. Therefore, we aim to develop a new drug delivery system based on the synthesis of amphiphilic structures that are capable of self assembling into nano-micelles which will be a water-soluble delivery system for the diclofenac. The amphiphilic structure consists of a hydrophilic moiety of triethylene glycol (TEG), polyethylene glycol PEG 400, or PEG 600 linked with the hydrophobic drug diclofenac through an ester linkage. The diclofenac derivatives were successfully synthesized as confirmed by nuclear magnetic resonance. Moreover, the formation of the micellar structure of the synthesized amphiphilic derivatives was confirmed by atomic force microscopy obtaining a spherical shape of the micelles with average diameters of 200 nm for Dic-PEG400-Dic, and 110 nm for Dic-PEG600-Dic. The critical micelle concentration has been determined as 2.7 × 10 -3 mg mL -1 for Dic-PEG400-Dic, and 1 × 10 -4 mg mL -1 for Dic-PEG600-Dic. The in vitro diclofenac release profile by esterase enzyme was conducted and showed almost complete conversion to free diclofenac within 35 h in the case of Dic-PEG400-Dic micelles and more than 85% of Dic-PEG600-Dic micelles. Then the anti-inflammatory activity was determined by testing the TNF-α production in LPS-stimulated Balb/c mice. Diclofenac micelles significantly suppressed TNF-α production after a 5 mg kg -1 dose was given. The developed micelles showed TNF-α inhibition up to 87.4% and 84% after 48 hours of treatment in the case of Dic-PEG400-Dic and Dic-PEG600-Dic micelles respectively in comparison to 42.3% in the case of diclofenac alone. Dic-PEG400-Dic micelles showed the most potent anti-inflammatory activity with improved TNF-α suppression through time progress. Therefore, the developed nano-micelles provide a facile synthetic approach to enhance diclofenac water solubility, improve the anti-inflammatory effect and achieve a sustained release profile to get better patient compliance., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Introduction: The determination of skeletal maturity stages is very important in orthodontic treatment planning, especially skeletal discrepancies in growing individuals. A hand-wrist radiograph is considered the most accurate approach for skeletal maturity detection. Dental calcification stages have been suggested as an alternative diagnostic method to decrease radiation exposure. The recent study is aimed at detecting the efficacy of dental calcification stages in assessing skeletal maturity during the prepubertal and pubertal growth periods., Methods: Patients' records were collected from the Aleppo Orthodontic Center. Dental maturity stages were assessed from a panoramic radiograph using the Demirjian method, while skeletal maturity stages were determined using the Björk method. Four permanent left mandibular teeth were included (canine, 1st premolar, 2nd premolar, and 2nd molar) for the study., Results: From 517 records, 295 records (145 males and 150 females) were included. The Spearman rank-order correlation coefficients between skeletal maturation and dental maturation were strong and statistically significant (ranging from 0.789 to 0.835). The highest correlation was between skeletal stages and the second molar ( r = 0.829 and 0.88 in males and females, respectively). Receiver operating characteristic (ROC ) curve suggested a high validity of the sum of dental stages for the four teeth in identifying MP3= stage (sensitivity was 70%, specificity was 92.77%, and ROC area was 0.81) but not for MP3cap (sensitivity was 50.85%, specificity was 81.36%, and ROC area was 0.66)., Conclusions: The correlation between the skeletal maturity stages and the dental calcification stages was high. The orthodontist can use the dental stages as a definite diagnostic tool for prepubertal growth period., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Ayah Jourieh et al.)

Background: Indomethacin is considered a potent nonsteroidal anti-inflammatory drug that could be combined with Paracetamol to have superior and synergist activity to manage pain and inflammation. To reduce the gastric side effect, they could be combined with Famotidine. Methodology . A codrug of Indomethacin and Paracetamol was synthesized and combined in solution with Famotidine. The quantification of the pharmaceutically active ingredients is pivotal in the development of pharmaceutical formulations. Therefore, a novel reverse-phase high-performance liquid chromatography (RP-HPLC) method was developed and validated according to the International Council for Harmonization (ICH) Q2R1 guidelines. A reverse phase C18 column with a mobile phase acetonitrile: sodium acetate buffer 60 : 40 at a flow rate of 1.4 mL/min and pH 5 was utilized., Results: The developed method showed good separation of the four tested drugs with a linear range of 0.01-0.1 mg/mL ( R 2  > 0.99). The LODs for FAM, PAR, IND, and codrug were 3.076 × 10 -9 , 3.868 × 10 -10 , 1.066 × 10 -9 , and 4.402 × 10 -9  mg/mL respectively. While the LOQs were 9.322 × 10 -9 , 1.172 × 10 -10 , 3.232 × 10 -9 , and 1.334 × 10 -8  mg/mL, respectively. Furthermore, the method was precise, accurate, selective, and robust with values of relative standard deviation (RSD) less than 2%. Moreover, the developed method was applied to study the in vitro hydrolysis and conversion of codrug into Indomethacin and Paracetamol., Conclusion: The codrug of Indomethacin and Paracetamol was successfully synthesized for the first time. Moreover, the developed analytical method, to our knowledge, is the first of its kind to simultaneously quantify four solutions containing the following active ingredients of codrug, Indomethacin, Paracetamol, and Famotidine mixture with added pharmaceutical inactive ingredients in one HPLC run., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2020 Mohyeddin Assali et al.)

Objective: Calcification of atherosclerotic plaque is traditionally associated with increased cardiovascular event risk; however, recent studies have found increased calcium density to be associated with more stable disease. 3-hydroxy-3-methylglutaryl coenzymeA reductase inhibitors or statins reduce cardiovascular events. Invasive clinical studies have found that statins alter both the lipid and calcium composition of plaque but the molecular mechanisms of statin-mediated effects on plaque calcium composition remain unclear. We recently defined a macrophage Rac (Ras-related C3 botulinum toxin substrate)-IL-1β (interleukin-1 beta) signaling axis to be a key mechanism in promoting atherosclerotic calcification and sought to define the impact of statin therapy on this pathway. Approach and Results: Here, we demonstrate that statin therapy is independently associated with elevated coronary calcification in a high-risk patient population and that statins disrupt the complex between Rac1 and its inhibitor RhoGDI (Rho GDP-dissociation inhibitor), leading to increased active (GTP bound) Rac1 in primary monocytes/macrophages. Rac1 activation is prevented by rescue with the isoprenyl precursor geranylgeranyl diphosphate. Statin-treated macrophages exhibit increased activation of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells), increased IL-1β mRNA, and increased Rac1-dependent IL-1β protein secretion in response to inflammasome stimulation. Using an animal model of calcific atherosclerosis, inclusion of statin in the atherogenic diet led to a myeloid Rac1-dependent increase in atherosclerotic calcification, which was associated with increased serum IL-1β expression, increased plaque Rac1 activation, and increased plaque expression of the osteogenic markers, alkaline phosphatase and RUNX2 (Runt-related transcription factor 2)., Conclusions: Statins are capable of increasing atherosclerotic calcification through disinhibition of a macrophage Rac1-IL-1β signaling axis.

Cancer is a major worldwide health problem, for which chemotherapy is a common treatment option. However drug toxicity and the development of resistance to chemotherapy are two main challenges associated with the traditional anticancer drugs. Combined pharmacological therapy based on different mechanisms might be an effective strategy in cancer treatment, and could exhibit a synergistic therapeutic efficacy. Herein, we aim to combine combretastatin A4 (CA4) and camptothecin (Cpt) chemically into a codrug through two hydrophilic linkers utilizing click chemistry to improve their water solubility and anticancer activity. The synthesized amphiphilic structure could self-assemble into a micelle structure as confirmed by atomic force microscopy (AFM) and dynamic light scattering (DLS), which showed a high stability and improved water solubility at pH 7.4, with a low critical micelle concentration (CMC) value of 0.9 mM. Moreover, in vitro hydrolysis was observed upon incubation of the hybrid compound with an esterase enzyme, which suggested a complete disassembly into the starting active drugs. Finally, cytotoxicity studies on HeLa cancer cells showed that the codrug demonstrated an enhanced (five fold) cytotoxicity as compared with the free drugs. In addition the combination index (CI) was <1, which suggests a synergistic activity for the codrug. Moreover, the tested concentrations of the codrug were not significantly cytotoxic to a noncancerous fibroblast cell line. The imaging of HeLa cells treated with FITC-loaded micelles showed a rapid internalization. In conclusion, the codrug of CA4 and Cpt might be a potential novel anticancer drug as it demonstrated a synergistic cytotoxic activity that might spare noncancerous cells., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Background Image reconstruction thickness may impact quantitative coronary artery calcium scoring (CACS) from lung cancer screening computed tomography (LCSCT), limiting its application in practice. Methods and Results We evaluated Agatston-based quantitative CACS from 1.25-mm LCSCT and cardiac computed tomography for agreement in 87 patients. We then evaluated Agatston-based quantitative CACS from 1.25-, 2.5-, and 5.0-mm slice thickness LCSCT for agreement in 258 patients. Secondary analysis included the impact of slice thickness on predictive value of 4-year outcomes. Median age of patients who underwent 1.25-mm LCSCT and cardiac computed tomography was 63 years (interquartile interval, 57, 68). CACS from 1.25-mm LCSCT and cardiac computed tomography demonstrated a strong Pearson correlation, R=0.9770 (0.965, 0.985), with good agreement. The receiver operating characteristic curve areas under the curve for cardiac computed tomography and LCSCT were comparable at 0.8364 (0.6628, 1.01) and 0.8208 (0.6431, 0.9985), respectively ( P=0.733). Median age of patients who underwent LCSCT with 3 slice thicknesses was 66 years (interquartile interval, 63, 73). Compared with CACS from 1.25-mm scans, CACS from 2.5- and 5.0-mm scans demonstrated strong Pearson correlations, R=0.9949 (0.9935, 0.996) and R=0.9478 (0.9338, 0.959), respectively, though bias was largely negative for 5.0-mm scans. Receiver operating characteristic curve areas under the curve for 1.25-, 2.5-, and 5.0-mm scans were comparable at 0.7040 (0.6307, 0.7772), 0.7063 (0.6327, 0.7799), and 0.7194 (0.6407, 0.7887), respectively ( P=0.6487). When using individualized high-risk thresholds derived from respective receiver operating characteristic curves, all slice thicknesses demonstrated similar prognostic value. Conclusions Slice thickness is an important consideration when interpreting Agatston CACS from LCSCTs. Despite the absence of ECG gating, it appears reasonable to report CACS from either 1.25- or 2.5-mm slice thickness LCSCT to help stratify cardiovascular risk. Conversely, 5.0-mm scans largely underidentify calcium, limiting practical use within the established CACS values used to categorize cardiovascular risk.

The clinical significance of the relatively avirulent organ- ism, Lactobacillus, has been debated in the past. At times misdiagnosed as a contaminant, Lactobacillus has uncommonly been reported to cause intra-abdominal abscesses, peritonitis, meningitis, bacteremia, pneumonia and endocarditis, especially in the population of patients with underlying comorbid conditions including malignancy, diabetes, recent surgery or organ transplantation. We report a case of a 74-year-old male with Lactobacillus bacteremia leading to prosthetic valve infective endocarditis complicated by an aortic root abscess. He was managed with IV antibiotic therapy, ultimately penicillin G, and aortic valve replacement, and completely recovered after a period of rehabilitation. Several factors that predispose to Lactobacillus bacteremia were identified in our patient. This case further supports the proposition that Lactobacillus is not always a contaminant; when pathogenic, underlying disease conditions should be investigated.

Background: Nanomedicine is the medical application of nanomaterials that may have an infinite size with the range less than 100 nm. This science has provided solutions to many of the current limitations in the diagnosis and treatment of diseases. Therefore, the pharmacist's knowledge and awareness of nano-pharmaceutical drugs will increase their availability in the market, and will improve the patient's compliance to their drug therapy. This study aimed to determine the availability of nano-pharmaceutical drugs in Palestinian hospitals and evaluate the extent of pharmacist's knowledge about them., Methods: A cross-sectional study design questionnaire was used to determine the availability of nano-pharmaceutical drugs based on the database of the ministry of health in the Palestinian hospitals (governmental, private and non- governmental organizations). Moreover, the knowledge of these nano-pharmaceutical drugs among pharmacists working in Palestinian hospitals was assessed based on developed questionnaire from the literature of the pharmaceutical formulations and nano-formulations. The variables were analyzed using Statistical Package for Social Sciences (SPSS 22)., Result: Fifty six pharmacists from 27 hospitals in the West bank completed the survey. The results regarding the availability of nano-pharmaceutical drugs indicated only eight available in hospitals with a frequency range 0-39.3%. Moreover, pharmacist's knowledge in the pharmaceutical formulations was better than that in nano-formulations., Conclusions: The availability of nano-pharmaceutical drugs in Palestinian hospitals was not adequate due to the lack of various nano-pharmaceutical drugs. The knowledge among pharmacists regarding nano-pharmaceutical drugs should be improved by providing courses in nanomedicine during the undergraduate pharmacy programs.

Background: Statins are the first-line therapy for lowering high lipid levels. Atorvastatin calcium (AtC) is the most commonly prescribed statin. It inhibits 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase which converts HMG-CoA into mevalonic acid, a cholesterol precursor., Objective: To compound and evaluate the stability of AtC suspension (0.4% w/v) using commercial tablets or pure AtC powder as the source of the active pharmaceutical ingredient., Method: Several AtC suspension formulations were produced using commercial AtC tablets or AtC pure powder as the source of the active ingredient. The most suitable one in terms of general organoleptic properties and dissolution was selected for stability studies. For this purpose, samples of final suspensions were stored at room temperature and in the refrigerator. Assay, pH, organoleptic properties and microbial contamination were evaluated according to the USP specifications. High performance liquid chromatography was used for the analysis and quantification of AtC in the studied samples., Results: The obtained suspension (S4) had good organoleptic properties. It showed complete dissolution of AtC within 30 min. However, the suspension prepared from crushed tablet (S t 4) showed a better dissolution profile than that prepared from pure powder (S p 4). The prepared formula had unchanged pH, which remained around 9.9. S t and S p formulas were both free from microbial contamination. Both products showed good stability within at least the period of use of the 100 mL AtC bottles., Conclusions: AtC extemporaneous suspension was successfully prepared using tablets as a source of AtC or pure AtC powder. However, S t 4 had a better dissolution profile than S p 4. This study provides a solution for patients with swallowing difficulties or feeding tubes who are unable to take medicines in solid oral dosage forms. Community pharmacists can prepare the suspension using AtC tablets as the source of the active ingredient., Competing Interests: Competing interests: None declared.

Introduction: Interest in essential oils was recently revived with their popularity increasing in medicine, pharmacy, and aromatherapy. This study was performed to identify the chemical compositions of the essential oil of Ruta chalepensis growing wildly in three regions in Palestine and to assess and compare their antimicrobial and antioxidant activities., Methods: Identification of the essential oil was performed by gas chromatography coupled with mass spectrometry (GC-MS). Antimicrobial activity was tested against Staphylococcus aureus , Escherichia coli , Pseudomonas aeruginosa , Methicillin-Resistant Staphylococcus aureus , and Candida albicans by using minimum inhibitory concentration (MIC) assay, while antioxidant activity was analyzed by using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging method., Results: The essential oils of R. chalepensis from Jerusalem and Hebron regions have almost identical components; the major compounds identified were linalyl acetate and β -linalool; these essential oils exerted potential antioxidant and antibacterial activities. On the other hand, the major components of the plant essential oil from Jenin region were 2-undecanone and 2-nonanone, which exhibited potential antifungal activity., Conclusions: The phytoconstituents and antioxidant and antimicrobial properties of the essential oil of R. chalepensis from different regions in Palestine were established in this study. The obtained results indicate possible applications for R. chalepensis in the treatment of various infectious and noninfectious diseases.

An automated system to perform titration and standard addition in monosegemented flow analysis by employing the simultaneous multiple injection is described. The system was controlled by aPC-AT-386 microcomputer through a home-made parallel interface, employing a diode array spectrophotometer as detector. Software was written in QuickBasic 4.5 to control the system and for data acquisition. A three-way solenoid valve was used in conjunction with a proportional injector to add the titrant solution or the standard solution to the sample, to carry out titration or standard addition, respectively. Only one standard solution was used in each procedure and different quantities of titrant or standard were added to the sample by controlling the time interval in which the solenoid valve was switched on. Titration and standard addition curves similar to those of the manual methods were obtained in both cases, since the sample dispersion was very low due to the air bubbles of the monosegment. The titration system was evaluated through the determination of Fe(II) with a KMnO4 standard solution in pharmaceutical preparations. The standard addition process was assessed by determining Cr(VI) in natural waters and domestic wastewater using the diphenylcarbazide method. The results obtained in both methodologies did not differ significantly from the reference methods at a 95% confidence level.